Allogeneic CD34+ hematopoietic stem cell boost for prolonged severe cytopenias following CAR T-cell therapy in B-cell acute lymphoblastic leukemia. A retrospective analysis on behalf of the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC)

Allogeneic CD34+ hematopoietic stem cell boost for prolonged severe cytopenias following CAR T-cell therapy in B-cell acute lymphoblastic leukemia. A retrospective analysis on behalf of the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Allogeneic CD34+ hematopoietic stem cell boost for prolonged severe cytopenias following CAR T-cell therapy in B-cell acute lymphoblastic leukemia. A retrospective analysis on behalf of the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC) Águeda Molinos-Quintana, Nuria Martinez-Cibrian, Anna Alonso-Saladrigues, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4843995/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Hematological toxicity is the most common long-term adverse event after CAR T-cell therapy. Severe cytopenias not resolving over time may result in life-threatening infection or bleeding and the best clinical practice to treat this persisting cytopenias after CAR-T is not well established. Eleven heavily pretreated patients with B-ALL and prolonged cytopenia after CAR-T therapy were successfully treated with an allogeneic CD34 + hematopoietic stem cell (HSC) boost. The median time from CAR T-cell infusion to donor CD34 + HSC boost was 2.8 months and median CD34 + selected dose was 4 x10 6 /kg of recipient weight. The median time to hematological recovery in all three cell lineages was 20 days (range 12–60). One-year event free survival was significantly different for patients relapsing before 6 months post-transplantation (14.3%) vs after 6 months post-transplantation (75%). With a median follow-up after HSC boost of 12 months, overall survival (OS) at 24 months was 31.2% with a median OS of 21 months (95% CI 6.2–35.7). All causes of death were related to disease relapse. In conclusion, we confirm that allogeneic CD34 + HSC boost is an effective and safe therapeutic option that should be considered in patients with primary poor graft function persisting beyond 60–90 days after CAR-T Health sciences/Medical research/Stem-cell research Biological sciences/Cancer/Cancer stem cells Allogeneic stem cell boost CD19 CAR T-cells Prolonged cytopenias hematotoxicity relapsed/refractory acute lymphoblastic leukemia Figures Figure 1 INTRODUCTION Chimeric antigen receptor (CAR) T-cell therapy has a remarkable impact on the outcome of pediatric and adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) ( 1 – 3 ). The management of early toxicities including cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) has been well established. However, real-world clinical experience has shown that hematological toxicity leading to peripheral-blood cytopenias is one of the most common and severe long-term adverse effects ( 4 ). Moreover, severe cytopenias not only affect the quality of life and prolong hospitalization, but may also result in life-threatening bleeding and infectious events, being a major driver of the morbidity and mortality observed after CAR T-cell therapy. Hematotoxicity after CAR T cell administration can be multifactorial and closely associated with CAR-T and disease-associated inflammation in addition to baseline bone marrow (BM) reserve ( 5 , 6 ). However, the underlying pathophysiology of prolonged cytopenias after CAR T-cell infusion remains poorly understood and represents a clinical challenge with a paucity of data to guide management ( 7 , 8 ). Therefore, severe cytopenias not resolving over time can be a major clinical problem. In this setting, several off-label approaches have been described to address this issue, including transfusion support, use of granulocyte colony stimulators, thrombopoietin analogues and erythroid stimulators. Hematopoietic stem cell (HSC) boost has also been used to treat poor graft function after CAR-T cell therapy mainly based on cryopreserved autologous infusion ( 9 – 12 ). However, the experience using unmanipulated allogeneic CD34 + HSC boost remains anecdotal. METHODS We conducted a multicenter retrospective study including 11 pediatric and adult patients with r/r B-ALL treated with second generation (4-1BB-based) anti-CD19 CAR-T therapy. All patients received allogeneic unmanipulated donor-derived CD34 + boost for the treatment of prolonged and severe cytopenias in six spanish institutions from July 2018 to January 2024. The data cutoff date was June 1, 2024 when all CD34 + HSC boost infused patients had a minimum follow-up of 6 months or had experienced disease relapse or death. Clinical and laboratory data were collected during routine evaluations and extracted from the GETH-TC (Grupo Español de Trasplante Hematopoyético y Terapia Celular) database and RedCap. All clinical investigation was conducted according to the principles of the Declaration of Helsinki and was approved by the relevant local institutional ethics committee (Code: 0600-N-22). Informed consent was obtained from all subjects protected by the GETH-TC. Event-free survival (EFS) was calculated from the time to CD34 + boost infusion to event considered as relapse or mortality of any cause. RESULTS Eleven patients who received an allogeneic CD34 + HSC boost to treat prolonged cytopenia after CAR-T cell therapy were analyzed. The indication for receiving CAR-T cell therapy in all 11 patients was relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Median time from allo-HSCT to relapse was 6 months (range 3 to 24.1), and from allo-HSCT to CAR T-cell infusion 8.6 months (range 5.3–20.9). Therefore, most patients (73%) received CAR-T cell therapy for the treatment of relapse after < 1 year post transplantation. Median age was 27 years (range 8–46). Varnimcabtagene autoleucel (ARI-0001) was the most common cellular therapy product infused (8 patients) followed by tisagenlecleucel (2 patients) and JCAR017 in one patient; all of them being 4-1BB-based constructs. One patient received a CAR T-cell reinfusion for early B-cell recovery (< 3months). Patient´s characteristics are described in Table 1 . Table 1 Preceding allogeneic stem cell transplant characteristics Characteristics Number of patients (%). N:11 Donor type Matched related donor (10/10) 0 (0) Mismatched related donor (haploidentical) 6 (54.5) Matched unrelated donor (10/10) 4 (36.4) Mismatched unrelated donor 1 (9.1) Source of stem cells Bone marrow 1 ( 9 ) Peripheral blood 10 (91) Conditioning regimen Mieloablative with TBI 4 (36.4) Mieloablative without TBI 5 (45.5) Reduced intensity 2 (18.1) Primary or secondary post-transplant engraftment failure 0 Poor graft function* 3 (27.4) Relapse after allo-SCT (months), median (range) 6 (3-24.1) *Poor graft function: delayed or incomplete hematopoietic recovery despite evidence of complete donor chimerism post allo-SCT in the absence of other explanations, such as disease relapse, drugs, or infections ( 13 ) Regarding previous treatments, most patients had received ≥ 4 prior treatment lines including blinatumomab and inotuzumab in 2 and 5 patients, respectively, prior to leukapheresis. All of them had suffered ≥ 2 prior ALL relapses (Table 2 ). At the time of lymphodepletion (LD), 9 patients had 5% BM blasts. Two out of eleven patients had extramedullary disease (central nervous system involvement), one isolated and one combined with BM infiltration. Table 2 Pre-CAR T-cell therapy characteristics Characteristics Number of patients n (%) n:11 Age, median (range), years 27 (8–46) Female, n (%) 8 (73) CAR-T cells ≤ 1 year after Allo-SCT, n (%) 8 (73) Time after last Allo-SCT, median (range), months 8.6 (5.3–20.9) Disease status / CAR indication Two relapses Three relapses > 3 relapses 4 (36.4) 5 (45.5) 2 ( 18 ) Prior lines of therapy. No (%) 2 3 4 5 ≥6 1 ( 9 ) 2 ( 18 ) 3 ( 27 ) 2 ( 18 ) 3 ( 27 ) All prior therapy (pre-leukapheresis) Prior blinatumomab Prior inotuzumab Prior chemotherapy regimen including fludarabine 2 ( 18 ) 5 (45.5) 6 (54.5) Last treatment pre-leukapheresis Dexametasone +/- hydrea +/- intrathecal Inotuzumab-based Atenuated conventional chemotherapy (hyperCVAD-like) No treatment relapse pre-leukapheresis 2 ( 18 ) 5 (45.5) 1 ( 9 ) 3 ( 27 ) Bridging chemotherapy regimen Atenuated conventional chemotherapy FLU/CLO-based chemotherapy Blinatumomab Inotuzumab Radiotherapy No bridging therapy 6 (54.5) 0 0 2 ( 18 ) 0 3 ( 27 ) CTCAE v.5 grade 4 cytopenias after bridging therapy, n (%) 6 (54.5) Infections after bridging therapy, n Bacteremia 3 Viral infection 2 Stenotrophomona maltophila pneumonia 1 Disease burden prior-infusion, n (%) No detectable disease Low-disease burden ( 5% blast) High tumor burden (> 5% lasts) with CNS Isolated extramedullary disease (CNS) 4 (36.4) 4 (36.4) 1 ( 9 ) 1 ( 9 ) 1 ( 9 ) Lymphodepletion CF + FLU (dose), n (%) Dose: CF (1000 mg/m2) + FLU (120 mg/m 2 ) Dose: CF (900 mg/m2) + FLU (90 mg/m 2 ) Additional LD: Rituximab 375 mg/m 2 11 (100%) 2 ( 18 ) 9 (82) 2 ( 18 ) Complete blood counts prior-lymphodepletion (LD) Median ANC cells x 10 9 /L (95% CI) Median platelet count, x 10 9 /L (95% CI) Median hemoglobin, g/dL (95% CI) Blood transfusion 7 days prior to LD n (%) Platelet transfusion 3 days prior to LD n (%) 0.7 (0.02–1.38) 29 (6.7–51.3) 10.1 (9.5–10.7) 5 (45.4) 7 (63.6) Maintained severe neutropenia (ANC cells x 10 9 /L < 0.5) and/or platelet count < 50 x 10 9 /L for more than 4 weeks pre-CAR-T infusion, n (%) 6 (54.5) Baseline cytopenias assessed at the beginning of the LD are available in Table 2 . Maintained severe neutropenia (ANC cells x 10 9 /L < 0.5) and/or platelet count < 50 x 10 9 /L for ≥ 4 weeks pre-CAR-T infusion was documented in 6/11 patients (54.4%). Red blood cells transfusions within 7 days prior to LD occurred in 45% and platelet transfusion within 3 days prior to LD in 63.6% of patients. After infusion, CRS occurred in 81.8% of patients although only one patient reached severe CRS ≥ 3. No ICANS were documented in any of eleven patients. Immune effector cell-associated HLH-like syndrome occurred in one patient (Table 3 ). At day 28 post infusion, the overall remission rate with incomplete hematologic recovery was 100%. All eleven patients were negative for the measurable residual disease (MRD) Table 3 Post CAR T-cell therapy Characteristics Number of patients (n:11) CAR product, n (%) Tisagenlecleucel Varnimcabtagene autoleucel (ARI-0001) Lisocabtagene maraleucel (JCAR017) 2 (18.2) 8 (72.7) 1 (9.1) CAR-T cell x 10 6 /Kg, median (range) 1 (0.05-5) Toxicity after infusion: - No CRS - CRS, n (%) CRS grade 1 CRS grade 2 CRS grade ≥ 3 - Immune effector cell-associated HLH-like syndrome 2 (18.2) 9 (81.8) 4 (44.5) 4 (44.5) 1 (11.1) 1 ( 9 ) - ICANS n (%) 0 - Anti-cytokine therapy, n (%) Tocilizumab Corticosteroids Anakinra / Siltuximab Vasopressors Oxygen therapy 4 (36.4) 3 (27.3) 2 (18.2) 1 (9.1) 4 (36.4) Cytopenias not resolved by day 28, n/n (%) ANC cells x 10 9 /L < 0.5 Platelet count < 25 x 10 9 /L Hemoglobin 0.5 after G-CSF support 11/11 (100) 11/11 (100) 11/11 (100) 10/11 (90.9) 10/11 (90.9) 2/10 ( 20 ) Cytopenias not resolved by month 3, n/n (%) ANC cells x 10 9 /L < 0.5 Platelet transfusion dependence Blood transfusion dependence HSC boost previous to 3 months 9/11 (81.8) 7/9 (77.8) 5/9 (55.6) 6/9 (66.7) 2/11 (18.2) Reasons that led to boost performance, n/n (%) ANC cells x 10 9 /L < 0.5 + transfusion dependence ANC cells x 10 9 /L 0.5 7/11 (63.6) 2/11 (18.2) 2/11 (18.2) Evaluation D28 RCi* 11/11 (100%) MRD negativity, n 11/11 (100) *RCi: Complete remission with incomplete hematologic recovery As far as early myelotoxicity after CAR-T is concerned, all eleven patients developed severe neutropenia and/or thrombocytopenia that persisted on day 28 after infusion, most of them being refractory to therapeutic approaches such as growth factors support. Only 2/10 patients achieved ANC cell > 0.5x 10 9 /L after G-CSF. Cytopenias did not resolve by month 3 in nine patients: six of them had neutropenia grade 4 (66.7%), and five (55.6%) and six (66.7%) had platelet and blood transfusion dependence, respectively (Table 3 ). The other two patients received early CD34 + HSC boost before 3 months after CAR T-cell infusion. In most cases (10 out of 11 patients), the BM aspirate was hypocellular and without dysplasia prior to the boost. Only 1 patient showed normocellular BM aspirate with predominance of the red-cell precursors but peripheral cytopenia. Some life-threatening infections were observed prior to the CD34 + boost: three cases of gram-negative bloodstream infections ( Pseudomona aeruginosa , Escherichia Coli and Klebsiella pneumoniae ), a gram-positive catheter-related infection, one case of listeria as an enteroinvasive gastrointestinal infection and one patient suffered from cytomegalovirus infection. In addition, six breakthrough invasive fungal infections were documented, five of them were possible or probable invasive aspergillosis and one mucormycosis infection. Also, one patient presented a hemorrhagic event due to thrombopenia. The median time from CAR T-cell infusion to donor CD34 + HSC boost was 2.8 months (range 1.5–4.9). Median CD34 + selected dose was 4 x10 6 /kg of recipient weight (range 1.6–14.2). Median CD3 + T cells dose was 8.3 x10 3 /kg of recipient weight (range 1.14-40) out of seven patient´s with available information. Full donor chimerism pre-CD34 + boost infusion was documented in all patients. No conditioning was used previous to the boost and no toxicity such as acute graft versus host disease (aGVHD) or CRS was documented afterwards. Overall, all eleven patients had improved cytopenia following CD34 + HSC boost. The median time to complete hematological recovery after boost was 20 days (range 12–60) defined as hematological improvement in all three cell lineages (hemoglobin ≥ 8 g/dL, platelets ≥ 25x10 9 /L and neutrophils ≥ 0.5x10 9 /L for three consecutive days) without the need for subsequent transfusion or growth factor support. The median time from CD34 + boost to first neutrophil counts > 1.0x10 9 /L was 13 days (range 7–16), to platelets ≥ 50x10 9 /L was 20 days (range 14–249) and to hemoglobin ≥ 10 g/dL was 35 days (range 5–47) in 10 out of 11 patients. The individual patient profile is available in Table 4 . Table 4 Stem cell boost results. Stem cell boost (SCB) Neutrophil engraftment after SCB Platelet and hemoglobin engraftment after SCB Complete hematological recovery** # Day after CAR-T Indication for SC boost Previous BM status Total infused cells (x 10 6 CD34 + /Kg) Day of ANC > 0.5 x10 9 /L* First day of ANC > 1 x10 9 /L Last day G-CSF support Day of engraftment Platelet > 25 x 10 9 /L Transfusion independent Day of platelet count > 50 x 10 9 /L Hemoglobin level > 8 g/dL Transfusion independent Hemoglobin level > 10 g/dL Day after boost 1 106 Pancytopenia and severe infections Hypoplastic without megakaryocytes. Hemo-phagocytosis 4 12 11 11 15 25 22 25 22 2 90 Pancytopenia Hypoplastic 7 9 10 11 12 249 35 35 35 3 46 Pancytopenia - - 14 14 13 11 - 13 - 14 4 53 Pancytopenia and severe infections Hypoplastic 14,2 10 14 No 14 21 21 Not reached 21 5 58 Pancytopenia Absent 8,7 13 11 1 12 20 12 20 13 6 135 Pancytopenia Hypoplastic - 11 9 8 20 20 20 39 20 7 83 Pancytopenia Hypoplastic without megakaryocytes 3,4 16 16 8 60 214 60 47 60 8 109 Pancytopenia Absent 3,6 12 12 8 12 19 3 47 12 9 77 Pancytopenia Hypoplastic 1,6 12 15 6 16 20 13 20 20 10 72 Pancytopenia Normo- cellular 3,4 10 14 17 14 18 14 35 17 11 147 Transfusion dependency Hypoplastic 5,3 14 14 13 11 14 1 5 14 Median (range) 83 (46–147) 4 (1.6–8.6) 12 ( 9 – 16 ) 14 ( 9 – 16 ) 11 ( 1 – 17 ) 14 (11–60) 20 (14–249) 17 (1–60) 35 (5–47) 20 (12–60) *Day of ANC > 0.5 x10 9 /L for three consecutive days; ** Complete hematological recovery defined as hematological improvement in all three cell lineages (hemoglobin ≥ 8 g/dL, platelets ≥ 25x10 9 /L and neutrophils ≥ 0.5x10 9 /L for three consecutive days) without the need for subsequent transfusion or growth factor support Regarding outcomes, event free survival (EFS) at last follow-up was 27,3% (3/11) with a median EFS of 10 months (95% CI 2.45–17.5). Respective values of EFS for patients relapsing before or after 6 months post-transplantation was 14.3% vs 75% at 12 months, respectively (p = 0.016). Median EFS was not reached for patients who relapsed > 6 months after transplant vs 4 months (95% CI 1.4–6.56) for those relapsing < 6 months after allo-HSCT (Fig. 1 ). With a median follow-up after CD34 + HSC boost of 12 months (95% CI 9.3–28.8), overall survival (OS) at 12 and 24 months was 51.9% and 31.2% respectively with a median OS of 21 months (95% CI 6.27–35.73). All causes of death after CD34 + HSC boost were related to disease relapse. DISCUSSION Hematological toxicity is the most common long term adverse event after CAR T-cell therapy. Recently, the international expert panel (EHA and EBMT) referred to it as a novel category of toxicity called immune effector cell–associated hematotoxicity (ICAHT). They defined late-ICAHT when cytopenias occurring + 30 after CAR T-cell infusion ( 14 ). Hematopoietic count recovery after CAR T-cell infusion often follows a biphasic trajectory with intermittent recovery followed by one or subsequent dips ( 7 , 15 ) and usually, gradual recovery is the likely trajectory even without intervention. However, some patients can develop very severe BM aplasia and profound cytopenias can be persistent and refractory to therapeutic measures such as thrombopoietin receptor agonists ( 16 ). Unfortunately, the best clinical practice to treat this persisting cytopenias is not well established. Allogeneic CD34 + HSC boost has been recently included in a propose treatment algorithm ( 8 ) despite the experience with this strategy for restoring hematological recovery after CAR-T remains anecdotal particularly in r/r ALL-B patients. Previous experience on eleven patients treated with CD34 + HSC boost from three different retrospective studies is summarized in Table 5 and in line with our results ( 17 , 18 , 19 ). Concerning to timing, previous reported mean time from CAR-T infusion to CD34 + HSC boost was between 2.1 and 5.9 months, similar to our 2.8 months. Successful hematological improvement has been described in nine out of eleven patients. The other two patients died after CD34 + HSC boost because of an hemorrhagic event and relapse, respectively. Previous data of mean time to recovery of neutropenia and transfusion independence occurred between 14–33 days after CD34 + HSC boost similar to our mean time of 20 days. Although there was no uniformity in the hematological criteria of recovery, the authors considered the CD34 + HSC boost to be successful. Table 5 Previous experience with Allo-SCT boost after CAR T-cell therapy Reference author (year) Rejeski et al. 2022 ( 17 ) Mullanfiroze et al. 2022 ( 18 ) Lipssitt et al. 2022 ( 19 ) Number of patients 3 7 1 Mean age years (range) 34 (23–44) 15 ( 10 – 27 ) 21 Acute lymphoblastic leukemia (ALL) 2 ALL 7 ALL 1 ALL Median total number of infused CD34 + cells/Kg 5.3 x 10 6 /kg (3-7.5 x 10 6 ) 6.75 x 10 6 /Kg (2.5–11.2 x 10 6 ) 5.1 x 10 6 cells/Kg on day + 69 Previous severe CRS ≥ grade 3 0/3 (0%) 1/7 (14%) No Previous allo-SCT ≤ 1 year 2/3 (67%) 1/7 (14%) 1/1 Baseline bone marrow reserve (pre-LD) 4,5 y 7 CAR-Hematotox score BM aspirate pre-LD demonstrated hypocellularity in 5 of 7 and effacement with blasts in 2 of 7. Severe baseline cytopenia prior to LD Mean time since CART19 to stem cell boost (range) 5.9 months (1.4–11.4) 2.6 months 2.1 months Median time Neutrophils > 1 x 109/L without GCSF, days (range) n.a 42 (11–192)** n.a Blood transfusion independent, day post boost (range) n.a 33 (4-106)** n.a Day of platelet engraftment after boost (range) 15 ( 14 – 16 ) 33 (7–73)** 16 Day of neutrophil engraftment* after boost 14 ( 6 – 21 ) n.a 13 In complete response after last follow-up n.a 2/7 1/1 *Neutrophil engraftment was defined as the first of 3 consecutive days achieving a sustained absolute neutrophil count (ANC) > 500/mL without growth factor support. Platelet engraftment was defined as a platelet count > 20 gr/l and transfusion independence > 7 days. ** Only 5 of 7 patients were evaluable for response to HSC boost since 1 died of a gastrointestinal hemorrhage and 1 relapsed at day 38 after HSC boost Our series of r/r B-ALL patients contributes to a better understanding of timing and hematopoiesis restoration after allogeneic CD34 + HSC boost as an effective and safe therapeutic measure. Hence, it minimizes the time at risk of morbidity and mortality-related of profound cytopenias post CAR T-cell. In our experience, most physicians´ rationale for allogeneic-CD34 + boost was primary poor graft function after CAR T-cell, defined by: (i) failure to ever achieve count recovery in at least one lineage (neutrophils ≥ 0.5x10 9 /L despite growth factor support and/or platelets ≥ 25 x10 9 /L and hemoglobin ≥ 8 g/dL in the absence of transfusion) after CAR T-cell therapy; (ii) a hypoplastic/absent bone marrow; (iii) the absence of relapse; and (iv) the presence of donor cells as detected by BM or peripheral blood chimerism studies. The toxicity profile between CAR-T and CD34 + HSC boost was dominated not only by hematological toxicity but also by severe infections mainly by bacterial (45.5%) and/or invasive fungal infections (54.5%). This study has several relevant limitations. It was retrospective, uncontrolled, and limited to small patient numbers. But we observed a potential benefit of shortening the phase of critical neutropenia to control a high percentage of severe infectious events. Overall, multiple factors (hematopoietic reserve, BM infiltration and CRS related systemic inflammation) may influence the development of late-ICAHT after CAR T-cell therapy ( 7 , 15 , 20 – 22 ). Based on these known risk factors a score (CAR HEMATOTOX) has been developed to identify patients at high risk for prolonged cytopenias ( 15 ). However, it is important to note that the score remains to be validated for adult and pediatric patients with B-cell precursor ALL; so we have not calculated this score in the present study but we have described this risk factors individually. Previous cytopenias in highly pre-treated patients have been frequent characteristics of our patients highlighting the impact of BM reserve in late cytopenias ( 7 , 20 , 21 ). It should be noted that most of them were also allo-transplanted in the previous 12 months. On the contrary, development of high grade of CRS and the associated inflammatory stress with or without immune effector cell–associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) could exert myelosuppressive effects, but appears to play a greater role in development of early and not prolonged cytopenias ( 3 , 5 , 7 , 22 , 23 ). That´s in agreement with our series of patients with late-ICAHT because only two patients presented IEC-HS or CRS grade 4 after CAR T-cell therapy with also demonstration of phagocytosis in the BM aspirate just not responding to anakinra as a therapeutic intervention previous to HSC boost in one of them. However, it is noteworthy that more than 80% of patients presented any grade of CRS as some degree of inflammatory stress despite the fact that most of them were infused with low tumor burden and in aliquots (ARI 0001). In addition, high marrow disease infiltration associated to possible basal low levels of hematopoietic progenitor cells has not been associated to late-ICAHT in our cohort of patients with only 2/11 (18%) patients with blast > 5% pre-LD. Regarding the dose of CD34 + HSC infused, the concept has been long used in Allo-SCT and poor graft function considering that CD34 + cell dose/kg recipient weight was optimal and desired > 3x10 6 /kg ( 10 , 24 – 25 ). Remarkably, Klyuchnikov et al. reported that the CD3 + cell dose in the graft was significantly associated with the development of aGVHD and they observed that patients without aGVHD received a median of 8 x 10 3 CD3 + /kg ( 26 ). In the setting of CD34 + HSC boost after CART19, dose information is limited. In our cohort of patients, CD34 + cell dose/kg recipient weight was > 3x10 6 /kg in 10 out of 11 patients. The median CD3 + dose was mainly below 9 x10 3 /kg, although one patient received 4 x 10 4 /Kg of CD3 + and no aGVHD or cGVHD was observed. Finally, outcomes of EFS and survival showed at least similar results in comparison with trials and published real-practice outcome data ( 1 – 2 – 27 – 29 ). Outcomes are discouraging in the subgroup of patients who relapse early < 6 months after Allo-HSCT similar to outcomes recently published by Bader et al. ( 30 ). Interestedly, Rejeski et al. ( 15 ) and Penack et al. ( 31 ) found a stronger association of severe cytopenia with relapse and no pronounced association with non-relapse mortality (NRM). In contrast, some real-world analysis found a relatively high NRM at 24 months after CAR T-cell infusion ( 18 , 32 ). In this regard, in our cohort of patients with profound cytopenias, mortality was only related to leukemia relapse and no infections or NRM was documented. On the other hand, the impact of this lower doses of lymphocytes CD3 + in the selected CD34 + graft, compared to donor lymphocyte infusion and the impact on relapse is not yet determined. In this sense, the CD34 + HSC boost together with an increasing dose of CD3 + could be explore in the future. In addition, maintenance treatment might be offered as recently suggested by Gabelli et al ( 33 ) after hematological recovery after CD34 + HSC boost to improve EFS and OS. In summary, to the best of our knowledge this is the largest multicentre cohort study of ALL-B patients successfully treated with CD34 + HSC boost to treat late-ICAHT after CAR-T. Based on our results, for patients with prior extensive cytotoxic treatment post Allo-HSCT which present a primary poor graft function persisting beyond 60–90 days after CAR-T, strong consideration should be given to providing a CD34 + HSC boost if the original donor is available. There is an obvious exception of the unrelated umbilical cord blood donor source in pediatric patients. It should be noted that the response time of the unrelated donor is expected to be longer than related-donor, so it may be necessary to be more proactive, especially if the cytopenias are associated with uncontrolled infections or significant comorbidity beyond 30 days after CAR-T cell infusion. Future challenges include the identification of a pre-infusion hematologic toxicity score in r/r ALL-B population to optimize patient selection in larger cohorts as well as elaborating a treatment consensus on this therapeutic approach including optimal timing and more information about optimal CD34 + boost and CD3 + lymphocytes doses. Declarations Competing Interests: Authors declare there are not any competing financial interests in relation to the work described. References Rives S, Maude SL, Hiramatsu H, Baruchel A, Bader P, Bittencourt H, et al. 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Blood 2023;142(10):865–877 doi: 10.1182/blood.2023020578 Jain T, Olson TS, Locke FL. How I treat cytopenias after CAR T-cell therapy. Blood. 2023;141(20):2460–2469. doi: 10.1182/blood.2022017415 . Cuadrado MM, Szydlo RM, Watts M, Patel N, Renshaw H, Dorman J et al. Predictors of recovery following allogeneic CD34+-selected cell infusion without conditioning to correct poor graft function. Haematologica 2020. 105 ( 11 ):2639–2646 Shahzad M, Siddiqui RS, Anwar I, Chaudhary SG, Ali T, Naseem M, et al. Outcomes with CD34-selected stem cell boost for poor graft function after allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis. Transplant Cell Ther. 2021;27(10):877. e1-877.e8. Gagelmann N, Wulf GG, Duell J, Glass B, van Heteren P, von Tresckow B, et al. Hematopoietic stem cell boost for persistent neutropenia after CAR T-cell therapy: a GLA/DRST study. Blood Adv. 2023;7(4):555–559. doi: 10.1182/bloodadvances.2022008042 . Kharfan-Dabaja MA, Kumar A, Ayala A, Aljurf M, Nishihori T, Rebecca Marsh R, et al. Standardizing Definitions of Hematopoietic Recovery, Graft Rejection, Graft Failure, Poor Graft Function, and Donor Chimerism in Allogeneic Hematopoietic Cell Transplantation: A Report on Behalf of the American Society for Transplantation and Cellular Therapy. Transplantation and Cellular Therapy. 2021; 27: 642–649 Rejeski K, Greco R, Onida F, Sánchez-Ortega I, Bonini C, Sureda A, et al. An international survey on grading, diagnosis, and management of immune effector cell-associated hemato-toxicity (ICAHT) following CAR T-cell therapy on behalf of the EBMT and EHA. Hemasphere. 2023;7(5):e889. Rejeski K, Perez A, Sesques P, Hoster E, Berger C, Jentzsch L, et al. CAR-HEMATOTOX: a model for CAR T-cel l related hematologic toxicity in relapsed/ refractory large B-cell lymphoma. Blood.2021;138(24):2499–2513. Drillet G, Lhomme F, De Guiberrt S, Manson G, Houot R. Prolonged thrombocytopenia after CAR T-cell therapy: the role of thrombopoietin receptor agonists Blood Adv. 2023;7(4):537–540. doi: 10.1182/bloodadvances.2022008066 . Rejeski K, Burchert A, Iacoboni G, Sesques P, Francesky L, Bücklein V, et al. Safety and feasibility of stem cell boost as a salvage therapy for severe hematotoxicity after CD19 CAR T-cell therapy. Blood Adv. 2022;6(16): 4719–4725. Mullanfiroze K, Lazareva A, Chu J, Williams L, Burridge S, Silva J, et al. CD34+-selected stem cell boost can safely improve cytopenias following CAR T-cell therapy. Blood Adv. 2022;6(16):4715–4718. Lipsitt A, Beattie L, Harstead E, Li Y, Goorha S, Maron G, et al. Allogeneic CD34 + selected hema-topoietic stem cell boost following CAR T-cell therapy in a patient withprolonged cytopenia and active infection. Pediatr Blood Cancer.2023;70(3):e30166 Nahas GR, Komanduri KV, Pereira D, Goodman M, Jimenez AM, Beitinjaneh A, et al. Incidence and risk factors associated with a syndrome of persistent cytopenias after CAR-T cell therapy (PCTT). Leuk Lymphoma. 2020;61(4):940943. Taneja A, Jain T. CAR-T-OPENIA: chimeric antigen receptor T-cell therapy-associated cytopenias. EJHaem. 2021;3(Suppl 1):32–38. doi: 10.1002/jha2.3505 . Juluri KR, Wu V, Voutsinas JM, Hou J, Hirayama AV, Mullane E, et al. Severe cytokine release syndrome is associated with hematologic toxicity following CD19 CAR T cell therapy. Blood Adv. 2022;6(7): 2055–2068. Jain T, Knezevic A, Pennisi M, Chen Y, Ruiz JD, Purdon TJ, et al. Hematopoietic recovery in patients receiving chimeric antigen receptor T-cell therapy for hematologic. Blood Adv. 2020;4(15):3776–3787 Rangarajan HG, Crowell SA, Towerman AS, Shenoy SS. CD34-selected stem cell boost as therapy for late graft rejection following allogeneic transplantation for sickle cell disease. Bone Marrow Transplant. 2022;57(10):1592–1594. Shahzad M, Siddiqui RS, Anwar I, Chaudhary SG, Ali T, Naseem N, Ahmed TF, et al. Outcomes with CD34-selected stem cell boost for poor graft function after allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis. Transplant Cell Ther. 2021;27(10):877.e1–877.e8. Klyuchnikov E, El-Cheikh J, Sputtek A, Lioznov M, Calmels B, Furst S et al. CD34.-Selected Stem Cell Boost without Further Conditioning for Poor Graft Function after Allogeneic Stem Cell Transplantation in patients with Hematological Malignancies. Biol Blood Marrow Transplant 20 (2014) 382e386 Schultz LM, Eaton A, Baggott C, Rossoff J, Prabhu S, Keating AK, et al Outcomes after nonresponse and relapse post-tisagenlecleucel in children adolescents, and young adults with b-cell acute lymphoblastic leukemia. J Clin Oncol (2023) 41(2):354–63. doi: 10.1200/JCO.22.01076 Pasquini MC, Hu ZH, Curran K, Laetsch T, Locke F, Rouce R, et al. Real world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv (2020) 21:5414–24. doi: 10.1182/bloodadvances.2020003092 Laetsch TW, Maude SL, Rives S, Hiramatsu H, Bittencourt H, Bader P, et al. Three-year update of tisagenlecleucel in pediatric and young adult patients with Relapsed/Refractory acute lymphoblastic leukemia in the ELIANA trial. J Clin Oncol (2023) 41(9):1664–9. doi: 10.1200/JCO.22.00642 Bader P, Alonso A, Attarbaschi A, Bodmer N, Boing H, Burridge S, et al. Treatment of post-transplant relapse in children, adolescents and young adults with BCP ALL using CD19-CAR-T: A European retrospective analysis of real-world data. Hemasphere. 2023; 7(Suppl): e239539e. Penack O, Pecznski C, Koenecke C, Polge E, Kuhnl A, Fegueux N et al. Severe cytopenia after CD19 CAR T-cell therapy: a retrospective study from the EBMT Transplant Complications Working Party. J Immunother Cancer. 2023;11(4):e006406. doi: 10.1136/jitc-2022-006406 . Bethge WA, Martus P, Schmitt M, Holtick U, Subklewe M, von Tresckow B et al. GLA/DRST real-world outcome analysis of car T-cell therapies for large B-cell lymphoma in Germany. Blood 2022;140:349–58 Gabelli M, Oporto Espuelas M, Bonney DK, Burriedge S, Farish S, Hedges E, et al. Maintenance therapy for early loss of B-cell aplasia after CD19 CAR T-cell therapy. Blood Adv (2023). doi: 10.1182/bloodadvances.2023011168 Additional Declarations The authors have declared there is NO conflict of interest to disclose. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4843995","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":337291831,"identity":"d94ac888-53fd-407b-8284-0aca61856dd3","order_by":0,"name":"Águeda Molinos-Quintana","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-4972-917X","institution":"University Hospital Virgen del Rocío","correspondingAuthor":true,"prefix":"","firstName":"Águeda","middleName":"","lastName":"Molinos-Quintana","suffix":""},{"id":337291832,"identity":"64e31eb7-a38f-4ec7-876f-96313c83c252","order_by":1,"name":"Nuria Martinez-Cibrian","email":"","orcid":"","institution":"Hospital Clinic of Barcelona","correspondingAuthor":false,"prefix":"","firstName":"Nuria","middleName":"","lastName":"Martinez-Cibrian","suffix":""},{"id":337291833,"identity":"c6773c8e-9d50-4e39-9c3a-2c914c421e6f","order_by":2,"name":"Anna Alonso-Saladrigues","email":"","orcid":"","institution":"Hospital Sant Joan de Déu de Barcelona,","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Alonso-Saladrigues","suffix":""},{"id":337291834,"identity":"ff668744-caa4-4338-9329-cfc4fe6a3991","order_by":3,"name":"Victor Galán","email":"","orcid":"","institution":"Hospital Universitario La Paz","correspondingAuthor":false,"prefix":"","firstName":"Victor","middleName":"","lastName":"Galán","suffix":""},{"id":337291835,"identity":"af188449-9d90-4377-8e6b-5b329189946c","order_by":4,"name":"Rebeca Bailén","email":"","orcid":"","institution":"HGU Gregorio Marañón","correspondingAuthor":false,"prefix":"","firstName":"Rebeca","middleName":"","lastName":"Bailén","suffix":""},{"id":337291836,"identity":"c1fb5e9d-9796-4590-a02b-dcd268412b7f","order_by":5,"name":"Susana Buendía-López","email":"","orcid":"","institution":"Peditric University Hospital del Niño Jesús, Madrid. Spain","correspondingAuthor":false,"prefix":"","firstName":"Susana","middleName":"","lastName":"Buendía-López","suffix":""},{"id":337291837,"identity":"0b6a8ade-70b6-4987-8647-5bcacea2c7fc","order_by":6,"name":"Carolina Fuentes","email":"","orcid":"","institution":"Hospital Universitario La Fe","correspondingAuthor":false,"prefix":"","firstName":"Carolina","middleName":"","lastName":"Fuentes","suffix":""},{"id":337291838,"identity":"d4b4043d-154c-4499-b550-972451f5aef3","order_by":7,"name":"Mi Kwon","email":"","orcid":"https://orcid.org/0000-0002-3855-7774","institution":"Univesidad Complutense de Madrid","correspondingAuthor":false,"prefix":"","firstName":"Mi","middleName":"","lastName":"Kwon","suffix":""},{"id":337291839,"identity":"95954f6f-c058-4b00-a4ab-ad43d9236d03","order_by":8,"name":"Marta González-Vincent","email":"","orcid":"","institution":"Department of Stem Cell Transplantation,","correspondingAuthor":false,"prefix":"","firstName":"Marta","middleName":"","lastName":"González-Vincent","suffix":""},{"id":337291840,"identity":"00fbd52d-2261-4ec3-bf1d-15ec09974f2e","order_by":9,"name":"Concepción Pérez de Soto","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Concepción","middleName":"Pérez","lastName":"de Soto","suffix":""},{"id":337291841,"identity":"b38f5e19-b02e-4476-a4c7-e0e6fccde9ad","order_by":10,"name":"Berta Gonzalez","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Berta","middleName":"","lastName":"Gonzalez","suffix":""},{"id":337291842,"identity":"f01e715d-9cda-4824-b9d3-2984b9d20b97","order_by":11,"name":"s rives","email":"","orcid":"","institution":"unknown","correspondingAuthor":false,"prefix":"","firstName":"s","middleName":"","lastName":"rives","suffix":""},{"id":337291843,"identity":"09a3e56f-6e29-4ec5-8c44-79080d9af4d6","order_by":12,"name":"José María Pérez-Hurtado","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"José","middleName":"María","lastName":"Pérez-Hurtado","suffix":""},{"id":337291844,"identity":"b1fa8520-6d2d-4144-926b-9942824f982b","order_by":13,"name":"Valentin Ortiz-Maldonado","email":"","orcid":"","institution":"Hospital Clínic de Barcelona","correspondingAuthor":false,"prefix":"","firstName":"Valentin","middleName":"","lastName":"Ortiz-Maldonado","suffix":""},{"id":337291845,"identity":"0f2dab64-732e-4ffc-9ef2-ec1d1f0a9008","order_by":14,"name":"José A Pérez-Simón","email":"","orcid":"https://orcid.org/0000-0003-3616-6101","institution":"Department of Hematology of the University Hospital Virgen del Rocío, Instituto de Biomedicina (IBIS/CSIC/CIBERONC), Universidad de Sevilla","correspondingAuthor":false,"prefix":"","firstName":"José","middleName":"A","lastName":"Pérez-Simón","suffix":""}],"badges":[],"createdAt":"2024-08-01 18:00:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4843995/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4843995/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":64713290,"identity":"a260fbb2-b7ec-4114-8d53-05a61de7453c","added_by":"auto","created_at":"2024-09-18 02:12:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":163706,"visible":true,"origin":"","legend":"\u003cp\u003eEvent free survival for patients who received an allogeneic CD34\u003csup\u003e+ \u003c/sup\u003eHSC boost after CAR T-cell therapy and prior allo-HSCT: A) Kaplan-Meier curve for the whole series of patients. B) Kaplan-Meier curve for patients who relapsed \u0026gt; 6 months after allo-HSCT vs early relapses \u0026lt; 6 months. C) Overall survival\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4843995/v1/3a8743020942cd1c521ffcc0.png"},{"id":65613168,"identity":"474d1243-05e7-47e6-9333-b0c6e029b532","added_by":"auto","created_at":"2024-09-30 13:48:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":887117,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4843995/v1/02d9c7b9-96c5-4eaa-9367-1f6f378d891e.pdf"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Allogeneic CD34+ hematopoietic stem cell boost for prolonged severe cytopenias following CAR T-cell therapy in B-cell acute lymphoblastic leukemia. A retrospective analysis on behalf of the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC)","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eChimeric antigen receptor (CAR) T-cell therapy has a remarkable impact on the outcome of pediatric and adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The management of early toxicities including cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) has been well established. However, real-world clinical experience has shown that hematological toxicity leading to peripheral-blood cytopenias is one of the most common and severe long-term adverse effects (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Moreover, severe cytopenias not only affect the quality of life and prolong hospitalization, but may also result in life-threatening bleeding and infectious events, being a major driver of the morbidity and mortality observed after CAR T-cell therapy.\u003c/p\u003e \u003cp\u003eHematotoxicity after CAR T cell administration can be multifactorial and closely associated with CAR-T and disease-associated inflammation in addition to baseline bone marrow (BM) reserve (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). However, the underlying pathophysiology of prolonged cytopenias after CAR T-cell infusion remains poorly understood and represents a clinical challenge with a paucity of data to guide management (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Therefore, severe cytopenias not resolving over time can be a major clinical problem. In this setting, several off-label approaches have been described to address this issue, including transfusion support, use of granulocyte colony stimulators, thrombopoietin analogues and erythroid stimulators. Hematopoietic stem cell (HSC) boost has also been used to treat poor graft function after CAR-T cell therapy mainly based on cryopreserved autologous infusion (\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). However, the experience using unmanipulated allogeneic CD34\u003csup\u003e+\u003c/sup\u003e HSC boost remains anecdotal.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eWe conducted a multicenter retrospective study including 11 pediatric and adult patients with r/r B-ALL treated with second generation (4-1BB-based) anti-CD19 CAR-T therapy. All patients received allogeneic unmanipulated donor-derived CD34\u003csup\u003e+\u003c/sup\u003e boost for the treatment of prolonged and severe cytopenias in six spanish institutions from July 2018 to January 2024. The data cutoff date was June 1, 2024 when all CD34\u003csup\u003e+\u003c/sup\u003e HSC boost infused patients had a minimum follow-up of 6 months or had experienced disease relapse or death.\u003c/p\u003e \u003cp\u003eClinical and laboratory data were collected during routine evaluations and extracted from the GETH-TC (Grupo Espa\u0026ntilde;ol de Trasplante Hematopoy\u0026eacute;tico y Terapia Celular) database and RedCap. All clinical investigation was conducted according to the principles of the Declaration of Helsinki and was approved by the relevant local institutional ethics committee (Code: 0600-N-22). Informed consent was obtained from all subjects protected by the GETH-TC.\u003c/p\u003e \u003cp\u003eEvent-free survival (EFS) was calculated from the time to CD34\u003csup\u003e+\u003c/sup\u003e boost infusion to event considered as relapse or mortality of any cause.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eEleven patients who received an allogeneic CD34\u003csup\u003e+\u003c/sup\u003e HSC boost to treat prolonged cytopenia after CAR-T cell therapy were analyzed. The indication for receiving CAR-T cell therapy in all 11 patients was relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Median time from allo-HSCT to relapse was 6 months (range 3 to 24.1), and from allo-HSCT to CAR T-cell infusion 8.6 months (range 5.3\u0026ndash;20.9). Therefore, most patients (73%) received CAR-T cell therapy for the treatment of relapse after \u0026lt;\u0026thinsp;1 year post transplantation. Median age was 27 years (range 8\u0026ndash;46). Varnimcabtagene autoleucel (ARI-0001) was the most common cellular therapy product infused (8 patients) followed by tisagenlecleucel (2 patients) and JCAR017 in one patient; all of them being 4-1BB-based constructs. One patient received a CAR T-cell reinfusion for early B-cell recovery (\u0026lt;\u0026thinsp;3months). Patient\u0026acute;s characteristics are described in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePreceding allogeneic stem cell transplant characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of patients (%). N:11\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDonor type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMatched related donor (10/10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMismatched related donor (haploidentical)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (54.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMatched unrelated donor (10/10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (36.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMismatched unrelated donor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (9.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSource of stem cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone marrow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeripheral blood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (91)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConditioning regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMieloablative with TBI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (36.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMieloablative without TBI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (45.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReduced intensity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (18.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary or secondary post-transplant engraftment failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePoor graft function*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (27.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapse after allo-SCT (months), median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (3-24.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e*Poor graft function: delayed or incomplete hematopoietic recovery despite evidence of complete donor chimerism post allo-SCT in the absence of other explanations, such as disease relapse, drugs, or infections (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding previous treatments, most patients had received \u0026ge; 4 prior treatment lines including blinatumomab and inotuzumab in 2 and 5 patients, respectively, prior to leukapheresis. All of them had suffered \u0026ge; 2 prior ALL relapses (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). At the time of lymphodepletion (LD), 9 patients had\u0026thinsp;\u0026lt;\u0026thinsp;5% blasts in BM and, among them, 5 had negative measurable residual disease (MRD) while two patients had high tumor burden with \u0026gt;\u0026thinsp;5% BM blasts. Two out of eleven patients had extramedullary disease (central nervous system involvement), one isolated and one combined with BM infiltration.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePre-CAR T-cell therapy characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of patients n (%) n:11\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, median (range), years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (8\u0026ndash;46)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (73)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAR-T cells \u0026le; 1 year after Allo-SCT, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (73)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime after last Allo-SCT, median (range), months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.6 (5.3\u0026ndash;20.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease status / CAR indication\u003c/p\u003e \u003cp\u003eTwo relapses\u003c/p\u003e \u003cp\u003eThree relapses\u003c/p\u003e \u003cp\u003e\u0026gt; 3 relapses\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (36.4)\u003c/p\u003e \u003cp\u003e5 (45.5)\u003c/p\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior lines of therapy. No (%)\u003c/p\u003e \u003cp\u003e2\u003c/p\u003e \u003cp\u003e3\u003c/p\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e5\u003c/p\u003e \u003cp\u003e\u0026ge;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll prior therapy (pre-leukapheresis)\u003c/p\u003e \u003cp\u003ePrior blinatumomab\u003c/p\u003e \u003cp\u003ePrior inotuzumab\u003c/p\u003e \u003cp\u003ePrior chemotherapy regimen including fludarabine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e5 (45.5)\u003c/p\u003e \u003cp\u003e6 (54.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLast treatment pre-leukapheresis\u003c/p\u003e \u003cp\u003eDexametasone +/- hydrea +/- intrathecal\u003c/p\u003e \u003cp\u003eInotuzumab-based\u003c/p\u003e \u003cp\u003eAtenuated conventional chemotherapy (hyperCVAD-like)\u003c/p\u003e \u003cp\u003eNo treatment relapse pre-leukapheresis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e5 (45.5)\u003c/p\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBridging chemotherapy regimen\u003c/p\u003e \u003cp\u003eAtenuated conventional chemotherapy\u003c/p\u003e \u003cp\u003eFLU/CLO-based chemotherapy\u003c/p\u003e \u003cp\u003eBlinatumomab\u003c/p\u003e \u003cp\u003eInotuzumab\u003c/p\u003e \u003cp\u003eRadiotherapy\u003c/p\u003e \u003cp\u003eNo bridging therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (54.5)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCTCAE v.5 grade 4 cytopenias after bridging therapy, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (54.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfections after bridging therapy, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBacteremia 3\u003c/p\u003e \u003cp\u003eViral infection 2\u003c/p\u003e \u003cp\u003eStenotrophomona maltophila pneumonia 1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease burden prior-infusion, n (%)\u003c/p\u003e \u003cp\u003eNo detectable disease\u003c/p\u003e \u003cp\u003eLow-disease burden (\u0026lt;\u0026thinsp;5% blast)\u003c/p\u003e \u003cp\u003eHigh-disease burden (\u0026gt;\u0026thinsp;5% blast)\u003c/p\u003e \u003cp\u003eHigh tumor burden (\u0026gt;\u0026thinsp;5% lasts) with CNS\u003c/p\u003e \u003cp\u003eIsolated extramedullary disease (CNS)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (36.4)\u003c/p\u003e \u003cp\u003e4 (36.4)\u003c/p\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphodepletion CF\u0026thinsp;+\u0026thinsp;FLU (dose), n (%)\u003c/p\u003e \u003cp\u003eDose: CF (1000 mg/m2)\u0026thinsp;+\u0026thinsp;FLU (120 mg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003cp\u003eDose: CF (900 mg/m2)\u0026thinsp;+\u0026thinsp;FLU (90 mg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003cp\u003eAdditional LD: Rituximab 375 mg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (100%)\u003c/p\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e9 (82)\u003c/p\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplete blood counts prior-lymphodepletion (LD)\u003c/p\u003e \u003cp\u003eMedian ANC cells x 10\u003csup\u003e9\u003c/sup\u003e/L (95% CI)\u003c/p\u003e \u003cp\u003eMedian platelet count, x 10\u003csup\u003e9\u003c/sup\u003e/L (95% CI)\u003c/p\u003e \u003cp\u003eMedian hemoglobin, g/dL (95% CI)\u003c/p\u003e \u003cp\u003eBlood transfusion 7 days prior to LD n (%)\u003c/p\u003e \u003cp\u003ePlatelet transfusion 3 days prior to LD n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.7 (0.02\u0026ndash;1.38)\u003c/p\u003e \u003cp\u003e29 (6.7\u0026ndash;51.3)\u003c/p\u003e \u003cp\u003e10.1 (9.5\u0026ndash;10.7)\u003c/p\u003e \u003cp\u003e5 (45.4)\u003c/p\u003e \u003cp\u003e7 (63.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaintained severe neutropenia (ANC cells x 10\u003csup\u003e9\u003c/sup\u003e/L\u0026thinsp;\u0026lt;\u0026thinsp;0.5) and/or platelet count\u0026thinsp;\u0026lt;\u0026thinsp;50 x 10\u003csup\u003e9\u003c/sup\u003e/L for more than 4 weeks pre-CAR-T infusion, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (54.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBaseline cytopenias assessed at the beginning of the LD are available in Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Maintained severe neutropenia (ANC cells x 10\u003csup\u003e9\u003c/sup\u003e/L\u0026thinsp;\u0026lt;\u0026thinsp;0.5) and/or platelet count\u0026thinsp;\u0026lt;\u0026thinsp;50 x 10\u003csup\u003e9\u003c/sup\u003e/L for \u0026ge;\u0026thinsp;4 weeks pre-CAR-T infusion was documented in 6/11 patients (54.4%). Red blood cells transfusions within 7 days prior to LD occurred in 45% and platelet transfusion within 3 days prior to LD in 63.6% of patients.\u003c/p\u003e \u003cp\u003eAfter infusion, CRS occurred in 81.8% of patients although only one patient reached severe CRS \u0026ge; 3. No ICANS were documented in any of eleven patients. Immune effector cell-associated HLH-like syndrome occurred in one patient (Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). At day 28 post infusion, the overall remission rate with incomplete hematologic recovery was 100%. All eleven patients were negative for the measurable residual disease (MRD)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePost CAR T-cell therapy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of patients (n:11)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAR product, n (%)\u003c/p\u003e \u003cp\u003eTisagenlecleucel\u003c/p\u003e \u003cp\u003eVarnimcabtagene autoleucel (ARI-0001)\u003c/p\u003e \u003cp\u003eLisocabtagene maraleucel (JCAR017)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (18.2)\u003c/p\u003e \u003cp\u003e8 (72.7)\u003c/p\u003e \u003cp\u003e1 (9.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAR-T cell x 10\u003csup\u003e6\u003c/sup\u003e/Kg, median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.05-5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eToxicity after infusion:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- No CRS\u003c/p\u003e \u003cp\u003e- CRS, n (%)\u003c/p\u003e \u003cp\u003eCRS grade 1\u003c/p\u003e \u003cp\u003eCRS grade 2\u003c/p\u003e \u003cp\u003eCRS grade \u0026ge; 3\u003c/p\u003e \u003cp\u003e- Immune effector cell-associated HLH-like syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (18.2)\u003c/p\u003e \u003cp\u003e9 (81.8)\u003c/p\u003e \u003cp\u003e4 (44.5)\u003c/p\u003e \u003cp\u003e4 (44.5)\u003c/p\u003e \u003cp\u003e1 (11.1)\u003c/p\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- ICANS n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Anti-cytokine therapy, n (%)\u003c/p\u003e \u003cp\u003eTocilizumab\u003c/p\u003e \u003cp\u003eCorticosteroids\u003c/p\u003e \u003cp\u003eAnakinra / Siltuximab\u003c/p\u003e \u003cp\u003eVasopressors\u003c/p\u003e \u003cp\u003eOxygen therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (36.4)\u003c/p\u003e \u003cp\u003e3 (27.3)\u003c/p\u003e \u003cp\u003e2 (18.2)\u003c/p\u003e \u003cp\u003e1 (9.1)\u003c/p\u003e \u003cp\u003e4 (36.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCytopenias not resolved by day 28, n/n (%)\u003c/p\u003e \u003cp\u003eANC cells x 10\u003csup\u003e9\u003c/sup\u003e/L\u0026thinsp;\u0026lt;\u0026thinsp;0.5\u003c/p\u003e \u003cp\u003ePlatelet count\u0026thinsp;\u0026lt;\u0026thinsp;25 x 10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003cp\u003eHemoglobin\u0026thinsp;\u0026lt;\u0026thinsp;8 g/dL\u003c/p\u003e \u003cp\u003eG-CSF administration\u003c/p\u003e \u003cp\u003eANC cell x 10\u003csup\u003e9\u003c/sup\u003e/L\u0026thinsp;\u0026gt;\u0026thinsp;0.5 after G-CSF support\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11/11 (100)\u003c/p\u003e \u003cp\u003e11/11 (100)\u003c/p\u003e \u003cp\u003e11/11 (100)\u003c/p\u003e \u003cp\u003e10/11 (90.9)\u003c/p\u003e \u003cp\u003e10/11 (90.9)\u003c/p\u003e \u003cp\u003e2/10 (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCytopenias not resolved by month 3, n/n (%)\u003c/p\u003e \u003cp\u003eANC cells x 10\u003csup\u003e9\u003c/sup\u003e/L\u0026thinsp;\u0026lt;\u0026thinsp;0.5\u003c/p\u003e \u003cp\u003ePlatelet transfusion dependence\u003c/p\u003e \u003cp\u003eBlood transfusion dependence\u003c/p\u003e \u003cp\u003eHSC boost previous to 3 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9/11 (81.8)\u003c/p\u003e \u003cp\u003e7/9 (77.8)\u003c/p\u003e \u003cp\u003e5/9 (55.6)\u003c/p\u003e \u003cp\u003e6/9 (66.7)\u003c/p\u003e \u003cp\u003e2/11 (18.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReasons that led to boost performance, n/n (%)\u003c/p\u003e \u003cp\u003eANC cells x 10\u003csup\u003e9\u003c/sup\u003e/L\u0026thinsp;\u0026lt;\u0026thinsp;0.5\u0026thinsp;+\u0026thinsp;transfusion dependence\u003c/p\u003e \u003cp\u003eANC cells x 10\u003csup\u003e9\u003c/sup\u003e/L\u0026thinsp;\u0026lt;\u0026thinsp;0.5\u003c/p\u003e \u003cp\u003eTransfusion dependence, ANC cells x 10\u003csup\u003e9\u003c/sup\u003e/L\u0026thinsp;\u0026gt;\u0026thinsp;0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7/11 (63.6)\u003c/p\u003e \u003cp\u003e2/11 (18.2)\u003c/p\u003e \u003cp\u003e2/11 (18.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEvaluation D28 RCi*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11/11 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMRD negativity, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11/11 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e*RCi: Complete remission with incomplete hematologic recovery\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAs far as early myelotoxicity after CAR-T is concerned, all eleven patients developed severe neutropenia and/or thrombocytopenia that persisted on day 28 after infusion, most of them being refractory to therapeutic approaches such as growth factors support. Only 2/10 patients achieved ANC cell\u0026thinsp;\u0026gt;\u0026thinsp;0.5x 10\u003csup\u003e9\u003c/sup\u003e/L after G-CSF. Cytopenias did not resolve by month 3 in nine patients: six of them had neutropenia grade 4 (66.7%), and five (55.6%) and six (66.7%) had platelet and blood transfusion dependence, respectively (Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The other two patients received early CD34\u0026thinsp;+\u0026thinsp;HSC boost before 3 months after CAR T-cell infusion.\u003c/p\u003e \u003cp\u003eIn most cases (10 out of 11 patients), the BM aspirate was hypocellular and without dysplasia prior to the boost. Only 1 patient showed normocellular BM aspirate with predominance of the red-cell precursors but peripheral cytopenia.\u003c/p\u003e \u003cp\u003eSome life-threatening infections were observed prior to the CD34\u003csup\u003e+\u003c/sup\u003e boost: three cases of gram-negative bloodstream infections (\u003cem\u003ePseudomona aeruginosa\u003c/em\u003e, \u003cem\u003eEscherichia Coli and Klebsiella pneumoniae\u003c/em\u003e), a gram-positive catheter-related infection, one case of listeria as an enteroinvasive gastrointestinal infection and one patient suffered from cytomegalovirus infection. In addition, six breakthrough invasive fungal infections were documented, five of them were possible or probable invasive aspergillosis and one mucormycosis infection. Also, one patient presented a hemorrhagic event due to thrombopenia.\u003c/p\u003e \u003cp\u003eThe median time from CAR T-cell infusion to donor CD34\u0026thinsp;+\u0026thinsp;HSC boost was 2.8 months (range 1.5\u0026ndash;4.9). Median CD34\u003csup\u003e+\u003c/sup\u003e selected dose was 4 x10\u003csup\u003e6\u003c/sup\u003e/kg of recipient weight (range 1.6\u0026ndash;14.2). Median CD3\u003csup\u003e+\u003c/sup\u003eT cells dose was 8.3 x10\u003csup\u003e3\u003c/sup\u003e/kg of recipient weight (range 1.14-40) out of seven patient\u0026acute;s with available information. Full donor chimerism pre-CD34\u0026thinsp;+\u0026thinsp;boost infusion was documented in all patients. No conditioning was used previous to the boost and no toxicity such as acute graft versus host disease (aGVHD) or CRS was documented afterwards.\u003c/p\u003e \u003cp\u003eOverall, all eleven patients had improved cytopenia following CD34\u003csup\u003e+\u003c/sup\u003e HSC boost. The median time to complete hematological recovery after boost was 20 days (range 12\u0026ndash;60) defined as hematological improvement in all three cell lineages (hemoglobin\u0026thinsp;\u0026ge;\u0026thinsp;8 g/dL, platelets\u0026thinsp;\u0026ge;\u0026thinsp;25x10\u003csup\u003e9\u003c/sup\u003e/L and neutrophils\u0026thinsp;\u0026ge;\u0026thinsp;0.5x10\u003csup\u003e9\u003c/sup\u003e/L for three consecutive days) without the need for subsequent transfusion or growth factor support. The median time from CD34\u003csup\u003e+\u003c/sup\u003e boost to first neutrophil counts\u0026thinsp;\u0026gt;\u0026thinsp;1.0x10\u003csup\u003e9\u003c/sup\u003e/L was 13 days (range 7\u0026ndash;16), to platelets\u0026thinsp;\u0026ge;\u0026thinsp;50x10\u003csup\u003e9\u003c/sup\u003e/L was 20 days (range 14\u0026ndash;249) and to hemoglobin\u0026thinsp;\u0026ge;\u0026thinsp;10 g/dL was 35 days (range 5\u0026ndash;47) in 10 out of 11 patients. The individual patient profile is available in Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStem cell boost results.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"13\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eStem cell boost (SCB)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003e\u003cem\u003eNeutrophil engraftment after SCB\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c12\" namest=\"c9\"\u003e \u003cp\u003e\u003cem\u003ePlatelet and hemoglobin engraftment after SCB\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u003cem\u003eComplete hematological recovery**\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e#\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDay after CAR-T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIndication\u003c/p\u003e \u003cp\u003efor SC boost\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePrevious BM status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTotal infused cells (x 10\u003csup\u003e6\u003c/sup\u003e CD34\u003csup\u003e+\u003c/sup\u003e/Kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eDay of ANC\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003e\u0026gt;\u0026thinsp;0.5 x10\u003c/em\u003e\u003csup\u003e\u003cem\u003e9\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e/L*\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003eFirst day of ANC\u0026thinsp;\u0026gt;\u0026thinsp;1 x10\u003c/em\u003e\u003csup\u003e\u003cem\u003e9\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e/L\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eLast day\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eG-CSF support\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDay of engraftment Platelet\u0026thinsp;\u0026gt;\u0026thinsp;25 x 10\u003csup\u003e9\u003c/sup\u003e/L Transfusion\u003c/p\u003e \u003cp\u003eindependent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eDay of\u003c/p\u003e \u003cp\u003eplatelet count\u0026thinsp;\u0026gt;\u0026thinsp;50 x 10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eHemoglobin level\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;8 g/dL\u003c/p\u003e \u003cp\u003eTransfusion independent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eHemoglobin level\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;10 g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eDay after boost\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePancytopenia and severe infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHypoplastic without megakaryocytes. Hemo-phagocytosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e22\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePancytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHypoplastic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e249\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e35\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePancytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e14\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePancytopenia and severe infections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHypoplastic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14,2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNot reached\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e21\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePancytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAbsent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8,7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e13\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e135\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePancytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHypoplastic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e20\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePancytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHypoplastic without megakaryocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3,4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e214\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e60\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePancytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAbsent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3,6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e12\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePancytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHypoplastic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1,6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e20\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePancytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNormo-\u003c/p\u003e \u003cp\u003ecellular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3,4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e17\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e147\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTransfusion dependency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHypoplastic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5,3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e14\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83\u003c/p\u003e \u003cp\u003e(46\u0026ndash;147)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003cp\u003e(1.6\u0026ndash;8.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003cp\u003e(\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13 CR14 CR15\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14\u003c/p\u003e \u003cp\u003e(\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13 CR14 CR15\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e11\u003c/p\u003e \u003cp\u003e(\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e14\u003c/p\u003e \u003cp\u003e(11\u0026ndash;60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e20\u003c/p\u003e \u003cp\u003e(14\u0026ndash;249)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e17\u003c/p\u003e \u003cp\u003e(1\u0026ndash;60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e35\u003c/p\u003e \u003cp\u003e(5\u0026ndash;47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e \u003cp\u003e20\u003c/p\u003e \u003cp\u003e(12\u0026ndash;60)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"13\"\u003e\u003cem\u003e*Day of ANC\u0026thinsp;\u0026gt;\u0026thinsp;0.5 x10\u003c/em\u003e\u003csup\u003e\u003cem\u003e9\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e/L for three consecutive days;\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"13\"\u003e\u003cem\u003e** Complete hematological recovery defined as hematological improvement in all three cell lineages (hemoglobin\u0026thinsp;\u0026ge;\u0026thinsp;8 g/dL, platelets\u0026thinsp;\u0026ge;\u0026thinsp;25x10\u003c/em\u003e\u003csup\u003e\u003cem\u003e9\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e/L and neutrophils\u0026thinsp;\u0026ge;\u0026thinsp;0.5x10\u003c/em\u003e\u003csup\u003e\u003cem\u003e9\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e/L for three consecutive days) without the need for subsequent transfusion or growth factor support\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding outcomes, event free survival (EFS) at last follow-up was 27,3% (3/11) with a median EFS of 10 months (95% CI 2.45\u0026ndash;17.5). Respective values of EFS for patients relapsing before or after 6 months post-transplantation was 14.3% vs 75% at 12 months, respectively (p\u0026thinsp;=\u0026thinsp;0.016). Median EFS was not reached for patients who relapsed\u0026thinsp;\u0026gt;\u0026thinsp;6 months after transplant vs 4 months (95% CI 1.4\u0026ndash;6.56) for those relapsing\u0026thinsp;\u0026lt;\u0026thinsp;6 months after allo-HSCT (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). With a median follow-up after CD34\u003csup\u003e+\u003c/sup\u003e HSC boost of 12 months (95% CI 9.3\u0026ndash;28.8), overall survival (OS) at 12 and 24 months was 51.9% and 31.2% respectively with a median OS of 21 months (95% CI 6.27\u0026ndash;35.73). All causes of death after CD34\u003csup\u003e+\u003c/sup\u003e HSC boost were related to disease relapse.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eHematological toxicity is the most common long term adverse event after CAR T-cell therapy. Recently, the international expert panel (EHA and EBMT) referred to it as a novel category of toxicity called immune effector cell\u0026ndash;associated hematotoxicity (ICAHT). They defined late-ICAHT when cytopenias occurring\u0026thinsp;+\u0026thinsp;30 after CAR T-cell infusion (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Hematopoietic count recovery after CAR T-cell infusion often follows a biphasic trajectory with intermittent recovery followed by one or subsequent dips (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) and usually, gradual recovery is the likely trajectory even without intervention. However, some patients can develop very severe BM aplasia and profound cytopenias can be persistent and refractory to therapeutic measures such as thrombopoietin receptor agonists (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Unfortunately, the best clinical practice to treat this persisting cytopenias is not well established. Allogeneic CD34\u003csup\u003e+\u003c/sup\u003e HSC boost has been recently included in a propose treatment algorithm (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) despite the experience with this strategy for restoring hematological recovery after CAR-T remains anecdotal particularly in r/r ALL-B patients. Previous experience on eleven patients treated with CD34\u003csup\u003e+\u003c/sup\u003e HSC boost from three different retrospective studies is summarized in Table \u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e and in line with our results (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Concerning to timing, previous reported mean time from CAR-T infusion to CD34\u003csup\u003e+\u003c/sup\u003e HSC boost was between 2.1 and 5.9 months, similar to our 2.8 months. Successful hematological improvement has been described in nine out of eleven patients. The other two patients died after CD34\u0026thinsp;+\u0026thinsp;HSC boost because of an hemorrhagic event and relapse, respectively. Previous data of mean time to recovery of neutropenia and transfusion independence occurred between 14\u0026ndash;33 days after CD34\u003csup\u003e+\u003c/sup\u003e HSC boost similar to our mean time of 20 days. Although there was no uniformity in the hematological criteria of recovery, the authors considered the CD34\u0026thinsp;+\u0026thinsp;HSC boost to be successful.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrevious experience with Allo-SCT boost after CAR T-cell therapy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReference author (year)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRejeski et al. 2022 (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eMullanfiroze et al. 2022\u003c/em\u003e (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLipssitt et al. 2022 (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean age years (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (23\u0026ndash;44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute lymphoblastic leukemia (ALL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 ALL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 ALL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 ALL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian total number of infused CD34\u003csup\u003e+\u003c/sup\u003e cells/Kg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.3 x 10\u003csup\u003e6\u003c/sup\u003e/kg (3-7.5 x 10\u003csup\u003e6\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.75 x 10\u003csup\u003e6\u003c/sup\u003e/Kg (2.5\u0026ndash;11.2 x 10\u003csup\u003e6\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.1 x 10\u003csup\u003e6\u003c/sup\u003e cells/Kg on day\u0026thinsp;+\u0026thinsp;69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious severe CRS \u0026ge; grade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0/3 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/7 (14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious allo-SCT \u0026le; 1 year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2/3 (67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1/7 (14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline bone marrow reserve (pre-LD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4,5 y 7\u003c/p\u003e \u003cp\u003eCAR-Hematotox score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eBM aspirate pre-LD\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003edemonstrated hypocellularity in 5 of 7 and effacement with blasts in 2 of 7.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSevere baseline cytopenia prior to LD\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean time since CART19 to stem cell boost (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.9 months (1.4\u0026ndash;11.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.1 months\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian time Neutrophils\u0026thinsp;\u0026gt;\u0026thinsp;1 x 109/L without GCSF, days (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en.a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (11\u0026ndash;192)**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.a\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood transfusion independent, day post boost (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en.a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (4-106)**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en.a\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay of platelet engraftment after boost (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (7\u0026ndash;73)**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay of neutrophil engraftment* after boost\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en.a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn complete response after last follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en.a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1/1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003e*Neutrophil engraftment was defined as the first of 3 consecutive days achieving a sustained absolute neutrophil count (ANC)\u0026thinsp;\u0026gt;\u0026thinsp;500/mL without growth factor support. Platelet engraftment was defined as a platelet count\u0026thinsp;\u0026gt;\u0026thinsp;20 gr/l and transfusion independence\u0026thinsp;\u0026gt;\u0026thinsp;7 days.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003e** Only 5 of 7 patients were evaluable for response to HSC boost since 1 died of a gastrointestinal hemorrhage and 1 relapsed at day 38 after HSC boost\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOur series of r/r B-ALL patients contributes to a better understanding of timing and hematopoiesis restoration after allogeneic CD34\u003csup\u003e+\u003c/sup\u003e HSC boost as an effective and safe therapeutic measure. Hence, it minimizes the time at risk of morbidity and mortality-related of profound cytopenias post CAR T-cell. In our experience, most physicians\u0026acute; rationale for allogeneic-CD34\u003csup\u003e+\u003c/sup\u003e boost was primary poor graft function after CAR T-cell, defined by: (i) failure to ever achieve count recovery in at least one lineage (neutrophils\u0026thinsp;\u0026ge;\u0026thinsp;0.5x10\u003csup\u003e9\u003c/sup\u003e/L despite growth factor support and/or platelets\u0026thinsp;\u0026ge;\u0026thinsp;25 x10\u003csup\u003e9\u003c/sup\u003e/L and hemoglobin\u0026thinsp;\u0026ge;\u0026thinsp;8 g/dL in the absence of transfusion) after CAR T-cell therapy; (ii) a hypoplastic/absent bone marrow; (iii) the absence of relapse; and (iv) the presence of donor cells as detected by BM or peripheral blood chimerism studies. The toxicity profile between CAR-T and CD34\u003csup\u003e+\u003c/sup\u003e HSC boost was dominated not only by hematological toxicity but also by severe infections mainly by bacterial (45.5%) and/or invasive fungal infections (54.5%). This study has several relevant limitations. It was retrospective, uncontrolled, and limited to small patient numbers. But we observed a potential benefit of shortening the phase of critical neutropenia to control a high percentage of severe infectious events.\u003c/p\u003e \u003cp\u003eOverall, multiple factors (hematopoietic reserve, BM infiltration and CRS related systemic inflammation) may influence the development of late-ICAHT after CAR T-cell therapy (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Based on these known risk factors a score (CAR HEMATOTOX) has been developed to identify patients at high risk for prolonged cytopenias (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). However, it is important to note that the score remains to be validated for adult and pediatric patients with B-cell precursor ALL; so we have not calculated this score in the present study but we have described this risk factors individually. Previous cytopenias in highly pre-treated patients have been frequent characteristics of our patients highlighting the impact of BM reserve in late cytopenias (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). It should be noted that most of them were also allo-transplanted in the previous 12 months. On the contrary, development of high grade of CRS and the associated inflammatory stress with or without immune effector cell\u0026ndash;associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) could exert myelosuppressive effects, but appears to play a greater role in development of early and not prolonged cytopenias (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). That\u0026acute;s in agreement with our series of patients with late-ICAHT because only two patients presented IEC-HS or CRS grade 4 after CAR T-cell therapy with also demonstration of phagocytosis in the BM aspirate just not responding to anakinra as a therapeutic intervention previous to HSC boost in one of them. However, it is noteworthy that more than 80% of patients presented any grade of CRS as some degree of inflammatory stress despite the fact that most of them were infused with low tumor burden and in aliquots (ARI 0001). In addition, high marrow disease infiltration associated to possible basal low levels of hematopoietic progenitor cells has not been associated to late-ICAHT in our cohort of patients with only 2/11 (18%) patients with blast\u0026thinsp;\u0026gt;\u0026thinsp;5% pre-LD.\u003c/p\u003e \u003cp\u003eRegarding the dose of CD34\u003csup\u003e+\u003c/sup\u003e HSC infused, the concept has been long used in Allo-SCT and poor graft function considering that CD34\u0026thinsp;+\u0026thinsp;cell dose/kg recipient weight was optimal and desired\u0026thinsp;\u0026gt;\u0026thinsp;3x10\u003csup\u003e6\u003c/sup\u003e/kg (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Remarkably, Klyuchnikov et al. reported that the CD3\u003csup\u003e+\u003c/sup\u003e cell dose in the graft was significantly associated with the development of aGVHD and they observed that patients without aGVHD received a median of 8 x 10\u003csup\u003e3\u003c/sup\u003e CD3\u003csup\u003e+\u003c/sup\u003e/kg (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). In the setting of CD34\u003csup\u003e+\u003c/sup\u003e HSC boost after CART19, dose information is limited. In our cohort of patients, CD34\u003csup\u003e+\u003c/sup\u003e cell dose/kg recipient weight was \u0026gt;\u0026thinsp;3x10\u003csup\u003e6\u003c/sup\u003e/kg in 10 out of 11 patients. The median CD3\u0026thinsp;+\u0026thinsp;dose was mainly below 9 x10\u003csup\u003e3\u003c/sup\u003e/kg, although one patient received 4 x 10\u003csup\u003e4\u003c/sup\u003e/Kg of CD3\u0026thinsp;+\u0026thinsp;and no aGVHD or cGVHD was observed.\u003c/p\u003e \u003cp\u003eFinally, outcomes of EFS and survival showed at least similar results in comparison with trials and published real-practice outcome data (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan additionalcitationids=\"CR3 CR4 CR5 CR6 CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Outcomes are discouraging in the subgroup of patients who relapse early\u0026thinsp;\u0026lt;\u0026thinsp;6 months after Allo-HSCT similar to outcomes recently published by Bader et al. (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Interestedly, Rejeski et al. (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) and Penack et al. (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) found a stronger association of severe cytopenia with relapse and no pronounced association with non-relapse mortality (NRM). In contrast, some real-world analysis found a relatively high NRM at 24 months after CAR T-cell infusion (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). In this regard, in our cohort of patients with profound cytopenias, mortality was only related to leukemia relapse and no infections or NRM was documented. On the other hand, the impact of this lower doses of lymphocytes CD3\u003csup\u003e+\u003c/sup\u003e in the selected CD34\u0026thinsp;+\u0026thinsp;graft, compared to donor lymphocyte infusion and the impact on relapse is not yet determined. In this sense, the CD34\u0026thinsp;+\u0026thinsp;HSC boost together with an increasing dose of CD3\u0026thinsp;+\u0026thinsp;could be explore in the future. In addition, maintenance treatment might be offered as recently suggested by Gabelli et al (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e) after hematological recovery after CD34\u003csup\u003e+\u003c/sup\u003e HSC boost to improve EFS and OS.\u003c/p\u003e \u003cp\u003eIn summary, to the best of our knowledge this is the largest multicentre cohort study of ALL-B patients successfully treated with CD34\u0026thinsp;+\u0026thinsp;HSC boost to treat late-ICAHT after CAR-T. Based on our results, for patients with prior extensive cytotoxic treatment post Allo-HSCT which present a primary poor graft function persisting beyond 60\u0026ndash;90 days after CAR-T, strong consideration should be given to providing a CD34\u003csup\u003e+\u003c/sup\u003e HSC boost if the original donor is available. There is an obvious exception of the unrelated umbilical cord blood donor source in pediatric patients. It should be noted that the response time of the unrelated donor is expected to be longer than related-donor, so it may be necessary to be more proactive, especially if the cytopenias are associated with uncontrolled infections or significant comorbidity beyond 30 days after CAR-T cell infusion.\u003c/p\u003e \u003cp\u003eFuture challenges include the identification of a pre-infusion hematologic toxicity score in r/r ALL-B population to optimize patient selection in larger cohorts as well as elaborating a treatment consensus on this therapeutic approach including optimal timing and more information about optimal CD34\u003csup\u003e+\u003c/sup\u003e boost and CD3\u003csup\u003e+\u003c/sup\u003e lymphocytes doses.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting Interests: \u0026nbsp;\u003c/strong\u003eAuthors declare there are not any competing financial interests in relation to the work described.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRives S, Maude SL, Hiramatsu H, Baruchel A, Bader P, Bittencourt H, et al. 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J Clin Oncol (2023) 41(2):354\u0026ndash;63. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.22.01076\u003c/span\u003e\u003cspan address=\"10.1200/JCO.22.01076\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePasquini MC, Hu ZH, Curran K, Laetsch T, Locke F, Rouce R, et al. Real world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv (2020) 21:5414\u0026ndash;24. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/bloodadvances.2020003092\u003c/span\u003e\u003cspan address=\"10.1182/bloodadvances.2020003092\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLaetsch TW, Maude SL, Rives S, Hiramatsu H, Bittencourt H, Bader P, \u003cem\u003eet al. Three-year update of tisagenlecleucel in pediatric and young adult patients with\u003c/em\u003e Relapsed/Refractory acute lymphoblastic leukemia in the ELIANA trial. J Clin Oncol (2023) 41(9):1664\u0026ndash;9. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.22.00642\u003c/span\u003e\u003cspan address=\"10.1200/JCO.22.00642\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBader P, Alonso A, Attarbaschi A, Bodmer N, Boing H, Burridge S, et al. Treatment of post-transplant relapse in children, adolescents and young adults with BCP ALL using CD19-CAR-T: A European retrospective analysis of real-world data. Hemasphere. 2023; 7(Suppl): e239539e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePenack O, Pecznski C, Koenecke C, Polge E, Kuhnl A, Fegueux N et al. Severe cytopenia after CD19 CAR T-cell therapy: a retrospective study from the EBMT Transplant Complications Working Party. J Immunother Cancer. 2023;11(4):e006406. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/jitc-2022-006406\u003c/span\u003e\u003cspan address=\"10.1136/jitc-2022-006406\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBethge WA, Martus P, Schmitt M, Holtick U, Subklewe M, von Tresckow B et al. GLA/DRST real-world outcome analysis of car T-cell therapies for large B-cell lymphoma in Germany. Blood 2022;140:349\u0026ndash;58\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGabelli M, Oporto Espuelas M, Bonney DK, Burriedge S, Farish S, Hedges E, et al. Maintenance therapy for early loss of B-cell aplasia after CD19 CAR T-cell therapy. Blood Adv (2023). doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/bloodadvances.2023011168\u003c/span\u003e\u003cspan address=\"10.1182/bloodadvances.2023011168\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Allogeneic stem cell boost, CD19 CAR T-cells, Prolonged cytopenias, hematotoxicity, relapsed/refractory acute lymphoblastic leukemia","lastPublishedDoi":"10.21203/rs.3.rs-4843995/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4843995/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHematological toxicity is the most common long-term adverse event after CAR T-cell therapy. Severe cytopenias not resolving over time may result in life-threatening infection or bleeding and the best clinical practice to treat this persisting cytopenias after CAR-T is not well established.\u003c/p\u003e \u003cp\u003eEleven heavily pretreated patients with B-ALL and prolonged cytopenia after CAR-T therapy were successfully treated with an allogeneic CD34\u003csup\u003e+\u003c/sup\u003e hematopoietic stem cell (HSC) boost. The median time from CAR T-cell infusion to donor CD34\u003csup\u003e+\u003c/sup\u003e HSC boost was 2.8 months and median CD34\u003csup\u003e+\u003c/sup\u003e selected dose was 4 x10\u003csup\u003e6\u003c/sup\u003e/kg of recipient weight. The median time to hematological recovery in all three cell lineages was 20 days (range 12\u0026ndash;60). One-year event free survival was significantly different for patients relapsing before 6 months post-transplantation (14.3%) vs after 6 months post-transplantation (75%). With a median follow-up after HSC boost of 12 months, overall survival (OS) at 24 months was 31.2% with a median OS of 21 months (95% CI 6.2\u0026ndash;35.7). All causes of death were related to disease relapse.\u003c/p\u003e \u003cp\u003eIn conclusion, we confirm that allogeneic CD34\u003csup\u003e+\u003c/sup\u003e HSC boost is an effective and safe therapeutic option that should be considered in patients with primary poor graft function persisting beyond 60\u0026ndash;90 days after CAR-T\u003c/p\u003e","manuscriptTitle":"Allogeneic CD34+ hematopoietic stem cell boost for prolonged severe cytopenias following CAR T-cell therapy in B-cell acute lymphoblastic leukemia. A retrospective analysis on behalf of the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-18 02:12:13","doi":"10.21203/rs.3.rs-4843995/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6d41f532-47a2-4909-bf03-daf10f954111","owner":[],"postedDate":"September 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":35727329,"name":"Health sciences/Medical research/Stem-cell research"},{"id":35727330,"name":"Biological sciences/Cancer/Cancer stem cells"}],"tags":[],"updatedAt":"2024-09-30T13:40:25+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-18 02:12:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4843995","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4843995","identity":"rs-4843995","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}