Postibrutinib outcomes in patients with mantle cell lymphoma

The United States Food and Drug Administration and the European Medicines Agency approved ibrutinib for treatment of patients with mantle cell lymphoma (MCL) who have received at least 1 prior therapy based on a phase 2 trial demonstrating a 68% response rate (RR) with a median progression-free survival (PFS) of 13.9 months.¹  Long-term follow up of these patients demonstrated that 31% remained free from progression and 47% were alive at 2 years.²  A second phase 2 trial (MCL 2001, SPARK) essentially confirmed these findings, reporting a median PFS of 10.5 months with an overall survival (OS) rate of 61% at 18 months.³  Despite this significant efficacy, primary resistance to ibrutinib appears to occur in one third of all patients and acquired resistance appears to be universal. Although mutations in the BTK binding site have been identified, the mechanisms of ibrutinib resistance remain unclear and are likely multiple.^4-6 

After several investigators from early trials noted the challenges associated with treating patients with ibrutinib-resistant MCL, an observation also reported in CLL,⁷  we performed a large, international, retrospective cohort study of all patients with MCL that experienced disease progression while receiving ibrutinib across 15 international sites. The aim of the study was to improve our understanding of patient outcomes and potentially to identify risk factors associated with survival.

After approval by institutional review boards, patients were identified by investigators at each site and were considered eligible if they had experienced disease progression while receiving ibrutinib, either in the context of a clinical trial (either PCYC-1104 or MCL 2001) or commercial supply. Research was conducted with informed consent, in accordance with the Declaration of Helsinki. Medical records were evaluated for clinical characteristics, pathologic and radiologic data, and therapies used pre- and postibrutinib. Morphologic and immunohistochemical data were reported by the investigator at each site based on interpretation of local pathology reports. The date for each assessment of morphology, Ki67, and karyotype was reported along with the number of intervening therapies between assessment and treatment (either ibrutinib or first postibrutinib therapy). No central pathology review was performed. Treatment was considered to have occurred if the patient received at least 1 dose of that drug. The investigator at each site reported response based on standard International Working Group Criteria; there was no central review. OS was defined as time from time zero (T0; eg, date of cessation of ibrutinib) until death from any cause or the last date the patient was known to be alive. PFS was defined as time from T0 until investigator-assessed progression, death from any cause, or the last date that the investigator was certain that progression had not yet occurred. Time-to-event statistics were estimated using the Kaplan-Meier method. Cox proportional hazard regression was used to calculate hazard ratios (HRs) and test statistical significance.

The primary objective was to describe the OS of patients with MCL after cessation of ibrutinib as a result of disease progression. The secondary objective was to determine the association between key clinical and treatment variables and OS.

A total of 114 patients—85 men and 29 women—treated at 15 different academic centers in the United States, the United Kingdom, Germany, and Poland met criteria for inclusion in this analysis. Ninety-five patients were treated with single-agent ibrutinib on a clinical trial and 19 patients were treated with commercially available ibrutinib.

The characteristics of all patients before the start of ibrutinib are described in Table 1. The median age at the start of ibrutinib was 68 years (range, 46-85). The median number of systemic therapies administered before ibrutinib was 3 (range, 0-10; induction plus consolidation/maintenance was counted as 1 regimen). The investigator-reported best RR to the last treatment before ibrutinib was 46.7%, including a 20.9% complete response (CR) rate. The average time from the last dose of the prior treatment to the start of ibrutinib was 2 months (range, 0-59). Of the 109 patients who had been adequately staged before the start of ibrutinib, all but 2 were stage 3 (n = 11) or 4 (n = 96). Eighteen patients had been noted to have blastoid morphology MCL at some point before ibrutinib, although 29 patients with nonblastoid morphology were not histologically re-evaluated between the last prior therapy and the start of ibrutinib. The median maximum lymph node size at the start of ibrutinib was 5 cm, and 12 patients had bulky disease ≥10 cm. The Mantle Cell Lymphoma International Prognostic Index (MIPI) score was low, intermediate, and high in 23%, 31%, and 46% of patients, respectively. Ki67 was evaluated in 18 patients immediately before the start of ibrutinib, with a median score of 30%. Among the 47 other patients with a reported Ki67 at any time in the past, 34 (72%) had a Ki67 >30%. Karyotype had been evaluated immediately before ibrutinib or was noted to be abnormal at some point in the past in 32 patients, 13 with a complex karyotype (≥3 abnormalities) and 4 with an abnormal but not complex karyotype.

The investigator-reported best RR to ibrutinib was 55% (43% partial response [PR], 12% CR), with 35% of patients having a best response of progressive disease. The overall median duration of ibrutinib was 4.7 months (range, 0.7-43.6, 95% confidence interval [CI], 3.8-5.7) and 8.6 months (95% CI, 7.4-12.1) among responders. All patients experienced progressive disease while taking ibrutinib, but 2 patients stopped ibrutinib because of toxicity and one stopped for reasons that were not reported.

BTK mutation status was assessed at relapse in 10 patients. In 2 patients who received ibrutinib for 12.1 months and 12.6 months, respectively, BTK was found to contain the C481S mutation. In 8 patients with wild-type postibrutinib BTK, the median duration of ibrutinib was 3.3 months; only one of these patients experienced a durable response of >1 year.

Patient characteristics and risk factors were available for 104 patients at the time of ibrutinib cessation. Of the 104 patients with available data, 31 (30%) received no additional systemic antilymphoma therapy after cessation of ibrutinib, whereas 73 patients (70%) received at least 1 additional course of treatment. In a univariate analysis of the MIPI score before ibrutinib, age at start of ibrutinib, performance status at start of ibrutinib, white blood cell count, and lactate dehydrogenase, the number of prior therapies, the response to ibrutinib, and the duration of ibrutinib, only age (HR, 0.94, 95% CI, 0.90-0.99, P = .0221) and prior MIPI scores (HR 0.32, 95% CI, 0.15-0.68, P = .0029) were associated with the use of postibrutinib therapy. The characteristics of the 73 patients who received subsequent treatment are described in Table 2. The median age at start of the first subsequent treatment was 67 years (range, 47-85). The median time from stopping ibrutinib to start of the first subsequent treatment was 0.3 months (range, 0-21.7, 95% CI, 0.2-0.5). All but 14 patients received subsequent treatment within 1 month, whereas 2 patients were observed for more than 1 year before receiving subsequent therapy. Both patients received lenalidomide and remained on treatment for 4.0 and 5.6 months, respectively. One patient was subsequently re-treated with ibrutinib and responded again. The MIPI score was low, intermediate, and high in 15%, 29%, and 56%, respectively. The median Ki67 in the 12 patients evaluated immediately before start of the first postibrutinib therapy was 80%. Among the 7 patients that had Ki67 measured immediately before ibrutinib and immediately before the first subsequent therapy, the percentage of positive cells increased from 10% to 20%, 90% to 95%, 40% to 50%, 80% to 95%, 30% to 80%, and 60% to 95% in 6 and remained stable at 40% in 1 patient. Karyotype was assessed immediately before the first subsequent treatment in 9 patients and was normal in 6 and complex in 3.

A total of 61 of 73 patients were evaluable for response. Local clinicians reported that 13 patients (19%) achieved PR, and 5 (7%) achieved CR. The median PFS after first subsequent treatment was 1.9 months (95% CI, 1.0-2.6).

Sixty-seven patients underwent a second postibrutinib therapy. The average time from first to second subsequent therapy was 2.4 months (95% CI, 1.4-3.3).

Survival data were available for all 114 subjects. The median OS from diagnosis was 54 months (95% CI, 43-70). At the time of analysis, 29 patients (25%) were still alive, whereas 85 (75%) had died. The causes of death were lymphoma (n = 79), treatment-related toxicity (n = 3), unrelated (n = 2), and not reported (n = 1). The median OS of all patients after cessation of ibrutinib was 2.9 months (95% CI, 1.6-4.9). The median OS of patients not receiving subsequent treatment after ibrutinib failure was 0.8 months (95% CI, 0.3-1.4; Figure 1). Among the patients who received postibrutinib therapy, the median OS from the start of the first subsequent treatment was 5.8 months (95% CI, 3.7-10.4; Figure 1). The median OS of the 12 patients who received bendamustine was 19.2 months (95% CI, 1.7 to not reached) compared with 5.7 months (95% CI, 3.1-7.5) in patients not receiving bendamustine (P = .230). The median OS of the 13 patients that received cytarabine was 3.7 months (95% CI, 0.8-12.0) compared with 6.1 months (95% CI, 4.2-10.4) in patients not receiving cytarabine (P = .435). The median OS of the 19 patients who received lenalidomide was 6.8 months (95% CI, 2.8 to not reached) compared with 5.7 months (95% CI, 2.7-10.4) in patients not receiving lenalidomide (P = .390). For patients who received subsequent treatment after ibrutinib failure, univariate Cox regression analysis of MIPI score before ibrutinib; MIPI score before first subsequent treatment; best response to ibrutinib; duration of ibrutinib; and subsequent treatment with bendamustine, cytarabine, and lenalidomide revealed that only MIPI score before ibrutinib (HR 1.81; 95% CI, 1.32-2.49; P = .0002) and duration of ibrutinib (HR, 0.96; 95% CI, 0.93-1.00; P = .0465) were associated with OS from time of stopping ibrutinib. Multivariate Cox regression analysis including MIPI score before first postibrutinib therapy and treatment with bendamustine, cytarabine, and lenalidomide revealed that there were no factors significantly associated with OS from the start of the postibrutinib therapy. Of 5 patients who underwent allogeneic stem cell transplantation as part of therapy immediately after ibrutinib failure, 4 died (3 from lymphoma and 1 from toxicity). Stem cell transplantation that occurred after second or later subsequent treatment was not reported.

The results of this large international observational study are consistent with a recent single-center study of MCL⁸  and multicenter study of CLL,⁷  and highlight the challenges that people with MCL and their treating physicians face on a daily basis. Although the RR and side-effect profile of ibrutinib are unprecedented in MCL, long-term remissions remain elusive, and the outcomes of patients that experience ibrutinib appears to be poor.

Unfortunately, these results are not surprising. The poor outcome of patients after more effective therapy is not new to lymphoma. After the introduction of rituximab to the standard cyclophosphamide, doxorubicin, vincristine, prednisone (known as “CHOP”) regimen in diffuse large B-cell lymphoma, it became clear that patients experiencing treatment failure had worse outcomes.⁹  The patients reported here had received a median of 3 prior therapies and the majority was refractory to the last therapy before ibrutinib. Many of these patients had likely already exhausted most standard therapies before receiving ibrutinib. In addition, the best RR to ibrutinib among these patients was only 55%, with a median duration of ibrutinib of only 4.7 months, suggesting that the group was enriched for a more treatment-resistant disease compared with published data that included ongoing responders. This is consistent with the relatively high proportion of patients with blastoid morphology and elevated Ki67 before the start of ibrutinib. Although one third of patients received no additional treatment after ibrutinib, only MIPI score before ibrutinib and advanced age were associated with no further therapy, suggesting that disease (eg, rapid progression) and patient-related factors (eg, comorbidities) trumped the availability of additional drugs in the decision to offer further treatment. Despite these factors, some patients had good outcomes after ibrutinib failure. Not surprisingly, the univariate analysis suggested that patients with less aggressive disease before ibrutinib and a longer duration of response to ibrutinib had better outcomes after ibrutinib failure. However, after ibrutinib failure, neither MIPI score nor choice of therapy stood out as predicting a superior outcome in multivariate analysis. It is unclear why MIPI score before the start of ibrutinib was more statistically significant than MIPI score after ibrutinib failure, but it may be a factor of limited patient numbers postibrutinib. Of note, the median OS from diagnosis of the entire cohort was only 54 months, suggesting that even in the ibrutinib and lenalidomide era, there remains considerable room for improvement.

An interesting question that arises from these data are how to optimally sequence therapy for people with MCL. It could be argued that it is reasonable to “save” ibrutinib for use in patients that are refractory to other standard therapies given the low probability of response to those treatments after ibrutinib failure. One hypothetical rationale for this approach is the concept that ibrutinib exposure favors growth of more resistant subclones. Although this may be a reasonable approach, caution should be used when interpreting the average survival of patients in this study. Because time on ibrutinib was associated with survival after ibrutinib failure, some patients may have a better outcome with postibrutinib treatment than the outcomes reported here. OS data from the international phase 3 trial of bendamustine-rituximab with or without ibrutinib as front-line therapy for MCL (NCT01776840) may shed some light on this concept.

A second issue that merits discussion is the development of postibrutinib therapies. Our data highlight the fact that existing therapies appear unlikely to overcome unfavorable tumor biology and that mechanism-based agents or combinations will be required. One challenge that will be faced by investigators evaluating treatments in the postibrutinib space is the rapid progression of disease after cessation of ibrutinib. The average time from stopping ibrutinib to starting subsequent treatment was only 0.3 months in our cohort, and several patients did not receive subsequent treatment at all, perhaps partly because of rapid disease progression. Traditional studies that require a 28-day washout period are likely to face poor accrual and will likely enroll only those rare patients with particularly indolent disease, therefore not reflecting a real-world population. Given the short half-life and limited toxicity of ibrutinib, investigators may consider allowing continuation of ibrutinib during the screening period and up until the start of the next experimental therapy. Although it has not yet been validated in the relapsed/refractory setting, given the impact of proliferation on prognosis and treatment, investigators should consider reporting the MIPI-c¹⁰  at the start of each therapy using Ki67 derived from an up-to-date tissue sample.

We found a C481S mutation in 2 of 10 patients assessed at 3 centers. The same mutation has been reported in chronic lymphocytic leukemia and MCL (1 patient from this series was included in an earlier publication).^2,11  These numbers are small but consistent with the hypothesis that BTK mutation as a mechanism of ibrutinib resistance in MCL is not common and that other mechanisms are likely more relevant. Activating mutations in PLCg2 have been reported in ibrutinib-resistant chronic lymphocytic leukemia but were not identified in 9 patients evaluated in this cohort. Interestingly, an activating mutation in CARD11 has been associated with resistance to ibrutinib in diffuse large B-cell lymphoma¹²  and has been reported in 1 patient with MCL and primary ibrutinib resistance.¹³  Larger cohorts will be required to identify new mechanisms of resistance and better estimate their prevalence.

In addition to the patient selection bias described before, our study is subject to similar biases faced by other retrospective studies. Some patient variables were not available or may not have been reported, in particular for patients receiving postibrutinib therapy at other centers. Despite the large sample size, there was limited statistical power to evaluate all possible predictors of survival such as preibrutinib therapies. It is possible that some postibrutinib therapies may be superior to others but our data do not currently support that hypothesis. Response assessments for patients not treated on clinical trials were estimated by the local clinician and may not be as accurate as time-based outcomes. Morphology and Ki67 can be challenging to interpret without central review. However, as reported with other therapies, it appears likely that the Ki67 is higher after ibrutinib failure than before the start of ibrutinib. Because Ki67 tends to rise over time,¹⁴  we considered valid those cases where Ki67 was reported immediately before the therapy in question. Similarly, morphology tends to become more aggressive over time, with evolution toward blastoid morphology. Therefore, patients with reported classic morphology were interpreted as being unknown if at least one course of treatment occurred between the assessment and the treatment in question.

In summary, our data suggest that people with MCL who experience ibrutinib failure have poor outcomes with limited therapeutic options. It is probably reasonable to conclude that patients with less aggressive disease are likely to do better after ibrutinib failure and that there is insufficient evidence to recommend 1 therapy over another at this time. For patients with highly treatment-resistant MCL, a very brief time on ibrutinib, and highly proliferative tumors, it may be reasonable to discuss the supportive/palliative care given the low probability of durable benefit and high probability of toxicity arising from aggressive treatment regimens. Similarly, patients with highly treatment-refractory MCL who achieve a good response to ibrutinib may be considered for allogeneic stem cell transplantation given the low probability of long-term survival after ibrutinib failure. There is an urgent need for clinical trials that incorporate translations research to better define resistance mechanisms with the aim of preventing ibrutinib failure and of developing new options in the postibrutinib setting.

Contribution: P.M., K.M., J.P.L., K.A.B., and Z.C. designed the research, performed the data analysis, and wrote the paper; and P.M., K.M., J.P.L., J.R., A.G., N.W.-J., S.R., R.A., D.I., T.P., S.S., E.K., K.N., W.J., R.A., E.C., S.S., J.B., C.P., M.E.W., M. Dreyling, P.M.B., S.C.-K., M. DiLiberto, R.R.F., and K.A.B. provided patient-level data and performed data analysis.

Conflict-of-interest disclosure: P.M. has been a consultant for Janssen, Acerta, Gilead, Celgene, Novartis, Bayer, and Genentech, and a speaker for Genentech and Janssen. J.P.L. has been a consultant for Pharmacyclics. J.R. has been a speaker for Pharmacyclics, Janssen, and Celgene, and has served on the Advisory Board for Celgene. A.G. has served on the Advisory Board for Pharmacyclics, Celgene, and Acerta, and has been a speaker for Pharmacyclics, Janssen, and Takeda. S.R. has been a consultant for Roche, Janssen, KiTE, Celgene, and Pharmacyclics. W.J. has received research funding from Janssen. C.P. has been a consultant for Abbvie. M.E.W. received research funding from Pharmacyclics and Janssen. M. Dreyling has served on the Advisory Board and been a speaker for Janssen. P.M.B. has been a consultant for Abbvie, and Pharmacyclics. R.R.F. has been a consultant for Pharmacyclics. K.A.B. received research funding from Janssen and Pharmacyclics.

Correspondence: Peter Martin, Weill Cornell Medical College, 525 East 68th St, New York, NY 10065; e-mail: pem9019@med.cornell.edu.