Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy characterized by poor clinical prognosis. In the past, standard frontline treatments involved the use of combinations including cytotoxic chemotherapeutic agents or strenuous chemo-immunotherapy with subsequent stem cell transplantation. However, recently, a number of new targeted therapies have been introduced in an attempt to ameliorate some of the side effects observed with cytotoxic agents.
One clinician who has been intimately involved in this paradigm shift to targeted therapeutics is Michael Wang, MD, co-leader of the B-cell Lymphoma Moon Shot program at MD Anderson Cancer Center. He headed the clinical study (NCT01236391) that ultimately led to the November 2013 FDA approval of the first-in-class Bruton's tyrosine kinase inhibitor ibrutinib for the treatment of patients with MCL (N Engl J Med 2013;369:507-516).
Regarding the current trends noted in the treatment of MCL, Wang noted, “There has been a tendency for a minimization of—or a complete move away from—the use of cytotoxic chemotherapy-containing regimens for MCL. Increasingly, targeted therapies, such as the Bruton's tyrosine kinase inhibitors ibrutinib or acalabrutinib or the BCL-2 inhibitor venetoclax, are being evaluated in clinical studies alone or in combination with CD20-targeting monoclonal antibodies such as rituximab or ofatumumab.”
At the 15th International Conference on Malignant Lymphoma, Wang presented results from a number of ongoing clinical studies at MD Anderson.
Ibrutinib + Rituximab Combination
Ibrutinib and Rituximab in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma or Older Patients With Newly Diagnosed Mantle Cell Lymphoma
In this single-institution, phase II study, treatment-naïve patients over the age of 65 years with MCL received a combination of ibrutinib and rituximab (NCT01880567). Patients having a Ki67 protein level of 50 percent or greater or blastoid/pleomorphic histology were excluded from this study. Patients received 560 mg ibrutinib orally daily for each 28-day cycle until disease progression or discontinuation for any reason occurred. Rituximab was administered via IV infusion at 375 mg/m2 over 4-8 hours on days 1, 8, 15, and 22 (+/- 1 day) of cycle 1; on day 1 of cycles 3-8; and on day 1 of every other cycle thereafter up to 2 years.
A total of 42 patients were enrolled with a median age of 71 years (range: 65-84 years). For these patients, 69 percent attained a complete response (CR), while 26 percent and 5 percent had a best response of partial response (PR) and stable disease, respectively, affording an objective response rate (ORR) of 95 percent. A total of 65 percent of patients had no minimal residual disease (MRD) at best response.
“At the median follow-up of 24 months, both the median progression-free survival (PFS) and overall survival (OS) values had not been reached,” Wang noted.
Regarding the study's results thus far, he stated, “The combination of ibrutinib plus rituximab was very effective and safe as a frontline therapy for MCL in elderly patients; this strategy provides an excellent frontline alternative to chemotherapy in elderly patients with MCL.”
Ibrutinib, Rituximab, and Consolidation Chemotherapy in Treating Young Patients With Newly Diagnosed Mantle Cell Lymphoma
In this study, treatment-naïve MCL patients 65 years or younger received the combination of ibrutinib plus rituximab as induction therapy in Part A of this study (NCT02427620). Once CR status was attained, in Part B of the study, participants received a shortened (4-cycle) course of rituximab plus cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, dexamethasone, methotrexate, and cytarabine (R-HCVAD/R-MTX) as consolidation chemotherapy.
In total, 50 patients were enrolled in this single-institution study. For Part A, 90 percent of the patients achieved a CR, while 10 percent showed a PR, providing an ORR of 100 percent. “Bone marrow flow cytometry analyses at the time of best response showed that 91 percent of these patients attained MRD-negative status,” Wang added. The median PFS and OS values were not reached by the time of analysis; however, the 3-year rates for these metrics were 89 percent and 100 percent, respectively.
“In treatment-naïve young MCL patients, the combination of ibrutinib plus rituximab followed by short course R-HCVAD/R-MTX induced durable and profound remissions. This strategy demonstrated excellent efficacy and safety, and importantly, minimized patient exposure to chemotherapy.”
Ibrutinib + Venetoclax Combination
Study of Ibrutinib Combined With Venetoclax in Subjects With Mantle Cell Lymphoma (SYMPATICO)
In this phase III study, the efficacy and safety of concurrently administered ibrutinib plus the BCL-2 inhibitor venetoclax are being evaluated in patients with relapsed/refractory MCL (NCT03112174). This trial has an initial open-label safety run-in period that is followed by a double-blind randomized portion.
In the safety run-in phase, patients received 560 mg ibrutinib QD plus venetoclax starting at 20 mg, followed by 50 mg, 100 mg, 200 mg, and 400 mg QD in subsequent weeks as part of a dose ramp-up over 5 weeks for the final dose of 400 mg QD. After the safety run-in period, patients were then randomized in a 1:1 manner to either ibrutinib plus venetoclax or ibrutinib plus placebo. At 24 months, venetoclax or placebo was discontinued, and ibrutinib was continued until unacceptable toxicity or progressive disease was noted.
The primary endpoints for the safety run-in phase are frequency of tumor lysis syndrome (TLS) and dose-limiting toxicities (i.e., grade 3 or higher non-TLS adverse events observed during the 5 week or greater dose-limiting toxicity assessment period). A total of 21 patients with relapsed/refractory MCL were enrolled in the safety run-in phase of this study, and of these patients, 15 were deemed to be at high risk for TLS and six were considered at low risk for TLS.
All patients displayed treatment-emergent adverse events (TEAEs); a total of 12 patients (10 high-risk and two low-risk) had grade 3/4 events. The most commonly observed TEAEs were diarrhea (15 patients; 10 high-risk and five low-risk) and fatigue (11 patients; six high-risk and 5 low-risk). Three deaths occurred in this study. One death was of a low-risk patient with progressive disease and splenic MCL and occurred 30 days or more after last dose as a result of retroperitoneal hemorrhage; this was considered to be unrelated to either investigational drug. Two deaths of high-risk patients, which occurred more than 30 days after last dose, were due to MCL.
“There was one incident of a laboratory-determined case of TLS in a high-risk patient; however, there were no clinical cases of TLS,” Wang noted. “In addition, dose-limiting toxicities were fairly infrequent, being noted in three of 21 patients.
“Based on the data obtained in the safety run-in phase of the study, the use of concurrent ibrutinib plus venetoclax was recommended per protocol for use in patients at low or high risk for developing TLS,” he explained. “The ongoing phase III randomized period is evaluating the efficacy, as measured by PFS, and the safety of the ibrutinib plus venetoclax combination versus that of ibrutinib plus placebo.”
CAR T Therapy (Lisocabtagene Maraleucel)
Study Evaluating the Safety and Pharmacokinetics of JCAR017 in B-cell Non-Hodgkin Lymphoma (TRANSCEND-NHL-001)
In this phase I, dose-finding TRANSCEND-NHL-002 study, patients with relapsed/refractory MCL who had one or more prior systemic therapy were treated with the CD19-targeting CAR T-cell therapy lisocabtagene maraleucel (liso-cel). Two distinct dosing levels were evaluated; dose level 1 was at 50 × 106 total CAR T cells, while dose level 2 was 100 × 106 CAR T cells.
As of the data cutoff, a total of nine patients with relapsed/refractory MCL had been included in this study: six at dose level 1 and three at dose level 2. Four of these patients (44%) developed serious TEAEs, while five had grade 3/4 TEAEs, including anemia, neutropenia, and hypophosphatemia. Importantly, three patients experienced grade 1 cytokine release syndrome (CRS), an important TEAE for those patients undergoing CAR T-cell therapy. As a result of CRS, one patient received tocilizumab and corticosteroids.
The ORR was 78 percent (four of six patients at dose level 1 and three out of three patients at dose level 2). Two patients receiving liso-cel at dose level 1 were able to maintain a CR for 281 and 378 days, respectively, until the last day of follow-up.
“In this phase I study, liso-cel treatment showed tolerable toxicity and displayed clinical activity in patients with relapsed/refractory MCL,” Wang said.
Ibrutinib + Umbralisib Combination
A Phase I/Ib Safety and Efficacy Study of the PI3K-delta Inhibitor TGR-1202 and Ibrutinib in Patients With CLL or MCL
In this multi-center, phase I/Ib study, which was led by Matthew Davids, MD, MMSc, from Dana-Farber Cancer Institute, the combination of ibrutinib and the PI3K-δ inhibitor umbralisib was evaluated in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or MCL (Lancet Haematol 2019; 6: e38-e47).
The goal of this study was to evaluate the safety and efficacy of this unique combination therapy, as well as to determine the phase II dosage for umbralisib in this combination. When asked why this particular combination of targeted therapies was utilized, Davids replied, “We hypothesized that even if a mutant clone arose that was resistant to one of the drugs, it was less likely that the same clone would harbor mutations which conferred resistance to both drugs tested, as the drugs inhibit two distinct targets in the B-cell receptor pathway.”
In this study, a total of 42 patients received at least one dose of study drug (21 each for CLL and MCL). Serious adverse events were noted in 12 patients, including adrenal insufficiency, atrial fibrillation, elevated lipase levels, hypophosphatemia, infections, and transaminitis. No dose-limiting toxicities were observed in this study and, consequently, the optimal dosing for umbralisib was determined to be 800 mg QD.
“For those patients with CLL, a high level of activity was noted for this combination; however, the benefit of the two-drug combination over ibrutinib alone in the MCL patients was less clear,” Davids commented. “Further studies would be needed to better evaluate efficacy in both these B-cell malignancies. To our knowledge, the results presented in our study mark the first clinical data for BTK/PI3K-δ inhibitor combination in B-cell malignancies.”
Future MCL Research
When asked what he thought some important developments were for MCL basic science research, Davids noted that a challenge in the field has been the limited availability of models. “The development of different longer-lived MCL cell lines may be helpful to enhance our knowledge of MCL biology.”
One example Davids cited is the work of Lalit Sehgal, MPhil, PhD, at Ohio State University, who is co-culturing primary MCL cells with human mesenchymal stem cells that can support their growth for more than 4 weeks (Blood 2018;132:2859).
“Another area which will have an impact on future MCL therapies is the increased use of enhanced cell-free DNA analyses,” Davids said. “This impact will be in two areas: first, more sensitive analyses will allow researchers to better ascertain minimal residual disease status and, second, these results will allow the rapid identification of pathologic genetic variants causing resistance, permitting a monitoring of the disease's genetic evolution and possibly eventually guiding therapeutic intervention.”
Other interesting approaches under investigation include bromodomain and extra-terminal domain (BET) inhibitors.
For example, “preclinical data suggest that BET inhibitors such as JQ1, as a result of its influence on PD-L1 expression in MCL cells, may be potential candidates to pair with checkpoint inhibitors (Blood 2015;126:822),” Davids stated.
Preclinical studies performed with the BET inhibitor birabresib (MK-8628/OTX015) showed synergy with the immunomodulatory drug pomalidomide, the mTOR inhibitor everolimus, and the BTK inhibitor ibrutinib (ESMO Open 2018;3:e000387).
When asked about what he envisioned for the future of MCL therapy, Wang replied, “We have moved from the chemotherapy era of lymphoma treatment, to the targeted therapy era, and into the current cell therapy era. In the future, we will continue pursuing multi-omics and biologic mechanisms behind MCL and other lymphomas toward understanding each patient's disease, overcoming treatment resistance, and enabling us to develop personalized therapies for each patient.”
Research Efforts at MD Anderson's B-Cell Lymphoma Moon Shot Program
In December 2012, MD Anderson launched the Moon Shot Program with the central goals of improving cancer prevention, early detection, and treatment. This program is divided into 10 different initiatives based on different forms of cancer. Recently, Oncology Times conducted an interview with Richard Champlin, MD, Co-Chair of the B-Cell Lymphoma Moon Shot Program at MD Anderson.
Could you tell us a bit about the B-Cell Lymphoma Moon Shot Program?
“We are focusing our research efforts by targeting B-cell lymphoma from three distinctly powerful treatment strategies: targeted therapy, cellular therapy, and immunotherapy. The targeted therapy group is headed by the B-Cell Lymphoma Moon Shot Co-Chair, Michael Wang, MD. The cellular therapy effort is headed by myself, while the immunotherapy team is headed by Sattva Neelapu, MD.”
Have you seen any tangible results from this program?
“As a result of the clinical trials being led by Dr. Wang, the targeted therapy of ibrutinib, a Bruton's tyrosine kinase inhibitor, has received FDA approval for treatment of mantle cell lymphoma and chronic lymphocytic leukemia, two B-cell malignancies.”
What are some other interesting developments within this program?
“Some very interesting findings have been noted in cellular therapy research being conducted by Katy Rezvani, MD, PhD, and Elizabeth Shpall, MD, around chimeric antigen receptor natural killer (CAR-NK) cells. Results from some pre-clinical mouse-based studies were published last year (Leukemia 2018;32:520-531).”
Are those cells similar to CAR T cells?
“They are, in that these cells target malignant B cells using the same CD19 recognition motif that the modified T cells do; however, these are modified NK cells. This has important implications for patient treatment. Unlike T cells, which need to be obtained from the patient prior to modification, these NKs can be obtained from cord blood banks, which are supplied by mothers who donate their umbilical cords and placentas after delivery.”
What are the larger implications for this research?
“T cells from another person can produce a severe toxicity graft-versus-host disease, so for CAR-T, autologous T cells from the patient are chosen to avoid this complication. However, NKs do not have that same liability, so we can select NK cells from another person, a normal donor. We use our umbilical cord bank as a source of healthy NK cells, allowing this to be an ‘off-the-shelf’ product, whereby the donated cells could be modified in large quantities, which would have significant cost benefits for the therapy.
“Additionally, since these cells are young and vital, one would expect their efficacy to be greater than that of autologous T cells from B-cell lymphoma patients, which are damaged by the prior treatment of their disease. To further enhance the efficacy of these CAR-NKs, in addition to functionalization with the CD19-targeting domain, the cord blood sourced NKs were also modified with a gene encoding IL-15 (which further drives NK cell expansion and persistence).
What is the relevance for patients with B-cell lymphomas?
Since CD19 is often overexpressed on malignant B cells, these CAR-NKs could be used to target those cancers which share this feature, including malignancies such as diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia. Dr. Rezvani is also evaluating this general approach of CAR NK cells to treat leukemia and myeloma, as well as solid tumors.