A Review of Selected Presentations From the All-Virtual 62nd ASH Meeting and
Exposition • December 5-8, 2020
Acalabrutinib Monotherapy in Patients With Relapsed/Refractory Mantle Cell Lymphoma: Long-Term Efficacy and Safety Results From a Phase 2 Study
Mantle cell lymphoma (MCL) is a rare, aggressive form of B-cell non-Hodgkin lymphoma (NHL).1-4 Although standard treatments yield high response rates, the median overall survival for patients with MCL is a few years, and the disease relapses in nearly all cases. Acalabrutinib is a next-generation Bruton tyrosine kinase (BTK) inhibitor that is approved by the US Food and Drug Administration (FDA) for patients with previously treated MCL. The open-label, multicenter phase 2 ACE-LY-004 trial evaluated acalabrutinib (100 mg twice daily) in patients with relapsed or refractory MCL.5,6 Eligible patients had the t(11;14)(q13;q32) translocation and/or cyclin D1 overexpression. They had received up to 5 prior therapies. The trial enrolled patients with measurable nodal disease and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 through 2. The primary endpoint was the investigator-assessed objective response rate (ORR) according to the Lugano criteria.7
The study enrolled 124 patients with MCL, including 26 patients (21%) with blastoid/pleomorphic disease.6 The patients’ median age was 68 years (range, 42-90), and they had received a median of 2 prior therapies (range, 1-5). Of the 124 patients, 93 (75%) had Ann Arbor stage IV disease, and 46 (37%) had a bulky tumor measuring at least 5 cm. Assessment with the simplified MCL International Prognostic Index (MIPI) score indicated intermediate risk in 54 patients (44%) and high risk in 21 patients (17%). Refractory disease was noted in 30 patients (24%).
An initial analysis, reported after a median follow-up of 26 months, identified an ORR of 81% and a complete response (CR) rate of 43%.6 The median duration of response was 26 months, and the estimated 24-month duration of response rate was 52.4%. After a median follow-up of 38.1 months, 24 patients (19%) remained on acalabrutinib.6 Thirty-one patients remained in follow-up and were evaluable for survival assessment.6 Among the 100 patients (81%) who had discontinued acalabrutinib, the most common reasons for discontinuation included disease progression (60%) and adverse events (AEs; 11%).
The ORR was 81%, with a CR rate of 48%.6 The median duration of response was 28.6 months (95% CI, 17.5-39.1 months). At 36 months, the duration of response was estimated to be 41.9% (95% CI, 31.7%-51.8%). The median duration of response was 36.7 months in patients with a low Ki-67 index (<50%) and 15.3 months in patients with a high Ki-67 index (≥50%). The median progression-free survival (PFS) was 22.0 months (95% CI, 16.6-33.3 months), and the estimated 36-month PFS rate was 37.2% (95% CI, 28.2%-46.1%; Figure 1). The median overall survival was not reached (95% CI, 36.5 months to not estimable; Figure 2). The median PFS was 35.8 months in patients with a low Ki-67 index and 6.4 months in patients with a high Ki-67 index. The median PFS was 24.8 months in patients who had received 3 or more prior regimens, 13.8 months in patients who had received prior treatment with a proteasome inhibitor, 27.7 months in patients who had received a prior stem cell transplant (SCT), and 24.9 months in patients previously treated with lenalidomide. Samples evaluable for minimal residual disease (MRD) were available for 30 patients. Six of these patients had a CR and undetectable MRD; undetectable MRD status was maintained at the most recent assessment.
AEs led to dose delays in 50 patients (40%) and to dose modifications in 2 patients (2%). A total of 57 patients (46%) died, most commonly from disease progression (31%) or AEs (5%). Grade 3/4 AEs of clinical interest included infection (17%), cardiac events (5%), bleeding events (4%), and hypertension (2%). No new safety concerns emerged during additional follow-up.
References
1. Jain P, Wang M. Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management. Am J Hematol. 2019;94(6):710-725.
2. Owen C, Berinstein NL, Christofides A, Sehn LH. Review of Bruton tyrosine kinase inhibitors for the treatment of relapsed or refractory mantle cell lymphoma. Curr Oncol. 2019;26(2):e233-e240.
3. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390.
4. Vose JM. Mantle cell lymphoma: 2017 update on diagnosis, risk-stratification, and clinical management. Am J Hematol. 2017;92(8):806-813.
5. Wang M, Rule S, Zinzani PL, et al. Durable response with single-agent acalabrutinib in patients with relapsed or refractory mantle cell lymphoma. Leukemia. 2019;33(11):2762-2766.
6. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study [ASH abstract 2040]. Blood. 2020;136(suppl 1).
7. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
Combination of Ibrutinib With Rituximab in Previously Untreated Older Patients With Mantle Cell Lymphoma—A Phase II Clinical Trial
Previous trials have shown that the combination of rituximab plus ibrutinib is effective in patients who have relapsed/refractory MCL. In a 4-year analysis of a phase 2 trial, treatment with rituximab plus ibrutinib led to a CR rate of 58%.1 The median PFS was 43 months.
An investigator-initiated phase 2 trial evaluated ibrutinib plus rituximab in treatment-naive patients ages 65 years and older.2 The trial enrolled patients with nonblastoid/pleomorphic MCL and a Ki-67 index of less than 50%. Their largest tumor was less than 10 cm. A CR was confirmed via positron emission tomography (PET)/computed tomography, bone marrow biopsy/aspiration, and/or endoscopies with random biopsies.
The trial enrolled 50 patients, with a median age of 71 years (range, 65-84 years).2 Most patients (94%) had bone marrow involvement. Disease risk was considered high in 50%, intermediate in 38%, and low in 6%. A history of atrial fibrillation was reported in 23%; this condition was controlled before enrollment. The level of Ki-67 was less than 30% in 75% of patients and between 30% to 50% in 25% of patients.
There were 3 patients who discontinued treatment during the first 3 cycles after developing AEs, and they were excluded from the efficacy analysis. Among patients in the intention-to-treat population, the ORR was 90%, with a CR rate of 62%. MRD negativity was reported in 87%. After a median follow-up of 43 months (range, 6-52 months), the median PFS (Figure 3) and median overall survival were not reached.
Four patients developed progressive disease (after 4, 10, 13, and 33 months of treatment). Among the 5 patients who died, the cause was disease progression in 3 cases and unknown in 2 cases. All deaths occurred while patients were off the study. Twenty-seven patients left the study, for reasons such as atrial fibrillation (n=10), other cardiac issues (n=3), and disease progression (n=4).
Overall, 34% of patients developed atrial fibrillation.2 Among these patients, 18% had no history of atrial fibrillation. The median time to onset of atrial fibrillation was 9.4 months (range, 1.3-48) from the initiation of treatment. The most common hematologic grade 3/4 AEs were neutropenia (8%), thrombocytopenia (4%), and anemia (4%). The most common nonhematologic grade 3/4 AEs were atrial fibrillation (22%), fatigue (18%), diarrhea (14%), and myalgia (14%). The study investigators noted that the increased incidence of arrhythmia likely reflected the high number of cardiovascular risk factors in these patients. They suggested that baseline evaluation of cardiac heath and cardiovascular risk factor modification should be components of management with rituximab plus ibrutinib.
References
1. Jain P, Romaguera J, Srour SA, et al. Four-year follow-up of a single arm, phase II clinical trial of ibrutinib with rituximab (IR) in patients with relapsed/refractory mantle cell lymphoma (MCL). Br J Haematol. 2018;182(3):404-411.
2. Jain P, Yixin Y, Zhao S, et al. Combination of ibrutinib with rituximab (IR) in previously untreated older patients with mantle cell lymphoma (MCL)—a phase II clinical trial [ASH abstract 2042]. Blood. 2020;136(suppl 1).
Adverse Events in Clinical Trials of Ibrutinib and Acalabrutinib for B-Cell Lymphoproliferative Disorders: A Systematic Review and Network Meta-Analysis
Ibrutinib, a first-generation BTK inhibitor, is associated with an elevated risk for cardiovascular AEs, including atrial fibrillation, hypertension, and bleeding.1 Acalabrutinib binds more selectively than ibrutinib to BTK, which may result in fewer cardiovascular events and other AEs. A systematic review and network meta-analysis evaluated the AEs described in prospective trials of ibrutinib and acalabrutinib among patients with B-cell lymphoproliferative disorders.2 The study included single-arm and randomized prospective trials of ibrutinib alone, ibrutinib plus anti-CD20 therapy, and acalabrutinib alone. Trials that investigated a BTK inhibitor plus chemotherapy were excluded. Augmented Bayesian network meta-analysis and meta-regression techniques were used to compare the safety profiles of the treatments.
The study analyzed data from 27 prospective clinical trials, which included a total of 29 study arms and 3207 patients.2 The most common AEs of any grade in patients treated with ibrutinib were diarrhea (46%; 95% CI, 36%-55%), myalgias/arthralgias (37%; 95% CI, 38%-46%), and fatigue (33%; 95% CI, 24%-42%). Among patients treated with acalabrutinib, the most common AEs of any grade were headache (37%; 95% CI, 26%-48%), diarrhea (30%; 95% CI, 20%-41%), and peripheral edema (21%; 95% CI, 15%-28%). Cases of any-grade bleeding and bruising were reported in 41% (95% CI, 30%-52%) of patients treated with acalabrutinib vs 32% of those treated with ibrutinib (95% CI, 23%-41%). Any-grade hypertension occurred in 23% (95% CI, 15%-32%) of patients treated with ibrutinib vs 6% (95% CI, 1%-11%) of those treated with acalabrutinib. Any-grade atrial fibrillation was reported in 9.1% vs 2.5%, respectively.
The difference favoring acalabrutinib was significant for any-grade hypertension (odds ratio [OR], 0.26; 95% CI, 0.17-0.40; P<.0001), grade 3 hypertension (OR, 0.15; 95% CI, 0.08-0.27; P<.0001), any-grade atrial fibrillation (OR, 0.35; 95% CI, 0.18-0.66; P=.0012), and grade 3 atrial fibrillation (OR, 0.04; 95% CI, 0.01-0.25; P=.0009; Figure 4).2 Acalabrutinib was also associated with a reduced rate of grade 3 or higher bleeding or bruising (P=.021) and a reduced rate of grade 3 or higher infections (P=.003). The results suggest that the safety profile of acalabrutinib may be superior to that of ibrutinib, particularly in terms of cardiovascular AEs.
References
1. Pineda-Gayoso R, Alomar M, Lee DH, Fradley MG. Cardiovascular toxicities of Bruton’s tyrosine kinase inhibitors. Curr Treat Options Oncol. 2020;21(8):67.
2. Hilal T, Hillegass WB, Gonzalez-Velez M, Leis JF, Rosenthal AC. Adverse events in clinical trials of ibrutinib and acalabrutinib for B-cell lymphoproliferative disorders: a systematic review and network meta-analysis [ASH abstract 1317]. Blood. 2020;136(suppl 1).
Safety and Preliminary Efficacy in Patients With Relapsed/Refractory Mantle Cell Lymphoma Receiving Lisocabtagene Maraleucel in TRANSCEND NHL 001
Patients with MCL who develop progressive disease after treatment with a BTK inhibitor have a poor prognosis, with response rates ranging from 25% to 42%, and a median overall survival of 10 months or less after salvage therapy.1-4 Lisocabtagene maraleucel is an investigational chimeric antigen receptor (CAR) T-cell product that targets CD19. The CAR T-cell product is administered with a defined ratio of engineered CD8-positive and CD4-positive T cells. The open-label, multicenter, phase 1 TRANSCEND-NHL-001 trial evaluated lisocabtagene maraleucel among patients with B-cell malignancies. After 3 days of lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2), patients received lisocabtagene maraleucel at 1 of 2 doses: 50 × 106 CAR-positive T cells or 100 × 106 CAR-positive T cells. Lisocabtagene maraleucel yielded an ORR of 73%, with a CR rate of 53% in patients who had relapsed or refractory large B-cell lymphoma.5 Grade 3 cytokine-release syndrome was observed in 2% of patients, and neurologic events occurred in 10%.
The patients with MCL in the TRANSCEND-NHL-001 trial had received 2 or more prior lines of therapy, including a BTK inhibitor, an alkylating agent, and an anti-CD20 agent.6 The enrollment criteria included patients who had undergone hematopoietic SCT and who had secondary central nervous system lymphoma. The patients had an ECOG performance status of 0 to 2, with adequate heart and kidney function. Among patients with mantle cell lymphoma, 44 underwent leukapheresis. Lisocabtagene maraleucel or a nonconforming product was administered to 33 patients. Results were presented for 32 patients treated with lisocabtagene maraleucel: 6 at the lower dose level and 26 at the higher dose level. The patients had a median age of 67 years (range, 36-80), and 27 (84%) were male. A total of 13 patients (41%) had MCL with blastoid morphology, 23 (72%) had a Ki-67 value of at least 30%, and 7 (22%) had a TP53 mutation. The patients had received a median of 3 prior therapies (range, 1-7), 81% had disease refractory to their last therapy, and 53% received bridging therapy.
The median follow-up was 5.9 months (range, 0.4-24.8).6 According to investigator assessment, the ORR was 84%, with a CR rate of 66% (Figure 5). The median time to first CR or partial response (PR) was 0.95 months (range, 0.9-2.0). The ORR was 100% in the patients with a TP53 mutation, 83% in those with a Ki-67 value of 30% or higher, and 77% in those with blastoid morphology. The median duration of response was not reached. Maximum lisocabtagene maraleucel expansion was observed 10 days after infusion (Figure 6). Long-term persistence of lisocabtagene maraleucel was observed in 67% of patients (4/6) at 1 year and in 33% of patients (1/3) at 2 years. Enrollment of patients with MCL into the cohort receiving the higher dose level is continuing.
The most common treatment-emergent AEs were cytokine-release syndrome (50%), anemia (47%), and neutropenia (47%). The most common treatment-emergent AEs of grade 3 or higher were neutropenia (44%), anemia (38%), and thrombocytopenia (31%). Two patients developed grade 5 AEs considered related to lisocabtagene maraleucel. Dose-limiting toxicities observed in 2 patients included 1 case of tumor lysis syndrome and 1 case of neutropenia/thrombocytopenia. Grade 3 or higher cytokine-release syndrome occurred in 1 patient (3%), and neurologic AEs of grade 3 or higher occurred in 11 patients (34%). In 3 patients (9%), cytokine-release syndrome or neurologic events required admission to an intensive care unit. Grade 3 or higher events include prolonged cytopenias in 11 patients (34%), infections in 5 patients (16%), hypogammaglobulinemia in 3 patients (9%), and tumor lysis syndrome in 1 patient (3%).
References
1. Cheah CY, Seymour JF, Wang ML. Mantle cell lymphoma. J Clin Oncol. 2016;34(11):1256-1269.
2. Epperla N, Hamadani M, Cashen AF, et al. Predictive factors and outcomes for ibrutinib therapy in relapsed/refractory mantle cell lymphoma—a “real world” study. Hematol Oncol. 2017;35(4):528-535.
3. Jain P, Kanagal-Shamanna R, Zhang S, et al. Long-term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib. Br J Haematol. 2018;183(4):578-587.
4. Martin P, Maddocks K, Leonard JP, et al. Postibrutinib outcomes in patients with mantle cell lymphoma. Blood. 2016;127(12):1559-1563.
5. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852.
6. Palomba ML, Gordon LI, Siddiqi T, et al. Safety and preliminary efficacy in patients with relapsed/refractory mantle cell lymphoma receiving lisocabtagene maraleucel in TRANSCEND NHL 001 [ASH abstract 118]. Blood. 2020;136(suppl 1).
A Pilot Study of Acalabrutinib With Bendamustine/Rituximab Followed by Cytarabine/Rituximab for Untreated Mantle Cell Lymphoma
No consensus exists regarding the optimal induction regimen for treating MCL in young, fit patients.1 The use of treatment regimens consisting of high-dose cytarabine followed by autologous SCT has improved response rates and PFS, but not overall survival.2,3 Treatment with bendamustine plus rituximab followed by cytarabine plus rituximab has yielded high rates of CR and MRD negativity.4 A single-arm, single-institution pilot study evaluated the addition of acalabrutinib to this regimen.5 The primary endpoint was successful stem cell mobilization, defined as a CD34-positive cell yield that exceeded 2 × 106/kg following a maximum of 5 sessions of leukapheresis. Key endpoints included the rates of overall response, CR, and MRD. Eligible patients were ages 18 to 70 years, had treatment-naive MCL, and were candidates for autologous SCT. Patients received 6 cycles of 28 days each. Treatment throughout the first 3 cycles consisted of bendamustine (90 mg/m2 on days 1 and 2), rituximab (375 mg/m2 on day 1), and acalabrutinib (100 mg twice daily on days 1-28). Treatment during cycles 4 through 6 consisted of cytarabine (2 g/m2 every 12 hours on days 1 and 2), rituximab (375 mg/m2 on day 1), and acalabrutinib (100 mg twice daily on days 1-7 and days 22-28). After 6 cycles, patients underwent MRD testing and PET. Responses were evaluated according to the Lugano classification.6
The report provided data for 12 evaluable patients.5 Their median age was 57 years (range, 52-66), and 92% were male. Eleven patients had stage IV disease, and 1 patient (8%) had stage III disease. All of the patients had an ECOG performance status of 0 or 1. MIPI scores were low in 33%, intermediate in 42%, and high in 25%.
After a median follow-up of 11 months, the ORR was 83%, including a CR rate of 75%.5 None of the patients with a response developed relapsed disease. The median number of CD34-positive stem cells collected from each patient was 3.84 × 106 (range, 2.77 × 106 to 5.9 × 106). MRD assessment was pending.
Serious grade 4 hematologic AEs included lymphopenia and thrombocytopenia, each observed in all patients, and leukopenia and neutropenia, each observed in 83% of patients. Grade 3 anemia occurred in 66% of patients. All serious nonhematologic AEs were grade 3. These events included febrile neutropenia in 3 patients (25%), and diarrhea, elevated levels of alanine aminotransferase, and infusion reaction, each observed in 1 patient (8%). Therapy was discontinued in 2 patients who developed prolonged thrombocytopenia. No significant bleeding events or cases of treatment-related mortality were reported.
References
1. Cortelazzo S, Ponzoni M, Ferreri AJM, Dreyling M. Mantle cell lymphoma. Crit Rev Oncol Hematol. 2020;153:103038.
2. Eskelund CW, Kolstad A, Jerkeman M, et al. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016;175(3):410-418.
3. 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.
4. Armand P, Redd R, Bsat J, et al. A phase 2 study of rituximab-bendamustine and rituximab-cytarabine for transplant-eligible patients with mantle cell lymphoma. Br J Haematol. 2016;173(1):89-95.
5. Guy D, Watkins M, Wan F, et al. A pilot study of acalabrutinib with bendamustine/rituximab followed by cytarabine/rituximab (R-ABC) for untreated mantle cell lymphoma [ASH abstract 2057]. Blood. 2020;136(suppl 1).
6. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
LOXO-305, A Next-Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated Mantle Cell Lymphoma, Waldenström’s Macroglobulinemia, and Other Non-Hodgkin Lymphomas: Results From the Phase 1/2 BRUIN Study
The mechanisms of resistance to covalent BTK inhibition in patients with MCL have not been fully described, and survival outcomes after treatment with a covalent BTK inhibitor are poor.1-3 LOXO-305 is a potent, selective, noncovalent inhibitor of BTK that has shown nanomolar binding against wild-type and C481-mutated BTK in cell and enzyme assays.4,5 In xenograft models, sustained BTK inhibition has been observed with LOXO-305 throughout the dosing interval. The multicenter phase 1/2 BRUIN study evaluated LOXO-305 in patients with advanced B-cell malignancies who had previously received at least 2 systemic treatments.6 LOXO-305 was administered orally in 28-day cycles. The doses ranged from 25 to 300 mg daily, and dose escalation followed a standard 3 + 3 protocol. The primary endpoints were the maximum tolerated dose and the recommended phase 2 dose. Intrapatient dose escalation to a previously cleared dose level was allowed. Responses were assessed according to either the Lugano classification or criteria from the International Workshop on Waldenström’s Macroglobulinemia.
The trial enrolled 203 patients in a phase 1 dose-escalation and expansion cohort (25-300 mg/day) and 120 patients in a phase 2 cohort (200 mg/day).6 The safety population included 61 patients with MCL, 26 with Waldenström macroglobulinemia, and 66 with other types of NHL. Among these groups, the median ages were 69 years, 68 years, and 68 years, respectively (overall range, 27-87). Patients in the 3 disease cohorts had previously received a median of 3 or 4 therapies (range, 1-11), and 12 had previously received CAR T-cell therapy. Prior exposure to a BTK inhibitor was reported in 93% of the patients with MCL, 69% of those with Waldenström macroglobulinemia, and 37% of those with other B-cell malignancies. Most patients discontinued their prior BTK inhibitor because of disease progression.
Pharmacokinetic analysis showed dose-dependent linear increases in the plasma concentration of LOXO-305 across the entire dose range. Plasma exposures exceeded the BTK 90% maximal inhibitory concentration at daily doses of 100 mg or higher.
Across the entire population of 323 patients, the most common AEs of any grade were fatigue (20%), diarrhea (17%), and confusion (13%). No grade 4 AEs were observed. Grade 3 AEs included fatigue (1%), hypertension (1%), and hemorrhage (<1%). AEs of special interest included bruising (16%) and rash (11%). No dose-limiting toxicities were reported, and the maximum tolerated dose was not reached. LOXO-305 was discontinued in 5 patients (1.5%) owing to treatment-related AEs. The recommended phase 2 dose of LOXO-305 was 200 mg daily.
Among the 56 patients with MCL, the ORR was 52% (95% CI, 38%-65%), with a CR rate of 25%.6 Among the 52 patients with MCL previously treated with a BTK inhibitor, the ORR was also 52%, with a CR rate of 25%. The ORR was 64% (9/14) in patients who had undergone prior SCT and 100% (2/2) in patients who had received prior CAR T-cell therapy. The maximum percent change in the sum of the products of the diameters from baseline is shown in Figure 7. After a median follow-up of 6 months (range, 0.7-18.3+), responses were ongoing in 83% of patients (24/29).
Among 19 patients with Waldenström macroglobulinemia, the ORR was 68% (95% CI, 33%-87%), based on a PR rate of 47% (n=9) and a minimal response rate of 21% (n=4). Among the 13 patients who had received prior treatment with a BTK inhibitor, the ORR was 69% (39% PR rate, 31% minimal response rate). For the patients with other NHL subtypes, the ORRs were as follows: 75% for Richter transformation, 50% for follicular lymphoma, 22% for marginal zone lymphoma, and 24% for diffuse large B-cell lymphoma (DLBCL). Responses were ongoing in 10 of 13 patients (77%) with Waldenström macroglobulinemia and 5 of 6 patients (83%) with Richter transformation.
References
1. 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.
2. Ondrisova L, Mraz M. Genetic and non-genetic mechanisms of resistance to BCR signaling inhibitors in B cell malignancies. Front Oncol. 2020;10:591577.
3. Martin P, Maddocks K, Leonard JP, et al. Postibrutinib outcomes in patients with mantle cell lymphoma. Blood. 2016;127(12):1559-1563.
4. Brandhuber B, Gomez E, Smith S, et al. LOXO-305, a next generation reversible BTK inhibitor, for overcoming acquired resistance to irreversible BTK inhibitors [SHO abstract S216]. Clin Lymphoma Myeloma Leuk. 2018;18(suppl 1).
5. Mato A, Flinn IW, Pagel JM, et al. Results from a first-in-human, proof-of-concept phase 1 trial in pretreated B-cell malignancies for LOXO-305, a next-generation, highly selective, non-covalent BTK inhibitor [ASH abstract 501]. Blood. 2019;134(suppl 1).
6. Wang ML, Shah NN, Alencar AJ, et al. LOXO-305, a next generation, highly selective, non-covalent BTK inhibitor in previously treated mantle cell lymphoma, Waldenström’s macroglobulinemia, and other non-Hodgkin lymphomas: results from the phase 1/2 BRUIN study [ASH abstract 117]. Blood. 2020;136(suppl 1).
One-Year Follow-Up of ZUMA-2, the Multicenter, Registrational Study of KTE-X19 in Patients With Relapsed/Refractory Mantle Cell Lymphoma
KTE-X19, now also known as brexucabtagene autoleucel, is an autologous CAR T-cell therapy that is directed at the CD19 antigen. This agent is FDA-approved for the treatment of patients with relapsed or refractory MCL. The single-arm, open-label, phase 2 ZUMA-2 study evaluated KTE-X19 in patients with relapsed or refractory MCL who had received 1 to 5 prior therapies, including a BTK inhibitor.1,2 After leukapheresis, patients could receive optional, protocol-specified bridging therapy. Conditioning chemotherapy consisted of fludarabine (30 mg/m2) and cyclophosphamide (500 mg/m2) administered on days –5, –4, and –3 before the CAR T-cell infusion. On day 0, patients received a single infusion of 2 × 106 KTE-X19 cells/kg. The primary endpoint was the ORR according to the Lugano classification, as assessed by independent review.3 After a median follow-up of 12.3 months, the primary efficacy analysis showed an ORR of 93%, with a CR rate of 67%.1
An updated analysis from the ZUMA-2 study continued to show durable responses among patients with MCL who received KTE-X19.2 This analysis provided efficacy data for 60 patients. After a median follow-up of 17.5 months (range, 12.3-37.6), the ORR was 92% (95% CI, 82%-97%), with a CR rate of 67%. At the data cutoff, responses were ongoing in 29 of the 60 patients (48%). Among the 40 patients who had achieved a CR, responses were ongoing in 28 (70%). The median values were not reached for the duration of response (95% CI, 14 months to not evaluable), PFS (95% CI, 10 months to not evaluable; Figure 8), and overall survival (95% CI, range not evaluable). The ongoing response rate was consistent across adverse prognostic groups based on age, sex, MCL morphologic characteristics, Ki-67 proliferation index, disease stage, simplified MIPI score, and TP53 mutation.
No new safety signals were observed with additional follow-up.2 There were no new cases of cytokine-release syndrome and no new grade 5 events since the prior report. In the safety population of 68 patients, the most common AEs of any grade that were present at 6 months or later after infusion included neutropenia (21%), thrombocytopenia (21%), and anemia (19%). The most common AEs of grade 3 or higher were neutropenia (16%), thrombocytopenia (13%), and decrease in white blood cell count (9%).
Peak levels of engineered T cells were higher in patients with an ongoing response at 12 months and in those who initially had a response and then relapsed by 12 months as compared with patients who never achieved a response. Among the 57 evaluable patients, 48 (84%) had detectable B cells at baseline. Among patients with an ongoing response at 12 months, B-cell recovery increased through 24 months, whereas levels of genetically engineered T cells decreased. No association was observed between CAR T-cell levels measured at 2 weeks after the infusion and B-cell aplasia.
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. Wang ML, Munoz J, Goy A, et al. One-year follow-up of ZUMA-2, the multicenter, registrational study of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma [ASH abstract 1120]. Blood. 2020;136(suppl 1).
3. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
Predictive Power of Early, Sequential MRD Monitoring in Peripheral Blood and Bone Marrow in Patients With Mantle Cell Lymphoma Following Autologous Stem Cell Transplantation With or Without Rituximab Maintenance; Final Results From the LyMa-MRD Project, Conducted on Behalf of the LYSA Group
The phase 3 LyMa trial evaluated rituximab maintenance therapy after autologous SCT in patients with MCL.1,2 The trial enrolled 299 patients ages 66 years or younger at diagnosis. All patients first received 4 courses of induction therapy (rituximab, dexamethasone, cytarabine, and a platinum derivative) followed by autologous SCT. Patients were then randomly assigned to 3 years of observation or rituximab (375 mg/m2 every 2 months). The 4-year event-free survival rate was 79% with rituximab maintenance vs 61% with observation (P<.001), and the 4-year PFS rate was 83% vs 64%, respectively (P<.001). Rates of overall survival were also better with rituximab maintenance (89% vs 80%; P=.04).
The LyMa-MRD project investigated the prognostic significance of MRD status both before and after autologous SCT and assessed the value of combining MRD status with findings from PET to predict outcome.2 Polymerase chain reaction assays targeted to clonal immunoglobulin gene rearrangements were used to assess MRD in the blood and bone marrow at 3 French reference laboratories. MRD assays had a sensitivity of 10-4.
A total of 220 patients were evaluable for MRD and included in this analysis.2 MRD negativity in the peripheral blood was 77% before autologous SCT vs 94% after the procedure. MRD negativity in the bone marrow was 64% before autologous SCT vs 81% after. Patients with undetectable bone marrow MRD before SCT had a longer median PFS (56.2 months vs 49.9 months in those with detectable MRD; P=.0295; Figure 9). The median overall survival was not reached vs 60.8 months, respectively (P=.0407). Undetectable MRD in the peripheral blood before SCT was also associated with a longer median PFS (60.8 vs 34.9 months; P<.0001) and longer median overall survival (60.8 vs 39.6 months; P<.0001). MRD status after autologous SCT did not correlate with median overall survival. MRD negativity in the bone marrow after autologous SCT was associated with a longer median PFS (P=.0261), but not with longer overall survival.
Among patients with undetectable MRD in the bone marrow before autologous SCT, the median PFS was 58.2 months with rituximab maintenance vs 48.8 months with observation (P=.0405; Figure 10).2 The median overall survival was longer with rituximab maintenance (58.2 vs 52.2 months; P=.0395). Among patients with undetectable MRD in the blood before transplant, the median PFS was longer with rituximab maintenance therapy than with observation (58.2 vs 52.2 months; P=.0260), but the median overall survival was similar (58.2 months vs not reached; P=.1326). According to the results of peripheral blood analysis after autologous SCT, MRD negativity was associated with a longer median PFS (58.2 vs 48.8 months; P=.0072), but the median overall survival was similar (58.2 vs 52.2 months). The median overall survival in patients with a negative PET result and concomitant undetectable MRD in the blood before transplant was superior to that in patients with a positive PET result and detectable MRD in the blood (P=.0002). According to the results of analyses performed after autologous SCT, a negative PET result and undetectable MRD were associated with a superior median PFS (blood, P<.0001; bone marrow, P=.0082) and a superior median overall survival (blood, P<.0001; bone marrow, P=.0474).
References
1. Le Gouill S, Thieblemont C, Oberic L, et al; LYSA Group. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017;377(13):1250-1260.
2. Callanan M, Macintyre E, Delfau-Larue MH, et al. Predictive power of early, sequential MRD monitoring in peripheral blood and bone marrow in patients with mantle cell lymphoma following autologous stem cell transplantation with or without rituximab maintenance; final results from the LyMa-MRD project, conducted on behalf of the LySa group [ASH abstract 120]. Blood. 2020;136(suppl 1).
Highlights in Mantle Cell Lymphoma From the 62nd American Society of Hematology Annual Meeting and Exposition: Commentary
Ian Flinn, MD, PhD
Director of Lymphoma Research
Sarah Cannon Research Institute
Tennessee Oncology
Nashville, Tennessee
Several studies presented at the 62nd American Society of Hematology (ASH) meeting provided important information for the management of mantle cell lymphoma. Data were presented for treatments such as Bruton tyrosine kinase (BTK) inhibitors, chimeric antigen receptor (CAR) T-cell therapy, LOXO-305, and venetoclax, lenalidomide, and rituximab.
BTK Inhibitors
BTK inhibitors have become an extremely important therapy for patients with relapsed mantle cell lymphoma. For most patients who develop relapsed disease after chemoimmunotherapy, with or without a stem cell transparent, second-line therapy is now firmly established as a BTK inhibitor. The first BTK inhibitor to gain approval from the US Food and Drug Administration (FDA) was ibrutinib.1 More recently, the BTK inhibitors acalabrutinib and zanubrutinib were approved.2,3 At the ASH meeting, Dr Michael Wang presented long-term efficacy and safety results from a phase 2 study of acalabrutinib monotherapy in 124 patients with relapsed/refractory mantle cell lymphoma.4 The long-term efficacy analysis showed that the remissions were durable. The median duration of response was 28.6 months. Some remissions have lasted more than 2 years. The median progression-free survival was 22 months. For some patients, particularly those with a complete remission, the progression-free survival was considerably longer. The results from this analysis reaffirm previous data suggesting that acalabrutinib may be better tolerated than ibrutinib.5 Acalabrutinib was associated with little of the atrial fibrillation that has been seen with ibrutinib.6 No new safety signals were identified. Acalabrutinib is a well-tolerated oral monotherapy for patients with relapsed mantle cell lymphoma. The question of which BTK inhibitor to use in a particular patient often comes down to adverse events. Based on the adverse event profile, acalabrutinib might be the preferential choice in patients with mantle cell lymphoma who have relapsed after a prior therapy.
Acalabrutinib appears to work exceedingly well in patients with mantle cell lymphoma that is not highly proliferative. For example, outcomes were better in patients with a Ki-67 index of less than 50%, which applies to the majority of those with mantle cell lymphoma.4 The median progression-free survival was 35.8 months in patients with a Ki-67 index of less than 50% vs 6.4 months in patients with a Ki-67 index of 50% or higher. Otherwise, acalabrutinib appeared to work well across the different prognostic groups.
The fact that BTK inhibitors work so well in patients with mantle cell lymphoma raises the question of whether these agents should be moved earlier in the course of treatment. Many different trials have evaluated the use of BTK inhibitors as frontline therapy, administered either with or before chemotherapy.7,8 Dr Preetesh Jain presented a study of older patients with mantle cell lymphoma treated with ibrutinib and rituximab, providing an important step toward the use of BTK inhibitors earlier in the treatment course.9 The trial enrolled previously untreated patients ages 65 years and older. The combination of ibrutinib and rituximab led to an overall response rate of 90%, including a complete response rate of 62%. The rate of undetectable minimal residual disease was 87%. Compared with chemoimmunotherapy, these results are very strong, or even better, especially in this older patient population.10
A substantial number of patients developed cardiac adverse events. Atrial fibrillation was reported in 22% of patients.9 In fairness to the study, enrollment encompassed patients with a history of atrial fibrillation. However, this rate of atrial fibrillation is still high, even after accounting for these patients.
Based on the results of this study, it may be possible to maintain this high response rate—but reduce the adverse events—by using a second-generation BTK inhibitor that is associated with less atrial fibrillation. The use of acalabrutinib or zanubrutinib might lead to less toxicity. This study is important because the results showed that moving a nonchemoimmunotherapy approach to frontline treatment achieved excellent results among patients with mantle cell lymphoma. Upcoming studies will likely evaluate a similar approach using other BTK inhibitors that might improve the adverse event profile. The results of this study might prove to be practice-changing for the group of patients who are not candidates for frontline treatment with very aggressive chemoimmunotherapy or stem cell transplant. Early treatment with a BTK inhibitor might be an important option for these patients.
CAR T-Cell Therapy
Dr Michael Wang presented long-term follow-up for patients with relapsed/refractory mantle cell lymphoma in the phase 2 ZUMA-2 trial, which evaluated KTE-X19 (brexucabtagene autoleucel).11 In 2020, brexucabtagene autoleucel received accelerated approval from the FDA for the treatment of patients with relapsed or refractory mantle cell lymphoma. This approval was based on earlier results from ZUMA-2.12 The initial study showed high rates of overall and complete response. The long-term follow-up analysis, performed at a median follow-up of 17.5 months, showed very long remissions. Among 60 evaluable patients, 29 (48%) remained in an ongoing response. A complete response was maintained in 28 of 40 patients (70%). At 15 months, the rate of progression-free survival was 59%.
The ZUMA-2 study enrolled patients with a poor prognosis who were difficult to treat.11,12 It was challenging to enroll these patients into the trial because of their advanced stage and significant symptoms. It is exciting to see early signs of a plateau in the progression-free survival curves. It will be necessary to follow patients for much longer to confirm the improvement. The follow-up analysis of ZUMA-2 did not identify any new safety signals.11 However, the initial report showed a high incidence of adverse events.12
A concern with CAR T-cell therapy is the toxicity profile, particularly cytokine-release syndrome and neurologic events. Brexucabtagene autoleucel is unique in that it has a CD28 signaling domain.12 Lisocabtagene maraleucel is a CAR T-cell therapy that uses the 4-1BB construct.13 Dr M. Lia Palomba presented safety and preliminary efficacy results for patients with relapsed/refractory mantle cell lymphoma treated with lisocabtagene maraleucel in the phase 1 TRANSCEND trial.14 The trial evaluated 2 different dose levels. The patients had received 2 or more lines of prior therapy, including a BTK inhibitor and an anti-CD20 agent. The eligibility criteria were similar to those in ZUMA-2.
The analysis provided data for 32 treated patients. The high response rates were similar to those reported in ZUMA-2.12 The overall response rate was 84%, including a response rate of 66%.14 The follow-up was relatively short, at a median of 5.9 months. It appeared that the adverse event profile was somewhat better than that for brexucabtagene autoleucel.15 The improvement in adverse events is important among these patients, who are often ill and difficult to treat. A therapy with fewer adverse events will permit treatment of more patients. There is also the possibility of moving treatment earlier in the natural history of the disease, which would have the greatest impact.
The data from these 2 trials are exciting. Confirmation of the results in follow-up analyses may change treatment of patients with mantle cell lymphoma.
LOXO-305
Treatment is currently unclear for patients with mantle cell lymphoma who develop progressive disease during second-line therapy with a BTK inhibitor. This question is a recent one, as it was not too long ago that the median survival of patients with mantle cell lymphoma was just a few years. Treatment with first-line and second-line therapies now leads to much longer median survival. There are several potential options for third-line therapy. LOXO-305 is a next-generation BTK inhibitor that is not covalently bound,16,17 in contrast to the BTK inhibitors approved by the FDA. Patients can develop mutations that render those BTK inhibitors ineffective. These mutations are most common among patients with chronic lymphocytic leukemia. They also arise in mantle cell lymphoma, even though these patients do not develop the same cysteine 481 mutation that occurs in chronic lymphocytic leukemia. The mutations are likely attributable to multiple mechanisms.
Dr Michael Wang presented results for patients with previously treated non-Hodgkin lymphoma who received LOXO-305 in a phase 1/2 trial.18 The study enrolled 61 patients with mantle cell lymphoma, 93% of whom had received prior treatment with a BTK inhibitor. Among patients with mantle cell lymphoma, the overall response rate was 52% in the entire cohort and also 52% among those patients who had previously received a BTK inhibitor. It was exciting to see these results. In general, when ibrutinib fails to achieve a response, a switch to zanubrutinib or acalabrutinib will not be successful. These drugs share the same mechanism of action and binding site. A response would be likely if treatment with ibrutinib was discontinued owing to intolerance, but not resistance.
More research is required to determine why LOXO-305 is effective in these patients. The trial did not report the reasons why patients had discontinued their previous BTK treatment, whether it was owing to resistance or adverse events. Further follow-up is needed to determine the median progression-free survival. However, it is important that there may be another BTK inhibitor for these patients. LOXO-305 is currently in trials that will hopefully lead to FDA approval.
Venetoclax, Lenalidomide, and Rituximab
Dr Mats Jerkeman presented the results of a phase 1 study of venetoclax, lenalidomide, and rituximab in patients with relapsed or refractory mantle cell lymphoma.19 As monotherapies, venetoclax and lenalidomide each have substantial activity in patients with mantle cell lymphoma.20,21 However, single agents are not appealing in this setting.
The trial by Dr Jerkeman established doses for these drugs.19 The preliminary results showed high efficacy for the triplet regimen. A caveat is that only 18% of patients had received previous treatment with a BTK inhibitor (ibrutinib). This regimen would need to be evaluated in a population with a higher rate of prior treatment with BTK inhibitors. These initial data should not lead to widespread adoption of this regimen in the community. Further follow-up is needed as more patients are accrued to the trial. However, it is important to continue to explore later-line treatment strategies for this difficult-to-manage patient population.
Disclosure
Dr Flinn reports the following disclosures. Consultancy (all payments made to Sarah Cannon Research Institute, not to the physician): AbbVie, AstraZeneca, BeiGene, Genentech, Gilead Sciences, Great Point Partners, Iksuda Therapeutics, Janssen, Juno Therapeutics, Kite Pharma, MorphoSys, Novartis, Nurix Therapeutics, Pharmacyclics, Roche, Seattle Genetics, Takeda, TG Therapeutics, Unum Therapeutics, Verastem, and Yingli Pharmaceutical. Research grants (all payments made to Sarah Cannon Research Institute, not to the physician): AbbVie, Acerta Pharma, Agios, ArQule, AstraZeneca, BeiGene, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Curis, Forma Therapeutics, Forty Seven, Genentech, Gilead Sciences, IGM Biosciences, Incyte, Infinity Pharmaceuticals, Janssen, Juno Therapeutics, Karyopharm Therapeutics, Kite Pharma, Loxo, Merck, MorphoSys, Novartis, Pfizer, Pharmacyclics, Portola Pharmaceuticals, Rhizen Pharmaceuticals, Roche, Seattle Genetics, Takeda, Teva, TG Therapeutics, Trillium Therapeutics, Triphase Research and Development Corp., Unum Therapeutics, and Verastem.
References
1. de Claro RA, McGinn KM, Verdun N, et al. FDA approval: ibrutinib for patients with previously treated mantle cell lymphoma and previously treated chronic lymphocytic leukemia. Clin Cancer Res. 2015;21(16):3586-3590.
2. Calquence [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals, LP; 2019.
3. Brukinsa [package insert]. San Mateo, CA: BeiGene USA, Inc; 2019.
4. Wang M, Rule S, Zinzani PL, et al. Acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study [ASH abstract 2040]. Blood. 2020;136(suppl 1).
5. Owen C, Berinstein NL, Christofides A, Sehn LH. Review of Bruton tyrosine kinase inhibitors for the treatment of relapsed or refractory mantle cell lymphoma. Curr Oncol. 2019;26(2):e233-e240.
6. Ganatra S, Sharma A, Shah S, et al. Ibrutinib-associated atrial fibrillation. JACC Clin Electrophysiol. 2018;4(12):1491-1500.
7. Wang ML, Jain P, Lee HJ, et al. Frontline treatment with ibrutinib plus rituximab (IR) followed by short course R-hyperCVAD/MTX is extremely potent and safe in patients (age ≤ 65 years) with mantle cell lymphoma (MCL)—results of phase-II window-1 clinical trial [ASH abstract 3987]. Blood. 2019;134(suppl 1).
8. Phillips TJ, Smith SD, Jurczak W, et al. Safety and efficacy of acalabrutinib plus bendamustine and rituximab (BR) in patients with treatment-naive (TN) or relapsed/refractory (R/R) mantle cell lymphoma (MCL) [ASH abstract 4144]. Blood. 2018;132(1 suppl).
9. Jain P, Yixin Y, Zhao S, et al. Combination of ibrutinib with rituximab in previously untreated older patients with mantle cell lymphoma (MCL)—a phase II clinical trial [ASH abstract 2042]. Blood. 2020;136(suppl 1).
10. Maddocks K. Update on mantle cell lymphoma. Blood. 2018;132(16):1647-1656.
11. Wang ML, Munoz J, Goy A, et al. One-year follow-up of ZUMA-2, the multicenter, registrational study of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma [ASH abstract 1120]. Blood. 2020;136(suppl 1).
12. 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.
13. Makita S, Imaizumi K, Kurosawa S, Tobinai K. Chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma: opportunities and challenges. Drugs Context. 2019;8:212567.
14. Palomba ML, Gordon LI, Siddiqi T, et al. Safety and preliminary efficacy in patients with relapsed/refractory mantle cell lymphoma receiving lisocabtagene maraleucel in TRANSCEND NHL 001 [ASH abstract 118]. Blood. 2020;136(suppl 1).
15. Reagan PM, Friedberg JW. Axicabtagene ciloleucel and brexucabtagene autoleucel in relapsed and refractory diffuse large B-cell and mantle cell lymphomas [published online January 15, 2021]. Future Oncol. doi:10.2217/fon-2020-0291.
16. Brandhuber B, Gomez E, Smith S, et al. LOXO-305, a next generation reversible BTK inhibitor, for overcoming acquired resistance to irreversible BTK inhibitors [SHO abstract S216]. Clin Lymphoma Myeloma Leuk. 2018;18(suppl 1).
17. Mato A, Flinn IW, Pagel JM, et al. Results from a first-in-human, proof-of-concept phase 1 trial in pretreated B-cell malignancies for LOXO-305, a next-generation, highly selective, non-covalent BTK inhibitor [ASH abstract 501]. Blood. 2019;134(suppl 1).
18. Wang ML, Shah NN, Alencar AJ, et al. LOXO-305, a next generation, highly selective, non-covalent BTK inhibitor in previously treated mantle cell lymphoma, Waldenström’s macroglobulinemia, and other non-Hodgkin lymphomas: results from the phase 1/2 BRUIN study [ASH abstract 117]. Blood. 2020;136(suppl 1).
19. Jerkeman M, Kolstad A, Niemann CU, et al. Venetoclax, lenalidomide and rituximab for patients with relapsed or refractory mantle cell lymphoma—data from the Nordic Lymphoma Group NLG-MCL7 (VALERIA) phase I trial: stopping treatment in molecular remission is feasible [ASH abstract 122]. Blood. 2020;136(suppl 1).
20. Eyre TA, Walter HS, Iyengar S, et al. Efficacy of venetoclax monotherapy in patients with relapsed, refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor therapy. Haematologica. 2019;104(2):e68-e71.
21. Zinzani PL, Vose JM, Czuczman MS, et al. Long-term follow-up of lenalidomide in relapsed/refractory mantle cell lymphoma: subset analysis of the NHL-003 study. Ann Oncol. 2013;24(11):2892-2897.