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Combinations are the Future for Chemotherapy-Free MCL Treatments

Jason Harris
Published Online:5:28 PM, Mon April 23, 2018

Michael Wang, MD
The B-Cell Lymphoma Moon Shot Program at The University of Texas MD Anderson Cancer Center wants to increase the cure rate of the disease from 30% to 60% within 5 years. In a presentation at the 22nd Annual International Congress on Hematologic Malignancies, Michael Wang, MD, detailed results from 3 clinical trials that may help make that 5-year goal into a reality for patients with mantle cell lymphoma (MCL).

In the ACE-LY-004 trial, investigators assessed acalabrutinib (Calquence) monotherapy in patients with relapsed/refractory disease. The FDA approved acalabrutinib for this indication in October 2017 based on these results.1 Wang, the co-leader of the B-Cell Lymphoma Moon Shot Program at MD Anderson and the founding director of the Mantle Cell Lymphoma Program of Excellence, served as principal investigator on the trial.

Patients (n = 124) received 100 mg of oral acalabrutinib twice daily. The median age of patients was 68 years (range, 42-90), most were male (80%), and 93% of patients had an ECOG performance status of 0 or 1. The median number of prior treatments was 2 (range, 1-5), which included stem cell transplant for 18% of patients, and the median time since diagnosis was 46.3 months. Those treated with a prior BTK inhibitor were excluded from the trial.

The objective response rate (ORR) was 81% (95% CI, 73%-87%) by investigator assessment and 80% (95% CI, 72%-87%) by independent review. The complete remission (CR) rate was 40% by both assessments.

Median progression-free survival (PFS) and overall survival (OS) were not reached. Twelve-month PFS was 67% (95% CI, 58%-75%) and 12-month OS was 87% (95% CI, 79%-92%).

The most common adverse events (AEs) of any grade were anemia (46%), thrombocytopenia (44%), headache (39%), neutropenia (36%), diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%). The most common grade ≥3 AEs were neutropenia (15%), thrombocytopenia (12%), anemia (10%), and diarrhea (3.2%). Serious AEs associated with acalabrutinib included hemorrhage, infections, and atrial fibrillation.

While acalabrutinib is approved as a monotherapy, Wang is convinced that combinations will deliver the best outcomes for patients with MCL treated on chemotherapy-free regimens. 

“I believe that, in the future, chemotherapy-free treatment should include 3 or 4 agents,” he said. “That will really beat the chemotherapy.”

Two studies involving combinations more closely align with the direction he expects the field to take.

In a phase I/II trial, investigators evaluated oral lenalidomide (Revlimid) plus rituximab (Rituxan) in relapsed/refractory MCL. Fifty-two patients who received 1 to 4 previous lines of treatment were enrolled in this single-arm, open-label trial at MD Anderson from February 2006 to July 2009.2

Phase I (n = 14) results established 20 mg of daily oral lenalidomide as the maximum tolerated dose (MTD). In phase II, 44 patients were assigned to the MTD of lenalidomide on days 1 to 21 of a 28-day cycle plus 375 mg/m2 of intravenous rituximab in 4 weekly doses during cycle 1 only. Treatment in both phases continued until disease progression, stem cell transplantation, or severe toxicity.

In the phase II efficacy results, the combination induced a median PFS of 11.1 months (range, 8.3-24.9). After a median follow-up of 23.1 months, median OS was 24.3 months (range, 19.8-not reached). The median duration of response was 18.9 months (range, 17-not reached).

ORR was 57%, with 16 (36%) CRs and 9 (20%) partial remissions. Ten (23%) patients had stable disease and 9 (20%) had progressive disease.

The most common grade 3/4 adverse events (AEs) in phase II were neutropenia (65.9%) and lymphopenia (36.3%). Only 2 patients (5%) experienced grade 3 febrile neutropenia.

As important as treatment is for relapsed/refractory patients, Wang said that MD Anderson takes the view that frontline therapy is absolutely crucial in MCL: “The frontline therapy could kill all the mantle cell lymphoma with the first strike, and therefore eliminating any chance for secondary resistance and causing long-term remission. If ideally optimized, we think frontline therapy is the shortcut to the cure.”

However, a strong response requires intensive therapy, which can cause toxicity and secondary malignancies. To find a way around those negative outcomes, investigators explored ibrutinib (Imbruvica) plus rituximab after consolidation with fewer courses of intense chemoimmunotherapy.3

Patients aged ≤65 years began enrolling in a 2-part, phase II single-center clinical trial in June 2015. In part 1, patients received ibrutinib/rituximab combination treatment until best response. Patients then underwent a shortened course of intense chemoimmunotherapy in Part 2.

Patients (n = 50) were assigned to 560 mg of continuous oral ibrutinib daily and 375 mg/m2 weekly rituximab. Rituximab was administered 4 times during the first 28-day cycle, then on day 1 of cycles 3 to 12. Intense chemoimmunotherapy consisted of rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternating every 28 days with rituximab plus high-dose methotrexate-Ara C.

Those in CR after initial ibrutinib/rituximab treatment received 4 additional treatments of intense chemoimmunotherapy. Patients in partial remissions or progression who responded to intensive chemoimmunotherapy received an additional 2 cycles after achieving CR.

Wang said that, if the patient achieved CR, the combination would reduce hyper-CVAD exposure from upward of 8 cycles to just 4, improving survival while also reducing toxicity.

Among the evaluable patients, the ORR was 100%, with an 80% rate of CR. Wang said that all patients achieved CR after 4 cycles of chemotherapy.

“We have, for the first time, a chemotherapy-free combination that achieved a response of 100% with a very high [complete remission] rate,” he said.
 
 
References:
  1. Wang M, Rule S, Zinzani PL, et al. Efficacy and safety of acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma in the phase 2 ACE-LY-004 study. Presented at: 2017 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta. Abstract 155.
  2. Wang M, Fayad L, Wagner‐Bartak N, et al. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol. 2012;13(7):716-723. doi: 10.1016/S1470-2045(12)70200-0.
  3. Wang M, Lee HJ, Thirumurthi S, et al. Chemotherapy-free induction with ibrutinib-rituximab followed by shortened cycles of chemo-immunotherapy consolidation in young, newly diagnosed mantle cell lymphoma patients: a phase II clinical trial. Presented at: ASH Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA. Abstract 147.


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