Intrathecal Rituximab in Pediatric CD20-positive Central Nervous System Limited Lymphoproliferative Disease: Report of Two Cases and Literature Review

Intrathecal Rituximab in Pediatric CD20-positive Central Nervous System Limited Lymphoproliferative Disease: Report of Two Cases and Literature Review | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 11 March 2025 V1 Latest version Share on Intrathecal Rituximab in Pediatric CD20-positive Central Nervous System Limited Lymphoproliferative Disease: Report of Two Cases and Literature Review Authors : Hui Gao , Ningning Zhang , ChunJu Zhou , Ling Jin , Jing Yang , Shuang Huang , Meng Zhang , Nan Li , Tianyou Wang , and Yanlong Duan [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174168211.12145651/v1 Published Annals of Hematology Version of record Peer review timeline 210 views 143 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Isolated central nervous system (CNS) involvement due to posttransplantation proliferative disorder (PTLD) is even rarer, with only a few cases reported in the literature. CNS involvement in patients with mature B-cell non-Hodgkin’s (NHL) and PTLD confers a significantly worse prognosis as compared to patients without CNS lymphoma disease. Treatment of primary CNS lymphoma (PCNSL) is challenging due to resistance to conventional cytotoxic and intrathecal chemotherapy. Here, we report the successful use of intrathecal rituximab in two pediatric cases of CD20+ isolated CNSL that had failed to respond to standard chemotherapy, intravenous rituximab and Epstein-Barr virus (EBV)-specific cellular therapy. However, after repeated intrathecal administration of rituximab, both patients’ clinical symptoms were alleviated, which has created opportunities for further treatments. We emphasise that intrathecal rituximab may be a safe and effective option for the treatment of pediatric CNSL. The literature on this topic was also reviewed. Intrathecal Rituximab in Pediatric CD20-positive Central Nervous System Limited Lymphoproliferative Disease: Report of Two Cases and Literature Review Huixia Gao 1* , Ningning Zhang 2* , Chunju Zhou 3 ，Ling Jin 1 , Jing Yang 1 , Shuang Huang 1 , Meng Zhang 1 , Nan Li 1 , Tianyou Wang 4 , and Yanlong Duan 1# * These authors contributed equally to this work. 1 Medical Oncology Department, Pediatric Oncology Center，Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, China, 100045; 2 Department of Imaging, Beijing Children’s Hospital, Capital Medical University, China, 100045; 3 Department of Pathology, Beijing Children’s Hospital, Capital Medical University, China, 100045; 4 Hematology Center, Beijing Children’s Hospital, Capital Medical University; National Center for Children’s Health; Beijing Key Laboratory of Pediatric Hematology Oncology; Key Laboratory of Major Diseases in Children, Ministry of Education; National Key Discipline of Pediatrics, Capital Medical University; China, 100045. # Corresponding author: Yanlong Duan, Email: Abstract Isolated central nervous system (CNS) involvement due to posttransplantation proliferative disorder (PTLD) is even rarer, with only a few cases reported in the literature. CNS involvement in patients with mature B-cell non-Hodgkin’s (NHL) and PTLD confers a significantly worse prognosis as compared to patients without CNS lymphoma disease. Treatment of primary CNS lymphoma (PCNSL) is challenging due to resistance to conventional cytotoxic and intrathecal chemotherapy. Here, we report the successful use of intrathecal rituximab in two pediatric cases of CD20+ isolated CNSL that had failed to respond to standard chemotherapy, intravenous rituximab and Epstein-Barr virus (EBV)-specific cellular therapy. However, after repeated intrathecal administration of rituximab, both patients’ clinical symptoms were alleviated, which has created opportunities for further treatments. We emphasise that intrathecal rituximab may be a safe and effective option for the treatment of pediatric CNSL. The literature on this topic was also reviewed. Key words : intrathecal therapy; primary central nervous system lymphoma; post-transplantation lymphoproliferative disease; rituximab; children Introduce Primary central nervous system lymphoma (PCNSL) is an aggressive type of extranodal non-Hodgkin lymphoma (NHL) and accounts for 2% of primary central nervous system (CNS) tumors [1,2] . Post-transplantation proliferative disorder(PTLD) is a rare complication in high-risk allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, and isolated CNS involvement by PTLD is even rarer, with few cases reported in literature [3,4] . The etiology and pathogenesis of PCNSL remain unclear and treatment recommendations are not clearly established. Treatment of systemic PTLD with reduction of immunosuppression, chemotherapy, monoclonal antibody therapy (rituximab) and cellular therapy is well described, but treatment of isolated CNS involvement by PTLD is more challenging because many chemotherapy agents and rituximab are poorly tolerated across the blood–brain barrier [4,5] , and outcome for patients with PCNSL is substantially worse than that of patients with similar stage of systemic NHL [6,7] . More effective therapies are needed to improve survival and published reports suggest that intrathecal delivery of therapy may improve the outcome. Rituximab, a monoclonal antibody directed against the CD20 antigen on B-cells, induces apoptosis, complement activation and antibody-dependant cellmediated cytotoxicity [8] . Systemic administration of rituximab is an effective therapy for extracranial PTLD [9,10]. However, the localisation of PTLD in the CNS remains a particular challenge. The rituximab CSF levels after administration of intravenous rituximab to five patients with CD20-positive CNS lymphoma were approximately 0.1– 0.2% of serum levels [11,12] . This is a limiting factor in the use of systemic rituximab for the treatment of CNS-PTLD. Possible options to circumvent this barrier would be an intravenous dose escalation or intrathecal rituximab treatment [12] . Czyzewski et al. [13] published a study describing intrathecal rituximab therapy in a group of eight children with CNS-Epstein-Barr virus (EBV)-PTLD, and intrathecal rituximab was used as first-line treatment, all patients were well tolerated and had no adverse reactions after epidural puncture, except for one who had a brief episode after the third intrathecal therapy, and the symptoms disappeared immediately after taking diazepam. In this report, intrathecal rituximab was used to treat two pediatric patients with isolated CNSL and no adverse events of the treatment were observed, which opens up possibilities for further treatment. However, clinical experience with this route of administration is very limited, especially in children. We also review the literature on this rare disease. Case Report Case one A 12-year-old girl was admitted to hospital with the chief complaint of ”liver failure”. Physical examination of the liver, spleen and lymph nodes was unremarkable, repeated routine blood tests showed a reduction of three lines, bone marrow biopsy results supported hepatitis related aplastic anemia. This was successfully treated with steroids, gamma globulin and cyclosporine. She had a 10/10 allele-matched unrelated donor allo-HSCT and the engraftment rate was 99.2%. Blood and plasma EBV loads were negative pre- and post-transplant. Four months after transplantation, she developed headache with EBV PCR was strongly positive in the cerebrospinal fluid (CSF, 3.7×10 4 ~5.1×10 5 copies/ml), but showed low levels in the blood (<500 copies/ml). Magnetic resonance imaging (MRI) of the head showed multiple abnormal signals in the brain(Fig.1A-C). Immunosuppressant was reduced and weekly intravenous administration of rituximab (375 mg/m 2 for 4 weeks) was administered in combination with CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone) chemotherapy and EBV-specific cellular therapy until EB viremia in CSF turned negative at 6 months post-transplant. Eight months after transplantation, she developed a twisted mouth accompanied by weakness in the left limbs. Further MRI showed enlargement of the original lesions and new abnormal signals (Figure 1D-F). Positron emission tomography (PET)/CT during the same period was shown in Figure 2A. She underwent stereotactic brain biopsy, which revealed EBV-associated diffuse large B-cell lymphoma (DLBCL) (Figure 3). EBV PCR was strongly positive (5.5×10 4 ~ 3.6×10 6 copies/ml) in both the brain lesion and CSF. There was no systemic evidence of lymphadenopathy on the whole-body PET/CT scan, and the blood and serum EBV PCR continued to show only low levels of EBV (<500 copies/ml), suggesting an isolated CNS PTLD. She underwent the China Net Childhood Lymphoma-mature B-cell-NHL-2017 regimen (CNCL-B-NHL-2017) [7] . Her clinical condition progressed and a second MRI scan 2 courses of chemotherapy after the initial imaging showed progressive disease with mass effect. All of these suggested that conventional treatment was not sufficient to effectively control the disease. Eleven months after transplantation, we tried to give the patient intrathecal rituximab monotherapy (25mg, twice a week for a total of 4 times, followed by once a week for 8 times) combined with intravenous rituximab (375mg/m2) once a week. Specifically, 25mg of rituximab was dissolved in 3ml of sodium chloride solution and administered over 3-5 minutes. Antihistamines and methylprednisolone were given prior to the intrathecal administration of rituximab. Treatment was well tolerated with no immediate side effects. After 3 weeks of intrathecal therapy, the CSF EBV DNA load became negative and the MRI scan also showed an overall improvement with reduced oedema. The patient underwent surgical resection of the intracranial tumour (approximately 80% excision) at 14 months post-transplant and continued weekly intrathecal rituximab therapy, followed by local brain radiotherapy at 16 months post-transplant. Her most recent MRI scan shows only calcified, inactive lesions (Figure 2B), and a recent PET/CT scan showed resolution of the original intracerebral hypermetabolic lesions (Figure 2C). All immunosuppression disappeared, her primary disease remained in remission with full donor chimerism now 4 years after transplantation. She has returned to full-time schooling and has made an almost complete neurological recovery. Figure 1 Progression of MRI images at diagnosis and after therapies. (A-C) MRI at diagnosis(+4 months after HSCT).Multiple punctate hypersignals in the white matter of the left frontal lobe(red arrow). Multiple abnormal signals in the right temporal lobe, basal ganglia and bilateral cerebellar hemispheres were new lesions. (D-F) MRI after intrathecal administration of rituximab (375 mg/m 2 for 4 weeks) combined with R-CHOP chemotherapy and the following CNCL-B-NHL-2017 regimen. The tumour did not respond to R-CHOP therapy or the CNCL-B-NHL-2017 regimen, but increased in size during therapy. The tumour, with a maximum diameter of 99 mm, was located in the right cerebellar hemisphere and partially invaded the left cerebellar hemisphere. Within 4 months, multiple abnormal signals from the original lesions enlarged and new abnormal signals appeared, accompanied by apparent enhancement and oedema. Figure 2 Changes in PET/CT and MR after intrathecal rituximab and surgical resection. (A)PET/CT showed intracerebral hypermetabolic lesions in the right temporal lobe with surrounding edema signals. The patient received intrathecal and intravenous rituximab, then underwent surgical resection (approximately 80% excision) and continued weekly intrathecal rituximab therapy,followed by local brain radiotherapy. (B) After radiotherapy, MRI scan showed resolution of the presenting lesion. (C) PET/CT showed only inactive signals in the original lesion. Figure 3 The tumor biopsy at diagnosis. A: The tumor biopsy, H&E (magnification ×4). B: The tumor biopsy, H&E (magnification ×20). C: Immunohistochemistry of the tumor showed positive for CD20 (CD20 antibody staining, magnification ×20). D: The in situ hybridization showed positive signal for EBER (magnification ×20). Case 2 A 5-year-old male was diagnosed with X-linked lymphoproliferative disease (XLP) when he presented with EBV-associated haemophagocytic lymphohistiocytosis (HLH) for 7 months. This was successfully treated with steroids, etoposide and intravenous rituximab. However, he readmitted to hospital because of a limp gait, crooked mouth, and decreased muscle strength. MRI scan shows a space-occupying mixed signal lesion in the basal ganglia area measuring (28×44×31) millimetres (Figures 4A-C). No other systemic lesions were detected on the concurrent whole-body PET/CT scan. CSF analysis was positive for EBV PCR (2.2×10 4 ~ 1.6×10 6 copies/ml), while his blood EBV PCR was detected with a low sensitivity of less than 500 copies/ml. Serum and CSF specimens were negative for encephalitis-related antibodies. The CNS lesion was biopsied and showed clonal B-cell lymphoproliferation with EBV positivity (Fig. 5), consistent with EBV-associated diffuse large B-cell lymphoma (DLBCL) involving only the CNS. Based on previous experience and with the written informed consent of his parents, the child patient received a combination of intrathecal rituximab (25mg) and intravenous rituximab (375mg/m 2 ) once a week for 9 times in total. On the fourth day of combination therapy, the child’s body temperature returned to stable levels and he was well tolerated with no dose-related toxicity. The repeat MRI scan 5 weeks later showed clear improvements with reduced oedema and less prominent ring-enhancing lesions. After a total of nine doses of intrathecal rituximab, his CSF EBV PCR became negative, his neurological symptoms improved, and no other adverse events were noted during the nine courses of combination therapy. He then received a 10/10 allele-matched unrelated donor HSCT. One month after transplantation, an MRI scan showed a significant reduction in the size of the lesions, and no new lesions were found (Figure 4D-F). At the time of this report, the patient was 1.5 years post-transplant with no neurological symptoms, no evidence of PTLD or chronic GVHD, and the patient was fully chimeric with complete immune reconstitution. Figure 4 MRI weighted gadolinium contrast enhanced images at diagnosis and after therapies. (A) Massive space-occupying mixed signal lesion in the right basal ganglia with an area of (28×44×31) mm, with haemorrhagic oedema in and around the lesion and compression of surrounding tissue. (B) Multiple patchy abnormal signals in the white matter of both lateral ventricles and frontoparietal lobes. (C) Patchy abnormal signals are seen in the left cerebellar hemisphere. (D-F) MRI showed a significant reduction of the lesions with no new lesions found. Figure 5 The cerebrum biopsy at diagnosis (magnification ×200). (A) Massive infiltration of atypical lymphocytes, H&E. (B) Immunohistochemistry showing that most tumour cells were positive for CD20 (CD20 antibody staining). (C) The in situ hybridisation signal for EBER was expressed in the lymphocytes. Literature Review PCNSL is a rare B-cell variant of NHL whose incidence is increasing, mainly due to the increasing number of organ transplants. CNS involvement of PTLD is very rare in patients after HSCT and only a few cases have been described in the literature. Here we summarized the data of 23 paediatric patients diagnosed with CD20+ isolated PCNSL or PTLD before or after HSCT [4,13,14,15] , including the 2 cases in this study. Details of patients’ treatments, outcomes and adverse events are shown in Table 1. A total of 169 doses of intrathecal or intraventricular rituximab were administered to the 23 patients. The median number of doses received by each patient was 6 (range, 2-20 doses). The median dose administered was 20 mg (range, 10-40 mg). Overall, intraventricular or intrathecal rituximab was well tolerated (Table 1). The most common adverse events were Grade 1 and 2 neuropathy with paresthesias and pain in four patients (17.4%), Grade 1/2 headache in two patients, allergy (mild pruritus, Grade 1/2) in one patient, and one patient experienced a brief (less than 5 minutes) seizure (Grade 4). These events were self-limited, occurring in the 48 hours following intrathecal or intraventricular rituximab and resolving within 24 hours. Nineteen patients (82.6%) of those treated with intraventricular or intrathecal rituximab, with or without other CNS-directed treatments, achieved CNS remission. These case series suggests that intrathecal/intraventricular rituximab has therapeutic efficacy and relatively limited toxicity. Table1 Clinical characteristics and treatment of 21 pediatric patients with PCNSL or CNS-PTLD in the literature References Sex/Age Type of CNS Rituximab IT/ I.vent. With IT/ After IT/ Toxicity (Grade I-IV AE) CNS Status Cause of death disease dose(mg)/doses(n) I.vent R I.vent R with Rituximab remission Denise et al [4] 4/M EBV-PTLD 20/6 IT-MTX+Arac — — Yes Alive — 4/M EBV-PTLD 20/6 TIT+CTLs — — Yes Alive — Wu et al [15] 18/M EBV-PTLD 20/2 DLT,2 — — Yes Alive — Ceppi et al [18] 17/M CD20 + PTLD 20-35/9 TIT — Neuropathy(I-II) Yes Alive — Headache(I-II)、Allergy(I-II) 15/M CD20 + PTLD 20/4 — — — No Dead TRM,PD 12/ F CD20 + PTLD 40/4 — — — PR Dead TRM 15/M CD20 + PTLD 25/14 — — — Yes Alive — 1/M CD20 + PTLD 15/2 — — — No Alive — 1/M CD20 + PTLD 20/7 TIT — — Yes Alive — 2/M CD20 + PTLD 10/11 TIT HSCT(2nd) — Yes Alive — 5/M CD20 + PTLD 20/8 TIT — — Yes Alive — 14/M PCNSL 10-25/6 IT MTX RT,HSCT Neuropathy(I-II) Yes Dead PD 5/M PCNSL 10/9 — HSCT Seizure (IV) Yes Dead other 16/M PCNSL 25/10 — — — Yes Dead PD 4/M PCNSL 25/3 TIT HSCT — Yes Alive — 4/M PCNSL 25/5 TIT HSCT — Yes Alive — 2/F PCNSL 10/4 TIT HSCT — Yes Alive — 7/M PCNSL 15/3 TIT — — Yes Alive — 15/M PCNSL 25/3 TIT — — Yes Alive — 4/M PCNSL 40/5 TIT RT*,TIT,HSCT Neuropathy(I-II) No Dead PD IT-Liposomal+ Ara-C Headache(I-II) W-S et al [21] 12/M CD20 + PCNSL 25/19 TIT,RT* HSCT Neuropathy(I-II) Yes Dead other This article 12/F EBV-PTLD 25/20 — surgical resection,RT* — Yes Alive — This article 5/M CD20 + PCNSL 25/9 — HSCT — Yes Alive — IT= intrathecal;TIT= triple intrathecal therapy; RT*= cranial radiation; HSCT= hematopoietic stem cell transplantation; PD= progression disease; TRM= treatment related mortality; PCNSL= primary central nervous system lymphoma; PTLD= post-transplant lymphoproliferative disorder; MTX= Methotrexate; CTL= cytotoxic T-lymphocytes; DLI= donor lymphocyte infusion; Ara-C= Cytarabine; Toxicities of intrathecal and intraventricular rituximab were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 scale. Discussion The prognosis of cerebral PTLD in children is poor, with a 3-year survival rate of only 0-13% with conventional therapy [16,17] . Given this poor prognosis, more effective therapies are needed to improve survival. Currently, results from multiple institutions and international retrospective studies [18] indicate that intrathecal or intraventricular administration of rituximab can be administered with limited associated toxicity in the majority of children with CD20+ CNS Burkitt’s Non-Hodgkin’s lymphoma, mature B and CD20+ B precursor acute lymphoblastic leukaemia or B-cell PTLD. The two cases we reported had a high EBV load before or after transplantation as part of their underlying disease and its presentation. Neither case had systemic PTLD and the affected lesion was isolated to the CNS. Intrathecal administration of rituximab was required to achieve a durable clinical response of CNSL after failure of other traditionally available therapies, including high-dose methotrexate, radiotherapy and intravenous rituximab. However, the optimal dose and regimen of intrathecal rituximab have not been established. A phase I trial of intraventricular rituximab in adult PCNSL showed that a dose of 25 mg twice weekly was well tolerated [19] . As the cerebrospinal fluid volume is the same in adolescents and adults, we used the adult dose and regimen for our patients [19,20] . We also found that EBV PCR viral load decreased with intrathecal treatment, and this correlated with clinical improvement and improvement on MR imaging. Intrathecal or intraventricular administration of rituximab is an option for this group of patients. Intrathecal or intraventricular administration of rituximab has been well reported in adult patients. Reports in paediatric patients have also been well tolerated and do not appear to cause more side effects. Wada-Shimosato et al. [21] reported a 12-year-old boy with CD20-positive PCNSL who achieved complete remission after repeated intraventricular rituximab administration (19 times in total). Except for a transient facial nerve palsy that occurred after the first intraventricular rituximab administration, which recovered within 30 minutes without intervention, no other adverse events were reported during the 19 courses of intraventricular rituximab therapy that the patient received. Bonney et al. [4] reported two paediatric CNS-PTLD patients who had failed to respond to standard chemotherapy, intravenous rituximab and EBV-specific cellular therapy, but achieved sustained complete remission after intrathecal rituximab. Similarly, Stephan et al. [22] reported the successful use of monoclonal antibody therapy delivered intrathecally via an Omaya reservoir in a 9-month-old infant with cerebral PTLD, with a good clinical response achieved and no major toxicities reported. In 2016, Ceppi et al. [18] reviewed a multicentre international study of 25 paediatric patients with CD20+ B-cell malignancies treated with intrathecal or intraventricular rituximab, with 72% of patients achieving CNS remissions, with or without other CNS-directed treatment. They observed relatively limited manifestations of toxicity, and these events are self-limited. Jaime-Perez et al. [23] tested the efficacy of intrathecal rituximab (10 mg) on 7 paediatric patients with CNS relapsed and refractory CD20+ acute lymphoblastic leukaemia, rituximab administration was well tolerated in their study, with no clinical evidence of neurotoxicity after 24 months of follow-up. In our study, the two cases had no side effects after intrathecal rituximab therapy. Other authors have also reported good tolerability of intrathecal rituximab [4,18,22,23] , with adverse events occurring in only a few cases. These reports suggest that intrathecal rituximab can be administered with limited toxicity and may be an effective alternative for PTLD-CNSL patients who have not responded well to conventional first-line therapy. A literature review of the efficacy of intrathecal or intraventricular rituximab in 23 pediatric patients with CD20+ isolated CNSL, together with the two cases reported in this study, showed that 19 cases (82.6%) achieved CNS remission with or without other CNS-directed treatments. Due to the use of different CNS-directed treatments in some cases, we cannot be sure about the specific effect of intrathecal/intraventricular rituximab. However, the generally very poor outcome of this group of patients suggests that rituximab played a role in the favourable response. In conclusion, intrathecal administration of rituximab appears to be a safe and promising strategy for paediatric patients with CD20+ isolated CNSL. Although our two patients responded well to intrathecal rituximab therapy, given current reports of different combinations of CNS-targeting agents, well-designed prospective clinical trials should be pursued to further evaluate the efficacy of intrathecal or intraventricular rituximab conducted in this group of difficult-to-treat children. We recommend and look forward to large-scale trials of this treatment approach. AUTHOR CONTRIBUTIONS Gao Huixia drafted the work and revised it critically for important intellectual content. Duan Yanlong conceived of the presented idea and revised it critically for important intellectual content. All authors have read and agreed to the final version. DATA AVAILABILITY STATEMENT Enquiries about data access should be made to the corresponding authors. CONFLICT OF INTEREST STATEMENT The authors declare no conflicts of interest. ETHICS STATEMENT Ethics approval is not required as per local HREC policy. CONSENT Written consent for publication was obtained from patient. REFERENCE [1] Han CH, Batchelor TT. Diagnosis and management of primary central nervous system lymphoma. Cancer. 2017;123:4314–4324. [2] Grommes C, DeAngelis LM. Primary CNS lymphoma. J Clin Oncol. 2017;35:2410–2418. [3] Suzuki M, Kosugi I, Terada T, Shirakawa K,Suzuki H, Kono S, et al. A case of Epstein-Barr virus associated post-transplant lymphoproliferative disorder with CNS involvement: pathological findings at both biopsy and autopsy. Neuropathology 2011; 31:440–445. [4] Bonney DK, Htwe EE, Turner A, Kelsey A, Shabani A,Hughes S, et al. Sustained response to intrathecal rituximab in EBV associated post-transplant lymphoproliferative disease confined to the central nervous system following haematopoietic stem cell transplant. Pediatr Blood Cancer 2012; 58:459–461. Reddy N, Rezvani K, Barrett AJ, Savani BN. Strategies to prevent EBV reactivation and post transplant lymphoproliferative disorders (PTLD) after allogeneic stem cell transplantation in high-risk patients. Biol Blood Marrow Transplant 2011; 17: 591–597. [6] Jagadeesh D, Woda BA, Draper J, Evens AM (2012) Post transplant lymphoproliferative disorders: risk, classification, and therapeutic recommendations. Curr Treat Options Oncol. [7] Evens AM, Roy R, Sterrenberg D, Moll MZ, Chadburn A, Gordon LI (2010) Post-transplantation lymphoproliferative disorders: diagnosis, prognosis, and current approaches to therapy. Curr Oncol Rep 12(6):383–394. [8] Svoboda J, Kotloff R, Tsai DE. Management of patients with posttransplant lymphoproliferative disorder: The role of rituximab. Transplant Int 2006;19:259–269. [9] Choquet S, Leblond V, Herbrecht R, et al. Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: Results of a prospective multicenter phase 2 study. Blood 2006;107:3053–3057. [10] Webber S, Harmon W, Faro A, et al. Anti-CD20 monoclonal antibody (rituximab) for refractory PTLD after pediatric solidorgan transplantation: Multicenter experience from a registry and from a prospective clinical trial. Blood (ASH Annual Meeting Abstracts) Nov. 2004;104:746. [11] van de Glind G, de Graaf S, Klein C, et al. Intrathecal rituximab treatment for pediatric post-transplant lymphoproliferative disorder of the central nervous system . Pediatr Blood Cancer 2008 ; 50 : 886 – 888. [12] Harjunpaa A, Wiklund T, Collan J, et al . Complement activation in circulation and central nervous system after rituximab (anti-CD20) treatment of B-cell lymphoma. Leuk Lymphoma 2001 ; 42 : 731 – 738. [13] Czyzewski K, Styczynski J, Krenska A, Debski R, Zajac-Spychala O, Wachowiak J, et al. Intrathecal therapy with rituximab in central nervous system involvement of post-transplant lymphoproliferative disorder. Leuk Lymphoma 2013; 54:503–506. [14] Valavoor SH, Ashraf Z, Narwal R, Ratnam S. Conservative management of post-transplant central nervous system lymphoma. Int Urol Nephrol (2013) 45:1219–1222. [15] M Wu, J Sun, Y Zhang, F Huang, H Zhou, et al. Intrathecal rituximab for EBV-associated post-transplant lymphoproliferative disorder with central nervous system involvement unresponsive to intravenous rituximab-based treatments: a prospective study. Bone Marrow Transplantation (2016) 51, 456–458. [16] Buell JF, Gross TG, Hanaway MJ, et al. Posttransplant lymphoproliferative disorder: Significance of central nervous system involvement. Transplant proc 2005;37:954–955. [17] Maecker B, Jack T, Zimmermann M, et al., Posttransplant lymphoproliferative disorders (PTLD) after solid organ transplantation in children: A multicenter analysis reveals CNS and/or bone marrow involvement as risk factors for poor survival. [18] Ceppi F, Weitzman S, Woessmann W, Davies K, Lassaletta A, Reismüller B, et al. Safety and efficacy of intrathecal rituximab in children with B cell lymphoid CD20 + malignancies: an international retrospective study. Am J Hematol. 2016; 91:486–491. [19] Rubenstein JL, Li J, Chen L, Advani R, Drappatz J, Gerstner E, et al. Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma. Blood. 2013; 121:745–751. [20] Drake JM, Kestle JR, Tuli S. CSF shunts 50 years on—past, present and future. Child Nerv Syst. 2004; 16:800–804. [21] Wada-Shimosato Y, Ikeda J,Tsujimoto S-I, Sasaki K, Yanagimachi M, et al. Intraventricular Rituximab in Pediatric CD20-positive Refractory Primary Central Nervous System Lymphoma. J Pediatr Hematol Oncol 2019; 41:571-573. [22] Stephan JL, Deist F, Le Blanche S, et al. Treatment of central nervous system B lymphoproliferative syndrome by local infusion of a B cell-specific monoclonal antibody. Transplantation 1992;54:246– 249. [23] Jaime-Perez JC, Rodriguez-Romo LN, GonzalezLlano O, Chapa-Rodríguez A, Gómez-Almaguer D. Effectiveness of intrathecal rituximab in patients with acute lymphoblastic leukaemia relapsed to the CNS and resistant to conventional therapy. Br J Haematol 2009;144: 794–795. Supplementary Material File (image1.emf) Download 5.67 MB File (image2.emf) Download 7.34 MB File (image3.emf) Download 12.02 MB File (image4.emf) Download 5.50 MB File (image5.emf) Download 9.83 MB Information & Authors Information Version history V1 Version 1 11 March 2025 Peer review timeline Published Annals of Hematology Version of Record 5 May 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords cns tumors immunotherapy lymphoblastic lymphoma pediatric hematology/oncology Authors Affiliations Hui Gao Beijing Shunyi District Maternal and Child Health Hospital View all articles by this author Ningning Zhang Capital Medical University Beijing Children's Hospital Imaging Centre View all articles by this author ChunJu Zhou Capital Medical University Beijing Children's Hospital Imaging Centre View all articles by this author Ling Jin Beijing Shunyi District Maternal and Child Health Hospital View all articles by this author Jing Yang Beijing Shunyi District Maternal and Child Health Hospital View all articles by this author Shuang Huang Beijing Shunyi District Maternal and Child Health Hospital View all articles by this author Meng Zhang Beijing Shunyi District Maternal and Child Health Hospital View all articles by this author Nan Li Beijing Shunyi District Maternal and Child Health Hospital View all articles by this author Tianyou Wang Beijing Shunyi District Maternal and Child Health Hospital View all articles by this author Yanlong Duan [email protected] Beijing Shunyi District Maternal and Child Health Hospital View all articles by this author Metrics & Citations Metrics Article Usage 210 views 143 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Hui Gao, Ningning Zhang, ChunJu Zhou, et al. Intrathecal Rituximab in Pediatric CD20-positive Central Nervous System Limited Lymphoproliferative Disease: Report of Two Cases and Literature Review. Authorea . 11 March 2025. DOI: https://doi.org/10.22541/au.174168211.12145651/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . Format Please select one from the list RIS (ProCite, Reference Manager) EndNote BibTex Medlars RefWorks Direct import Tips for downloading citations document.getElementById('citMgrHelpLink').addEventListener('click', function() { popupHelp(this.href); return false; }); $(".js__slcInclude").on("change", function(e){ if ($(this).val() == 'refworks') $('#direct').prop("checked", false); $('#direct').prop("disabled", ($(this).val() == 'refworks')); }); View Options View options PDF View PDF Figures Tables Media Share Share Share article link Copy Link Copied! Copying failed. Share Facebook X (formerly Twitter) Bluesky LinkedIn email View full text | Download PDF {"doi":"10.22541/au.174168211.12145651/v1","type":"Article"} Now Reading: Share Figures Tables Close figure viewer Back to article Figure title goes here Change zoom level Go to figure location within the article Download figure Toggle share panel Toggle share panel Share Toggle information panel Toggle information panel Go to previous graphic Go to next graphic Go to previous table Go to next table All figures All tables View all material View all material xrefBack.goTo xrefBack.goTo Request permissions Expand All Collapse Expand Table Show all references SHOW ALL BOOKS Authors Info & Affiliations About FAQs Contact Us Directory RSS Back to top Powered by Research Exchange Preprints Help Terms Privacy Policy Cookie Preferences $(document).ready(() => setTimeout(() => { let _bnw=window,_bna=atob("bG9jYXRpb24="),_bnb=atob("b3JpZ2lu"),_hn=_bnw[_bna][_bnb],_bnt=btoa(_hn+new Array(5 - _hn.length % 4).join(" ")); $.get("/resource/lodash?t="+_bnt); },4000)); (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a024eaf41c0441e2',t:'MTc3OTg4Mzg0MA=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();