The covalent BTK inhibitors ibrutinib, acalabrutinib, and zanubrutinib are approved by the FDA for the treatment of patients with relapsed/refractory MCL. Among patients who develop disease progression after treatment with a covalent BTK inhibitor, outcomes are poor, with a reported median OS of less than 9 months.1,2 Mechanisms of resistance to covalent BTK inhibitors in patients with MCL are not fully understood. BTK C481 mutations are uncommon in MCL; bypass alterations and epigenetic changes may be alternative mechanisms of resistance.3
Pirtobrutinib is a novel, highly potent, selective, noncovalent BTK inhibitor that has high selectivity for BTK. In preclinical studies, pirtobrutinib demonstrated activity against wild-type and BTK C481–mutated cells. Because pirtobrutinib binds reversibly, its binding is not affected by BTK turnover. Moreover, pirtobrutinib has sustained BTK inhibition throughout the dosing interval.4
The phase 1/2 BRUIN study is evaluating the efficacy and safety of pirtobrutinib in patients with hematologic malignancies, including MCL. In the phase 1 portion of the study, patients received pirtobrutinib at escalating doses of 25 mg to 300 mg once daily, with cohort expansion permitted at doses considered safe. In the phase 2 study, pirtobrutinib was administered at 200 mg once daily.4
At the 2021 ASH annual meeting, Michael Wang, MD, and colleagues presented updated results from the cohort of 134 patients with MCL in the BRUIN study.5 The patients’ median age was 70 years (range, 46-88 years), 78% were male, and 81% had classic morphology. Patients had received a median of 3 prior lines of systemic therapy (range, 1-9 prior lines). The most frequent prior therapies included anti-CD20 antibodies in 97%, chemotherapy in 91%, a BTK inhibitor in 90%, stem cell transplant (SCT) in 22%, an immunomodulatory drug in 17%, a BCL-2 inhibitor in 15%, and a proteasome inhibitor in 13%. Among the patients who discontinued BTK inhibitors, the cause was progressive disease in 83% of cases.
Among the 100 evaluable patients with MCL who had received previous treatment with a BTK inhibitor, pirtobrutinib led to an ORR of 51%, which consisted of CRs in 25% and PRs in 26%. Stable disease was reported in 16% of patients.5 Among the 11 evaluable patients who were naive to BTK inhibitors, pirtobrutinib led to an ORR of 82%, including CRs in 18% and PRs in 64%. Stable disease occurred in 9%. In subgroup analyses, the ORR was 64% among patients previously treated with SCT (n=28) and 50% in those previously treated with chimeric antigen receptor (CAR) T-cell therapy. After a median follow-up of 8.2 months in patients with a response, the median duration of response was 18 months (Figure 4). At the time of the analysis, 60% of responses were ongoing.
No dose-limiting toxicities were noted, and the maximum tolerated dose was not reached.5 The most common treatment-emergent AEs were fatigue (23%), bruising (22%), diarrhea (19%), neutropenia (18%), and contusion (17%). The most frequent AEs deemed treatment-related were bruising (15%), contusion (12%), and neutropenia (10%; 8% were grade 3/4). Six patients (1%) permanently discontinued pirtobrutinib owing to treatment-related AEs. The incidence of treatment-related atrial fibrillation/flutter was less than 1%. The randomized phase 3 BRUIN MCL-321 trial is comparing pirtobrutinib against an investigator’s choice of covalent BTK inhibitor in patients with BTK inhibitor-naive relapsed MCL.6
References
1. Hershkovitz-Rokah O, Pulver D, Lenz G, Shpilberg O. Ibrutinib resistance in mantle cell lymphoma: clinical, molecular and treatment aspects. Br J Haematol. 2018;181(3):306-319.
2. Cheah CY, Chihara D, Romaguera JE, et al. Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes. Ann Oncol. 2015;26(6):1175-1179.
3. Ondrisova L, Mraz M. Genetic and non-genetic mechanisms of resistance to BCR signaling inhibitors in B cell malignancies. Front Oncol. 2020;10:591577.
4. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901.
5. Wang M, Shah NN, Alencar AJ, et al. Pirtobrutinib, a next generation, highly selective, non-covalent BTK inhibitor in previously treated mantle cell lymphoma: updated results from the phase 1/2 BRUIN study [ASH abstract 381]. Blood. 2021;138(suppl 1).
6. ClinicalTrials.gov. Study of BTK inhibitor LOXO-305 versus approved BTK inhibitor drugs in patients with mantle cell lymphoma (MCL) (BRUIN-MCL-321). https://clinicaltrials.gov/ct2/show/NCT04662255. Identifier: NCT04662255. Accessed January 24, 2022.
Efficacy and Safety of Parsaclisib in Patients With Relapsed or Refractory Mantle Cell Lymphoma Not Previously Treated With a BTK Inhibitor: Primary Analysis From a Phase 2 Study (CITADEL-205)
Parsaclisib is a potent, selective next-generation phosphoinositide 3-kinase (PI3K) δ inhibitor that is being evaluated in patients with various hematologic malignancies. The phase 2 CITADEL-205 trial evaluated the efficacy and safety of parsaclisib in patients with relapsed/refractory MCL.1 Previous treatment with BTK inhibitors was permitted.
Amitkumar Mehta, MD, presented the primary efficacy and safety analyses for the BTK inhibitor–naive cohort of the CITADEL-205 trial.1 The cohort enrolled patients with relapsed or refractory MCL who had received 1 to 3 prior systemic regimens (that did not include PI3K or BTK inhibitors). The patients had an ECOG PS of 0 to 2, and documented cyclin D1 overexpression or a t(11;14) translocation.
A total of 108 patients were randomly assigned to receive parsaclisib at a weekly dose or a daily dose. Patients in the weekly dosing group (n=31) received parsaclisib at 20 mg once daily for 8 weeks followed by parsaclisib at 20 mg once weekly. Patients in the daily dosing group (n=77) received parsaclisib at 20 mg once daily, followed by 2.5 mg once daily given continuously. Following an interim analysis, enrollment was closed in the weekly dosing group, but continued in the daily dosing group. Daily dosing was selected as the recommended strategy. The CITADEL-205 analysis included patients in the daily dosing group and those initially assigned to weekly dosing who switched to daily dosing.
The patients’ median age was 72.0 years, and 79% were ages 65 or older.1 Most patients (80%) were male. The median time since MCL diagnosis was 3.6 years (range, 0.1-20.9 months), and 56% of patients had a high-risk MIPI score. At the data cutoff, 72% of patients had discontinued treatment, primarily owing to progressive disease (45%) or AEs (23%). The median treatment duration was 8.3 months (range, 0.1-30.0 months), and the median duration of follow-up was 22.9 months (range, 11.6-35.9 months).
According to an independent review committee, the ORR was 68.5% (with CRs in 18%) in all treated patients (N=108; Figure 5). The ORR was 70.1% (with CRs in 16%) in the daily dosing group (n=77).1 Assessment by investigators reported ORRs of 79.6% and 81.8%, respectively. Most first responses (89%) occurred by the time of the first disease assessment at 8 weeks. Regression of the target lesions was documented in 96% of evaluable patients (90 of 94). A reduction in the best percentage change from baseline of more than 50% was reported in 84% of patients. The median duration of response was 13.7 months in all treated patients and 12.1 months in the daily dosing group (Figure 6). The median PFS was 12.0 months vs 13.6 months, respectively. The median OS had not been reached. The overall OS rate was 90% at 6 months and 80% at 12 months.
The most frequent treatment-emergent AEs was diarrhea, reported in 34% of all treated patients and 40% in the daily dosing group. Other treatment-emergent AEs included pyrexia (18% and 17%, respectively), constipation (13% and 14%), rash (11% and 14%), asthenia (11% and 13%), neutropenia (11% and 12%), and cough (10% and 12%).1 The most common grade 3 or higher AEs was diarrhea, reported in 14% of all treated patients and 18% in the daily dosing group. Other grade 3 or higher AEs included neutropenia (8% and 9%, respectively), rash (3% and 4%), and nausea (2% and 3%). The most common grade 3/4 laboratory abnormalities included decreased neutrophils (11% in all treated patients and 11.5% in the daily dosing group), decreased platelets (9% and 7%, respectively), decreased hemoglobin (3% and 4%, respectively), alanine aminotransferase elevations (5% and 3%, respectively), and aspartate aminotransferase elevations (3% in both groups). Serious treatment-emergent AEs included diarrhea (9% in all treated patients and 13% in the daily dosing group), colitis (5% and 6.5%, respectively), hypokalemia (3% in each group), pyrexia (3% in each group), and rash (2% and 3%, respectively).1
The median time to onset of grade 3 or higher diarrhea was 4.3 months in all treated patients and 5.1 months in the daily dosing group. Diarrhea improved to grade 0 to 2 after a median of 11 days. The median time to onset of colitis was 3.1 months, and the median time to improvement to grade 0 to 2 was 20 days. In the daily dosing group, the most frequently occurring treatment-emergent AEs leading to dose modifications consisted of interruptions owing to diarrhea (14%) or neutropenia (9%), reductions owing to rash (3%), and discontinuations owing to diarrhea (16%) and colitis (6.5%). One death owing to a treatment-emergent AE was deemed related to parsaclisib by the investigator. This patient had leukocytosis, acute myelomonocytic leukemia, and acute kidney injury.
Reference
1. Mehta A, Trněný M, Walewski J, et al. Efficacy and safety of parsaclisib in patients with relapsed or refractory mantle cell lymphoma not previously treated with a BTK inhibitor: primary analysis from a phase 2 study (CITADEL-205) [ASH abstract 382]. Blood. 2021;138(suppl 1).
Rituximab and High-Dose Cytarabine/Dexamethasone (R-HAD) Plus Bortezomib Is Superior to R-HAD Only in Relapsed Mantle Cell Lymphoma: A Randomized Phase 3 Trial of the European MCL Network
The addition of cytarabine to standard chemotherapy improved PFS in the MCL Younger trial.1 Data have also shown significant PFS and OS benefits with the frontline administration of bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone compared with R-CHOP in patients with MCL who are ineligible for transplant.2 Martin Dreyling, MD, presented results of a phase 3 trial from the European MCL Network that evaluated the inclusion of both bortezomib and high-dose cytarabine in the treatment of older patients with MCL.3 The trial enrolled 128 patients with relapsed or progressive disease following 1 to 3 prior lines of therapy. The patients were randomly assigned to treatment with 4 cycles of rituximab, high-dose cytarabine, and dexamethasone either with bortezomib (administered at 1.5 mg/m2 subcutaneously on days 1 and 4 [R-HAD plus bortezomib]) or without bortezomib (R-HAD).3 Although the original plan was to allow patients with stable disease after 2 cycles to withdraw from the study, some patients with minor responses were permitted to receive the full 4 cycles.
The trial enrolled 63 patients to receive R-HAD plus bortezomib and 64 patients to receive R-HAD.3 Their median age was 69 years vs 71 years, respectively. In both groups, most patients were male (71% vs 80%). Ann Arbor stage IV MCL was reported in 65% of patients treated with R-HAD plus bortezomib and 77% of those in the R-HAD alone group. At study entry, 37% and 48% of patients, respectively, had high-risk disease according to their MIPI score. The median time since diagnosis was 3.9 years and 3.7 years, respectively. Previous treatment with only 1 prior line of therapy was reported in 79% and 62% of patients. Prior treatment with high-dose cytarabine was reported in 38% and 34% of patients.
The ORR was 63% with R-HAD plus bortezomib vs 45% with R-HAD (P=.049). The rate of CR was 28% vs 12% (P=.043), respectively. The rate of CR/unconfirmed CR was 42% vs 19% (P=.0062).3 The primary endpoint was TTF. In most cases, TTF was defined as nonachievement of PR after 2 cycles of treatment, which Dr Dreyling considered a limitation of the study design. In an intention-to-treat analysis, the median TTF after a median follow-up of 41 months was 12.0 months with R-HAD plus bortezomib vs 2.6 months with R-HAD (Figure 7). In an adjusted analysis to correct for the sequential study design, the HR was 0.68 (P=.045). In a secondary per-protocol analysis, the median TTF was 12.9 months with R-HAD plus bortezomib vs 2.6 months with R-HAD alone (HR, 0.60; P=.017).
Subgroup analyses suggested a differential benefit with bortezomib based on the MIPI risk group (P value for interaction, .024).3 There were insufficient patient numbers in the low-risk group (n=26) to draw major conclusions. However, there appeared to be a potential benefit with R-HAD plus bortezomib vs R-HAD alone in the intermediate-risk and high-risk groups. An analysis of TTF based on cytarabine exposure showed a benefit of bortezomib in patients who had not previously received cytarabine (median TTF, 16.0 vs 2.2 months; HR, 0.58; P=.031).
The median PFS was 15.4 months with R-HAD plus bortezomib vs 9.2 months with R-HAD, although this difference did not reach statistical significance (HR, 0.78; P=.21).3 There was no significant difference in the duration of response between the arms. Dr Dreyling noted that this trial was initiated 15 years ago, and it is now recognized that chemotherapy-based regimens have only modest activity in relapsed MCL. Although the sample size was small, the addition of bortezomib to R-HAD was associated with an extended TTF that was driven primarily by higher response rates. There were no significant differences in survival or toxicity.
Serious AEs occurred in 34% of patients treated with R-HAD plus bortezomib vs 50% of those treated with R-HAD. Dr Dreyling suggested that this finding indicated that the dose of bortezomib was well tolerated. Infections occurred in 9% of patients in each arm.3 The rates of grade 3/4 neurotoxicity were low and therefore not included in the presented data for serious AEs.
References
1. Hermine O, Hoster E, Walewski J, et al; European Mantle Cell Lymphoma Network. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016;388(10044):565-575.
2. Robak T, Jin J, Pylypenko H, et al; LYM-3002 investigators. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol. 2018;19(11):1449-1458.
3. Dreyling M, Hoster E, Bouabdallah K, et al. R-high dose cytarabine/dexamethasone (R-HAD) plus bortezomib is superior to R-HAD only in relapsed mantle cell lymphoma: a randomized phase 3 trial of the European MCL Network [ASH abstract 383]. Blood. 2021;138(suppl 1).
KTE-X19 in Relapsed or Refractory Mantle-Cell Lymphoma, a “Real-Life” Study From the DESCAR-T Registry and LYSA Group
Brexucabtagene autoleucel is a CD19-directed CAR T-cell therapy that is approved by the FDA for patients with relapsed/refractory MCL. The approval was based on results from the ZUMA-2 trial, in which brexucabtagene autoleucel demonstrated a higher rate of durable remissions among patients previously treated with up to 5 previous therapies, including a BTK inhibitor.1 At 12 months, the estimated rates of PFS and OS were 61% and 83%, respectively.
Charles Herbaux, MD, presented results of a real-world analysis of outcomes with brexucabtagene autoleucel in patients with MCL from the DESCAR-T registry.2 Patients in this registry had received treatment with commercial CAR T cells.2 The study included 57 registered patients with MCL, 51 of whom were enrolled in a French early access program (starting in January 2020) and 6 of whom enrolled after the end of this program. At the time of the analysis, CAR T-cell therapy had been ordered for 55 patients and administered to 48 patients. The median age of the enrolled patients was 67 years (range, 45-79 years), 89.5% were male, and 31.9% had high-risk disease (per MIPI) at diagnosis. Patients had received a median of 3 prior lines of treatment (range, 2-9 prior lines), and 38.2% had undergone a prior ASCT. In the treated set of 48 patients, 93.8% were male, 30.0% had high-risk disease (per MIPI), and 33.3% had undergone a prior ASCT.
Among patients who had received a CAR T-cell infusion, the median time from the CAR T-cell order to infusion was 56 days (range, 35-134 days).2 Bridging therapy was administered to 87.2% of patients. Bridging therapies consisted of anti-CD20 monoclonal antibodies in 64.3%, chemotherapy in 57.1%, BTK inhibitors in 26.2%, and immunomodulatory drugs in 14.3%. These therapies led to an ORR of 45.3%. After a median follow-up of 6 months since administration of CAR T-cell therapy (range, 3.3-6.2 months), the median OS was not reached in the treated set of patients (n=48) vs 1.5 months in the untreated set (n=7; Figure 8). Among patients who received brexucabtagene autoleucel and were evaluated for efficacy, the best ORR was 87.2%, including a CR in 63.8%. The median PFS was 6.3 months.
Cytokine release syndrome (CRS) was reported in 84.8% of patients (grade ≥3, 8.7%) and neurotoxicity occurred in 52.2% (grade ≥3, 8.7%).2 Treatment in an intensive care unit (ICU) was required by 28.3% of patients. The median duration of hospitalization was 4.5 days.2 Treatment included tocilizumab in 69.2 of patients and corticosteroids in 59%. Among the 48 treated patients, 8 patients died, including 6 from progressive disease, 1 from CRS, and 1 from candida septic shock. Cytopenias in the first month included neutropenia (69.6%), thrombocytopenia (67.4%), and anemia (67.4%). Cellular kinetics assessed in a subset of patients (n=14) showed a statistical trend toward a shorter time to maximal expansion in those with a response vs those without a response (P=.046).
Dr Herbaux concluded that in this real-world analysis of brexucabtagene autoleucel, the safety profile and ORR were in line with previously published data.2 There was, however, increased use of bridging therapy and possibly a shorter median PFS.2 He added that the findings support the use of brexucabtagene autoleucel in patients with relapsed/refractory MCL after unsuccessful treatment with chemotherapy and a BTK inhibitor.
References
1. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331-1342.
2. Herbaux C, Bret C, Di Blasi R, et al. KTE-X19 in relapsed or refractory mantle-cell lymphoma, a “real-life” study from the DESCAR-T Registry and LYSA Group [ASH abstract 743]. Blood. 2021;138(suppl 1).
Brexucabtagene Autoleucel for Relapsed/Refractory Mantle Cell Lymphoma: Real-World Experience From the US Lymphoma CAR T Consortium
A real-world analysis reported data for the patterns of use, safety, and efficacy of brexucabtagene autoleucel among patients with MCL enrolled in the US Lymphoma CAR T Consortium.1 The analysis included 107 patients from 14 centers in the United States who underwent leukapheresis between August 2020 and June 2021, with the intent of manufacturing brexucabtagene autoleucel. CAR T cells were administered to 95 patients. The remaining 12 patients did not receive infusions owing to manufacturing failure (n=6), death (n=5), or organ dysfunction (n=1).
Among the 95 treated patients, the median age was 67 years (range, 34-89 years). Most patients (80%) were male, and 12% had high-risk disease according to the simplified MIPI.1 Other factors included a Ki-67 score of 50% or higher in 57% of patients, a blastoid or pleomorphic morphology in 41%, TP53 mutation or deletion in 44%, and a complex karyotype in 29%. CNS involvement was present in 7% of patients, and 11% had bulky disease (≥10 cm). The patients had received a median of 3 prior lines of therapy (range, 1-10). Previous treatments included a BTK inhibitor in 82% and venetoclax in 35%. Most patients (78%) would not have met the ZUMA-2 eligibility criteria, primarily owing to their number and types of prior therapies, renal dysfunction, cytopenias, ECOG PS, and CNS involvement.
Bridging therapy was administered to 67% of patients, and most often consisted of BTK inhibitor–based therapy (n=20), rituximab plus chemotherapy with or without a corticosteroid (n=16), and a BTK inhibitor plus venetoclax-based therapy (n=9).1 The median time from leukapheresis to lymphodepletion chemotherapy was 23 days (range, 12-54 days). The median time from lymphodepletion to infusion with CAR T cells was 5 days (range, 4-12 days).
CRS was reported in 91% of patients (grade 3/4, 8%). Immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in 60% (grade 3/4, 35%).1 The median time to onset of CRS was 4 days (range, 0-11 days), and the median duration was 5 days (range, 1-33+ days). The median time to ICANS was 6 days (range, 1-15 days), and the median duration was 6 days (range, 2-144+ days). The maximum grade of CRS occurred at day 5. The maximum grade of ICANS was reported at day 7. Prior treatments included tocilizumab in 79% of patients and corticosteroids in 69% of patients. Admission to an ICU was required by 21% of patients, for a median of 3 days (range, 1-12 days). The investigators noted that the incidences of CRS and ICANS were comparable with those reported in the ZUMA-2 trial (91% and 63%, respectively).2 The use of tocilizumab and corticosteroids appeared to be more common in the real-world cohort.
The best ORR was 89%, which included CRs in 81%.1 The median time to an initial response was 30 days (range, 16-104 days). At day 30, the ORR (n=92) was 88%, including CRs in 66%. Responses deepened over time. After a median of 64 days (range, 22-135 days), a CR was reported in 12 of 20 patients with an initial PR and in 1 of 2 patients with stable disease. The median time to best response was 30 days (range, 16-168 days). Dr Wang noted that the best ORR was comparable with that reported in the ZUMA-2 trial (93%).2 In subgroup analyses, brexucabtagene autoleucel was active even in high-risk groups, including patients with a blastoid or pleomorphic morphology, TP53 alterations, high Ki-67, and CNS involvement. After a median follow-up of 6.7 months, the median duration of response was not reached, and the 6-month response rate was 70% (Figure 9). The median PFS was not reached (Figure 10). The rates of PFS were 66% at 6 months and 51% at 12 months. The 12-month PFS rate in the ZUMA-2 trial was 61%.2 The rates of OS were 81% at 6 months and 72% at 12 months. In ZUMA-2, the 12-month OS rate was 83%.2
Dr Wang noted that the patients in this real-world analysis are representative of the types of patients who receive brexucabtagene autoleucel in standard practice, with more high-risk features and broader characteristics. He concluded that treatment with brexucabtagene autoleucel was feasible and demonstrated similar safety and efficacy as reported in the ZUMA-2 trial.1
References
1. Wang Y, Jain P, Locke FL, et al. Brexucabtagene autoleucel for relapsed/refractory mantle cell lymphoma: real world experience from the US Lymphoma CAR T Consortium [ASH abstract 744]. Blood. 2021;138(suppl 1).
2. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331-1342.
Highlights in Mantle Cell Lymphoma From the 63rd American Society of Hematology Annual Meeting and Exposition: Commentary
Andre H. Goy, MD
A rich data set covering multiple aspects of the management of mantle cell lymphoma (MCL) was presented at the 63rd American Society of Hematology (ASH) annual meeting, held in December 2021. This article will review how these findings might impact the different settings of MCL therapy from frontline to maintenance, as well as relapsed/refractory disease.
Frontline Treatment
Dr Olivier Hermine presented the results of a large, randomized trial from the European MCL Network that evaluated the addition of high-dose cytarabine to immunochemotherapy before autologous stem cell transplant (ASCT) in patients ages 65 years or younger.1 Of note, patients did not receive any maintenance therapy in this trial. The primary endpoint was time to treatment failure (TTF). In the original report, at a median follow-up of 6 years, treatment with rituximab plus dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) was associated with significant improvement in TTF and progression-free survival (PFS) compared with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP),2 which confirmed the original observation from the phase 2 NORDIC 2 trial.3 Now, with the median follow-up nearly doubled at 11 years, the benefits with R-DHAP vs R-CHOP were sustained for both TTF (7.7 years vs 4.1 years; P<.0001) and PFS (8.0 years vs 4.3 years; P<.0001). The 10-year rate of overall survival was not significantly different (60% with R-DHAP vs 55% with R-CHOP; P=.12). Interestingly, the benefit of cytarabine was most pronounced in high-risk patients (defined as those with an intermediate/high-risk Mantle Cell Lymphoma International Prognostic Index [MIPI] score, high TP53, or the blastoid variant), in whom the median TTF was 7.6 years with R-DHAP vs 2.8 years with R-CHOP (P<.0001). Among these patients, R-DHAP doubled the median overall survival (10 years for R-DHAP vs 5 years for R-CHOP; P=.013). For a trial with no maintenance therapy, these results are impressive, even given the caveat of potential selection bias inherent to clinical trials, as suggested by real-world MCL series.4
This large, randomized trial established the importance of cytarabine-containing regimens as induction in younger MCL patients.2 The updated analysis, with close to 12 years of follow-up, confirmed the benefit of cytarabine, particularly in high-risk patients.1 This regimen (R-CHOP alternating with R-DHAP followed by ASCT) became the de facto control arm for subsequent studies, in particular the ongoing European TRIANGLE trial, which is evaluating whether the addition of ibrutinib can improve outcome in younger MCL patients.5 This trial includes a maintenance ibrutinib arm post-ASCT and one arm in which patients will proceed straight to maintenance after induction, without ASCT consolation. Results from this trial will continue to help to reshape the frontline management of younger MCL patients.
MCL patients who are elderly and/or ineligible for intensive therapy represent approximately two-thirds of the population. Dr Maria Chiara Tisi presented the long-term update of a phase 2 trial that evaluated rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients.6 The dose of cytarabine was 500 mg/m2 instead of 800 mg/m2 because of the toxicity reported with the higher dose in the original R-BAC trial.7 Previous data for this multicenter Italian study, which enrolled 58 patients with a median age of 71 years, was reported after a median of 3 years of follow-up. The objective response rate (ORR) was 91%, all complete responses (CRs), and the 2-year PFS rate was 81%.7 This recent update provided results after a median follow-up of 7 years. The PFS was 56% and the overall survival was 63%, including a high proportion (78%) of minimal residual disease (MRD)-negative patients at the end of induction, which dramatically impacted outcome. The median PFS was 12 months for MRD-positive patients vs not reached in MRD-negative patients (P=.05). At 8 years, 70% of patients were still disease-free in the MRD-negative group.
Results for the R-BAC500 regimen, although from a small phase 2 trial, are very promising. The data appear superior to those reported for bendamustine plus rituximab (BR), which had a CR rate of approximately 30% to 40% in several studies.8 A recent large, randomized Eastern Cooperative Oncology Group E1411 trial, which was presented at the 2021 American Society of Clinical Oncology annual meeting, compared BR vs BR plus bortezomib (BVR), followed by maintenance with rituximab alone or rituximab plus lenalidomide (R2).9 In this trial, the CR rate was higher for both treatment arms, at 59.7% with BR vs 66.3% with BVR. The median PFS was approximately 5 years. Of note, the R-BAC500 regimen also showed very durable responses, although the trial did not include maintenance. Outside of a clinical trial, R-BAC seems to be a very appropriate regimen, particularly in patients without high-risk molecular features and who are not candidates for high-dose or dose-intensive therapy. This regimen is now undergoing evaluation in combination with other agents, such as venetoclax (VR-BAC), using a stratification strategy from low risk to high risk based on the following factors: morphology (blastoid vs others), Ki-67 expression (≥30% vs <30%, and TP53 mutation/TP53 deletion (found in 21% and 13% of cases, respectively).10 Patients with low risk received 6 cycles of R-BAC, whereas high-risk patients received a maximum of 4 cycles of R-BAC followed by consolidation (4 months, 800 mg/day) and maintenance (20 months, 400 mg/day) with venetoclax. The trial is ongoing.
When treating with chemoimmunotherapy, high-risk features, such as high Ki-67, the blastoid variant, TP53 mutation/TP53 deletion, and/or complex karyotype, are associated with poor outcome regardless of the treatment regimen used.11 Although a 17p deletion is not common at baseline, the presence of TP53 mutations can be found in up to 20% to 25% of MCL patients at diagnosis. Numerous studies have shown the impact of TP53 mutations on outcome, even after high-dose therapy and ASCT.12,13 In the setting of relapsed/refractory MCL, TP53 aberrations are much more common and therefore justify a repeat biopsy when disease progresses. These patients do very poorly with all standard therapies, with the exception of Bruton’s tyrosine kinase (BTK) inhibitors and chimeric antigen receptor (CAR) T-cell therapy, which have shown durable responses. Combinations of biologic agents, such as R2 plus ibrutinib and venetoclax plus ibrutinib showed high CR rates (70%-80%) and durable responses, even in patients who were heavily pretreated and who had high-risk molecular features.14,15 These results have prompted efforts to bring novel therapies into the frontline management of MCL. Small phase 2 studies using doublets, such as R2 and rituximab plus ibrutinib, showed impressive rates of CRs and durable responses, as well.16,17 Building on these data, triplet therapy, particularly, R2 plus ibrutinib; lenalidomide, venetoclax, and rituximab; and ibrutinib, venetoclax, and obinutuzumab (in the OASIS trial18), showed remarkable activity, including high rates of MRD-negativity, even in patients with the TP53 mutation at study entry. At the 2021 ASH annual meeting, Dr Michael Wang presented the results of a small phase 1b study of acalabrutinib, venetoclax, and rituximab in 21 patients with treatment-naive MCL.19 An interesting finding from this trial was that the CR rate was 90%, and all CRs occurred in patients who were MRD negative. Although the follow-up is short, early MRD-negative CRs typically translate into very favorable long-term outcome in MCL. As in the field of chronic lymphocytic leukemia, the management of MCL will continue to evolve, relying less on chemotherapy to encompass nonchemotherapy options or the sequential use of nonchemotherapy agents followed by chemotherapy.
The WINDOW-1 trial explored a “window” with ibrutinib and rituximab, followed by a reduced number of cycles of rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyper-CVAD), with very promising results.20 The overall best response in part A of therapy (which was the ibrutinib and rituximab “window” before chemotherapy) was 100%, with a CR rate of 88%. At the end of induction therapy, the ORR was 100%, with CRs in 94%, and 78% of patients overall were MRD-negative.21 (There was no maintenance arm in this trial.) The WINDOW-2 trial is evaluating ibrutinib plus rituximab followed by venetoclax in the nonchemotherapy “window,” followed by R-hyper-CVAD consolidation, with stratification based on the extent of high-risk features.22 In current practice, next-generation sequencing can identify patients with high-risk features more easily than standard immunohistochemistry and/or fluorescence in situ hybridization. As we continue to reshape the management of MCL, it is likely we will use more nonchemotherapy options. Among the remaining questions is whether the patients still need chemotherapy afterward. Ongoing studies will help stratify patients based on the degree of high-risk molecular features. Finally, CAR T-cell therapy will be explored early on in very high-risk patients and/or those who are still MRD-positive after induction therapy.
Maintenance
The benefit of maintenance therapy was first established with rituximab after R-CHOP in elderly patients.23 These benefits are now recognized in both younger and elderly patients with MCL.24 Two studies at the 2021 ASH annual meeting evaluated data from the MCL R2 Elderly clinical trial from the European MCL Network. A presentation by Dr Vincent Ribrag reported on the maintenance phase of the trial, which compared R2 vs rituximab.25 This trial first randomly assigned patients to treatment with R-CHOP vs R-CHOP combined with cytarabine. Patients achieving a CR or partial response (PR) underwent a second randomization to receive maintenance therapy with rituximab vs R2 every 2 months for 2 years. The trial enrolled approximately 600 patients, 500 of whom received maintenance therapy. The 2-year rate of PFS was 76% in the R2 arm vs 60% in the rituximab arm. The improvement in the R2 arm might be attributable to the immunomodulatory effects of lenalidomide, which improves antibody-dependent cellular cytotoxicity and potentially clears further residual MCL cells. However, there was no difference in overall survival, partly owing to the use of novel agents that provide better salvage therapy in MCL. As expected, the rates of neutropenia and infection were higher in the R2 arm, but manageable.
Although the benefit of maintenance with rituximab has been extensively confirmed, there are remaining questions, such as the optimal duration of maintenance (2-3 years in most trials vs until disease progression in the original MCL study in elderly patients23) and how to improve on rituximab maintenance alone. The trial by Dr Ribrag explored the latter question, by adding lenalidomide to rituximab.25 The R2 regimen seemed superior in delaying progression, but it did not improve overall survival. In practice, rituximab is administered for 2 years to mitigate the potential cumulative toxicity that can occur over time, which includes hypogammaglobulinemia and increased risk of infections (eg, upper respiratory and sinus infections). The most important question is whether it will be possible to customize the need for and/or duration of maintenance. Without a doubt, patients with early CRs who are MRD-negative do better overall, but do patients who are MRD-negative after induction still benefit from maintenance?
Dr Marie-Helene Delfau provided interesting data at the 2021 ASH annual meeting regarding the impact of MRD on maintenance status in the MCL R2 Elderly trial.26 This trial nicely collected prospective data for MRD at multiple time points, with centralized processing of MRD via quantitative polymerase chain reaction, focusing on rearrangements in the immunoglobulin heavy chain VDJ junction (IGH) or IGH-BCL1. As mentioned previously, this trial compared R-CHOP vs R-CHOP alternating with high-dose cytarabine in elderly patients. At the end of induction, both arms had similar rates of MRD negativity: 42% with R-CHOP vs 36% with R-CHOP/R-HAD. Of note, these results differ from those reported with high-dose cytarabine in younger patients, which showed much higher rates of CR and MRD negativity that were achieved at earlier time points, thus explaining why TTF and PFS were superior in the high-dose cytarabine arm.2 Whether this difference is attributable to the intensity of the cytarabine is unclear. As expected, outcomes were worse in patients with detectable MRD at the end of treatment. The median PFS was 2.7 years in patients with detectable MRD vs 4.7 years in patients who were MRD-negative. Maintenance with rituximab alone had no impact on outcome, regardless of whether the patient was MRD-positive or MRD-negative after induction. In the R2 arm, only the MRD-negative patients benefited from maintenance therapy. Hypothetically, lenalidomide might help clear additional cells through its immunomodulatory effects and thereby improve outcome. Additional ongoing trials exploring the integration of other biologic agents, in particular BTK inhibitors, might help build better maintenance regimens, ideally guided by MRD status, to further delay recurrence and to continue to improve survival.27
Relapsed/Refractory Disease
The US Food and Drug Administration granted accelerated approval to brexucabtagene autoleucel in relapsed/refractory MCL based on results of the ZUMA-2 trial.28 The indication does not limit treatment to patients who had previously received BTK inhibitors, but encompasses patients with relapsed/refractory MCL after at least one line of therapy. Dr Yucai Wang presented results from a real-world study of brexucabtagene autoleucel in approximately 100 patients in the United States.29 A similar European study included 57 patients.30 Both of these studies enrolled heavily pretreated patients, who had received a median of 3 prior therapies. In the US series, in which patients had received up to 10 prior therapies, almost half of the patients had high-risk features (either high Ki-67 level, mutation and/or deletion of TP53, blastoid variant, or complex karyotype), and almost 80% would not have qualified for the ZUMA-2 trial based on eligibility criteria. Grade 3/4 cytokine release syndrome (CRS) occurred in 8% of patients, and grade 3/4 immune effector cell–associated neurotoxicity syndrome occurred in 35% of patients in the US real-world study. In comparison, in the ZUMA-2 trial, grade 3/4 CRS occurred in 15% of patients, and grade 3/4 neurotoxicity occurred in 31%. These adverse events are now better managed thanks to preemptive treatment with tocilizumab and/or corticosteroids, which were administered more frequently to patients in the real-world data series compared with those in the ZUMA-2 trial. The ORR at day 30 was 88%, with a CR rate of 66% in the US series, results that were similar to those reported in the ZUMA-2 trial, which showed an ORR of 93% and a CR rate of 67%. Early data for the duration of response appear similar to those reported in the ZUMA-2 trial, as well. Finally, as seen in the pivotal trial, a significant proportion of patients (12/20 in the US series) with an initial PR achieved a CR over time.
In the real-world analysis of brexucabtagene autoleucel conducted in Europe, 87% of patients had received bridging therapy.30 The best ORR was 87%, which included CRs in 64%. The rate of grade 3 or higher CRS was 8.7%, and the rate of grade 3 or higher neurotoxicity was also 8.7%. As in the US series, patients received higher amounts of tocilizumab and corticosteroids. Hypothetically, the lower rates of CRS and neurotoxicity might be related to the higher rates of bridging therapy. The take-home message from these real-world analyses is that CAR T-cell therapy with brexucabtagene autoleucel showed similar activity in real-world data as in the ZUMA-2 trial, in a very heavily pretreated population of patients who, in many cases, would not have qualified for the clinical trial based on eligibility criteria. CAR T-cell therapy is transforming the management of relapsed/refractory MCL, even in patients with high-risk disease, who have achieved robust and durable responses.28-30
Future research will focus on how to optimize the timing of CAR T-cell therapy in MCL, based on T-cell fitness (which is improved in patients who have received fewer prior therapies and no bendamustine). There is the potential that CAR T-cell therapy could be administered earlier in high-risk patients after induction. Other types of CAR T-cell therapy are also undergoing evaluation in MCL, including dual CAR T-cell therapy (targeting 19/20 and 20/22). Reports on bispecific antibodies at the 2021 ASH annual meeting are clearly showing the expanding potential of this newer form of T cell–engaging therapy. Glofitamab, for example, is a CD20 × CD3 bispecific antibody that showed an impressive ORR at 81%, with a CR rate at 66%, in patients with relapsed/refractory MCL, most of whom had received prior unsuccessful treatment with a BTK inhibitor.31
Several years ago, studies of PI3Kδ inhibitors in MCL showed a modest response rate with limited durability, and raised concern regarding toxicities, particularly liver toxicity.32 The phase 2 CITADEL trial evaluated parsaclisib, a PI3Kδ inhibitor that is 1000 times more selective than previous agents.33 Such higher selectivity may potentially lead to fewer off-target effects and immune-based interactions, and therefore less toxicity. Study results were presented by Dr Amitkumar Mehta for the subset of patients who had not received previous treatment with a BTK inhibitor, using parsaclisib at a weekly dose (n=31) or a daily dose (n=77) for 8 weeks.34 The ORR was promising, at 68.5% for all treated patients and 70.1% for the daily dosing group. The CR rates, however, were rather low, at 18% and 16%, respectively, and the median duration of response was 13.7 months and 12.1 months. These results are more promising than those reported for other PI3Kδ inhibitors, and tolerability was also improved. Future studies will explore combination regimens, although in the past, observed toxicity was a limiting factor for other combinations of PI3Kδ inhibitors, particularly those that use other biologic agents.
Covalent BTK inhibitors have transformed the management of chronic lymphocytic leukemia and MCL, but these treatments are not curative, and many patients will eventually relapse with a typically poor outcome. The mechanisms of resistance to BTK inhibition are still poorly understood; mutations of BTK binding site C481S have been described in chronic lymphocytic leukemia but seem less common in MCL. Downstream mutations in genes such as PLCG2 and other bypass changes are not well identified. Progression after BTK inhibitors in MCL is associated with dismal overall survival, except in patients treated with CAR T-cell therapy. Covalent BTK inhibitors share pharmacologic liabilities (eg, low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover, and can ultimately manifest as acquired resistance in some patients.35 To address these limitations, pirtobrutinib, a highly selective, noncovalent BTK inhibitor of both wild-type and C481-mutated BTK with equal low nM potency was developed. Dr Michael Wang presented data for pirtobrutinib, focusing on patients with relapsed/refractory MCL enrolled in the phase 1/2 BRUIN study.36 Among patients who had received a previous BTK inhibitor, the ORR rate was 51%, with a CR rate of 25%, whereas in the BTK inhibitor–naive population, the ORR was 82%, with a CR rate of only 18%. For all patients, the median duration of response was impressive, at 18 months. Across studies of BTK inhibitors, the rates of ORR and CR differ,37 which might reflect differences in patient populations, such as the number of prior therapies. Overall, however, the efficacy among the 3 first-generation agents is rather similar. An ongoing phase 3 trial is comparing pirtobrutinib with the investigator’s choice of a covalent BTK inhibitor in patients with relapsed MCL who have not received prior treatment with a BTK inhibitor.38
Conclusion and Summary
In summary, the challenges and poor outcomes observed with MCL since the early 1990s led to rewarding clinical research endeavors, which helped establish current standards and translated into improvements in both median PFS (>7-8 years) and median overall survival (>10-12 years). In spite of these advances, patients who have high risk according to the MIPI score, high Ki-67 (≥30%), or the blastoid variant still have a worse outcome, with a median overall survival of approximately 3 years. Furthermore, patients with high-risk molecular features, in particular TP53 mutations, experience a dismal outcome even after high-dose therapy, with a median overall survival of 1.8 years.
Acceleration in the development of novel therapies led to 6 newly approved drugs in relapsed/refractory MCL in the last 15 years (5 of them in the last 7 years), which translated into improved survival, thanks to their efficacy in patients who are refractory to chemoimmunotherapy and/or carry high-risk features.
Presentations at the 2021 ASH annual meeting provided data for different phases of MCL management that will continue to help refine the field, from frontline treatment to maintenance and/or consolidation, and to the relapsed/refractory setting. Meanwhile, progress in understanding the clinical, biologic, and molecular heterogeneity of MCL has expanded our appreciation of the spectrum of subentities across MCL. Combined with a growing number of additional molecular features that impact outcome—well beyond TP53 abnormalities—a new paradigm is emerging that turns away from a dichotomy based on dose intensity and age and turns toward less or no chemotherapy at all, in a growing number of MCL patients.
Improved access to routine diagnostics (in particular, next-generation sequencing) has the potential to impactfully guide treatment decisions across the different phases of therapy for each patient with MCL. Finally, real-world data at scale are needed to refine choices among the increasing number of options available in MCL and to identify the best sequence of care, an emerging critical question across oncology.
Disclosure
Dr Goy has served as an advisor or consultant for MJH Associates and Physicians’ Education Resource, LLC. He has received grants for clinical research from AstraZeneca.
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