The aim of this retrospective study was to investigate the safety and efficacy of allogeneic hematopoietic cell transplantation (alloHCT) in patients pre-treated with ibrutinib. Eligible were patients aged >18 years allotransplanted for chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) after prior exposure to ibrutinib who were registered with the EBMT registry. Seventy patients (CLL 48, MCL 22) were included. At the time of alloHCT, 73% of the patients were ibrutinib responsive. All patients except one engrafted, and acute GVHD grade 2–4 (3–4) was observed in 49% (12%) of 68 evaluable patients. The cumulative incidence of chronic GVHD was 54% 1 year after transplant. In the CLL group, 12-month non-relapse mortality, relapse incidence (RI), progression-free survival (PFS), and overall survival (OS) were 10, 30, 60, and 72%, respectively, and in the MCL group 5, 19, 76, and 86%, respectively. Pre-transplant ibrutinib failure and poor performance status predicted inferior RI, PFS and OS in the CLL group. In conclusion, ibrutinib does not affect the safety of a subsequent alloHCT. While the relatively high post-transplant relapse risk in ibrutinib-exposed patients with CLL deserves further study, in patients with MCL consolidating disease responses to ibrutinib with alloHCT seems to be a promising option.
Treatment options for patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) have substantially improved by the recent advent of novel drugs targeting molecular signaling pathways downstream the B cell receptor, or the BCL2-regulated intrinsic apoptotic pathway. Ibrutinib is an inhibitor of Bruton’s tyrosine kinase which was approved in 2013 and since then has rapidly become standard of care for relapsed or refractory (R/R) and high-risk CLL and R/R MCL [1,2,3,4,5,6,7]. However, ibrutinib is not a curative treatment in these indications, and patients with CLL or MCL who progress under ibrutinib still have a poor prognosis [3, 8,9,10], setting the stage for complementary therapies, such as cellular immunotherapy by allogeneic hematopoietic cell transplantation (alloHCT) and chimeric antigen receptor-engineered T cells (CARTs) [4, 7, 11, 12].
It is well acknowledged that alloHCT can provide durable disease clearance in a sizable proportion of patients with both R/R high-risk CLL and R/R MCL, mediated by graft-versus-leukemia (GVL) effects [11, 13,14,15,16,17]. Little is known, however, about the feasibility of alloHCT in patients with CLL/MCL who have been bridged to transplant with ibrutinib. Specifically, it is unknown if ibrutinib-induced remissions are stable enough to permit development of a sufficient GVL effect, i.e., if ibrutinib-sensitive CLL/MCL is as advantageous as chemoimmunotherapy (CIT)-sensitive disease in terms of long-term transplant outcome. It is also unclear if ibrutinib exposure does affect the safety of a subsequent alloHCT, and what the best strategy of pretransplant and peritransplant ibrutinib administration might be. Here, we present a retrospective study by the European Society for Blood and Marrow Transplantation (EBMT) addressing these questions. The results suggest that bridging with ibrutinib does not adversely affect engraftment, graft-versus-host disease (GVHD) risk, and non-relapse mortality (NRM) after alloHCT. While disease control after alloHCT with ibrutinib bridging appears to be excellent in MCL, a relatively high frequency of early relapses was observed in patients with CLL pre-exposed to ibrutinib, in particular if response to ibrutinib had been lost prior to transplant.
Patients and methods
EBMT is a voluntary organization comprising more than 600 transplant centers mainly from Europe. Accreditation as a member center requires submission of minimal essential data (MED-A form) from all consecutive patients to a central registry in which patients may be identified by the diagnosis of underlying disease and type of transplantation. Informed consent for transplantation and data collection was obtained locally according to regulations applicable at the time of transplantation. Since 1 January 2003, all transplant centers have been required to obtain written informed consent prior to data registration with the EBMT following the Helsinki Declaration 1975.
This was a registry-based retrospective multicenter study including patients 18 years or above who underwent a first alloHCT for CLL or lymphoma between 2013 and 2016, and had been treated with ibrutinib at any time before transplant (EBMT study code LWP 2013-N-03/CMWP 44204425). Since specific drug exposure is not routinely reported on the MED-A form, a survey was sent to all EBMT centers performing allotransplants in order to identify eligible patients. Baseline patient, disease, and transplant data of consecutive patients who were indicated by participating centers as meeting the eligibility criteria for this study were collected from MED-A forms. Centers were contacted to provide additional data, including pre-transplant treatment details and updated follow-up information. This analysis is restricted to patients with CLL (including transformed CLL and B-prolymphocytic leukemia) and MCL. The institutional review boards of the EBMT Lymphoma and Chronic Malignancies Working Parties approved the study.
For the purpose of this analysis, stable disease and progressive disease were grouped together as chemorefractory disease. Complete response and partial response were categorized as chemosensitive disease. Ibrutinib failure was defined as documented non-response or progression under ibrutinib, or ibrutinib discontinuation with subsequent re-treatment with alternative agents for any reason. Conditioning intensity assignment was done centrally on the basis of the individual drug and irradiation doses administered according to the Working Group definitions .
Primary endpoint was NRM at 12 months post transplant, defined as time from alloHCT to death in the absence of prior relapse or progression. Secondary endpoints comprised overall survival (OS), progression-free survival (PFS), GVHD-free and relapse-free survival (GRFS), incidence of disease relapse or progression (RI), incidences of acute and chronic GVHD, and engraftment. OS was defined as the time from alloHCT to death from any cause, and PFS as the time from alloHCT to CLL/MCL relapse or progression or death from any cause, whatever came first. GRFS was defined as time from alloHCT to grade 3-4 acute GVHD, extensive chronic GVHD, relapse/progression, or death from any cause . RI was defined as time from alloHCT to relapse or progression. Probabilities of OS and PFS were calculated using the Kaplan–Meier estimate and compared using the log-rank test. Exploratory multivariate comparisons of survival times and estimations of hazard ratios were calculated using Cox regression models using ibrutinib failure, disease status, and performance status as covariates. Relapse and NRM events were considered as competing risks. For cumulative incidence of chronic GVHD, death from any cause was considered as a competing risk. Cumulative incidence curves for RI were compared using the Gray’s test. Exploratory multivariate analyses for relapse incidences were performed using a competing risk proportional subdistribution hazards regression model using the same covariates as in the Cox models. Calculations were performed using R version 3.3.2 (R Foundation for Statistical Computing, Vienna, Austria) and GraphPad Prism software (release 5.0; San Diego, CA, USA). All statistical tests were two-sided with significance levels set at 0.05. Data were analyzed as of 30 June 2017.
Role of the funding source
There was no external funding source for this study. All authors had access to the raw data. The corresponding author had full access to all of the data in the study and had final responsibility for the decision to submit for publication.
Patients and procedures
Altogether, 70 patients were identified who met the eligibility criteria for this analysis and had follow-up information available. Diagnosis at alloHCT was untransformed CLL in 41 patients, B-PLL in one patient, Richter transformation (RT) in 6 patients, and MCL in 22 patients. Of 39 patients with untransformed CLL and information available, 72% met the criteria for poor-risk CLL as defined in the 2014 EBMT/ERIC position paper  (pathway inhibitor failure 26%, R/R CLL with TP53 lesion and/or del 11q 46%) at alloHCT. Patients with CLL/B-PLL had received a median of 2 (range 1–9) treatment lines prior to ibrutinib including idelalisib in one patient. They had been on ibrutinib for a median of 231 (range 39–671) days. In 27 patients (56%), ibrutinib was continued until conditioning or until the day of alloHCT, whereas it was stopped earlier in the remainder. Best response to ibrutinib was reported as CR in 6%, PR in 85%, SD in 8%, and progression in 2% of the patients. Ibrutinib exposure times for patients with best response SD and were 230d (65–413). Thirty-five patients (73%) were still responsive at the time of ibrutinib discontinuation, while 11 patients (23%) had either lost their response or never responded to ibrutinib. In the two remaining patients, reason for discontinuation and disease status at discontinuation were unknown. Both were subsequently treated with idelalisib and proceeded to transplant in PR. In addition, three of the ibrutinib-resistant patients were put on a follow-up treatment with idelalisib but none responded. Since one of them achieved a CR with CIT, overall disease status at alloHCT was sensitive in 38 patients (79%) and refractory in 10 patients (21%) with CLL.
Patients with MCL had received a median of 1.5 treatment lines (range 1–4) including autoHCT in 19/22 patients (86%) prior to ibrutinib. With 149 days (range 59–271), ibrutinib exposure had been significantly shorter than in the CLL group (P = 0.03, Mann–Whitney test). Similar to the CLL cohort, ibrutinib had been stopped within 14 days prior to transplant in about half of the patients. Best response to ibrutinib was CR in 45%, PR in 41%, SD in 9%, and progression in 5% of the patients. Ibrutinib exposure duration was 81 and 123d, respectively, for the two SD patients. Four patients did no longer respond to ibrutinib at drug discontinuation, but two of them could be rescued by CIT and bortezomib-based therapy, respectively, so overall the disease status was sensitive in sensitive in 17 patients (77%), refractory in 2 patients (9%), and unknown in 3 patients (14%) with MCL.
In both entities, donors were matched related or unrelated in the vast majority of patients, with peripheral blood being the predominant stem cell source. Details on patient and transplant characteristics are given in Tables 1 and 2.
Engraftment, GVHD, and NRM
Among all 70 patients, there was one primary engraftment failure (in the cord blood recipient). All other patients engrafted with a median time to reach neutrophils of >0.5/nl and platelets of >20/nl of 16 (9–68) and 13 (5–36) days post transplant, respectively. Time to engraftment was not significantly different between patients who had withdrawn ibrutinib within 14 days prior to transplant and those who stopped ibrutinib earlier (neutrophils > 0.5/nl 17 (9–16) days vs. 16 (10–68) days, P = 0.57; platelets > 20/nl 14 (6–36) days vs. 13 (5–22) days, P = 0.56).
Acute GVHD grade 2–4 (3–4) was observed in 49% (12%) of 68 evaluable patients, and the cumulative incidence of overall and extensive chronic GVHD was 54% (95%CI 38–66%) and 38% (95%CI 18–58%) 1 year after transplant in 53 and 52 evaluable patients at risk, respectively. The proportion of patients developing acute and/or chronic GVHD was not significantly different between patients who had withdrawn ibrutinib within 14 days prior to transplant and those who stopped ibrutinib earlier (grade 2–4 acute GVHD 42 vs. 53%, P = 0.46; chronic GVHD 45% vs. 58%, P = 0.33). In 6 of the 26 patients (23%) with chronic GVHD, complete resolution of GVHD symptoms was reported during follow-up. Five patients died of non-relapse-related causes (GVHD 2, infection 2, secondary malignancy 1), resulting in a 1-year NRM of 10% (95% CI 0–43%) and 5% (95%CI 0–66%) for the CLL and MCL groups, respectively (Fig. 1a).
Relapse and survival
In the CLL cohort, 16 patients had relapse/progression at a median of 3.7 (1–14.5) months post alloHCT. Four of these were re-treated with ibrutinib with or without DLI, but none responded though two of them had been still responsive to ibrutinib at the time of transplant. One of these patients subsequently received idelalisib and venetoclax without success, and finally died of RT after a second alloHCT. Two additional patients were treated with idelalisib with one durable response (in CR at the last follow-up 8 months after relapse). Specific retreatment information was not available for the remaining patients. Median OS after relapse was 124 days for the 10 patients progressing within 6 months post transplant but not reached for the 6 patients with longer progression-free interval (P = 0.112; Suppl. Figure).
With a median follow-up of survivors of 12 (2–36) months, RI, PFS, GRFS, and OS at 1 year after alloHCT in the CLL group were 30% (95%CI 12–48%), 60% (95%CI 43–73%), 31% (95%CI 18–46%), and 72% (95%CI 58–88%) (Fig. 1b–d). By univariate and exploratory multivariate comparisons, prior ibrutinib failure and poor performance status were risk factors for unfavorable RI, PFS, and OS (Table 3, Fig. 2, Suppl. Table). In addition, a longer time from diagnosis to alloHCT was associated with a significant OS disadvantage (HR 0.31 (0.11–0.89); P = 0.029). In contrast, age, gender, TP53 status, pretreatment prior to ibrutinib, time interval between ibrutinib discontinuation and transplant, disease status at alloHCT, Richter transformation, center experience, TCD, conditioning intensity, and donor source had no significant impact on any endpoint. The median duration of ibrutinib exposure had been 8 months (231 days). Although the proportion of patients with ibrutinib failure was not significantly different between those patients who had been on ibrutinib for 8 months or longer vs those with shorter exposition (30 vs. 25%, P = 0.75), significantly fewer post HCT relapses occurred in the group with longer exposure if only patients still responding at the time of transplant were considered (7 vs 39%, P = 0.043).
Of the 22 patients with MCL, 4 had disease recurrence 1–7 months post transplant, translating into 12-month RI, PFS, GRFS, and OS of 19% (95%CI 1–53%), 76% (95%CI 52–85%), 62% (95%CI 38–79%), and 86% (95%CI 71–100%) after a median follow-up of survivors of 13 (2–29) months (Fig. 1b–d). Re-treatment information was available for three of them: one patient was not retreated and rapidly died, another one was re-exposed to ibrutinib with transient response but died of PD 8 months after relapse, and the third patient experienced MCL clearance after DLI. The low number of events precluded a comprehensive risk factor analysis in the MCL group, but notably PFS was significantly worse in patients who had failed ibrutinib compared to the remainder (Fig. 3).
Although patients with CLL or MCL discontinuing ibrutinib for undergoing alloHCT have been mentioned in many ibrutinib study reports, a systematic analysis of the safety and efficacy of alloHCT subsequent to ibrutinib treatment is missing. This is of particular concern since ibrutinib-induced responses may be less stable upon withholding the drug (in favor of transplant) compared to CIT-induced responses in both CLL and MCL [20, 21], and because ibrutinib has immune-modulating properties which might interfere with GVL and GVHD [22, 23]. The results presented here indicate that engraftment as well as acute and chronic GVHD did not show patterns inferior to those reported for ibrutinib-naive patients undergoing allotransplant [24, 25]. Most importantly, the incidence of NRM was remarkably low in the present study in both entities, suggesting that ibrutinib pre-exposure does not appear to be associated with increased safety risks in patients proceeding to alloHCT.
In contrast, with 30% at 1 year the cumulative incidence of early relapse events in the CLL group of the present analysis seems to be higher than the RI known from ibrutinib-naive CLL alloHCT series [26,27,28,29]. For instance, in the prospective CLL3X trial of German CLL Study Group the 12-month RI was 16% , and in a recent large registry study of the EBMT it was 14% (95%CI, 13–15%) . Even in the ibrutinib-sensitive patients of the present study the 24% 12-month RI appears unusually high. Although our series may represent a particularly high risk selection, another explanation for this discrepancy might be that the remissions induced by ibrutinib are not sustainable enough to control the disease until GVL effects become effective some months after transplant. The observation that early relapses were virtually absent in those patients who had been on ibrutinib for 8 months or longer prior to transplant (and thus might have experienced a more profound suppression of the leukemic clone) is in keeping with this hypothesis. Therefore this data supports earlier suggestions advocating that patients with R/R CLL should be on ibrutinib at least until maximum response before proceeding to alloHCT . Alternatively, response could be deepened by alternate inhibitors, such as venetoclax, but the interactions between BCL2 blockers and alloHCT are still unexplored. Another option for avoiding early relapse could be ibrutinib maintenance post-transplant, although interference with GVL effects could be of concern.
Alternatively or in addition, imminent RT escaping ibrutinib-mediated suppression of untransformed CLL clones could account for a part of the early relapse events. This hypothesis is not only consistent with the observation that the risk of early relapse is declining with increasing duration of pre-transplant ibrutinib exposure, but also supported by the very poor survival of the patients with early relapse (in contrast to that of patients with late relapse), and by the fact that ibrutinib retreatment was largely unsuccessful in patients with early disease recurrence. Unfortunately, information on the type of relapse (RT or untransformed CLL) as well as on retreatment details was largely unavailable, precluding more robust conclusions on this issue.
On the other hand, early relapse was a particular problem in those patients who underwent alloHCT with a history of prior ibrutinib failure, with less than 50% surviving progression-free the first year after transplant. Although it seems that effective alternative pathway inhibitors, such as venetoclax, have been rarely used in the patients developing ibrutinib resistance in the series investigated here, the present study does not support strategies of delaying intended transplants until loss of response to ibrutinib . Alternatively, CARTs might be an option for ibrutinib-resistant patients , but there is no CART construct approved for CLL available to date.
In contrast to the CLL group, in the MCL cohorts early relapse did not appear to be increased compared to recent single-center or registry studies on MCL allotransplants in ibrutinib-naive patients. This was particularly true for the 16 ibrutinib-sensitive patients of our series, where only a single relapse was observed. Along with the low NRM incidence this translated into 12-month PFS rates of more than 75% for the whole MCL sample and more than 90% for the ibrutinib-sensitive subset. Even if taking into account the still wide confidence interval, this compares favorably to ibrutinib-naive MCL allotransplants where the 12-month PFS largely did not exceed 60% [16, 17, 32]. Thus, ibrutinib bridging appears to be a promising approach for improving feasibility and efficacy of alloHCT in R/R MCL. Vice versa, alloHCT seems to be a worthwhile consolidation strategy in patients with R/R MCL responding to ibrutinib, given the 18–24 months median remission duration reported for ibrutinib monotherapy [6, 33], and the poor outlook of patients with MCL progression under ibrutinib .
As expected, GRFS was considerably lower than PFS in both CLL and MCL transplants. This may reflect the fact that chronic GVHD (which is the main driver of GRFS) is closely associated with GVL in particular in CLL [13, 34]. However, it has to be taken into account that chronic GVHD is characterized by a large variance in clinical appearance and severity, and can resolve or decrease over time. Therefore the clinical impact of chronic GVHD events may be weighed differently than relapse and NRM events, especially in potentially fatal but GVL-sensitive entities.
Apart from the typical caveats of a registry study, limitations of the present analysis consist in the sample size and the relatively short follow-up. However, the observation time of 12 months is clearly sufficient to allow valid conclusions on the absence of an increased NRM risk after ibrutinib exposure, and also to draw attention to the possibility of an increased relapse risk in particular in patients with CLL who have failed ibrutinib. Moreover, it is the first study that provides a structured outcome analysis of patients undergoing alloHCT for CLL and MCL in the ibrutinib era, and of the concept of consolidating ibrutinib-induced responses with alloHCT. Although the outcome at least of our MCL group seems promising given the limited durability of ibrutinib-induced responses in R/R MCL [6, 33], the aim of the present study was not to weigh the two treatment options (staying on ibrutinib vs. switching to alloHCT) against each other. Instead we wanted to aid decision making by providing information about the risks, benefits, practical execution, and timing of moving from ibrutinib to alloHCT once this step is considered.
In conclusion, ibrutinib does not appear to affect the safety of a subsequent alloHCT. However, an increased early relapse rate compared to ibrutinib-naive settings can be observed in both ibrutinib-sensitive and ibrutinib-resistant patients with CLL after allotransplantation. While the latter require alternative bridging strategies, the relapse risk of ibrutinib-sensitive patients might be overcome by longer pre-transplant ibrutinib exposure or maintenance strategies. In contrast, disease control after alloHCT seems to be excellent in patients with ibrutinib-sensitive R/R MCL, suggesting that allotransplant consolidation may be a promising option for improving the poor outlook of this high-risk population.
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The authors acknowledge all collaborating EBMT Investigators and Institutions that contributed cases to this study.
PD and MM: designed and performed research, analyzed data, and wrote the paper; SD: performed research, analyzed data; AB: designed and performed research, analyzed data; PB, MS, AN, CS, JC, DN, LM, EV, IS, HS, NA, JF, DR, PL, JP, MvG, ND, HL-W, TB, GW, WB, DB, SS, MC, MS, and CPF performed research; NK, SM, and JS designed and performed research.
Conflict of interest
PD: Consultancy for AbbVie, Roche and Janssen; consultancy and speakers bureau for Gilead; speakers bureau for Kite Pharma. MM: Consultancy and Speakers bureau for Sanofi, MSD, Octapharma, Pfizer, MAATPharma, Novartis. CPF: Consultancy, speakers bureau and travel grants from Janssen. MvG: Consultancy for Gilead and Janssen; speakers bureau for Abbvie, Gilead, Janssen and Roche; Educational support from Gilead. TB: Consultancy for Riemser; travel grants from Astellas, Alexion, Celgene, Abbvie. SS: Consultancy, Speakers bureau, travel grants and research funding from AbbVie, Amgen, Celgene, Gilead, GSK, Roche, Janssen, Novartis, Pharmacyclics. SM: Speakers bureau for Roche; travel grant from Gilead. JS: Consultancy and Speakers bureau for AbbVie, Gilead, Janssen, Roche, Sanofi; research funding from Genzyme, Sanofi, GSK, Novartis, Abbvie. The remaining authors declare that they have no conflict of interest.
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Dreger, P., Michallet, M., Bosman, P. et al. Ibrutinib for bridging to allogeneic hematopoietic cell transplantation in patients with chronic lymphocytic leukemia or mantle cell lymphoma: a study by the EBMT Chronic Malignancies and Lymphoma Working Parties. Bone Marrow Transplant 54, 44–52 (2019). https://doi.org/10.1038/s41409-018-0207-4
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Annals of Hematology (2019)
Indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2019
Bone Marrow Transplantation (2019)