Induction treatment with ibrutinib and rituximab was safe and active in patients with mantle cell lymphoma aged 65 years or younger, allowing for fewer cycles of subsequent chemotherapy with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone thereby reducing toxicity.
Induction treatment with ibrutinib (Imbruvica) and rituximab (Rituxan) was safe and active in patients with mantle cell lymphoma (MCL) aged 65 years or younger, allowing for fewer cycles of subsequent chemotherapy with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HCVAD) thereby reducing toxicity, according to data from a phase 2 WINDOW-1 study (NCT02427620) published in The Lancet Oncology.1
Among all 131 patients in the study, the overall response rate (ORR) was 98% (95% CI, 95%-100%), with a complete response (CR) rate of 87% (95% CI, 80%-92%) and a partial response (PR) rate of 11% (95% CI, 7%-18%), meeting the primary end point of the study.
For part A of the trial specifically, where patients received induction ibrutinib plus rituximab, the ORR at 16 weeks was 89% (95% CI, 83%-94%) among 129 evaluable patients, with a CR rate of 14% (95% CI, 8%-21%).
“A chemotherapy-free ibrutinib/rituximab induction followed by [a] short course of consolidative chemotherapy with R-HCVAD and methotrexate/cytarabine is a feasible and active frontline treatment option for patients with MCL,” Michael Wang, MD, of The University of Texas MD Anderson Cancer Center, and colleagues, wrote in the paper.
For patients with MCL who are younger than 65 years, intensive chemoimmunotherapy, such as R-HCVAD alternating with methotrexate/cytarabine, or a regimen comprised of rituximab plus dose-intensified cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without autologous hematopoietic stem cell transplant and rituximab maintenance, serve as the standard options in the first-line treatment setting.
Although these regimens are known to produce high CR rates and durable remissions, they have also been linked with a significant risk of myelosuppression, hospitalization, toxicity, deaths, infections, and the development of secondary cancers.
WINDOW-1 was launched to assess the safety and activity of an initial chemotherapy-free period with ibrutinib plus rituximab, followed by a shortened course of R-HCVAD and alternating methotrexate/cytarabine consolidation treatment. R-HCVAD was selected because it has served as the backbone of first-line regimens administered at MD Anderson for the past 2 decades and clinical teams at the institution have been able to successfully manage those on the regimen.
The investigator-initiated, single-center, single-arm trial was conducted at MD Anderson and enrolled those with previously untreated MCL who were aged 65 years or younger, had a serum bilirubin of less than 1.5 mg/dL, a creatinine clearance of 30 mL/min or more, an ECOG performance status of 0 to 2, and cardiac ejection fraction of 50% or more by echocardiogram.
Those with uncontrolled medical conditions, active hepatitis B or C virus infection, and uncontrolled atrial fibrillation, were excluded.
The study was comprised of 2 parts. In part A, or the induction phase, ibrutinib was given orally at a daily dose of 560 mg in combination with rituximab, which was administered intravenously (IV) at a dose of 375 mg/m2once a week during the first cycle, then on day 1 of cycles 3 through 12. Induction treatment was given for up to 12 cycles, or until CRs were achieved, responses plateaued, disease progression, intolerable toxicity, or withdrawn consent.
Investigators examined patients for response every 2 cycles, and those who achieved a CR in part A were then entered into part B, where they received short-course R-HCVAD. In cycle 1, they were given IV rituximab at 375 mg/m2 on day 1, IV cyclophosphamide at 300 mg/m2 once every 12 hours for 6 doses on days 2 through 4, IV mesna at 600 mg/m2 by continuous infusion on days 2 and 3, IV vincristine at 1.4 mg/m2 on day 5, IV doxorubicin at 50 mg/m2 given 1 day after the last dose of cyclophosphamide, and dexamethasone at 40 mg orally or IV on days 1 through 4, alternating with rituximab plus high-dose methotrexate/cytarabine.
In cycle 2, IV rituximab was given at 375 mg/m2 on day 1, IV methotrexate was given at 200 mg/m2 for 2 hours and then 800 mg/m2 for 22 hours on day 2, cytarabine was given at 3 mg/m2 for 4 doses on days 3 and 4, 50 mg of oral citrovorum rescue was given 12 hours following methotrexate, and granulocyte-colony stimulating factor was given subcutaneously at a daily dose of 480 μg 24 to 36 hours after cytarabine.
Those who achieved CR after part A were given 4 cycles of R-HCVAD alternating with high-dose methotrexate/cytarabine and were then observed. Those in part A who did not experience a CR received 2 cycles on part B and if they had CR after 2 cycles, they were given 2 more cycles for a total of 4. Those without a CR were also given 2 more cycles and were re-evaluated. If these patients experienced a CR following the 4 cycles, they were given 4 more cycles, equating to 8 cycles.
Notably, the protocol was amended to incorporate ibrutinib/rituximab maintenance therapy of those considered to be high risk, as most of those who experienced disease progression on the study were noted to fall into the high-risk category.
The primary end point of the study was ORR after part A, and secondary end points were progression-free survival (PFS), overall survival (OS), CR, duration of response (DOR), and toxicities for both portions of the study.
Between June 12, 2015, and December 6, 2018, a total of 131 patients were enrolled to WINDOW-1. The median age was 56 years (range, 49-60), 79% were male, 92% were White, 99% had an ECOG performance status ranging from 0 to 1, 9% had bulky disease, 88% had bone marrow involvement, and 86% had gastrointestinal involvement.
Moreover, 36% of patients had high-risk disease, 33% had intermediate-risk disease, and 31% had low-risk disease per biological Mantle Cell Lymphoma International Prognostic Index score. Moreover, 50% of 117 patients had high Ki-67, defined as 30% or higher. Eleven percent of 127 patients were noted to have aggressive disease, and 32% of 34 patients had TP53 aberrations.
A total of 131 patients were enrolled to part A and received the induction regimen, and 129 of these patients were evaluable for best response. A total of 11 patients did not receive the part B regimen, and the reasons for this included: chemotherapy refusal (n = 6), disease progression on part A (n = 2), development of second cancer (n = 1), toxicity (n = 1), and withdrawn consent (n = 1). A total of 118 patients received the part B regimen and were evaluable for best response. The intention-to-treat analysis included information on all 131 patients.
Additional data from a post-hoc analysis revealed that response rates observed in part A were comparable between those with high-risk (n = 58) and low-risk (n = 59) disease, at 98% and 100%, respectively (P = .31), as well as between those with blastoid or pleomorphic disease (n = 15) or those with classical disease (n = 112), at 99% and 98%, respectively (P = .60).
Another post-hoc analysis examining response rates by TP53 status demonstrated that ORRs were comparable between those with (n = 11) and without (n = 23) these aberrations, at 91% and 100%, respectively (P = .14). CR rates, however, were found to be lower in those with TP53 positivity vs those without, at 55% and 91%, respectively (P = .046).
Eighty-eight percent of 130 patients were in CR at the end of part A, and 90% of 131 patients were evaluable for response in part B. The best ORR after part B was 90% (95% CI, 84%-95%), with a CR rate of 89% (95% CI, 83%-94%) and a PR rate of 1.0% (95% CI, 0.2%-4.2%). Of the 117 patients who achieved a CR in part B, 91% already experienced a CR in part A.
At a median follow-up of 42 months (range, 30-54), the median PFS or OS had not yet been reached. The 3-year PFS rate was 79% (95% CI, 70%-85%), and the 3-year OS rate was 95% (95% CI, 89%-98%). Moreover, the median DOR had not yet been reached.
Twenty-four patients experienced disease progression and 6 had died; 5 deaths were due to disease progression and 1 was due to an unknown reason. Only 1 of the patients who died experienced a central nervous system relapse after coming off the study.
As of January 15, 2021, 40% of patients were off the study for reasons such as disease progression (n = 25), patient choice (n = 21), intolerance (n = 4), secondary cancers (n = 2), and loss to follow-up. (n = 1). Patients had received a median of 7 cycles (range, 5-9) of treatment in part A and 4 cycles (range, 4-4) in part B.
Most toxicities were grade 1 or 2 in severity. The most common grade 3 or 4 hematologic toxicity in part A was lymphocytopenia (14%); the most common grade 3 or 4 non-hematologic effects included skin rash (12%), infections (8%), and fatigue (8%). No patients in part A discontinued treatment because of adverse effects (AEs).
Thirty-three percent of patients required dose reductions of ibrutinib because of grade 3 or 4 toxicity, which included low platelet counts and anemia (15%), fatigue (8%), skin rash (8%), and hypertension (3%). Six percent of patients had grade 3 hypertension, and 4% had atrial fibrillation or flutter in part A. Notably, no patients experienced ibrutinib-associated bleeding or atrial fibrillation that was grade 3 or higher in severity.
Hematologic AEs were noted to be more frequent in part B than in part A, and the most common grade 3 or 4 effects included lymphocytopenia (73%), leukocytopenia (32%), thrombocytopenia (30%), neutropenia (20%), and anemia (17%). The most frequent non-hematologic grade 3 or 4 toxicities in this part of the trial comprised fatigue (19%), elevated liver enzymes (11%), and myalgia (9%).
Dose reductions of chemotherapy was needed in 22% of patients because of grade 3 or 4 AEs that included neutropenia (12%), severe thrombocytopenia (8%), and elevated liver enzymes (2%). Four patients discontinued the trial because of serious toxicities; 2 did so because of sepsis, 1 did so because of pneumonia, and 1 patient decided to do so because of sepsis. No patients died from toxicity.
“The WINDOW-1 approach provides an active and safe chemotherapy-free treatment strategy for young patients with MCL. Our results pave the way for investigation of other novel targeted therapies in this patient population,” the study authors concluded. “The future of relatively less toxic targeted therapies, such as BTK inhibitors, as frontline therapy for patients with MCL is promising, and they have the potential to minimize chemotherapy cycles, thereby reducing toxicities.