Simplified Mantle Cell Lymphoma International Prognostic Index Research Articles

Ibrutinib Combined with Venetoclax in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Primary Analysis Results from the Randomized Phase 3 Sympatico Study

Background: Ibrutinib (Ibr) is a once-daily Bruton tyrosine kinase (BTK) inhibitor approved in multiple regions for patients (pts) with mantle cell lymphoma (MCL) who have received ≥1 prior therapy. Venetoclax (Ven) is a BCL-2 inhibitor approved in the US for pts with chronic lymphocytic leukemia and previously untreated acute myeloid leukemia. Ibr and Ven have distinct and complementary modes of action, and the combination has shown promising clinical activity in early phase studies in MCL (Tam, N Engl J Med 2018; Wang, J Hematol Oncol 2021). Here, we report the primary analysis results from the multinational, randomized, double-blind, phase 3 SYMPATICO (NCT03112174) study comparing Ibr+Ven vs Ibr + placebo (Pbo) in pts with relapsed/refractory (R/R) MCL. Methods: Pts aged ≥18 y with R/R MCL after 1-5 prior therapies were randomly assigned 1:1 to receive oral Ibr 560 mg once daily concurrently with oral Ven (standard 5-wk ramp-up to a target dose of 400 mg once daily) or Pbo for 2 y, followed by single-agent Ibr until progressive disease (PD) or unacceptable toxicity. Randomization was stratified based on ECOG PS, prior lines of therapy, and tumor lysis syndrome (TLS) risk based on tumor burden and CrCl. The primary endpoint was progression-free survival (PFS) by investigator (INV) assessment using Lugano criteria; pts without PD or death were censored at the last non-PD assessment (per global censoring rules). Additional sensitivity analyses included PFS assessment by independent review committee (IRC) and censoring per US FDA rules (Table). Key secondary endpoints were tested hierarchically in the following order: complete response (CR) rate by INV assessment, time to next treatment (TTNT), overall survival (OS, interim analysis), and overall response rate (ORR) by INV assessment. Results: A total of 267 pts were enrolled and randomly assigned to receive Ibr+Ven (n=134) or Ibr+Pbo (n=133). Median age was 68 y; 96% of pts had an ECOG PS of 0-1, 17% had ≥3 prior lines of therapy, and 22% were at increased risk for TLS. At baseline, pts in the Ibr+Ven vs Ibr+Pbo arms had median ages 69 vs 67 y, high-risk simplified MCL International Prognostic Index score 38% vs 31%, bulky disease ≥5 cm 46% vs 40%, bone marrow involvement 46% vs 41%, splenomegaly 31% vs 25%, and TP53 mutated 30% vs 28%; other baseline characteristics were generally similar between arms. With a median time on study of 51.2 mo, median PFS by INV assessment was significantly longer with Ibr+Ven vs Ibr+Pbo (31.9 vs 22.1 mo), with a hazard ratio (HR) of 0.65 (95% CI, 0.47-0.88; stratified log-rank P=0.0052) (Figure). PFS rates at 24 mo were 57% and 45% with Ibr+Ven and Ibr+Pbo, respectively. PFS benefit with Ibr+Ven vs Ibr+Pbo was generally consistent across prespecified subgroups, including those with blastoid variant or TP53-mutated MCL. Sensitivity analyses of PFS were consistent with the primary analysis (Table). Ibr+Ven significantly improved CR rates (54% vs 32%) and TTNT (median not reached [NR] vs 35.4 mo); at the current 51.2 mo median follow-up, median OS was 44.9 mo with Ibr+Ven vs 38.6 mo with Ibr+Pbo (HR 0.85 [95% CI, 0.62-1.19]) (Table). Median duration of treatment was 22.2 mo for the Ibr+Ven arm and 17.7 mo for the Ibr+Pbo arm; at the time of analysis, 30% of pts in the Ibr+Ven arm and 20% of pts in the Ibr+Pbo arm remained on single-agent Ibr. Grade ≥3 adverse events (AEs) occurred in 84% of pts with Ibr+Ven vs 76% with Ibr+Pbo; the most frequent (occurring in ≥5% of pts) were neutropenia (31% vs 11%), pneumonia (13% vs 11%), thrombocytopenia (13% vs 8%), anemia (10% vs 3%), diarrhea (8% vs 2%), leukopenia (7% vs 0%), MCL (7% vs 12%), atrial fibrillation (5% vs 5%), COVID-19 (5% vs 1%), and hypertension (4% vs 9%). Serious AEs occurred in 60% of pts in each arm. No clinical TLS occurred; laboratory TLS occurred in 5% and 2% of pts in the Ibr+Ven and Ibr+Pbo arms, respectively. COVID-19 deaths occurred in 10 pts in each arm and had no meaningful impact on PFS or OS HRs. Conclusion: The Ibr+Ven combination demonstrated a statistically significant improvement in PFS compared with Ibr+Pbo in pts with R/R MCL; CR rates and TTNT were also significantly improved with Ibr+Ven. OS was numerically but not significantly improved at this interim analysis. The safety profile of Ibr+Ven was consistent with known AEs for each agent, with no new safety signals observed. Overall, these results demonstrate a favorable benefit-risk profile for Ibr+Ven in pts with R/R MCL.

Traverse: A Phase 2, Open-Label, Randomized Study of Acalabrutinib in Combination with Venetoclax and Rituximab in Patients with Treatment-Naive Mantle Cell Lymphoma

Background and Significance: Despite advances in treatment for mantle cell lymphoma (MCL), no curative option exists. Currently, the majority of patients with treatment-naive (TN) MCL receive chemoimmunotherapy, which can result in prolonged remissions, but is associated with significant toxicity. Almost all patients inevitably relapse, and therefore, frontline chemotherapy-free options are being increasingly explored. Acalabrutinib is a highly selective, second-generation Bruton tyrosine kinase inhibitor (BTKi) approved for the treatment of adult patients with relapsed/refractory (R/R) MCL. In a phase 1b study in patients with TN MCL, acalabrutinib in combination with venetoclax and rituximab (AVR) demonstrated high rates of clinical and molecular response with an acceptable toxicity profile, supporting its continued development as a chemotherapy-free treatment option (Wang et al. Blood. 2021; Wang et al. Blood. 2022). Furthermore, the occurrence of complete responses (CRs) with clearance of minimal residual disease (MRD) in MCL clinical trials suggests that treatment may be stopped in these patients, as observed in patients with chronic lymphocytic leukemia who received combination therapy with venetoclax and rituximab. Study Design and Methods: TrAVeRse (NCT#05951959) is a phase 2, open-label, randomized, multicenter, international study of AVR in patients with TN MCL. Patients aged ≥18 years with an Eastern Cooperative Oncology Group performance status of 0-2 (3 if due to lymphoma), and Ann Arbor stage II, III, or IV disease are eligible. Key exclusion criteria are active central nervous system involvement by lymphoma or leptomeningeal disease, severe/life-threatening illness or medical condition, clinically significant cardiovascular disease, stroke, or intracranial hemorrhage within 6 months of enrollment, and any active uncontrolled infection. Approximately 125 patients will be screened to achieve a study population of 100 patients. During the induction phase, patients will receive oral acalabrutinib 100 mg twice daily (BID) in 28-day cycles for 13 cycles, starting at cycle 1; oral venetoclax once daily, starting at cycle 2 at a dose of 20 mg daily, with ramp-up to a maximum of 400 mg daily over 5 weeks for a total of 12 cycles; and intravenous rituximab 375 mg/m 2 on day 1 of every cycle for 12 cycles, starting at cycle 1. Patients who complete 13 cycles of AVR induction will be centrally tested for MRD status and continue to receive acalabrutinib 100 mg BID for 1 additional cycle (cycle 14) while awaiting disease response assessment and MRD results. Patients who achieve an MRD-negative CR (in peripheral blood at a threshold of 10 -5) at the end of induction will be randomly assigned in a 1:1 ratio to either continue to receive acalabrutinib 100 mg BID or to observation from cycle 15. Randomization will be stratified according to the simplified MCL International Prognostic Index [sMIPI] score (low [score, 0-3] and intermediate risk [4-5] vs high risk [6-11]), histologic features (blastoid or pleomorphic vs classical histology), and TP53 status (mutated vs unmutated). Those with an MRD-positive CR, partial response (PR), or stable disease (SD) at end of induction will continue to receive acalabrutinib 100 mg BID until disease progression, death, or unacceptable toxicity. Patients who progress during observation may be retreated with acalabrutinib 100 mg BID at relapse. The primary endpoint of this study is the MRD-negative CR rate at the end of AVR induction (ie, end of cycle 13). Secondary endpoints include MRD-negative CR rate at any point during the study, objective response rate and CR rate, duration of response, time to next treatment, progression-free survival, event-free survival, overall survival, safety, and tolerability. The study will also assess the feasibility of response-adapted treatment cessation for those who achieve MRD-negative CR after AVR induction and the efficacy of acalabrutinib retreatment in the subgroup of patients randomized to observation who subsequently relapse. Patients will be followed for 36 months post last patient randomized. Enrollment is planned to begin Q3 of 2023 including sites in North America, Australia, and Europe. Summary: This study will evaluate the efficacy of AVR, a chemotherapy-free triplet combination therapy, in patients with TN MCL.

Evaluation of clinical parameters and biomarkers in older, untreated mantle cell lymphoma patients receiving bendamustine-rituximab.

Mantle cell lymphoma (MCL) is clinically and biologically heterogeneous. While various prognostic features have been proposed, none currently impact therapy selection, particularly in older patients, for whom treatment is primarily dictated by age and comorbidities. Herein, we undertook a comprehensive comparison of clinicopathological features in a cohort of patients 60 years and older, uniformly treated with bendamustine and rituximab, with a median survival of >8 years. The strongest prognostic indicators in this cohort were a high-risk call by a simplified MCL international prognostic index (s-MIPI) (HR: 3.32, 95% CI: 1.65-6.68 compared to low risk), a high-risk call by MCL35 (HR: 10.34, 95% CI: 2.37-45.20 compared to low risk) and blastoid cytology (HR: 4.21, 95% CR: 1.92-9.22 compared to classic). Patients called high risk by both the s-MIPI and MCL35 had the most dismal prognosis (HR: 11.58, 95% CI: 4.10-32.72), while those with high risk by either had a moderate but clinically relevant prognosis (HR: 2.95, 95% CI: 1.49-5.82). A robust assay to assess proliferation, such as MCL35, along with stringent guidelines for cytological evaluation of MCL, in combination with MIPI, may be a strong path to risk-stratify older MCL patients in future clinical trials.

Brexucabtagene Autoleucel for Relapsed or Refractory Mantle Cell Lymphoma in Standard-of-Care Practice: Results From the US Lymphoma CAR T Consortium.

Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication. Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines. Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis. In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

Pharmacokinetics, Safety, and Efficacy of Acalabrutinib in Chinese Patients with Relapsed/Refractory Mantle Cell Lymphoma and Other B-Cell Malignancies: An Open-Label, Multicenter Phase 1/2 Trial

Background: Acalabrutinib (Acala), a highly selective covalent inhibitor of Bruton tyrosine kinase with minimal off-target activity, is approved by the Food and Drug Administration (FDA) for the treatment of relapsed/refractory (R/R) mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The pivotal studies that supported Acala's approval were conducted predominantly in Europe and North America, with limited representation from Asian populations. This phase 1/2 study (NCT03932331) assessed the pharmacokinetics (PK), safety, and efficacy of Acala in Chinese patients (pts) with R/R MCL and other advanced B-cell malignancies. Methods: In phase 1, adult pts with R/R B-cell malignancies received a single dose of Acala 100 mg orally (day 1/cycle 0) followed by a 2-day washout period and subsequent treatment with Acala 100 mg orally twice daily in 28-day cycles, until progressive disease (PD) or treatment discontinuation (TD) for any other reason. Blood samples were collected to assess PK characteristics of Acala and its major metabolite, ACP-5862. In phase 2, adult pts with R/R MCL and ECOG status ≤2 received Acala 100 mg orally twice daily in 28-day cycles until PD or TD. Primary efficacy endpoint was overall response rate (ORR) per Lugano classification for non-Hodgkin lymphoma (Cheson 2014) assessed by blinded independent central review (BICR). Secondary endpoints were investigator (INV)-assessed ORR; BICR- and INV-assessed time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results: Patients were enrolled at 14 sites in China from April 29, 2020, to March 2, 2021. In phase 1, 14 pts were screened and 12 received treatment (CLL, n=4; follicular lymphoma, n=4; MCL, n=1; diffuse large B-cell lymphoma, n=1; SLL, n=2). At data cutoff (May 6, 2022), 7 pts were receiving Acala and 5 had TD (PD, n=4; AE, n=1). Acala exhibited time-independent PK and moderate to high variability (parent drug and metabolite), rapid drug absorption, approximately 2-fold higher exposure of metabolite than parent drug, rapid elimination of Acala and ACP-5862, and no significant accumulation of either parent drug or metabolite after multiple dosing (Table 1). In phase 2 (MCL cohort), 45 pts were screened; 34 were enrolled (phase 1, n=1; phase 2, n=33), all received ≥1 dose of Acala, and were included in the safety and efficacy analyses. The MCL cohort was predominantly male (88.2%), median age was 63 y, 73.5% had ECOG status 0, 64.7% had extranodal disease, 35.3% had bone marrow involvement, 5.9% had high simplified MCL International Prognostic Index score, and median number of prior anticancer therapy regimens was 3 (range 1-5). Median duration of treatment was 14.0 mo (range 1.2-23.6). ORR by BICR was 82.4% (95% CI 65.5-93.2); CR rate was 35.3%, median TTR was 1.8 mo (range 1.6-3.7), and estimated 12-mo DOR rate was 62.7% (95% CI 41.5-78.0); median DOR was not reached. INV assessments were generally concordant with BICR assessments for ORR (73.5% [95% CI 55.6-87.1]), CR rate (38.2%), median TTR (1.9 mo; range 1.6-3.7), and estimated 12-mo DOR rate (65.5% [95% CI 42.1-81.3]). Estimated 12-mo PFS rate was 51.5% (95% CI 33.3-67.0) by BICR and 58.3% (95% CI 39.9-72.9) by INV. Estimated 12-mo OS was 84.5% (95% CI 66.6-93.3).Twenty-nine pts (85.3%) reported AEs of any grade; 15 pts (44.1%) had grade ≥3 AEs, most commonly anemia (8.8%, n=3) and decreased neutrophil count (8.8%, n=3) (Table 2). AEs led to treatment discontinuation in 3 pts (8.8%) due to aplastic anemia (n=1), thrombocytopenia (n=1), and gastrointestinal infection (n=1). Six pts (17.6%) had serious AEs. Fatal AEs were reported in 2 pts (aplastic anemia [n=1], multiple organ dysfunction syndrome [n=1]). There were no cases of atrial fibrillation, major hemorrhage, hypertension, second primary malignancies, or tumor lysis syndrome. Conclusions: This is the first study to evaluate Acala PK, safety, and efficacy in a Chinese population with R/R B-cell malignancies. Acala was rapidly absorbed and showed no signs of accumulation after multiple doses. Treatment with Acala provided high response rates in the R/R MCL cohort, with efficacy results similar to those of the pivotal, global ACE-LY-004 study in a predominantly Caucasian population with R/R MCL (Wang M et al. Lancet 2018;391:659-67). Acala had a tolerable safety profile in Chinese pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Matching-Adjusted Indirect Comparisons of the Efficacy and Safety of Acalabrutinib Versus Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma

Introduction: Acalabrutinib (Acala) and ibrutinib (Ibr), as single agents, are both highly effective Bruton tyrosine kinase inhibitors approved for the treatment of relapsed/refractory mantle cell lymphoma and chronic lymphocytic leukemia. Both are given as continuous oral treatments until disease progression or unacceptable toxicity. In the absence of a head-to-head clinical study in this setting, this analysis aims to compare the efficacy and safety of Acala versus Ibr for the treatment of relapsed/refractory mantle cell lymphoma (MCL) using matching-adjusted indirect comparison (MAIC). This MAIC slightly differs from the published analysis by Telford et al (Clin Ther. 2019;41:2357-79) by using long-term follow-up data for efficacy outcomes and assessing whether the safety profile of Acala is sustained over a longer term when compared with Ibr. Methods: Individual patient data for Acala from LY-004 (38 months median follow-up) (Wang et al. ASCO 2021) were weighted to match the aggregate baseline characteristics of the Ibr monotherapy arm from a pooled analysis with 41.4 months median follow-up (Rule et al. Hematologica. 2019.04:e212). These baseline characteristics, Eastern Cooperative Oncology Group performance status, simplified MCL International Prognostic Index score, lactate dehydrogenase, prior lines of therapy, bulky disease, and blastoid histology, are potential prognostic variables (PVs). Pseudo-individual patient data were generated from the digitized Kaplan-Meier curves published in the aforementioned comparator trials. As the LY-004 trial is a single-arm trial, an unanchored MAIC was conducted to adjust for these PVs. The PVs selected were based on literature, clinical judgment, and demonstrated statistically significant association with progression-free survival (PFS) in univariate and multivariate regression analysis (Ahn et al. J Clin Oncol. 2020;39:576-85; Eichorst and Hallek. Hematol Am Soc Hematol Educ Prog. 2016;1:149-55). After matching, a weighted Cox proportional-hazards model was used to analyze PFS and overall survival (OS) while a weighted logistic regression model was used for comparative safety analysis (grade ≥3 adverse events [AEs]). Two-sided P<0.05 was considered statistically significant. Results: In the Acala vs Ibr comparison before matching, PFS and OS favored Acala and were statistically significant. After matching, PFS and OS numerically favored Acala but the difference was not significant (Table). In the Telford et al study, significant differences were observed in grade 3/4 atrial fibrillation (afib) and thrombocytopenia. Similarly, in the current analysis, rates of afib and thrombocytopenia were significantly lower with Acala vs Ibr. In addition, rates of grade 3/4 AEs were numerically lower with Acala than Ibr for neutropenia, pneumonia, and hypertension. Conclusions: Based on these MAIC results, in addition to a similar efficacy benefit vs Ibr, Acala was associated with a consistent safety profile over the long term. A limitation of this MAIC is not including all potential PVs as a trade-off to conserve the effective sample size. However, the use of longer follow-up data improved the robustness of the indirect comparisons of safety and efficacy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-term Outcomes With Ibrutinib Treatment for Patients With Relapsed/Refractory Mantle Cell Lymphoma: A Pooled Analysis of 3 Clinical Trials With Nearly 10 Years of Follow-up.

Long-term Outcomes With Ibrutinib Treatment for Patients With Relapsed/Refractory Mantle Cell Lymphoma: A Pooled Analysis of 3 Clinical Trials With Nearly 10 Years of Follow-up.

Safety and Efficacy of Acalabrutinib Plus Venetoclax and Rituximab in Patients with Treatment-Naïve (TN) Mantle Cell Lymphoma (MCL)

Safety and Efficacy of Acalabrutinib Plus Venetoclax and Rituximab in Patients with Treatment-Naïve (TN) Mantle Cell Lymphoma (MCL)

Evolving frontline immunochemotherapy for mantle cell lymphoma and the impact on survival outcomes

AbstractBecause there have been a dvances in frontline treatment for mantle cell lymphoma (MCL) over the last 2 decades, we sought to characterize the changes in frontline treatment patterns and their association with outcomes. Patients with newly diagnosed MCL from September 2002 through June 2015 were enrolled in a prospective cohort study, and clinical characteristics, treatment, and clinical outcomes were compared between patients diagnosed from 2002 to 2009 (Era 1) compared with 2010 to 2015 (Era 2). Patient age, sex, and simplified MCL International Prognostic Index (sMIPI) score were similar between the 2 groups. In patients age 65 years or younger, there was less use of rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-Hyper-CVAD) (16.1% vs 8.8%) but more use of rituximab plus maximum-strength cyclophosphamide, doxorubicin, vincristine, and prednisone (R-maxi-CHOP) alternating with rituximab plus high-dose cytarabine (R-HiDAC), also known as the Nordic regimen, and R-CHOP alternating with rituximab plus dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) (1.1% vs 26.4%) and less use of R-CHOP or R-CHOP-like regimens (64.5% vs 35.2%) but more use of R-bendamustine (0% vs 12.1%) in Era 2 (P < .001). These changes were associated with improved event-free survival (EFS; 5-year EFS, 34.3% vs 50.0%; P = .010) and overall survival (OS; 5-year OS, 68.8% vs 81.6%; P = .017) in Era 2. In patients older than age 65 years, there was less use of R-CHOP or R-CHOP-like therapy (39.0% vs 14.3%) and nonstandard systemic therapy (36.6% vs 13.0%) but more use of R-bendamustine (0% vs 49.4%). These changes were associated with a trend for improved EFS (5-year EFS, 25.4% vs 37.5%; P = .051) in Era 2. The shift from R-CHOP or R-CHOP-like regimens to R-bendamustine was associated with improved EFS (5-year EFS, 25.0% vs 44.6%; P = .008) in Era 2. Results from this prospective cohort study provide critical real-world evidence for improved outcomes with evolving frontline patterns of care in patients with MCL.

Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Long-Term Efficacy and Safety Results from a Phase 2 Study

Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Long-Term Efficacy and Safety Results from a Phase 2 Study

Long-Term Outcomes with Ibrutinib Versus the Prior Regimen: A Pooled Analysis in Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) with up to 7.5 Years of Extended Follow-up

Long-Term Outcomes with Ibrutinib Versus the Prior Regimen: A Pooled Analysis in Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) with up to 7.5 Years of Extended Follow-up

Matching-adjusted Indirect Comparisons of the Efficacy and Safety of Acalabrutinib Versus Other Targeted Therapies in Relapsed/Refractory Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma that can be either aggressive or indolent. Although MCL usually responds well to initial treatment with chemotherapy-based regimens, the disease often relapses or becomes refractory within a few years. Acalabrutinib is a highly selective, potent, covalent Bruton tyrosine kinase inhibitor with minimal off-target activity. WIthout head-to-head clinical trial data, estimation of the comparative efficacy and safety of new therapeutic entities provides valuable information for patients, clinicians, and health care payers. The objective of this analysis was to compare the efficacy and safety of acalabrutinib versus other targeted therapies employed for the treatment of relapsed/refractory MCL by using matching-adjusted indirect comparisons. Individual data from 124 patients treated with acalabrutinib in the Phase II ACE-LY-004 trial were adjusted to match average baseline characteristics of populations from studies using alternative targeted treatment regimens for relapsed/refractory MCL (for monotherapy: ibrutinib, bortezomib, lenalidomide, and temsirolimus; for combination therapies: ibrutinib+rituximab, bendamustine+rituximab, and lenalidomide+rituximab). Patient populations were matched on age, sex, race, Eastern Cooperative Oncology Group performance status, Simplified MCL International Prognostic Index score, tumor bulk, lactate dehydrogenase concentration, extranodal disease, bone marrow involvement, and number of previous treatment regimens. Outcomes assessed included overall response rate (ORR), complete response (CR) rate, overall survival (OS), progression-free survival (PFS), and adverse events. After matching, acalabrutinib was associated with significant increases in ORR and CR rate (estimated treatment difference [95% CI]) versus ibrutinib (ORR, 9.3% [0.3-18.3]; CR, 14.9% [5.4-24.3]), bortezomib (ORR, 50.6% [40.2-61.0]; CR, 18.8% [9.1-28.5]), lenalidomide (ORR, 38.1% [27.1-49.1]; CR, 43.5% [34.8-52.3]), and temsirolimus (ORR, 40.7% [31.0-50.4]; CR, 27.1% [19.2-35.0]). PFS (hazard ratio [95% CI]) with acalabrutinib was significantly increased versus bortezomib (0.36 [0.26-0.51]), lenalidomide (0.65 [0.48-0.89]), lenalidomide+rituximab (0.57 [0.35-0.93]), and temsirolimus (0.33 [0.24-0.45]). Acalabrutinib was associated with significantly increased OS (hazard ratio) versus bortezomib (0.36 [0.22-0.61]) and temsirolimus (0.32 [0.23-0.44]). The overall safety profile of acalabrutinib was similar or better compared with the monotherapies; however, infection risk increased versus bendamustine+rituximab, and anemia increased risk versus lenalidomide+rituximab and ibrutinib+rituximab. This comparison of targeted therapies used in the treatment of relapsed/refractory MCL showed that acalabrutinib has the potential to provide increased response rates, with trends for increased PFS and OS, and an improved safety profile.

Low absolute NK cell counts in peripheral blood are associated with inferior survival in patients with mantle cell lymphoma.

Although risk stratification of mantle cell lymphoma (MCL) is most frequently performed using the simplified MCL International Prognostic Index (sMIPI), the identification of host-related factors and tumor microenvironment, including absolute monocyte counts (AMC) and peripheral blood T lymphocyte subsets, especially absolute natural killer cell counts (ANKC) has been suggested to be critical in the prediction of prognosis and the guidance of treatment. This study was aimed at investigating whether peripheral blood ANKC and AMC at diagnosis had an impact on MCL prognosis. A total of 92 newly diagnosed MCL patients was enrolled in this retrospective study. Flow cytometric analysis was conducted on fresh peripheral blood samples with a FACSCalibur flow cytometer (BD Biosciences, San Jose, CA, USA). The median follow-up was 42 months (range, 2-144 months) and the median overall survival (OS) of all cases was 45 months. High AMC (> 0.6 × 109/L) was the parameter associated with inferior progression free survival (PFS) (P= 0.044) and poor OS (P= 0.028) while low ANKC (⩽ 0.1 × 109/L) was associated with unfavorable OS (P= 0.023) by univariable analysis. Multivariable analysis revealed that only low ANKC (⩽ 0.1 × 109/L) was statistically significant in worse OS (P= 0.009) independent of sMIPI. Low ANKC (⩽ 0.1 × 109/L) proved to be a significant predictor of inferior OS in patients with MCL.

Long-Term Follow-up of Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma

Long-Term Follow-up of Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma

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)

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)

Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open-label studies.

Ibrutinib is highly active in treating mantle cell lymphoma (MCL), an aggressive B-cell lymphoma. We pooled data from three ibrutinib studies to explore the impact of baseline patient characteristics on treatment response. Patients with relapsed/refractory MCL (n=370) treated with ibrutinib had an objective response rate (ORR) of 66% (20% complete response; 46% partial response); median duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were 18·6, 12·8 and 25·0months, respectively. Univariate analyses showed patients with one versus >one prior line of therapy had longer OS. Multivariate analyses identified that one prior line of therapy affected PFS; Eastern Cooperative Oncology Group (ECOG) performance status, simplified MCL international prognostic index (sMIPI) score, bulky disease, and blastoid histology affected OS and PFS. Patients with blastoid versus non-blastoid histology had similar time to best response, but lower ORR, DOR, PFS and OS. OS and PFS were longer in patients with better sMIPI, patients with ECOG performance status 0-1, non-bulky disease and non-blastoid histology. Additionally, the proportion of patients with poor prognostic factors increased with increasing lines of therapy. Together, results suggest that patient outcomes following treatment failure with ibrutinib are related to the natural biological evolution of the disease.

Negative prognostic impact of low absolute CD4+ T cell counts in peripheral blood in mantle cell lymphoma.

Tumor microenvironment and host immunity are closely related to outcome in patients with mantle cell lymphoma (MCL). However, few researchers have focused on the prognostic value of peripheral blood lymphocyte subsets counts. The purpose of this study was to investigate the prognostic value of lymphocyte subsets and absolute monocyte counts. Sixty‐eight patients were analyzed retrospectively. Absolute CD4+ T cell counts (ACD4C), CD8+ T cell counts, nature killer cell counts, and CD4/CD8 ratios were assessed by peripheral blood flow cytometry and correlated with clinical parameters and long‐term outcomes. The median follow‐up for all patients was 21 months and the median survival time was 44 months. The overall survival (OS) rate at 1, 3, and 5 years was 80%, 51%, and 41%, respectively. In our cohort, high absolute monocyte count, and low ACD4C and CD4/CD8 ratio were associated with unfavorable OS (P = 0.029, P = 0.027, and P = 0.045, respectively) by univariate analysis. Multivariate analysis indicated that low ACD4C was a significant predictor of unfavorable OS (P = 0.004) independent of the simplified MCL International Prognostic Index (P = 0.048) in patients treated with or without rituximab (P = 0.011). Low CD4+ T cell counts proved to be a significant predictor of unfavorable OS in patients with MCL.

Ibrutinib Vs Temsirolimus: Results from a Phase 3, International, Randomized, Open-Label, Multicenter Study in Patients with Previously Treated Mantle Cell Lymphoma (MCL)

IntroductionMCL is an aggressive B-cell lymphoma with a poor overall prognosis. For patients who fail initial therapy, conventional chemotherapy achieves only short-term remissions. Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton's tyrosine kinase that has been shown to be highly active for previously treated MCL patients (overall response rate [ORR] ~65%; complete response [CR] ~20%) in single-arm phase 2 studies. Temsirolimus has demonstrated significantly longer progression-free survival (PFS) vs investigator's choice. In this phase 3, randomized, open-label study (MCL3001 [RAY]), ibrutinib was compared with temsirolimus in patients with relapsed or refractory (R/R) MCL who had received ≥1 prior rituximab-containing therapy.MethodsPatients were randomized at a 1:1 ratio to receive oral ibrutinib (560 mg once-daily) or intravenous temsirolimus (175 mg: Days 1, 8, and 15 of Cycle 1; 75 mg: Days 1, 8, and 15 of subsequent cycles). Stratification factors were number of prior lines of therapy (1-2 vs ³3) and simplified MCL international prognostic index (sMIPI) risk (low [0-3] vs intermediate [4-5] vs high [6-11]). Patients in both arms received treatment until disease progression or unacceptable toxicity. Primary end point of the study was PFS, as assessed by an independent review committee (IRC). Secondary end points included ORR, overall survival (OS), time to next treatment (TTNT), time to worsening of lymphoma symptoms (measured by FACT-Lym lymphoma subscale), and safety.ResultsOverall, 280 patients were randomized to ibrutinib (n = 139) or temsirolimus (n = 141). Baseline disease characteristics and demographics were generally well balanced. Median age (range) was 68 years (34-88) and median number (range) of prior lines of therapy was 2 (1-9). Approximately two-thirds of the patients had intermediate- or high-risk disease. At the time of this analysis, median follow-up was 20.0 months. Ibrutinib was superior to temsirolimus for the primary end point of IRC-assessed PFS, with a statistically significant 57% reduction in the risk of progression or death (Figure 1). The median PFS was 14.6 months for the ibrutinib arm and 6.2 months for the temsirolimus arm, respectively. At a landmark of 2 years, the PFS rate is 41% in the ibrutinib arm vs 7% in the temsirolimus arm. PFS results were consistent across most assessed subgroups. Investigator-assessed PFS was consistent with the IRC results. IRC-assessed ORR was significantly higher for ibrutinib vs temsirolimus (71.9% vs 40.4%; p < 0.0001) with a CR rate of 18.7% vs 1.4%, respectively. Median OS was not reached with ibrutinib vs 21.3 months with temsirolimus, showing a positive trend toward patients in the ibrutinib arm (reduced risk of death by 24% [HR, 0.76; 95% CI, 0.53-1.09]). However, these results may have been confounded by 23% of patients that initially received temsirolimus crossing over to receive ibrutinib. A greater proportion of patients treated with ibrutinib vs temsirolimus avoided worsening of lymphoma symptoms throughout the study; 27% of ibrutinib patients had worsening vs 52% of temsirolimus patients. Median TTNT was not reached with ibrutinib vs 11.6 months with temsirolimus. Median treatment duration was 14.4 months for ibrutinib and 3.0 months for temsirolimus. Overall, 6.5% of subjects discontinued treatment due to AEs in the ibrutinib arm and 25.5% of subjects discontinued treatment due to AEs in the temsirolimus arm. The most common TEAEs with ibrutinib were diarrhea, fatigue, and cough, whereas with temsirolimus, thrombocytopenia, anemia, and diarrhea were most commonly observed (Table 1). Grade ³3 TEAEs were reported for 67.6% of ibrutinib patients vs 87.1% of temsirolimus patients; most frequent were thrombocytopenia, anemia, and neutropenia. When adjusted for exposure, TEAE incidence was consistently lower for the ibrutinib arm vs the temsirolimus arm.ConclusionsIbrutinib is superior to temsirolimus for PFS and ORR, and showed preferable tolerability. The results of this phase 3 trial confirm the efficacy and favorable safety profile of ibrutinib shown in phase 2 studies. Future concepts will investigate ibrutinib-based combination approaches for patients with R/R MCL. [Display omitted] [Display omitted] DisclosuresRule:Gilead: Research Funding; Celgene: Consultancy, Other: Travel reimbursement; J&J: Consultancy, Other: Travel reimbursement, Research Funding; Roche: Consultancy, Other: Travel reimbursement. Rusconi:Roche: Honoraria. Joao:Celgene, Novartis: Consultancy; Janssen, Roche: Membership on an entity's Board of Directors or advisory committees. Witzens-Harig:Pfizer: Honoraria, Research Funding; Roche: Honoraria. Hess:Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding; Janssen, Roche, , Celgene, Novartis: Consultancy. Balasubramanian:Janssen: Employment, Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Bandyopadhyay:Janssen: Employment. Sun:Janssen/J&J: Employment, Equity Ownership. Goldberg:Janssen: Employment. Bothos:Janssen: Employment. Traina:Janssen: Employment. Enny:Janssen: Employment. Rizo:Janssen: Employment. Vermeulen:Janssen: Employment.

Lymphoma Symptoms: Data from a Phase 3, International, Randomized, Open-Label, Multicenter Study in Patients with Previously Treated Mantle Cell Lymphoma (MCL) Treated with Ibrutinib Vs. Temsirolimus

IntroductionMCL is an incurable aggressive B-cell lymphoma with a poor overall prognosis. For patients with MCL who fail initial therapy (ie, with relapsed or refractory [R/R] disease), treatment options historically have been limited. While remission duration is generally short, the goal of therapy has been to achieve remission while balancing treatment-related toxicities. Consequently, a substantial proportion of patients continuously suffer from lymphoma symptoms and other disease signs, such as itching and trouble sleeping or concentrating. Additionally, worries and high emotional sensitivity lead to reduced functional status and well-being. Therefore, it is crucial to any treatment to maintain and improve the functional status and well-being of patients with R/R MCL for as long as possible throughout the treatment period.MethodsRAY (MCL3001) is a phase 3, randomized, open-label, multicenter study in patients with R/R MCL. Patients were randomized in a 1:1 ratio to receive ibrutinib (560 mg once daily) or temsirolimus (175 mg on days 1, 8, and 15 of Cycle 1; 75 mg on days 1, 8, and 15 of subsequent cycles). Stratification factors were the number of prior lines of therapy (1-2 vs ³3) and simplified MCL international prognostic index risk (low [0-3] vs intermediate [4-5] vs high [6-11]). Patients in both arms received treatment until disease progression or unacceptable toxicity. Primary end point of the study was progression-free survival (PFS), as assessed by an independent review committee. Lymphoma symptoms were assessed using the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) questionnaire lymphoma subscale. The FACT-Lym was administered before any tests, procedures, or other consultations, and was used until disease progression, death, or the clinical cutoff, whichever came first. Median time to worsening (TTW), a prespecified secondary end point, and time to clinically meaningful improvement (TTI) on the lymphoma subscale were estimated. Worsening was defined as a ≥ 5-point decrease from baseline and clinically meaningful improvement as a ≥ 5-point increase from baseline. TTW and TTI on the lymphoma subscale were examined using Kaplan-Meier methods.ResultsIn total, 280 patients were randomized to ibrutinib (n = 139) or temsirolimus (n = 141); 253 patients (ibrutinib, n = 130; temsirolimus, n = 123) provided FACT-Lym lymphoma subscale responses at baseline. Patients were compliant to therapy, and attrition was balanced between treatment arms. Disease characteristics and demographics at baseline (including FACT-Lym lymphoma subscale scores) were also generally well balanced. The study met its primary end point with a statistically significant 57% reduction in disease progression or death (PFS) with ibrutinib versus temsirolimus (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.32-0.58; p < 0.0001). The median PFS was 14.6 months for the ibrutinib arm and 6.2 months for the temsirolimus arm. When adjusted for exposure, incidence of TEAEs was lower for the ibrutinib arm than the temsirolimus arm. The proportion of patients with worsening from baseline on the FACT-Lym lymphoma subscale was lower for ibrutinib compared with temsirolimus (26.6% vs 51.8%, respectively). Median TTW was not reached with ibrutinib versus 9.7 weeks with temsirolimus, with a statistically significant reduction in the risk of worsening of 73% (p < 0.0001; Figure 1). The proportion of patients with a clinically meaningful improvement from baseline on the FACT-Lym lymphoma subscale was higher for ibrutinib compared with temsirolimus (61.9% vs 35.5%, respectively). Median TTI was shorter for ibrutinib compared with temsirolimus (6.3 weeks vs 57.3 weeks, respectively; HR, 2.19; p < 0.0001; Figure 2).ConclusionsRAY (MCL3001) is the first trial comparing different targeted approaches in R/R MCL. The presented data indicate that ibrutinib is associated with greater improvements and less worsening in lymphoma symptoms compared with temsirolimus, as measured by the lymphoma subscale of the FACT-Lym. These results suggest that the superior efficacy results and favorable safety profile of ibrutinib are accompanied by better lymphoma symptom outcomes, indicating significant clinical benefit for the majority of patients with R/R MCL. [Display omitted] [Display omitted] DisclosuresHess:Pfizer, Janssen, Roche, Mundipharma: Honoraria, Research Funding; Janssen, Roche, Celgene, Novartis: Consultancy. Rule:J&J: Consultancy, Other: Travel reimbursement, Research Funding; Roche: Consultancy, Other: Travel reimbursement; Celgene: Consultancy, Other: Travel reimbursement; Gilead: Research Funding. Jurczak:CELLTRION, Inc,: Research Funding. Rusconi:Roche: Honoraria. Witzens-Harig:Pfizer: Honoraria, Research Funding; Roche: Honoraria. Bandyopadhyay:Janssen: Employment. Goldberg:Janssen: Employment. Bothos:Janssen: Employment. Enny:Janssen: Employment. Vermeulen:Janssen: Employment. Traina:Janssen: Employment.

Mantle cell lymphoma: a model for risk-adapted treatment approach.

Mantle cell lymphoma (MCL) is a rare but unique subtype of non-Hodgkin B-cell lymphoma that is molecularly characterized by the chromosomal translocation, t(11;14) (q13;q32) leading to the aberrant expression of cyclin D1, although a few cases are positive for cyclin D2 or D3 without expression of cyclin D1 [1, 2]. In the current issue of the Blood Research, Kang et al. reported the results of nationwide retrospective analysis regarding clinical features and treatment outcomes of 131 patients with MCL [3]. This is one of the largest series focused on MCL, especially in Asian patients. In the study, they summarized clinical features and treatment outcomes of MCL and validated the prognostic value of simplified MIPI (Mantle cell lymphoma International Prognostic Index) in Korean MCL patients. Although many studies about other subtypes of lymphomas in Korea including retrospective analyses as well as clinical trials have been reported, there are just a few studies regarding Korean MCL patients. One of the reasons for the lack of studies is the relatively low incidence of MCL because it accounts only for 2% of B-cell lymphomas in Korea [4]. However, peculiar clinical characteristics of MCL different from other subtypes of non-Hodgkin lymphoma might be another reason. First of all, MCL occurs more commonly in elderly patients, and the majority cases of MCL initially follow indolent clinical course without symptoms. Although MCL responds to conventional chemotherapy regimens, the duration of response is relatively shorter than other subtypes, and repeated relapses ultimately lead to death in MCL. This extremely low curability of MCL with conventional chemotherapy has leaded to watch and wait strategy for asymptomatic patients or elderly patients similar to the treatment strategy for indolent lymphomas. However, some patients initially present as aggressive disease and need immediate intensive treatments. As a result, there is a wide spectrum of clinical behaviors and various treatment approaches in MCL [1, 5]. This heterogeneity associated with MCL might have made it hard to study. Owing to lengthy asymptomatic indolent period, MCL patients are commonly diagnosed with advanced stage disease after their extent of disease increased up to the state of producing significant symptoms. Thus, patients might have extensive lymphadenopathy, bone marrow invasion, splenomegaly, and frequent involvement of gastrointestinal tract at diagnosis, and almost all patients finally require treatments during their clinical course [6]. Therefore, the risk-stratification for MCL patients is mandatory for the determination of treatment strategy. As Kang et al. reported its prognostic value, the simplified MIPI incorporating age, performance status, serum lactate dehydrogenase level, and white blood cell count, can predict the survival outcome for patients with MCL [7]. Thus, the risk-adapted treatment approach according to the simplified MIPI might help physicians decide their treatment for MCL patients. As various initial treatment options became available in Korea from intensive treatments such as hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose cytarabine and methotrexate plus rituximab (R-hyper-CVAD) to standard chemotherapy regimens such as rituximab-CHOP and bendamustine-rituximab (BR), the risk-adapted application of treatment might lead to better survival outcome for MCL patients than that of this retrospective analysis. Especially, considering elderly patients might be more vulnerable to anthracycline-containing chemotherapy-related toxicity, bendamustine in combination with rituximab can be more appropriate for elderly frail patients with MCL. Indeed, the phase III trial comparing BR with R-CHOP demonstrated that BR had a similar response rate to R-CHOP, but BR had less hematologic toxicity as well as significantly lower progression rate than R-CHOP [8]. Furthermore, newer drugs such as Bruton's tyrosine kinase inhibitor (Ibrutinib) and PI3K inhibitor (Idelalisib) might become a useful treatment option for salvage as well as upfront treatment setting considering their promising outcomes in relapsed or refractory MCL patients [9, 10]. Taken together, this report contributes valuable information for the management of MCL patients through a nationwide retrospective analysis of large number of patients with MCL in Korea. A prospective study should be warranted in the near future to overcome the limits of this retrospective study.