Outcomes of Allogeneic Haematopoietic Transplant for Chronic Lymphocytic Leukaemia in the Modern Era

Outcomes of Allogeneic Haematopoietic Transplant for Chronic Lymphocytic Leukaemia in the Modern Era | 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 Outcomes of Allogeneic Haematopoietic Transplant for Chronic Lymphocytic Leukaemia in the Modern Era Nada Hamad, Luani Barge, Steven Tran, Glen Kennedy, David Ritchie, and 18 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4050578/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 There is limited data on the use and outcomes of allogeneic haematopoietic stem cell transplant (HSCT) in the modern era of chronic lymphocytic leukaemia (CLL) treatment. The aim of this study was to examine CLL transplant outcomes with a focus on patients exposed to pathway inhibitors (PI) prior to transplant. Data was collected through the Australian and New Zealand Transplant and Cellular Therapy Registry for all patients who underwent HSCT for CLL between 01/2009-12/2018. Transplant outcomes were compared between 2009-2013 (n=94) and 2014-2018 (n=50). There was a significant reduction in non-relapse mortality (NRM) from 42% (95%CI 31-52%) to 23% (95% CI 12-35%, p=0.02) between the periods however overall survival (OS), progression free survival and relapse were unchanged. Within the 2014-2018 cohort there was no difference in baseline characteristics between PI exposed (n=22) and naïve patients however 3-year OS was inferior in PI exposed patients: 54% (95%CI 35-82) compared to 91% (95%CI 80-100; p=0.03). In multivariate analysis, complete remission at the time of HSCT was associated with improved OS (hazard ratio [HR] 2.54, 95%CI 1.04-6.18). Allogeneic HSCT remains a viable treatment option for selected patients with CLL however the finding of inferior OS in PI exposed patients requires further study. Health sciences/Health care/Therapeutics/Immunotherapy Health sciences/Diseases/Cancer/Haematological cancer/Leukaemia/Chronic lymphocytic leukaemia Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction The past decade has seen significant advances in the treatment of chronic lymphocytic leukaemia (CLL). The availability of pathway inhibitors (PIs) namely, Bruton tyrosine kinase inhibitors (BTKi), BCL2 inhibitors (BCL2i) and phosphatidylinositol 3 kinase inhibitors (Pi3Ki) have resulted in improved patient outcomes(1-3). With safe and effective therapy for high risk or chemoimmunotherapy refractory patients, the number of patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) has been declining (4). However, disease progression or transformation remains the primary cause of death in patients with CLL (5). The graft versus leukaemia (GvL) effect afforded by HSCT provides the possibility for long term disease control and possibly cure in patients with relapsed/refractory disease, including in those with high-risk genetic lesions (6-10). The benefits of HSCT need to be weighed against the risk of graft versus host disease (GvHD) and non-relapse mortality (NRM) which are a particular concern in the, typically older, CLL population. The American and European Societies of Blood and Bone Marrow Transplantation and the European Research Initiative on CLL have provided updated recommendations, redefining high risk patients based on salvage options and patients’ transplant risk (11, 12). These updated guidelines are welcome at a time when HSCT may be underutilised due to a desire to avoid adverse outcomes and instead await the availability of the “next” available agent (11). The aim of this study was to report the outcomes of HSCT for CLL across Australia and New Zealand in the modern era of CLL treatment with a focus on trends over the last decade. Additionally, we sought to specifically examine outcomes of patients who received PIs prior to HSCT. Methods Data was collected from the Australian and New Zealand Transplant and Cellular Therapy (ANZTCT) Registry and included all patients who underwent HSCT for CLL in the absence of Richter’s transformation between January 2009 and December 2018. Additional information was gathered by questionnaires from centres regarding del17p, TP53, pre-transplant minimal residual disease (MRD) and treatment prior to HSCT. Patients provided written informed consent for their data to be collected and used for research purposes by ANZTCT prior to HSCT. This project was approved by the ANZTCT steering committee and covered the registry’s ethics approved protocol. Descriptive statistics were used to report patient and transplant characteristics. Post-transplant outcomes were estimated using the Kaplan-Meier method for survival and Gray’s test for cumulative incidence. Two five-year time periods, 2009-2013 and 2014-2018, were compared for transplant outcomes using log rank test for survival and Gray’s test for cumulative incidence estimates. Cause of death was compared between the two time periods using Fisher’s exact test. Sub-group analysis was performed on the 2014-2018 cohort for patients with and without PI exposure. Univariate analyses for factors associated with overall survival (OS), progression free survival (PFS), relapse rate and non-relapse mortality (NRM) were performed. This was followed by multivariate analysis of predefined variables including patient age, disease status, duration from diagnosis to transplant, prior number of therapies, del17p, donor relation and conditioning. Survival and progression are reported from the day of stem cell infusion. Acute GvHD (aGVHD) grade II-IV is reported and chronic GVHD (cGVHD) included all reported cases of any grade. Disease status was provided by centres at the time of transplant. Active disease includes stable disease, progressive disease and untreated relapse at the time of HSCT. Pathway inhibitors included BTKi, BCL2i, PI3Ki as these are the only agents approved in Australia and New Zealand. Neutrophil engraftment was defined as an absolute neutrophil count ≥0.5x10 6 /L and platelet engraftment was defined as a platelet count ≥20x10 6 /L. Results One hundred and forty-four patients from 14 centres in Australia and New Zealand were identified. Patient and transplant characteristics are shown in table 1. Data on TP53 mutation and IGVH status were available for only 5 and 1 patients respectively and were therefore not included. Transplant outcomes for 2009-2013 and 2014-2018 cohorts Ninety-four patients underwent transplantation between 2009-2013 and 50 from 2014 to 2018. Patients in the more recent cohort where more likely to have received FCR and PIs prior to transplantation and there was decreasing use of myeloablative conditioning over the period (table 1). Engraftment Median time to neutrophil engraftment was 16 days (range 8-32 days) and 17 days (range 6-25 days), platelet engraftment occurred at a median of 19 days (range 1-69) and 16 days (range 10-41 days) in the 2009-2013 and 2014-2018 cohorts respectively. GVHD The cumulative incidence of grade II-IV aGVHD at 100 days was 52% (95% CI 35-67) in the 2009-2013 cohort and 33% (95% CI 19-48, p=0.039) in the 2014-2018 cohort. The 5-year cumulative incidence of cGVHD reduced from 76% (95% CI 56-87) to 55% (95% CI 36-70, p=0.032) in the more recent period. CMV reactivation and disease At 1-year, the cumulative incidence of CMV reactivation was 40% (95% CI 25.6-54%) in the 2009-2013 cohort and 48.6% (95% CI 31.6-63.7%) in the 2014-2018 cohorts. Cumulative incidence of CMV disease was 2.3% (95% CI 1.7-10.5%) and 8.1% (95% CI 2.0-19.8%) at 1 year in the 2009-2013 and the 2014-2018 cohorts respectively. Survival and cause of death The median follow-up was 7.6 years (interquartile [IQ] range 6.3-8.4) and 5.0 years (IQ range 4.0-5.7) for the 2009-2013 and the 2014-2018 cohorts respectively. Five-year estimated OS, PFS, NRM and relapse rates between these cohorts are shown in figure 1. There was no difference in OS, PFS and relapse however 5 year NRM was significantly improved from 42% (95% CI 31-52) to 23% (95% CI 12-37, p=0.02). Among patients who experienced relapse, three-year OS from time of relapse was 59% (95% CI 40-86) and 58% (95% CI 36-94) in the 2009-2013 and the 2014-2018 cohorts respectively. There was no statistical difference in the reported cause of death between the two time periods (p=0.4, table 2). Transplant following pathway inhibitors Twenty-three patients received pathway inhibitors prior to allogeneic transplantation. A single patient transplanted in 2012 received ibrutinib prior to HSCT; the remaining PI exposed patients underwent transplantation between 2014-2018 (figure 2). Among those who received PI prior to HSCT, the median age was 54 years (range 25-66) and the median time from diagnosis to transplantation was 81 months (range 17 – 242.9). Six patients (32% with data available) had del17p detected prior to transplant. The median number of prior therapies was 3 (range 2-9). All patients had received prior chemoimmunotherapy. Of the 23 patients, 18 received ibrutinib, five received venetoclax (four of whom also received ibrutinib), three received idealisib and one received zanubrutinib. At the time of transplant four patients were in CR, 12 in PR, five had active disease and this information was not available in two patients. Donors were HLA-matched sibling donors in nine patients, unrelated in 13 and a there was a single mismatched related donor. Two patients received myeloablative conditioning. Median time to neutrophil and platelet engraftment was 15 days and 16 days respectively and did not differ from the group who did not receive PIs prior to HSCT. Acute GVHD occurred in 9 patients, cumulative incidence of grade II-IV aGVHD was 40% (95% CI 19-61) at 100 days. Cumulative incidence of cGVHD was 44% (19-66) at 5 years. Among patients transplanted between 2014-2018, there was no difference in baseline characteristics between those with and without PI exposure prior to HSCT besides prior CLL treatment. The median follow-up for PI naïve and PI exposed patients transplanted within this time period was 5.7years (IQ range 5.5-6.6) and 3.8 years (IQ range 2.9 – not reached). When comparing PI naïve to PI exposed patients, three-year OS survival was 91% (95% CI 80-100) versus 54% (95% CI 35-82, p=0.025, figure 3), PFS was 65% (95% CI 48-88) versus 44% (95% CI 27-71, p=0.19), NRM 9% (95% CI 1-25) versus 25% (95% CI 8-45, p=0.22) and relapse was 26% (95% CI 10-46) versus 32% (95% CI 14-52, p=0.61). Univariate and multivariate analyses In the univariate analysis, age, gender, interval from diagnosis to transplant, deletion 17p, prior PI exposure and Karnofsky performance status <80 were not associated with differences in OS, PFS, NRM or relapse rate. Active disease in comparison to diseases in CR was associated with OS, PFS and NRM with hazard ratios (HR) of 2.69 (95% CI 1.2-6.0, p=0.015), 2.1 (95% CI 1.05-4.19, p=0.04) and 2.84 (95% CI 1.12-7.23, p=0.03) respectively. Transplantation between 2014-2018 was associated with superior NRM, HR 2.01 (1.00-4.04, p=0.05). In a multivariate analysis, disease in CR as compared to active disease retained significance for OS (HR 2.54, 95% CI 1.04-6.18, p=0.04, figure 4) with a trend towards improved NRM (HR 2.73, 95% CI 0.98-7.64, p =0.06). Three or more prior lines of therapy was associated with relapse; HR 2.31 (95% CI 1.0-5.32, p=0.05). None of the other factors assessed retained significance for OS, PFS or NRM. Discussion We have presented outcomes of a large cohort of patients undergoing HSCT for CLL over the past decade. This spans a period of transition in CLL treatment worldwide and in our populations in Australia and New Zealand where government subsidised ibrutinib (December 2017 in Australia, December 2022 New Zealand) and venetoclax (March 2019 in Australia; December 2019 in New Zealand) have recently become available for selected patients. Prior to this, pathway inhibitors were not accessible or available only on clinical trials or compassionate access schemes. This is likely to reflect the profile of patients considered for HSCT for CLL in many other countries, particularly those where front-line PIs are not readily available, or have only become accessible recently. In the 2014-2018 cohort, we observed transplant outcomes comparable to that reported internationally using predominantly reduced intensity conditioning (7, 9, 10). Survival following transplant remains associated with the disease response at the time of HSCT, however is unaffected by 17p status, as has been previously demonstrated (7-9, 13-16). The importance of responding disease raises the question of minimal residual disease monitoring in selected patients in whom the next line of therapy may be HSCT. Improvements in NRM are crucial in CLL, where it remains a major driver of overall mortality following HSCT, particularly in older patients (16). The fall in NRM seen over the two periods in our study is likely multifactorial, in part due to avoidance of MAC and improved supportive care, in particular infection prevention and management, intensive care support and advances in management in GVHD that have been observed in HSCT more generally(17-19). Additionally, the later cohort had a lower incidence of both acute and chronic GVHD which may have contributed to improved NRM. There was no significant difference in GVHD prophylaxis between the groups however half of the patients included did not have this information reported to the registry. Difference in CLL treatment prior to transplant were noted between these two groups however it unclear if this may have contributed to the differences in NRM. The number of patients receiving transplant reduced by 42% over the two periods studied, mirroring trends observed in the USA and Europe (4). This might suggest a trend towards selection of fitter patients, however, besides prior CLL treatment, we did not identify a difference in patient demographics and disease characteristics between these periods. The efficacy of GvL has been well demonstrated in CLL, with tapering of immunosuppression and/or donor lymphocyte infusions being effectively utilised in some cases with excellent response in patients with early signs of relapse or positive minimal residual disease(10, 20). In our experience the 5-year cumulative incidence of relapse was 24%, with very few relapses after three years, possibly reflecting effective GvL. This sustained disease control following HSCT has been seen in other registry studies demonstrating only a quarter of patients who were alive and relapse free at 2 years went on to relapse at 10 years post transplant (16). In patients requiring additional treatment for CLL following HSCT, PIs have been effective with a response rate of 71% and two year PFS of 50% in a series of 56, largely PI naïve, patients treated with ibrutinib reported by the European Bone Marrow Transplant Registry and other smaller studies show similar results (15, 21, 22). Among patients undergoing transplantation between 2014-2018 we observed inferior OS in those treated with PIs prior to HSCT, with the disparity in survival becoming apparent only after one year. Due to the limited availability of PIs in Australia and New Zealand during this time, we were able to use contemporary non-PI exposed patients as a comparator, as opposed to historic controls. Possible contributors to the observed inferior survival include differences in immune reconstitution and infection risk, scarcity of available salvage options and possibly differences in patient or disease characteristics which were not captured in our registry data. These results differ from those reported by other studies, and may reflect the relatively high rate of patients with active disease, differences in access to salvage treatments or transplant, and supportive care practices (23-25). Importantly the two groups in our study remain small and ongoing research with larger cohorts is required. Limitations of this study include those typical of retrospective registry data. Follow up information was not available for all patients and there is the potential risk of reporting bias. Additional information regarding prior lines of therapy were only available for 93 (65%) of the patients. TP53 and IGVH mutation results were available for only 3% and <1% of patients respectively. This reflects the evolving access to these investigations in Australia and New Zealand during the studied time period. Transplant registries remain an important source of transplant outcome data. Overall, we have seen an improvement in NRM over the past decade in Australia and New Zealand among patients with CLL undergoing HSCT. The finding of reduced OS in patients with PI exposure in our registry is at odds with that reported elsewhere and warrants further investigation in to clinical practice in Australia and New Zealand with larger, ideally prospective, studies. Declarations Acknowledgements : Funding support provided by the Leukaemia Foundation Author Contributions: LB was responsible for designing the study, gathering the additional data from individual sites, interpreting the results, writing the manuscript. ST was responsible for extracting and analysing the data. GK, DR, DG, SM, AS, DP, TP, RD, SL, AB, PB, MG, SD, CC, CS, SB, PDC, SP, MH provided patient data, reviewed the manuscript and provided feedback. CT reviewed the manuscript and provided feedback. NH was responsible for conceptualising and designing the study, writing the manuscript and providing feedback. Competing interests: The authors declare no competing financial interests The datasets analysed during the current study are available from the ANZTCT registry on reasonable request. References Shanafelt TD, Wang XV, Kay NE, Hanson CA, O'Brien S, Barrientos J, et al. Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. N Engl J Med. 2019;381(5):432-43. Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, et al. Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. N Engl J Med. 2019;380(23):2225-36. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007. Gribben JG. How and when I do allogeneic transplant in CLL. Blood. 2018;132(1):31-9. Strati P, Parikh SA, Chaffee KG, Kay NE, Call TG, Achenbach SJ, et al. 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Survival, Nonrelapse Mortality, and Relapse-Related Mortality After Allogeneic Hematopoietic Cell Transplantation: Comparing 2003-2007 Versus 2013-2017 Cohorts. Ann Intern Med. 2020;172(4):229-39. Tournilhac O, Le Garff-Tavernier M, Nguyen Quoc S, Forcade E, Chevallier P, Legrand-Izadifar F, et al. Efficacy of minimal residual disease driven immune-intervention after allogeneic hematopoietic stem cell transplantation for high-risk chronic lymphocytic leukemia: results of a prospective multicenter trial. Haematologica. 2021;106(7):1867-75. Michallet M, Dreger P, Sobh M, Koster L, Hoek J, Boumendil A, et al. Ibrutinib as a salvage therapy after allogeneic HCT for chronic lymphocytic leukemia. Bone Marrow Transplant. 2020;55(5):884-90. Al-Sawaf O, Herling CD, Holtick U, Scheid C, Cramer P, Sasse S, et al. Venetoclax plus rituximab or obinutuzumab after allogeneic hematopoietic stem cell transplantation in chronic lymphocytic leukemia. Haematologica. 2019;104(5):e224-e6. Kim HT, Shaughnessy CJ, Rai SC, Reynolds C, Ho VT, Cutler C, et al. Allogeneic hematopoietic cell transplantation after prior targeted therapy for high-risk chronic lymphocytic leukemia. Blood Adv. 2020;4(17):4113-23. Lahoud OB, Devlin SM, Maloy MA, Roeker LE, Dahi PB, Ponce DM, et al. Reduced-intensity conditioning hematopoietic stem cell transplantation for chronic lymphocytic leukemia and Richter's transformation. Blood Adv. 2021;5(14):2879-89. Roeker LE, Dreger P, Brown JR, Lahoud OB, Eyre TA, Brander DM, et al. Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents. Blood Adv. 2020;4(16):3977-89. Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations The authors have declared there is NO conflict of interest to disclose. Supplementary Files Table1.xlsx Table2.xlsx 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-4050578","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":278292619,"identity":"f2154669-b148-485f-8efd-948918131a83","order_by":0,"name":"Nada 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Cameron","middleName":"","lastName":"Curley","suffix":""},{"id":278292636,"identity":"8c3e3988-decf-4418-879a-63982d0924c7","order_by":17,"name":"Caroline Stewart","email":"","orcid":"","institution":"Royal Brisbane and Women's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Caroline","middleName":"","lastName":"Stewart","suffix":""},{"id":278292637,"identity":"b1dff16f-3e43-4c60-abcd-4869e4775ecd","order_by":18,"name":"Constantine Tam","email":"","orcid":"","institution":"The Alfred","correspondingAuthor":false,"prefix":"","firstName":"Constantine","middleName":"","lastName":"Tam","suffix":""},{"id":278292638,"identity":"c60f4147-b758-4727-93cc-cf7e32d717f4","order_by":19,"name":"Shalini Balendran","email":"","orcid":"","institution":"The 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01:45:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4050578/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4050578/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52624245,"identity":"32e470ec-30e9-4c1f-b42f-20200a40aaaa","added_by":"auto","created_at":"2024-03-13 17:28:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":86203,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOutcomes between 2009-2013 and 2014-2018 cohorts\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4050578/v1/c4924a463449c517d98b4b16.png"},{"id":52625225,"identity":"72ff3a84-0bf1-472e-a261-172ee7359925","added_by":"auto","created_at":"2024-03-13 17:36:01","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":70806,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePathway inhibitor use prior to HSCT\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4050578/v1/e4b4a38f6f40d9c46eabcd4d.png"},{"id":52624248,"identity":"02b9f24a-c688-4411-a5d5-c0efb23bea81","added_by":"auto","created_at":"2024-03-13 17:28:00","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":45875,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 3. Overall \u0026nbsp;\u0026nbsp;survival by PI exposure in those undergoing transplant 2014-2018\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4050578/v1/95d4d779655fd936c0df99e0.png"},{"id":52624247,"identity":"7c1bfd04-1b49-4229-94d0-3386cf97a1eb","added_by":"auto","created_at":"2024-03-13 17:28:00","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":38376,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOverall survival by disease status at time of transplant\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4050578/v1/203801fbc9d0af9f6239a527.png"},{"id":54829851,"identity":"3a1d5b23-6424-4c8a-be80-793d7947d5d9","added_by":"auto","created_at":"2024-04-17 10:50:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":539406,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4050578/v1/179230d6-b272-4650-8315-de9349f05830.pdf"},{"id":52624244,"identity":"2da10f84-1fd2-43c8-89bc-5e367eb5eed0","added_by":"auto","created_at":"2024-03-13 17:28:00","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":11640,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4050578/v1/45a4803bec10361d003bac8c.xlsx"},{"id":52624243,"identity":"e30a792e-ddf9-4366-b210-f61dcd62faa7","added_by":"auto","created_at":"2024-03-13 17:28:00","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":9674,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4050578/v1/9a790f86c20810f86b93c794.xlsx"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Outcomes of Allogeneic Haematopoietic Transplant for Chronic Lymphocytic Leukaemia in the Modern Era","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe past decade has seen significant advances in the treatment of chronic lymphocytic leukaemia (CLL). The availability of pathway inhibitors (PIs) namely, Bruton tyrosine kinase inhibitors (BTKi), BCL2 inhibitors (BCL2i) and phosphatidylinositol 3 kinase inhibitors (Pi3Ki) have resulted in improved patient outcomes(1-3). With safe and effective therapy for high risk or chemoimmunotherapy refractory patients, the number of patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) has been declining (4). \u0026nbsp; However, disease progression or transformation remains the primary cause of death in patients with CLL (5). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe graft versus leukaemia (GvL) effect afforded by HSCT provides the possibility for long term disease control and possibly cure in patients with relapsed/refractory disease, including in those with high-risk genetic lesions (6-10). \u0026nbsp;The benefits of HSCT need to be weighed against the risk of graft versus host disease (GvHD) and non-relapse mortality (NRM) which are a particular concern in the, typically older, CLL population. \u0026nbsp; The American and European Societies of Blood and Bone Marrow Transplantation and the European Research Initiative on CLL have provided updated recommendations, redefining high risk patients based on salvage options and patients\u0026rsquo; transplant risk \u0026nbsp;(11, 12). These updated guidelines are welcome at a time when HSCT may be underutilised due to a desire to avoid adverse outcomes and instead await the availability of the \u0026ldquo;next\u0026rdquo; available agent (11). \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe aim of this study was to report the outcomes of HSCT for CLL across Australia and New Zealand in the modern era of CLL treatment with a focus on trends over the last decade. Additionally, we sought to specifically examine outcomes of patients who received PIs prior to HSCT.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eData was collected from the Australian and New Zealand Transplant and Cellular Therapy (ANZTCT) Registry and included all patients who underwent HSCT for CLL in the absence of Richter\u0026rsquo;s transformation between January 2009 and December 2018. \u0026nbsp;Additional information was gathered by questionnaires from centres regarding del17p, TP53, pre-transplant minimal residual disease (MRD) and treatment prior to HSCT. Patients provided written informed consent for their data to be collected and used for research purposes by ANZTCT prior to HSCT. This project was approved by the ANZTCT steering committee and covered the registry\u0026rsquo;s ethics approved protocol. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDescriptive statistics were used to report patient and transplant characteristics. Post-transplant outcomes were estimated using the Kaplan-Meier method for survival and Gray\u0026rsquo;s test for cumulative incidence. Two five-year time periods, 2009-2013 and 2014-2018, were compared for transplant outcomes using log rank test for survival and Gray\u0026rsquo;s test for cumulative incidence estimates. Cause of death was compared between the two time periods using Fisher\u0026rsquo;s exact test. Sub-group analysis was performed on the 2014-2018 cohort for patients with and without PI exposure. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUnivariate analyses for factors associated with overall survival (OS), progression free survival (PFS), relapse rate and non-relapse mortality (NRM) were performed. This was followed by multivariate analysis of predefined variables including patient age, disease status, duration from diagnosis to transplant, prior number of therapies, del17p, donor relation and conditioning. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSurvival and progression are reported from the day of stem cell infusion. Acute GvHD (aGVHD) grade II-IV is reported and chronic GVHD (cGVHD) included all reported cases of any grade. Disease status was provided by centres at the time of transplant. Active disease includes stable disease, progressive disease and untreated relapse at the time of HSCT. \u0026nbsp;Pathway inhibitors included BTKi, BCL2i, PI3Ki as these are the only agents approved in Australia and New Zealand. Neutrophil engraftment was defined as an absolute neutrophil count \u0026ge;0.5x10\u003csup\u003e6\u003c/sup\u003e/L and platelet engraftment was defined as a platelet count \u0026ge;20x10\u003csup\u003e6\u003c/sup\u003e/L.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eOne hundred and forty-four patients from 14 centres in Australia and New Zealand were identified. Patient and transplant characteristics are shown in table 1. Data on TP53 mutation and IGVH status were available for only 5 and 1 patients respectively and were therefore not included. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTransplant outcomes for 2009-2013 and 2014-2018 cohorts\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNinety-four patients underwent transplantation between 2009-2013 and 50 from 2014 to 2018. Patients in the more recent cohort where more likely to have received FCR and PIs prior to transplantation and there was decreasing use of myeloablative conditioning over the period (table 1). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEngraftment\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eMedian time to neutrophil engraftment was 16 days (range 8-32 days) and 17 days (range 6-25 days), platelet engraftment occurred at a median of 19 days (range 1-69) and 16 days (range 10-41 days) in the 2009-2013 and 2014-2018 cohorts respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eGVHD\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe cumulative incidence of grade II-IV aGVHD at 100 days was 52% (95% CI 35-67) in the 2009-2013 cohort and 33% (95% CI 19-48, p=0.039) in the 2014-2018 cohort. The 5-year cumulative incidence of cGVHD reduced from 76% (95% CI 56-87) to 55% (95% CI 36-70, p=0.032) in the more recent period. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCMV reactivation and disease\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAt 1-year, the cumulative incidence of CMV reactivation was 40% (95% CI 25.6-54%) in the 2009-2013 cohort and 48.6% (95% CI 31.6-63.7%) in the 2014-2018 cohorts. \u0026nbsp; Cumulative incidence of CMV disease was 2.3% (95% CI 1.7-10.5%) and 8.1% (95% CI 2.0-19.8%) at 1 year in the 2009-2013 and the 2014-2018 cohorts respectively. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eSurvival and cause of death\u0026nbsp;\u003c/u\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe median follow-up was 7.6 years (interquartile [IQ] range 6.3-8.4) and 5.0 years (IQ range 4.0-5.7) for the 2009-2013 and the 2014-2018 cohorts respectively. \u0026nbsp;Five-year estimated OS, PFS, NRM and relapse rates between these cohorts are shown in figure 1. There was no difference in OS, PFS and relapse however 5 year NRM was significantly improved from 42% (95% CI 31-52) to 23% (95% CI 12-37, p=0.02). Among patients who experienced relapse, three-year OS from time of relapse was 59% (95% CI 40-86) and 58% (95% CI 36-94) in the 2009-2013 and the 2014-2018 cohorts respectively. \u0026nbsp;There was no statistical difference in the reported cause of death between the two time periods (p=0.4, table 2). \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTransplant following pathway inhibitors\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwenty-three patients received pathway inhibitors prior to allogeneic transplantation. \u0026nbsp; A single patient transplanted in 2012 received ibrutinib prior to HSCT; the remaining PI exposed patients underwent transplantation between 2014-2018 (figure 2). Among those who received PI prior to HSCT, the median age was 54 years (range 25-66) and the median time from diagnosis to transplantation was 81 months (range 17 \u0026ndash; 242.9). Six patients (32% with data available) had del17p detected prior to transplant. The median number of prior therapies was 3 (range 2-9). All patients had received prior chemoimmunotherapy. Of the 23 patients, 18 received ibrutinib, five received venetoclax (four of whom also received ibrutinib), three received idealisib and one received zanubrutinib. At the time of transplant four patients were in CR, 12 in PR, five had active disease and this information was not available in two patients. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDonors were HLA-matched sibling donors in nine patients, unrelated in 13 and a there was a single mismatched related donor. Two patients received myeloablative conditioning. \u0026nbsp;Median time to neutrophil and platelet engraftment was 15 days and 16 days respectively and did not differ from the group who did not receive PIs prior to HSCT. Acute GVHD occurred in 9 patients, cumulative incidence of grade II-IV aGVHD was 40% (95% CI 19-61) at 100 days. Cumulative incidence of cGVHD was 44% (19-66) at 5 years. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong patients transplanted between 2014-2018, there was no difference in baseline characteristics between those with and without PI exposure prior to HSCT besides prior CLL treatment. The median follow-up for PI na\u0026iuml;ve and PI exposed patients transplanted within this time period was 5.7years (IQ range 5.5-6.6) and 3.8 years (IQ range 2.9 \u0026ndash; not reached). \u0026nbsp;When comparing PI na\u0026iuml;ve to PI exposed patients, three-year OS survival was 91% (95% CI 80-100) versus 54% (95% CI 35-82, p=0.025, figure 3), PFS was 65% (95% CI 48-88) versus 44% (95% CI 27-71, p=0.19), NRM 9% (95% CI 1-25) versus 25% (95% CI 8-45, p=0.22) and relapse was 26% (95% CI 10-46) versus 32% (95% CI 14-52, p=0.61). \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUnivariate and multivariate analyses\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the univariate analysis, age, gender, interval from diagnosis to transplant, deletion 17p, prior PI exposure and Karnofsky performance status \u0026lt;80 were not associated with differences in OS, PFS, NRM or relapse rate. Active disease in comparison to diseases in CR was associated with OS, PFS and NRM with hazard ratios (HR) of 2.69 (95% CI 1.2-6.0, p=0.015), 2.1 (95% CI 1.05-4.19, p=0.04) and 2.84 (95% CI 1.12-7.23, p=0.03) respectively. Transplantation between 2014-2018 was associated with superior NRM, HR 2.01 (1.00-4.04, p=0.05). \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn a multivariate analysis, disease in CR as compared to active disease retained significance for OS (HR 2.54, 95% CI 1.04-6.18, p=0.04, figure 4) with a trend towards improved NRM (HR 2.73, 95% CI 0.98-7.64, p =0.06). Three or more prior lines of therapy was associated with relapse; HR 2.31 (95% CI 1.0-5.32, p=0.05). None of the other factors assessed retained significance for OS, PFS or NRM.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe have presented outcomes of a large cohort of patients undergoing HSCT for CLL over the past decade. This spans a period of transition in CLL treatment worldwide and in our populations in Australia and New Zealand where government subsidised ibrutinib (December 2017 in Australia, December 2022 New Zealand) and venetoclax (March 2019 in Australia; December 2019 in New Zealand) have recently become available for selected patients. Prior to this, pathway inhibitors were not accessible or available only on clinical trials or compassionate access schemes. This is likely to reflect the profile of patients considered for HSCT for CLL in many other countries, particularly those where front-line PIs are not readily available, or have only become accessible recently.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the 2014-2018 cohort, we observed transplant outcomes comparable to that reported internationally using predominantly reduced intensity conditioning (7, 9, 10). \u0026nbsp; Survival following transplant remains associated with the disease response at the time of HSCT, however is unaffected by 17p status, as has been previously demonstrated (7-9, 13-16). The importance of responding disease raises the question of minimal residual disease monitoring in selected patients in whom the next line of therapy may be HSCT. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eImprovements in NRM are crucial in CLL, where it remains a major driver of overall mortality following HSCT, particularly in older patients (16). \u0026nbsp; The fall in NRM seen over the two periods in our study is likely multifactorial, \u0026nbsp;in part due to avoidance of MAC and improved supportive care, in particular infection prevention and management, intensive care support and advances in management in GVHD that have been observed in HSCT more generally(17-19). Additionally, the later cohort had a lower incidence of both acute and chronic GVHD which may have contributed to improved NRM. There was no significant difference in GVHD prophylaxis between the groups \u0026nbsp;however half of the patients included did not have this information reported to the registry. \u0026nbsp;Difference in CLL treatment prior to transplant were noted between these two groups however it unclear if this may have contributed to the differences in NRM. The number of patients receiving transplant reduced by 42% over the two periods studied, mirroring trends observed in the USA and Europe (4). This might suggest a trend towards selection of fitter patients, however, besides prior CLL treatment, we did not identify a difference in patient demographics and disease characteristics between these periods. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe efficacy of GvL has been well demonstrated in CLL, with tapering of immunosuppression and/or donor lymphocyte infusions being effectively utilised in some cases with excellent response in patients with early signs of relapse or positive minimal residual disease(10, 20). In our experience the 5-year cumulative incidence of relapse was 24%, with very few relapses after three years, possibly reflecting effective GvL. This sustained disease control following HSCT has been seen in other registry studies demonstrating only a quarter of patients who were alive and relapse free at 2 years went on to relapse at 10 years post transplant (16). \u0026nbsp; In patients requiring additional treatment for CLL following HSCT, PIs have been effective with a response rate of 71% and two year PFS of 50% in a series of 56, largely PI na\u0026iuml;ve, patients treated with ibrutinib reported by the European Bone Marrow Transplant Registry and other smaller studies show similar results (15, 21, 22).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong patients undergoing transplantation between 2014-2018 we observed inferior OS in those treated with PIs prior to HSCT, with the disparity in survival becoming apparent only after one year. Due to the limited availability of PIs in Australia and New Zealand during this time, we were able to use contemporary non-PI exposed patients as a comparator, as opposed to historic controls. Possible contributors to the observed inferior survival include differences in immune reconstitution and infection risk, scarcity of available salvage options and possibly differences in patient or disease characteristics which were not captured in our registry data. These results differ from those reported by other studies, and may reflect the relatively high rate of patients with active disease, differences in access to salvage treatments or transplant, and supportive care practices (23-25). Importantly the two groups in our study remain small and ongoing research with larger cohorts is required. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLimitations of this study include those typical of retrospective registry data. Follow up information was not available for all patients and there is the potential risk of reporting bias. Additional information regarding prior lines of therapy were only available for 93 \u0026nbsp;(65%) of the patients. TP53 and IGVH mutation results were available for only 3% and \u0026lt;1% of patients respectively. This reflects the evolving access to these investigations in Australia and New Zealand during the studied time period.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTransplant registries remain an important source of transplant outcome data. Overall, we have seen an improvement in NRM over the past decade in Australia and New Zealand among patients with CLL undergoing HSCT. The finding of reduced OS in patients with PI exposure in our registry is at odds with that reported elsewhere and warrants further investigation in to clinical practice in Australia and New Zealand with larger, ideally prospective, studies.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: Funding support provided by the Leukaemia Foundation \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u0026nbsp;LB was responsible for designing the study, gathering the additional data from individual sites, interpreting the results, writing the manuscript. ST was responsible for extracting and analysing the data. GK, DR, DG, SM, AS, DP, TP, RD, SL, AB, PB, MG, SD, CC, CS, SB, PDC, SP, MH provided patient data, reviewed the manuscript and provided feedback. CT reviewed the manuscript and provided feedback. NH was responsible for conceptualising and designing the study, writing the manuscript and providing feedback. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests: \u0026nbsp;\u003c/strong\u003eThe authors declare no competing financial interests\u003c/p\u003e\n\u003cp\u003eThe datasets analysed during the current study are available from the ANZTCT registry on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eShanafelt TD, Wang XV, Kay NE, Hanson CA, O\u0026apos;Brien S, Barrientos J, et al. Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. N Engl J Med. 2019;381(5):432-43.\u003c/li\u003e\n\u003cli\u003eFischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, et al. Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. N Engl J Med. 2019;380(23):2225-36.\u003c/li\u003e\n\u003cli\u003eFurman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007.\u003c/li\u003e\n\u003cli\u003eGribben JG. How and when I do allogeneic transplant in CLL. Blood. 2018;132(1):31-9.\u003c/li\u003e\n\u003cli\u003eStrati P, Parikh SA, Chaffee KG, Kay NE, Call TG, Achenbach SJ, et al. Relationship between co-morbidities at diagnosis, survival and ultimate cause of death in patients with chronic lymphocytic leukaemia (CLL): a prospective cohort study. Br J Haematol. 2017;178(3):394-402.\u003c/li\u003e\n\u003cli\u003eKramer I, Stilgenbauer S, Dietrich S, Bottcher S, Zeis M, Stadler M, et al. Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial. Blood. 2017;130(12):1477-80.\u003c/li\u003e\n\u003cli\u003eDreger P, Dohner H, Ritgen M, Bottcher S, Busch R, Dietrich S, et al. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010;116(14):2438-47.\u003c/li\u003e\n\u003cli\u003eSorror ML, Storer BE, Sandmaier BM, Maris M, Shizuru J, Maziarz R, et al. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol. 2008;26(30):4912-20.\u003c/li\u003e\n\u003cli\u003eBrown JR, Kim HT, Armand P, Cutler C, Fisher DC, Ho V, et al. Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome. Leukemia. 2013;27(2):362-9.\u003c/li\u003e\n\u003cli\u003eKhouri IF, Bassett R, Poindexter N, O\u0026apos;Brien S, Bueso-Ramos CE, Hsu Y, et al. Nonmyeloablative allogeneic stem cell transplantation in relapsed/refractory chronic lymphocytic leukemia: long-term follow-up, prognostic factors, and effect of human leukocyte histocompatibility antigen subtype on outcome. Cancer. 2011;117(20):4679-88.\u003c/li\u003e\n\u003cli\u003eDreger P, Ghia P, Schetelig J, van Gelder M, Kimby E, Michallet M, et al. High-risk chronic lymphocytic leukemia in the era of pathway inhibitors: integrating molecular and cellular therapies. Blood. 2018;132(9):892-902.\u003c/li\u003e\n\u003cli\u003eKharfan-Dabaja MA, Kumar A, Hamadani M, Stilgenbauer S, Ghia P, Anasetti C, et al. Clinical Practice Recommendations for Use of Allogeneic Hematopoietic Cell Transplantation in Chronic Lymphocytic Leukemia on Behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2016;22(12):2117-25.\u003c/li\u003e\n\u003cli\u003eSchetelig J, de Wreede LC, van Gelder M, Andersen NS, Moreno C, Vitek A, et al. Risk factors for treatment failure after allogeneic transplantation of patients with CLL: a report from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2017;52(4):552-60.\u003c/li\u003e\n\u003cli\u003ePaul S, Tsai HL, Lowery P, Fuchs EJ, Luznik L, Bolanos-Meade J, et al. Allogeneic Haploidentical Blood or Marrow Transplantation with Post-Transplantation Cyclophosphamide in Chronic Lymphocytic Leukemia. Biol Blood Marrow Transplant. 2020;26(3):502-8.\u003c/li\u003e\n\u003cli\u003eHahn M, Bottcher S, Dietrich S, Hegenbart U, Rieger M, Stadtherr P, et al. Allogeneic hematopoietic stem cell transplantation for poor-risk CLL: dissecting immune-modulating strategies for disease eradication and treatment of relapse. Bone Marrow Transplant. 2015;50(10):1279-85.\u003c/li\u003e\n\u003cli\u003evan Gelder M, de Wreede LC, Bornhauser M, Niederwieser D, Karas M, Anderson NS, et al. Long-term survival of patients with CLL after allogeneic transplantation: a report from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2017;52(3):372-80.\u003c/li\u003e\n\u003cli\u003ePenack O, Peczynski C, Mohty M, Yakoub-Agha I, Styczynski J, Montoto S, et al. How much has allogeneic stem cell transplant-related mortality improved since the 1980s? A retrospective analysis from the EBMT. Blood Adv. 2020;4(24):6283-90.\u003c/li\u003e\n\u003cli\u003eGooley TA, Chien JW, Pergam SA, Hingorani S, Sorror ML, Boeckh M, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363(22):2091-101.\u003c/li\u003e\n\u003cli\u003eMcDonald GB, Sandmaier BM, Mielcarek M, Sorror M, Pergam SA, Cheng GS, et al. Survival, Nonrelapse Mortality, and Relapse-Related Mortality After Allogeneic Hematopoietic Cell Transplantation: Comparing 2003-2007 Versus 2013-2017 Cohorts. Ann Intern Med. 2020;172(4):229-39.\u003c/li\u003e\n\u003cli\u003eTournilhac O, Le Garff-Tavernier M, Nguyen Quoc S, Forcade E, Chevallier P, Legrand-Izadifar F, et al. Efficacy of minimal residual disease driven immune-intervention after allogeneic hematopoietic stem cell transplantation for high-risk chronic lymphocytic leukemia: results of a prospective multicenter trial. Haematologica. 2021;106(7):1867-75.\u003c/li\u003e\n\u003cli\u003eMichallet M, Dreger P, Sobh M, Koster L, Hoek J, Boumendil A, et al. Ibrutinib as a salvage therapy after allogeneic HCT for chronic lymphocytic leukemia. Bone Marrow Transplant. 2020;55(5):884-90.\u003c/li\u003e\n\u003cli\u003eAl-Sawaf O, Herling CD, Holtick U, Scheid C, Cramer P, Sasse S, et al. Venetoclax plus rituximab or obinutuzumab after allogeneic hematopoietic stem cell transplantation in chronic lymphocytic leukemia. Haematologica. 2019;104(5):e224-e6.\u003c/li\u003e\n\u003cli\u003eKim HT, Shaughnessy CJ, Rai SC, Reynolds C, Ho VT, Cutler C, et al. Allogeneic hematopoietic cell transplantation after prior targeted therapy for high-risk chronic lymphocytic leukemia. Blood Adv. 2020;4(17):4113-23.\u003c/li\u003e\n\u003cli\u003eLahoud OB, Devlin SM, Maloy MA, Roeker LE, Dahi PB, Ponce DM, et al. Reduced-intensity conditioning hematopoietic stem cell transplantation for chronic lymphocytic leukemia and Richter\u0026apos;s transformation. Blood Adv. 2021;5(14):2879-89.\u003c/li\u003e\n\u003cli\u003eRoeker LE, Dreger P, Brown JR, Lahoud OB, Eyre TA, Brander DM, et al. Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents. Blood Adv. 2020;4(16):3977-89.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\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":"","lastPublishedDoi":"10.21203/rs.3.rs-4050578/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4050578/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThere is limited data on the use and outcomes of allogeneic haematopoietic stem cell transplant (HSCT) in the modern era of chronic lymphocytic leukaemia (CLL) treatment. The aim of this study was to examine CLL transplant outcomes with a focus on patients exposed to pathway inhibitors (PI) prior to transplant.\u003c/p\u003e\n\u003cp\u003eData was collected through the Australian and New Zealand Transplant and Cellular Therapy Registry for all patients who underwent HSCT for CLL between 01/2009-12/2018. Transplant outcomes were compared between 2009-2013 (n=94) and 2014-2018 (n=50). There was a significant reduction in non-relapse mortality (NRM) from 42% (95%CI 31-52%) to 23% (95% CI 12-35%, p=0.02) between the periods however overall survival (OS), progression free survival and relapse were unchanged. Within the 2014-2018 cohort there was no difference in baseline characteristics between PI exposed (n=22) and naïve patients however 3-year OS was inferior in PI exposed patients: 54% (95%CI 35-82) compared to 91% (95%CI 80-100; p=0.03). In multivariate analysis, complete remission at the time of HSCT was associated with improved OS (hazard ratio [HR] 2.54, 95%CI 1.04-6.18). Allogeneic HSCT remains a viable treatment option for selected patients with CLL however the finding of inferior OS in PI exposed patients requires further study.\u003c/p\u003e","manuscriptTitle":"Outcomes of Allogeneic Haematopoietic Transplant for Chronic Lymphocytic Leukaemia in the Modern Era","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-13 17:27:55","doi":"10.21203/rs.3.rs-4050578/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":"8389b072-1f6e-4ff3-a1ab-5fc84a8d43f7","owner":[],"postedDate":"March 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":29312307,"name":"Health sciences/Health care/Therapeutics/Immunotherapy"},{"id":29312308,"name":"Health sciences/Diseases/Cancer/Haematological cancer/Leukaemia/Chronic lymphocytic leukaemia"}],"tags":[],"updatedAt":"2024-04-17T10:41:57+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-13 17:27:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4050578","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4050578","identity":"rs-4050578","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}