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Outcomes of Cord Blood Transplantation Using Reduced Intensity Conditioning for Chronic Lymphocytic Leukemia: a Study on Behalf of Eurocord and Cord Blood Committee of Celular Therapy and Immunobiology Working Party(CTIWP), Chronic Malignancies Working Party(CMWP) of the EBMT and the Societé Française de Greffe de Moelle et Therapie Cellulaire (SFGM-TC)
Erick Xavier, Jérôme Cornillon, Annalisa Ruggeri, Patrice Chevallier, Jan J. Cornelissen, Niels S. Andersen, Natacha Maillard, Stephanie Nguyen, Didier Blaise, Eric Deconinck, Hendrik Veelken, Noel Milpied, Michel Van Gelder, Regis Peffault de Latour, Eliane Gluckman, Nicolaus Kröger, Johannes Schetelig, Vanderson Rocha
PII: S1083-8791(15)00322-5
DOI: 10.1016/j.bbmt.2015.04.026
Reference: YBBMT 53852
To appear in: Biology of Blood and Marrow Transplantation
Received Date: 19 February 2015 Accepted Date: 29 April 2015
Please cite this article as: Xavier E, Cornillon J, Ruggeri A, Chevallier P, Cornelissen JJ, Andersen NS, Maillard N, Nguyen S, Blaise D, Deconinck E, Veelken H, Milpied N, Van Gelder M, Peffault de Latour R, Gluckman E, Kröger N, Schetelig J, Rocha V, Outcomes of Cord Blood Transplantation Using Reduced Intensity Conditioning for Chronic Lymphocytic Leukemia: a Study on Behalf of Eurocord and Cord Blood Committee of Celular Therapy and Immunobiology Working Party(CTIWP), Chronic Malignancies Working Party(CMWP) of the EBMT and the Societé Française de Greffe de Moelle et Therapie Cellulaire (SFGM-TC), Biology of Blood and Marrow Transplantation (2015), doi: 10.1016/ j.bbmt.2015.04.026.
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Outcomes of Cord Blood Transplantation Using Reduced Intensity Conditioning for Chronic Lymphocytic Leukemia: a Study on Behalf of Eurocord and Cord Blood Committee of Celular Therapy and Immunobiology Working Party(CTIWP), Chronic Malignancies Working Party(CMWP) of the EBMT and the Societé Française de Greffe de Moelle et Therapie Cellulaire (SFGM-TC)
Erick Xavier1, Jérôme Cornillon2, Annalisa Ruggeri1,3, Patrice Chevallier4, Jan J Cornelissen5, Niels S. Andersen6, Natacha Maillard7, Stephanie Nguyen8, Didier Blaise9, Eric Deconinck10, Hendrik Veelken11, Noel Milpied12, Michel Van Gelder13, Regis Peffault de Latour14, Eliane Gluckman1, Nicolaus Kröger15, Johannes Schetelig*16, Vanderson Rocha*17
JS and VR shared the last authorship
1Eurocord, University Paris Diderot, Paris, France; 2Cancer Institute Lucien Neuwirth, Saint Etienne, France;
3Hospital Saint Antoine, Service d'Hématologie et Thérapie Cellulaire, AP-HP, UPMC Univ Paris 06, UMR-S 938, CEREST-TC EBMT, Paris, France; 4Hematology, Nantes University Hospital, Nantes, France;
5Hematology, Erasmus MC/Daniel Den Hoed, Rotterdam, Netherlands; 6Rigshospitalet, Department of Hematology, Copenhagen, Denmark; 7Service oncologie hématologique et thérapie cellulaire, CHU de Poitiers, Poitiers, France ;
8Pitie-Salpetriere Hospital, Paris, France; 9Paoli Calmettes Hospital, Marseille, France; 10Jean Minjoz Hospital, Besançon, France; 11Leiden University Medical Center, Leiden; 12University Hospital and University of Bordeaux, Bordeaux, France; 13Maastricht University Medical Center, Maastricht, Netherlands; 14Saint Louis Hospital, University Paris Diderot, Paris, France; 15University Medical Center Hamburg-Eppendorf - Department of Stem Cell Transplantation, Germany;
16University Hospital Carl Gustav Carus, Medical Department I & DKMS German Bone Marrow Donor Center, Dresden, Germany;
17Department of Clinical Haematology, Bone Marrow Transplantation Unit, Oxford University Hospitals NHS trust, United Kingdom;
Address for correspondence: Erick Xavier, MD
Eurocord Office, Hôpital Saint Louis, Paris, France 1, Av Claude Vellefaux 75010, Paris
erick_menezes@yahoo.com
Abstract
Outcomes after umbilical cord blood transplantation(UCBT) for chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL) are unknown. We analyzed outcomes of 68 patients with poor risk CLL/SLL who underwent reduced intensity(RIC) UCBT from 2004-2012. Median age was 57 years and follow-up 36 months; 17 patients had del17p/p53mutation, 19 patients had fludarabine refractory disease, 11 relapsed after ASCT, 8 had diagnosis of Prolymphocyte Leukemia, 4 Richter Syndrome and 8 were transplanted with progressive or refractory disease. The most common RIC used was CYFLUTBI in 82%; 15 patients received ATG. Most of the cord blood (CB) grafts were HLA mismatched and 76% received a double UCBT. Median total nucleated cells(TNC) collected was 4,7x107/Kg. The cumulative incidence^) neutrophil and platelet engraftment were 84% and 72% at 60 and 180 days respectively; day-100 GVHD(II-IV) was 43% and 3-year chronic GVHD 32%. CI of relapse, non-relapse mortality(NRM), overall survival(OS) and progression-free survival(PFS) at 3-years were, respectively, 16%, 39%, 54% and 45%. The use of low dose TBI regimens and fludarabine sensitive disease at transplantation were associated with acceptable PFS. In conclusion, use of UCBT-RIC seems to be feasible in poor-risk CLL/SLL and improved outcomes were observed in patients with fludarabine sensitive disease who received low dose TBI regimens.
Word count: Abstrat: 200 words; Text: 3617 words; Tables: 3 tables Figures: 3 figures References: 70
Keywords: umbilical cord blood transplantation, chronic lymphocytic leukemia, reduced intensity conditioning regimen
Introduction:
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course and survival can range from months to decades according to different biological features1,2. Poor-risk disease is characterized by mutations/deletions of the TP53 gene3'4,5,6,7, non-response or early relapse following purine analogue treatment (within 12 months) or relapse (less than 24 months) after purine analogue combination therapy8.
Until now, allogeneic stem cell transplantation has been accepted as standard of care in fit patients with poor-risk CLL8,9,10. Two drugs inhibiting down-stream signaling of the B-Cell-Receptor (BCRi), Ibrutinib and Idelalisib have recently been approved. These drugs expose a very favorable risk benefit profile for patients with refractory CLL/SLL11. Longer follow up is needed to better assess the safety and efficacy of these drugs but clearly they do not have the potential to eradicate the disease. Comparative studies with allogeneic stem cell transplantation (allo-HSCT) are lacking and this therapeutic tool is still the only to evoke graft-versus-leukemia effect that is highly active in achieving and maintaining disease-control even in advanced stages of CLL/SLL12,13. While the role of allo-HSCT in the therapeutic algorithm may have to be re-defined, allo-HSCT will maintain its place in the treatment of patients with refractory stages of CLL/SLL.
In recent years, the use of reduced intensity conditioning (RIC) regimens in al-lo-HSCT setting has become standard treatment even in poor-risk CLL and it may lead to cure14,15. Almost exclusively, outcomes on matched related or unrelated donor transplantation have been published and data on alternative stem cell donors are lacking. Generally, clinical experience with UCBT in poor-risk malignancies has increased in recent years specially with the use of double UCBT which allowed adult patients to proceed to allo-HSCT16. Nevertheless, no studies have yet addressed directly the role of UCBT specifically for CLL/SLL. Therefore, we analyzed results of unrelated UCBT in CLL/SLL patients, and identified risk factors associated with outcomes.
Methods:
Study Design/ Patients and definitions
The primary objective of this study was to describe progression-free survival (PFS) after UCBT and to identify risk factors in a retrospective based registry analysis. We analyzed adult patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Prolymphocyte Leukemia or Richter Syndrome who underwent a first unrelated and unmanipulated allogeneic UCBT, following reduced-intensity conditioning. Sixty-eight patients meeting the study criteria were registered with the Eu-rocord/EBMT databases from 2004-2012. All patients or legal guardians provided informed consent for the UCBT according to the Declaration of Helsinki.
The primary end-point was PFS, defined as the time from UCBT to relapse, disease progression or death. Secondary end-points were probability of OS defined as the probability of survival regardless of disease state at any point in time; incidence of neutrophil recovery, defined as first of 3 consecutive days with a neutrophil count of at least 0.5x109/L; acute GVHD at 100-day and chronic GVHD were diagnosed and graded according to published criteria17,18; relapse or progression, as defined by the centers; and NRM, defined as deaths without previous relapse or progression. Full donor chimerism was defined as the presence of more than 95% of the cells of donor origin, mixed chimerism as more than 5% but less than 95% donor cells and autologous recovery if less than 5% of donor cells. Data on the method of chimerism detection were not collected.
Statistical Analysis:
Median values and ranges are reported for continuous variables and percentages for categorical variables. The probabilities of OS and PFS were calculated using the Kaplan-Meier method and the log-rank test for univariate comparisons19. Cumulative incidence (CI) function using death as a competing event was used to estimate neutrophil and platelet engraftment, acute and chronic GVHD, and relapse.
The following variables were tested in the univariate analyses: age at UCBT, year of UCBT, gender, patient CMV serology prior to transplant, Hematopoietic stem cell transplantation comorbidity index (HCT-CI), Binet staging at diagnosis, intervals be-
tween diagnosis and UCBT, graft source (single/ double), CLL/SLL cytogenetic risk, disease status at transplant (complete remission (CR) vs no CR), conditioning regimen (low dose TBI vs others), ATG, GVHD prophylaxis (CsA+MMF vs others), number of courses of chemotherapy lines prior UCBT, previous ASCT, TNC/Kg of recipient's weight and number of HLA disparities. Multivariate analysis was performed using Cox proportional hazards regression model for PFS20. Variables that reached a p-value of 0.15 in the univariate analysis were included in the initial multivariate model and eliminated one at a time in a stepwise fashion in order to only keep variables that reached a p-value<of 0.05 in the final model. P-values were two-sided. Statistical analyses were performed with SPSS version 19 (Inc., Chicago, IL) and Splus (MathSoft, Inc., Seattle, WA).
Results
Patients and disease characteristics:
Patients and transplant characteristics are summarized in table 1. Sixteen patients received single and 52 double UCBT. Seventeen patients had del17p/p53mutation, 19 patients had fludarabine refractory disease, 11 relapsed after ASCT, 8 had diagnosis of Prolymphocytic Leukemia (PLL) and 4 Richter Syndrome (RS). Median age at UCBT was 57 years (26-68), median year of UCBT was 2009 and median follow-up was 36 months (3-98). Comorbidities were assessed according to the HCT-CI21 and scoring was as following: 40 patients had no comorbidity, 9 had score 1, 7 score 2, 9 score 3 and 1 score 4. Information on fludarabine exposure were retrieved from 67 out of 68 pts. Fludarabine refractory disease was classified as the disease that failed to respond to fludarabine based treatment or had progressive disease within 12 months after fludarabine-based combination regimen. Fifty-three patients were treated with fludarabine combination regimens. The other 14 pts were treated with alentuzumab based regimens as first line treatment and so forth were not considered fludarabine resistant.
Transplant outcomes Neutrophil and platelet engraftment
The cumulative incidence (CI) of neutrophil and platelet engraftment were 84±5% and 72±6% with a median time for engraftment of 22 (5-67) and 44 days (6-189), respectively. Patients who received previous ASCT had a higher incidence of neutrophil engraftment (100% vs 82%, p=0,03). Eleven patients did not engraft. Of these patients 8 died (5 died of early NRM causes without marrow reconstitution and 3 of relapse after autologous reconstitution). Three patients are alive with autolo-gous reconstitution (two of them relapsed and are on rescue treatment and one is alive after 13 months of transplantation without signs or symptoms of relapse). For the remaining 57 patients with neutrophil engraftment 36 had complete donor chimerism, 16 had mixed chimerism and 5 unknown.
CI of aGVHD at 100 days was 42±5% for grade II-IV and 19±5% for grade III-IV with a median time of onset of 26 days (9-95). The use of ATG (14% vs 45%, p= 0.02) was associated with a lower risk of grade II-IV aGVHD. Three years CI of cGVHD was 32±6% with a median time of onset of 138 days (90-393). Positive CMV serology prior UCBT (50% vs 22%, p=0.05) was associated with higher cGVHD incidence (table 2).
Twenty-five patients died of transplant related causes (10 infections, 4 post-transplant lymphoproliferative disease (PTLD), 3 aGVHD, 3 toxicity, 1 secondary lung cancer and 4 other causes). The cumulative incidence of NRM was 39%±6% at 3 years. Factors associated with lower NRM were: use of low dose TBI (2-4 Gy) conditioning regimen (34% vs 62%, p<0.001), <2 different chemotherapy lines (CTL) prior UCBT (18% vs 49%, p=0.02) and fludarabine-sensitive disease at UCBT (30% vs 61%, p= 0.009) (figure 1).
Relapse or Progression
The cumulative incidence of relapse or progression was 16±5% at 3 years. Median time to relapse or progression was 19 months (2-89 months) and fludarabine sensitive disease (13% vs 45%, p=0.04) was the only factor associated with lower incidence of relapse. No relapse outcome differences were observed from del17p and non 17p patients (figure 2). We analysed the impact of acute (p=0.66) and chronic GVHD (p=0.67) on relapse (in a time dependent fashion), but, probably due to low relapse rate, we could not find any statistical impact.
Twenty-three patients were transplanted in complete remission. Of these patients 15 were alive at last follow up and 8 died (1 of relapse after 36 months of transplantation and 7 died of NRM causes, mainly infection). Of the 15 patients alive, 3 relapsed with a median time of relapse of 11 months. Thirty seven patients were in partial remission, 18 patients died (4 of relapse with a median time to relapse of 19 months, 14 of NRM causes with a median survival of 3 months) and 19 patients are alive (16 without relapse with a median follow up of 45 months and 3 patients relapsed with a median time to relapse of 77 months). Eight patients had relapse-progressive disease prior UCBT, 6 of them died (2 of relapse with a median time to relapse of 7 months; 4 died of NRM with a median time to death of 2 months) and 2 are alive without relapse with a median follow up of 26 months.
Overall, 13 patients relapsed or progressed after UCBT. Eight out of these 13 patients were transplanted in partial remission or had refractory disease at transplant. From these 13 patients, 6 are alive (2 of them received treatment: 1 received R-bendamustine and other unknown treatment; 4 of them did not receive further treatment after relapse) and 7 died (2 of them after relapse following a second stem cell transplantation; 1 received clorambucil but progressed and 4 patients did not receive any further treatment).
OS and PFS
The probability of OS and PFS was 54%±6% and 45%±7% at 3 years. A negative CMV serology (70 vs 45%, p=0,03), the use of low dose TBI (58% vs 35%, p<0,001), <2 different CTL prior UCBT (59% vs 18%, p=0.01) and fludarabine-sensitive disease at UCBT (70% vs 21%, p<0,001) were associated with increased OS (table 2). The use of low dose TBI (49% vs 14%, p= 0,02), <2 different CTL
prior UCBT (66% vs 37%, p=0.04), fludarabine-sensitivity disease at UCBT (53% vs 21%, p= 0,001) and HCT-CI <2 (51% vs 25%, p=0,04) were associated with improved PFS (figure 3). Patients with fludarabine resistant disease at UCBT had frequently >3 different CTL and advanced stage disease prior UCBT. Thus, these three variables were intrinsically linked in this study. The collinearity was assessed through Fisher's exact test that demonstrated the association between fludarabine sensitivity with prior number of lines of chemotherapy (p=0.019) and disease status at transplantation (p=0.044).
Overall 38 patients died or relapsed. In a multivariate model for PFS the use of low dose TBI (HR : 4,16 (1,33-12,5); p=0,014), HCT-CI score < 2 (HR : 2,29 (1,05,2), p=0,05) and fludarabine sensitive disease at UCBT (HR: 3,07 (1,51-6,25); p=0,002) were associated with improved PFS (table 3).
Concerning the 4 patients diagnosed with Richter's syndrome, 3 patients died (2 of NRM causes and 1 of relapse after 8 months of transplantation and treatment rescue with chlorambucil was initiated but eventually disease progressed and the patient died 18 months after UCBT). Only one patient is alive after 27 months of follow up, without evidence of disease and with full donor chimerism. From the 8 PLL patients, 4 are alive (3 without relapse and with full donor chimerism, with a median follow up of 13 months after transplantation; 1 patient had autologous reconstitution and relapsed one year after transplantation, no further treatment was offered). Four patients died (3 of NRM and 1 relapsed within 16 months of a second stem cell transplantation) , with a median time to death was 3.8 months after UCBT.
Discussion:
This paper aimed to analyze the impact of UCBT in CLL/SLL patients. Since the validation of dUCBT in 2005 by the Minnesota group, UCBT has been extended as an alternative stem cells source to different malignant and non-malignant disorders in patients lacking suitable HLA donors12'16,22,23,24. Approximately 15-20% of patients lack HLA-identical siblings or HLA compatible unrelated donors25 and only a handful of cases evaluating alternative stem cell transplantation in CLL/SLL have been published so far. Bashey et al reported 7 CLL/SLL patients who underwent haploidentical transplant with 2-year OS ranging from 44-55%26. Dodero et al also reported 5 cases of CLL/SLL receiving T cell depleted haploidentical transplantation27. Rodrigues et al
reported 14 CLL/SLL cases transplanted using UCBT with encouraging results even for patients not in complete remission28. More recently, the Eurocord-EBMT group reported comparable outcomes of UCBT and matched unrelated donors for mature lymphoid malignancies including 22 CLL/SLL patients29 and the Chinese group reported outcomes of a large group of patients that underwent haploidentical T-cell replete transplantation30. Despite the increasing number of publications over the last years, stem cell transplantation using alternative donors such as UCBT in CLL/SLL is scarce in the literature.
This is the first study to date to directly evaluate outcomes and risk factors of UCBT for CLL/SLL. As expected in our study, most patients were transplanted with dUCBT and historically in adults it has been associated with higher PFS compared to sUCBT, but recent data have suggested similar outcomes if a reasonable number of nucleated cells (>2,5x108 TNC/kg) would have been used in sUCBT31,32. In our study the majority of recipients received adequate cell dose (>2.5) and we could not find outcome differences mainly due to the low number of patients receiving sUCBT.
Due to small sample sized study univariate analysis was used to identify risk factors associated with engraftment, GVHD, NRM, RI and OS. Although we expected lower engraftment rates in patients with advanced disease and consequently extensive marrow infiltration, rates of engraftment did not changed based on disease status or conditioning regimen and engraftment rate in CLL/SLL was as previously reported for other hematological malignancies16,33,34. Of the 11 patients who did not engraft, only 2 patients had available HLA antibodies analysis, which were both negative. Since the first publication of the impact of donor specific antibodies (DSA) in UCBT in 2010 other publications have addressed the role of DSA in UCBT35,36,37. Most transplant centers are performing anti-HLA antibodies before selecting the cord blood units, but this became a common practice specially after 2010, and in our series most patients received UCBT prior 2010 (48 patients). Unfortunately, we did not have data on the presence of anti HLA antibodies to be able to understand the incidence of graft failure in this series. The use of low dose TBI did not influence engraftment. Improved engraftment was observed in patients who had undergone previous ASCT, probably, because of higher degree of immune suppression prior allogeneic transplantation. This observation has been previously reported in UCBT38. Most
of ASCT were performed prior 2009, when data on prospective studies analyzing the impact of ASCT in overall survival were not yet available. Regarding acute and chronic GVHD, the incidence were quite high when compared to other hematological ma-lignancies28,33,39 which could be explained by the infrequent use of ATG, common use of double UCBT and high-risk disease status at transplantatio40,41,42.
Used as alternative stem cell source UCB has been indicated to patients usually in a very advanced/refractory stage of disease. In our study approximately 2/3 of our patients were transplanted for poor-risk disease (del 17p/p53mutation, fludara-bine refractory disease or diagnosis of PLL or RS) and higher tumor burden prior to RIC-UCBT has been associated with worst outcomes43. Importantly, the median age of our patients was 57 years, most of patients received three or more chemotherapy regimens prior transplantation and 15% of patients had HCT-CI >3 reflecting this poor-risk population and the burden of comorbidities, in which could in part explain the NRM reported. Higher comorbidity scores and type of conditioning regimen has long been associated with increased NRM and reduced PFS in CLL15,44. MAC has been associated with increased NRM when compared to RIC transplants14,45. Despite analyzing only patients undergoing RIC, an unexpectedly high-rate of NRM was observed (39%). This could be also due to delayed engraftment and immune reconstitution and a higher risk of infection associated with UCBT43,46,48,49.
We found three factors associated with improved PFS in multivariate analysis: the use of low-dose TBI, lower HCT-CI scores and fludarabine sensitive disease at UCBT. Patients who received low dose TBI had better PFS compared to patients who did not receive radiation and this was previously noticed by an analysis of the EBMT group28. Although, there has never been a prospective randomized comparison between TBI vs non-TBI regimens in the RIC setting, excellent long term outcomes have been reported in patients who underwent a reduced intensity TBI-based regimen in matched related donor (MRD) or matched unrelated donor (MUD) transplantation12,50. Low-dose TBI and low HCT-CI scores were associated with superior PFS due to lower NRM, these variables did not influence relapse. On the other hand, fludarabine sensitive disease was associated with lower NRM and lower relapse incidence.
Purine analogue resistant disease had poor PFS (refractory CLL/SLL had a 3-year PFS of 21%) mainly due to higher number of chemotherapy lines and more advanced disease at UCBT which could explain the higher associated NRM in this group of patients. Moreover, bacterial infections were the main cause of NRM and strategies to prevent it should be investigated in future studies on RIC-UCBT in CLL/SLL. Improvement in supportive therapy and infectious prophylaxis are currently ongoing for those patients highly immunosuppressed51. Due to delayed engraftment and higher risk of graft failure in UCBT, strategies to improve engraftment are in the spotlight of many clinical trials. Ex-vivo expansion of the cord blood unit is becoming an interesting field of research in different countries mainly in the USA. Different techniques of ex-vivo expansion (Notch, CXCR4 cell pathway or cytokines stimulations) are under research, but no preferable technique has come forth as standard one52,53. With earlier engraftment and higher engraftment rates the incidence of bacterial and fungal infections are rationally decreased.
Fludarabine refractory disease was also associated with higher incidence of relapse. Being NRM a competitive risk for disease relapse and knowing that NRM was high in patients with fludarabine refractory disease the actual relapse rate in this group of patients is indeed underestimated (maybe fludarabine refractory disease patients who died of early NRM would have experienced relapse if alive). Despite the poor-risk patient population in this study relapse incidence was relatively low which could be due to GVL effect that have can be active even in high-risk cytogenetic categories54,58. Analyzing only patients with available cytogenetics, no relapse outcome differences were observed from del17p and non 17p patients. This observation has been previously reported, thus reinforcing the GVL effect even in high-risk cytogenetic patients54. The role of minimal residual disease (MRD) prior transplantation in the setting of allo-HSCT for CLL has yet to be clearly defined. Different monitoring techniques and threshold turns difficult multi-centered studies and no cut-off values have been accepted worldwide55. Few studies have addressed the role of MRD prior transplantation in CLL and these studies are limited with small sample sized cohorts56. Instead of looking at MRD, a post transplant tool that is associated with relapse is the chimerism status post transplantation and can influence post transplant MRD once rapid T-cell engraftment is associated with lower MRD and relapse rate57.
In our study, the cumulative incidence of relapse in patients who achieved full donor chimerism before day 100 post UCBT was only 5% whereas in patients with mixed chimerism before day 100, the incidence of relapse was 36%. The immunologic reaction of the graft against the leukemic cells has been reported to decrease incidence of relapse59,60,61. Even with the impossibility to perform DLI after UCBT, several studies reported a strong GVL effect using UCBT without an increased incidence of chronic GVHD62,63. Another risk factor that has an impact in the relapse rate in CLL is the presence of bulky disease prior transplantation58,67. Unfortunately, the characteristics of size masses were not reported by the participating centers, therefore we could not assess the impact of bulky disease in this study.
Different strategies to overcome the poor prognosis of refractory CLL have been tried and with the advent of new therapeutic options (bcl-2 antagonists, bru-ton's kinase inhibitors, new monoclonal antibodies) that are effective and with lower toxicity even in chemo-resistant CLL/SLL, selection of patients for allo-HSCT is becoming more difficult due to high NRM even in RIC setting2,11,64,65. However, longer follow-up is needed to evaluate long term outcomes of these drugs and resistance to Bruton's kinase inhibitors has already been reported66. Still, better long-term disease-control post allo-HSCT may lead to better overall results in the long-term perspective. Although no potential cure has been described with novel therapy tools, pre-transplant cytoreduction could have an impact on post transplant outcomes and maintenance strategies after transplantation could be of a great value in reducing relapse rate, at least until GVL effect exerts its immunologic reaction on leukemic cells.
One could argue that our series of patients is biased once many studies have described a higher frequency of fludarabine refractory disease prior HSCT (this is one of the main indications for allogeneic stem cell transplantation in CLL)8. In fact in our series only 19 patients had fludarabine refractory disease but of the 48 patients without fludarabine resistant disease 3 had diagnosis of Richter transformation, 8 prolymphocytic leukemia, 12 had del 17 p and 3 del 11 q that are high risk features of disease.
Although there are intrinsic limitations of interpreting the results of a small sample sized study, this retrospective multi-center analysis shows favorable PFS in
this poor-risk CLL/SLL population. Overall, outcomes after UCBT seems to approach those of identical HLA-matched transplants14,15,67,68. Despite the low number of patients, the good results support the use of low-dose TBI (mainly CYFLUTBI) as a RIC regimen in UCBT. This approach has previously been associated with good outcomes69,70. In conclusion, RIC-UCBT using low dose TBI appears to be a valid option of allo-HSCT for CLL/SLL patients lacking a HLA matched donor. Strategies to enhance engraftment, optimization of infection prophylaxis and trials comparing different conditioning approaches are need to improve future outcomes.
Acknowledgements:
The authors thank the following physicians for contributing to this study: Anne Cor-by, Angers University Hospital, Angers, France; Anna Huynh, Purpan Hospital, Toulouse, France; Marta Sonia Gonzalez Perez, Hospital Clinico Universitario, Santiago de Compostela, Spain; Jan Yves Cahn A. Michallon Hospital, Grenoble, France; Mohamad Mohty, Saint-Antoine Hospital, Paris, France; Mauricette Michallet, Edouard Her-riot Hospital, Lyon, France; Jean Henri Bourhis, Institut Gustave Roussy, Villejuif, France; Thierry de Revel, Percy Hospital, Clamart, France; Christian Berthou, Morvan Hospital, Brest, France; Patrice Ceballos, Lapeyronie Hospital, Montpellier, France; Pascale Turlure, CHU Dupuytren, Limoges, France; Irene Donnini, Ospedale di Ca-reggi, Firenze, Italy; Simona Sica, Universita Cattolica S. Cuore, Rome, Italy.
We also thank all European Group for Blood and Marrow Transplantation (EBMT) centers and national registries for contributing patients to the study and data managers for their work. A special thanks to Chantal Kenzey and Fernanda Volt for helping in the development of this paper.
Financial Disclosures: The Authors have no financial disclosures to declare. Conflict of Interest:
The Authors have no conflict of interest to declare
Authorship statement: V.R. and A.R. designed the study. E.X. and J.C. collected data. E.X. and A.R. performed statistical analysis. E.X, V.R., A.R., E.G., M.V.G., J.S. and N.
K. wrote the article. P.C., J.J.C., N.S.A., N.M., S.N., D.B., E.D., H.V, N.M. and R.P.L. contributed to patients. All authors edited and approved manuscript.
Tablel: Patients and Transplant Characteristics
Median age, yrs 57 (27-68)
Diagnosis
CLL/SLL 56 (82%)
PLL 8 (12%)
RS 4 (6%)
Male 50 (74%)
Female 18 (26%)
Median year of UCBT 2009 (2004-2012)
Median time from diagnosis to UCBT 58 Months (3-360)
Binet staging at diagnosis (available for n=54)
Stage A ^ 18
Stage B 28
Stage C 09
Cytogenetics
Normal 13
Abnormal 35
Del17p/p53 mutation 17
Del 13q 8
Del11q 4
Trisomy 12 2
Complex 2
Others 2
Failed/ Not done 20
Previous auto-SCT
No 57 (84%)
Yes 11 (16%)
Single UCBT 16 (18%)
Double UCBT 52 (82%)
Conditioning Regimen
Cy-Flu-TBI (2-4 Gy) 57 (84%)
Flu-TBI (2-4Gy) 3 (4%)
Cy-Flu 2 (3%)
Cy-Flu-Thio 1 (2%)
Cy-Bu-Flu 2 (3%)
Bu-Flu-Thio 3 (4%)
GVHD Prophylaxis
CsA+MMF 61 (89%)
CsA+Prednisone 5 (7%)
CsA+MMF+MTX 1 (2%)
Tacro+MMF 1 (2%)
ATG No Yes 53 (78%) 15 (22%)
HLA compatibility (available for n=64) 0-1 HLA Mismatch >2 HLA Mismatches 19 (30%) 45 (70%)
Fludarabine refractoriness (available for n=67) Fludarabine refractory disease Fludarabine sensitive disease 19 (28%) 48 (72%)
HCT-CI (available for n=66) 0-2 (56) >2 (10)
Median TNC collected (available for n=64)
Single UCBT Double UCBT 3.70 x108 TNC/kg 5.04 x108 TNC/kg
Number of previous chemotherapy line (available for n=65) 1-2 previous lines of chemotherapy > 3 previous lines of chemotherapy 23 (35%) 42 (65%)
Disease status at transplant First CR Second CR Third or higher CR Partial remission Refractory/Resistant 17 (25%) 4 (6%) 2 (3%) 37 (54%) 8 (12%)
Abbreviations: UCBT, umbilical cord blood transplantation; Cy, cyclophosphamide; Flu, fludarabine; TBI, total body irradiation; Thio, thiotepa; Bu, busulfan; CsA, cyclosporine; MMF, mycophenolate mofetil; Tacro, tacrolimus; MTX, methotrexate; HCT-CI, hematopoietic cell transplantation comorbidity index; CR, complete remission;
Table 2: Table of outcomes in univariate analysis:
Variables % p value
Neutrophil Engraftment at 60 days
sUCBT vs dUCBT 84% vs 86% p=0.71
TNC<4.7 vs TNC>4.7 84% vs 78% p=0.55
HLA MM>2 vs HLA MM<2 82% vs 86% p=0.17
Low dose TBI vs no TBI 84% vs 83% p=0.11
Previous ASCT vs no ASCT 100% vs 82% p=0.03
Grade II-IV acute GVHD at 100 days
HLA MM>2 vs HLA MM<2 47% vs 35% p=0.47
sUCBT vs dUCBT 44% vs 38% p=0.43
TNC<4.7 vs TNC>4.7 34% vs 48% p=0.22
CR vs not in CR 24% vs 49% p=0.08
Use of ATG vs no ATG 14% vs 45% p=0.02
Chronic GVHD at 3 yrs
HLA MM>2 vs HLA MM<2 24% vs 37% p=0.74
CR vs not in CR 37% vs 33% p=0.68
sUCBT vs dUCBT 41% vs 32% p=0.45
Use of ATG vs no ATG 24% vs 41% p=0.30
TNC<4.7 vs TNC>4.7 37% vs 27% p=0.24
CMV positive vs CMV negative serostatus 50% vs 22% p=0.05
NRM at 3 yrs
TNC<4.7 vs TNC>4.7 34% vs 49% p=0.19
sUCBT vs dUCBT 46% vs 38% p=0.21
HCT-CI< 2 vs HCT-CI >2 36% vs 57% p=0.07
Age<57 yrs vs age>57 yrs 26% vs 52% p=0.07
CMV positive vs CMV negative serostatus 46% vs 27% p=0.09
Number CT lines prior UCBT<2 vs CT lines>2 18% vs 49% p=0.02
Fludarabine sensitive vs fludarabine refractory disease 30% vs 61% p=0.009
Low dose TBI vs no TBI 34% vs 62% p<0.001
Relapse Incidence at 3 yrs
sUCBT vs dUCBT 9% vs 14% p=0.24
CMV positive vs CMV negative serostatus 14% vs 13% p=0.51
CR vs not in CR 17% vs 11% p=0.23
Use of ATG vs no ATG 24% vs 10% p=0.18
TNC<4.7 vs TNC>4.7 14% vs 13% p=0.4
HLA MM>2 vs HLA MM<2 9% vs 16% p=0.9
Number CT lines prior UCBT<2 vs CT lines>2 15% vs 30% p=0.7
Fludarabine sensitive vs fludarabine refractory disease 13% vs 45% p=0.04
OS at 3 yrs
Age<57 yrs vs age>57 yrs 64% vs 42% p=0.07
sUCBT vs dUCBT 43% vs 55% p=0.22
HLA MM>2 vs HLA MM<2 58% vs 42% p=0.13
HCT-CI< 2 vs HCT-CI >2 58% vs 36% p=0.07
CMV positive vs CMV negative serostatus 45% vs 70% p=0.03
Number CT lines prior UCBT<2 vs CT lines>2 59% vs 18% ^^ p=0.01
Low dose TBI vs no TBI 58% vs 35% p<0.001
Fludarabine sensitive vs fludarabine refractory disease 70% vs 21% p<0.001
Abbreviations: TNC, total nucleated cells; ASCT, means autologous stem cell transplantation; NRM, non-relapse mortality; TBI, total body irradiation; GVHD, graft versus host disease; OS, overall survival; sUCBT and dUCBT, single and double umbilical cord blood transplantation; TNC, total nucleated cells; HLA MM, HLA mismatch; CT, chemotherapy; CMV, cytomegalovirus; HCT-CI, hematopoietic cell transplantation comorbidity index;
Table 3: Univariate and multivariate analysis for PFS at 3 yrs
Variable Univariate analysis Multivariate Analysis
HCT-CI < 2 vs HCT-CI>2 51% vs 25%, p=0.04 HR: 0.45 (0.20-1.00, p=0.05)
Low dose TBI vs No TBI 49% vs 14%, p=0.02 HR: 0.25 (0.08-0.78, p=0.017)
Fludarabine sensitive disease vs fludarabine refractory disease 57% vs 21%, p=0.001 HR: 0.32 (0.16-0.66, p=0.002)
Age<57 yrs vs Age>57 yrs 54% vs 34%, p=0.17 HR: 0.68 (0.35-1.33, p=0.26)
Abbreviations: HR, hazard ratio; TBI, total body irradiation; PFS, progression-free survival; HCT-CI: Hematopoietic cell transplantation comorbidity index;
Figure 1 - A- NRM according to fludarabine sensitivity (straight line represents fludarabine refractory CLL/SLL and dotted line fludarabine sensitive CLL/SLL); B- NRM according to the number of previous lines of chemotherapy (straight line represents patients that received>3 lines of chemotherapy and dotted <2 lines of chemotherapy prior UCBT).
Figure 2 - PFS according to del17p/p53mutations status
Not dell7p/p53mutations
....................L
Dell7p/p53niutations
Months
Figure 3 - A: Overall PFS from the entire cohort of patients; B: PFS according to fludara-bine sensitivity.
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Highlights:
• This is the first study directly addressing the role of UCBT specifically for CLL/SLL
• Umbilical cord blood transplantation seems feasible for poor-risk CLL/SLL patients
• Better outcomes in patients with fludarabine sensitive disease and low dose TBI conditioning
