Current Treatment Strategies in MCL

MANTLE CELL LYMPHOMAis a challenging disease that generally responds to initial treatment but inevitably relapses, making it incurable with standard chemotherapy.^1,2The clinical presentation of MCL varies widely. Some patients have an indolent disease course with longer survival, and others can have a very aggressive course with shorter survival, similar to acute leukemias.³

There is no curative therapy for MCL, with the rare exception of patients who achieve long-term disease-free survival following allogeneic stem cell transplantation (allo-SCT).⁴

Addressing the challenges in the treatment of patients with MCL, Wyndham Wilson, MD, commented, “Even if the initial treatment works, the disease comes back in virtually all patients. How long it will take to relapse and how long a second response may last depends largely on the patient’s response to the initial course of treatment and the biology of their disease, which can vary greatly from patient to patient.”⁵

Treatment Considerations in MCL

Several considerations should be addressed in treatment selection for MCL, including patient- and disease-related factors, expected therapy-related toxicities, and the overall goals of therapy.⁶Effective management of MCL requires awareness of current therapeutic approaches for a wide range of patient populations, clinical trials supporting the use of therapy in the frontline or relapsed/refractory (R/R) settings, newer therapeutic options and strategies, and emerging therapies to improve patient outcomes in MCL.⁷Although consensus guidelines for the treatment of patients with MCL are available,^8,9there is significant variation among regimens used in clinical practice, with no single accepted and approved standard of care in either the front-line or R/R settings.

Treatment Guidelines in MCL

NCCN guidelines on B-cell lymphomas provide separate treatment strategies for patients with MCL.⁸The guidelines include recommendations for induction therapy (with aggressive or less-aggressive treatments), first-line consolidation, second-line therapy, and second-line consolidation (Table 1).⁸

The European Society for Medical Oncology Guidelines provide treatment recommendations for patients with newly diagnosed and R/R MCL (Table 2).⁹

BTK INHIBITORS

A pair of agents, speci cally BTK inhibitors, are available in the treatment landscape of MCL. First, ibrutinib, a BTK inhibitor, was granted accelerated approval by the FDA in November 2013 for patients with MCL who have received at least 1 prior therapy.¹⁰Ibrutinib is considered standard of care in the second-line setting. The approval was based on data from the open-label phase II PCYC-1104 trial in which ibrutinib was studied in 111 previously treated patients with a median age of 68 years (Table 3).¹¹Most patients were heavily pretreated (≥3 prior treatments) and had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.

The registration trial for ibrutinib in MCL used the revised International Working Group response evaluation criteria for non-Hodgkin lymphoma (NHL) to assess response rates.¹¹Results from the registrational trial showed durable responses with ibrutinib in the R/R MCL population. Ibrutinib demonstrated an overall response rate (ORR) of 68%, complete remission (CR) rate of 21%, median progression-free survival (PFS) of 13.9 months, and duration of response (DOR) of 17.5 months (Table 4).¹¹Median overall survival (OS) was not reached; at 18 months, the estimated OS rate was 58%. In 2015, updated results were reported from the PCYC-1104 trial.¹²After a median follow-up of 26.7 months, the ORR was 67% (23% CR rate), median PFS was 13 months, median DOR was 17.5 months, and median OS was 22.5 months.

Ibrutinib has demonstrated safety in patients with R/R high risk MCL.¹³The most common adverse events (AEs) reported were fatigue (any grade, 43.3%; grade 3/4, 3.3%) and diarrhea (any grade, 42.5%; grade 3/4, 2.5%). The most common AEs of grade ≥3 were neutropenia (20.8%), thrombocytopenia (13.3%), and pneumonia (12.5%). Any-grade hemorrhagic AEs were reported in 45 patients (37.5%); major hemorrhagic AEs were uncommon (3; 2.5%). The median time to initial hemorrhagic AE was 84 days (range, 1-515), with a median duration of 22 days (95% CI, 8-31). Notably, atrial brillation (AF) was reported in 6% to 9% of patients and was grade 3/4 in 6 patients (5%). AEs led to dose reductions in 8 patients (6.7%).

However, Alaina Vrontikis, MD, and colleagues¹⁴have developed a proposed algorithm for the management of ibrutinib-related AF (IRAF). Their algorithm allows for the individualization of decisions in the management of IRAF based on patient preferences, disease, availability of other antineoplastic agents, and patient comorbidities. Branches of the algorithm involve the establishment of rate/rhythm control and the assessment of bleeding and stroke risk using the CHA2DS2-VASc score and HAS-BLED scoring.

In addition, acalabrutinib, a newer BTK inhibitor, was granted accelerated approval by the FDA in October 2017 for the treatment of patients with MCL who have received at least 1 prior therapy.¹⁵This agent also does not inhibit off-target kinases, such as epidermal growth factor receptor (EGFR) and interleukin 2-inducible T cell kinase (ITK).¹⁶Its approval was based on data from the open-label phase II ACE-LY-004 trial. Acalabrutinib was studied in 124 previously treated patients with a median age of 68 years (Table 5).¹⁷The median number of prior therapies was 2, and 24% were refractory to their most recent prior treatment. Most patients also had an ECOG PS 0 or 1. No patients with cardiovascular disease were included.

The registrational trial for acalabrutinib in MCL used the 2014 Lugano classification response criteria for NHL to assess response rates.17 After a median follow-up of 15.2 months, acalabrutinib demonstrated efficacy with an ORR of 81% and CR rate of 40% (Table 6)¹⁷; medians for DOR, PFS, and OS were not reached. At 12 months, acalabrutinib achieved rates of 67% for PFS, 72% for DOR, and 87% for OS. An independent review committee also assessed response using the 2007 International Working Group criteria and noted an ORR of 75% and CRs in 30% of patients.

Regarding safety, acalabrutinib has demonstrated an acceptable toxicity profile in patients with R/R high-risk MCL.¹⁷The most common AEs of any grade reported in the acalabrutinib study were headache (38%), diarrhea (31%), fatigue (27%), myalgia (21%), cough (19%), nausea (18%), and pyrexia (15%). The most common grade ≥3 AEs were neutropenia (11%), anemia (9%), and pneumonia (5%). AEs led to treatment discontinuations in 6% of patients.

Serious AEs reported in the acalabrutinib prescribing information include hemorrhage, infections, and AF.¹⁸In a database of 612 patients treated with acalabrutinib monotherapy across clinical trials, 18% of patients experienced grade ≥3 infections, most frequently pneumonia (4%). In this safety group, AF and atrial utter of any grade occurred in 3% of patients, with 1% having a grade 3 AE. Overall, bleeding, bruising, or petechiae AEs of any grade occurred in approximately 50% of patients, with AEs of grade ≥3 seen in 2%.

No head-to-head studies between acalabrutinib and ibrutinib have yet been performed in MCL, which researchers say would be needed to compare the safety pro les and clinical activity between the 2 BTK inhibitors.⁵If a head-to-head study was to be performed, use of the same response criteria and patient characteristics, which differed in the studies that led to each agent's approval, would allow for the data to be comparable. According to Michael Wang, MD, the principal investigator of the acalabrutinib trial, “[Acalabrutinib] is another potent [BTK] inhibitor that...seems to have a different side effect pro le compared with ibrutinib, so those who are intolerant of one inhibitor may be able to try the other.”⁵

CHEMOTHERAPY REGIMENS

Aside from BTK inhibitors, chemotherapy remains a go-to approach in the MCL eld. A standard regimen of cyclophosphamide, hydroxydaunomycin (doxorubicin), vincristine, and prednisone (CHOP) is frequently used. Response rates associated with CHOP for the treatment of MCL are rarely complete or durable compared with those observed in other aggressive lymphomas.¹⁹Therefore, more-intensive strategies have been explored, combining additional agents to improve the response rates and DOR.

During induction therapy, high-dose cytarabine (Ara-C) (HDAC; an antimetabolite pyrimidine analogue) or rituximab (Rituxan) may be used in combination with chemotherapy, usually followed by autologous stem cell transplantation (ASCT) in younger patients.^19,20The addition of rituximab to CHOP (R-CHOP) has been established as a standard-of-care regimen for first-line treatment of patients with MCL.8,9 R-CHOP is typically administered to patients who are elderly and considered intermediate to high risk, as well as those with R/R disease.²¹

Due to the limitations and relatively poor outcomes associated with chemotherapy, Peter Martin, MD, and colleagues have highlighted the potential for chemotherapy-free strategies in the treatment of MCL. According to Martin et al, “Thoughtfully directed nonchemotherapy agents might overcome some of the factors associated with a poor prognosis, such as TP53 mutation, and might resolve some of the challenges related to the toxicity and deliverability of standard chemotherapy regimens.”²²

CHEMOIMMUNOTHERAPY REGIMENS

Aside from targeted approaches and chemotherapy regimens, chemoimmunotherapy (CIT) can be administered in select populations. For example, the combination of the nitrogen mustard bendamustine plus rituximab (BR) has been adopted as an effective frontline regimen, particularly in older patients, due to its efficacy and safety versus R-CHOP.^7,23In an open-label phase III trial, Mathias J. Rummel, MD, and colleagues²⁴compared BR with R-CHOP in patients with newly diagnosed indolent lymphoma or MCL. Ninety-four of the 549 patients enrolled in the trial had diagnosed MCL. After a median follow-up of 45 months, the median PFS was 69.5 months in the BR group versus 31.2 months in the R-CHOP group (all histologies; P <.0001). Lower rates of AEs were observed with BR versus R-CHOP, including alopecia (0% vs 100% of patients who received &ge;3 cycles; P <.0001), hematologic toxicity (30% vs 68%; P <.0001); infections (37% vs 50%; P = .0025), peripheral neuropathy (7% vs 29%; P <.0001), and stomatitis (6% vs 19%; P <.0001).

In the open-label phase III BRIGHT trial, Ian W. Flinn, MD, PhD, and colleagues²⁵evaluated the efficacy and safety of BR versus R-CHOP or rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP) in patients with treatment-na&iuml;ve indolent NHL (iNHL) or MCL. Seventy-four of the 447 patients enrolled in the trial had diagnosed MCL. Initial study results showed that BR was noninferior to R-CHOP/R-CVP in patients with iNHL or MCL; the CR rate was 31% for BR versus 25% for R-CHOP/R-CVP (P =.0225 for noninferiority [0.88 margin]).

In the 5-year follow-up findings of the BRIGHT trial, OS was 82% in the BR arm versus 85% in the R-CHOP/R-CVP arm (P = .5461), with no statistical difference between the treatment arms.²⁶Among the patients with MCL, PFS was 40% in the BR group versus 14% in the R-CHOP/R-CVP group (P =.0035), and DOR was 66% in the BR group versus 57% in the R-CHOP/R-CVP group (P = .0134).

Moreover, the use of radioimmunotherapy (RIT) with yttrium-90 (90Y)-ibritumomab tiuxetan following 1 course of rituximab was evaluated in an open-label phase II trial of patients with R/R MCL.²⁷After a median follow-up of 22 months, 90Y-ibritumomab tiuxetan demonstrated an ORR of 31%. In the open-label phase II ECOG Study E1499,28 R-CHOP followed by 90Y-ibritumomab tiuxetan was evaluated in 56 patients with previously untreated MCL. Initial study results showed an improvement in response compared with historical controls when 90Y-ibritumomab tiuxetan was used to consolidate after CIT. In 2017, updated results were reported for the ECOG Study E1499.29 After a median follow-up of 9.8 years, the ORR was 82% and the CR/unconfirmed CR (CRu) rate was 55%, with a median time-to-treatment failure of 34 months versus the historical control of 18 months. Median OS was 7.9 years (not reached for patients &le;65 years vs 5.7 for patients >65 years; P = .07).

R-HYPERCVAD

The combination of rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dexamethasone alternating with rituximab, cyclophosphamide, vincristine, doxorubicin (Adriamycin), and dexamethasone plus high-dose methotrexate and cytarabine (R-hyperCVAD/MA) was investigated in a single-center phase II trial of patients with previously untreated MCL.³⁰Although the results of this trial showed impressive response rates, with an ORR of 97% and a CR rate of 87%, substantial toxicity, particularly for those ˃65 years, has been reported with R-hyperCVAD/MA and has led to complications administering this regimen as planned, resulting in decreased efficacy.^3,6,31Updated phase II results of this study were reported in 2016.³²After a median follow-up of 13.4 years, the median OS was 10.7 years and the 10-year cumulative incidence of therapy-related acute myeloid leukemia/myelodysplastic syndrome was 6.2%.

NORDIC REGIMEN

Additionally, the NORDIC regimen consists of frontline intensive induction CIT with dose-intensified R-CHOP (R-maxi-CHOP) alternating with rituximab plus HDAC (R-HDAC) for 6 cycles followed by ASCT.⁶In 2008, early results were reported for the nonrandomized phase II second Nordic MCL (NLG MCL-2) trial³³of the NORDIC regimen followed by BEAM or BEAC (carmustine [BCNU], etoposide, cytarabine [Ara-C], and melphalan or cyclophosphamide) plus ASCT. After a median follow-up of 3.4 years, the ORR was 96% and the CR rate was 54%, with an event-free survival (EFS) of 56%, PFS of 66%, and OS of 70%. No relapses were reported after 5 years in 160 patients &le;66 years enrolled in this trial. In 2012, updated results were reported for NLG MCL-2,³⁴showing continuing efficacy with a median EFS of 7.4 years; disease progression occurred in 6 of 160 patients more than 5 years after the conclusion of treatment. The latest trial results were published in 2016, demonstrating prolonged remissions without survival plateau.³⁵After a median follow-up of 11.4 years, the median OS was 12.7 years and the median PFS was 8.5 years.³⁵

Most patients with MCL are elderly or unsuitable for high-dose induction and ASCT, prompting the need for nonintensified approaches that are safe and effective in this patient population.^31,36The European MCL Network conducted a phase III trial comparing rituximab, fludarabine, and cyclophosphamide (R-FC) with R-CHOP as induction therapy in patients &ge;60 years with MCL.¹A total of 560 patients were enrolled in the trial; the median age was 70 years. Patients who responded to treatment underwent a second randomization to maintenance therapy with either rituximab or interferon alpha (IFN&alpha;). The OS rate at 4 years was 47% with R-FC versus 62% with R-CHOP (P = .005). The second randomization consisted of 316 patients who responded to induction therapy. After a median follow-up of 36 months, the median DOR was 23 months in the IFN&alpha; arm versus not reached in the rituximab maintenance arm (P <.001). After a median follow-up of 42 months, the median OS was 64 months in the IFN&alpha; group versus not reached in the rituximab maintenance arm (P = .005). At 4 years, the OS rate was 87% with maintenance rituximab versus 63% with IFN&alpha; (P = .005).

In a multivariate analysis of the Nordic MCL2 and MCL3 trials, Christian W. Eskelund, MD, and colleagues³⁷showed that the presence of TP53 mutations predicted worse survival outcomes in younger patients with MCL. These trials included 320 patients who were &le;66 years, had stage II to IV disease, and were considered fit for ASCT. The trial regimens consisted of induction of alternating R-maxi-CHOP and R-HDAC, subsequently followed with BEAM or BEAC high-dose chemotherapy and ASCT.

After a median follow-up of 9.2 years of the analysis, median PFS was 0.9 years in patients with TP53 mutations versus 10.2 years in patients not harboring TP53 mutations. Median OS was 1.8 years in patients with the mutations versus not reached in patients not harboring these mutations, and the median time to relapse was 1 year in patients with TP53 mutations versus 12.3 years in patients without. According to Eskelund and colleagues, &ldquo;TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy.&rdquo; Therefore, the authors recommended that patients with MCL with TP53 mutations be considered for alternative frontline treatment.³⁷

In a retrospective cohort analysis, Zachary Frosch, MD, and colleagues compared survival and toxicity in 38 transplant-eligible patients (&ge;60 years) who underwent R-CHOP or R-hyperCVAD with or without ASCT consolidation.³⁸After a median follow-up of 2.7 years, the median PFS was 1.6 years with R-CHOP alone, 3.2 years with R-CHOP and ASCT, and 4 years with R-hyperCVAD alone. Compared with R-CHOP alone, R-hyperCVAD was associated with an increased incidence of toxicity and therefore treatment discontinuation and transfusion requirement. Similar AE rates were observed for R-hyperCVAD alone and R-CHOP plus ASCT. Based on these results, older fit patients with MCL may benefit from intensifying therapy with R-hyperCVAD induction or R-CHOP followed by ASCT consolidation.

PROTEASOME INHIBITORS

Proteasome inhibitors are a class of agents used in a number of hematologic malignancies, including multiple myeloma and MCL. Bortezomib (Velcade), an inhibitor of the 26S proteasome, for example, was the first proteasome inhibitor approved by the FDA for the treatment of MCL in 2013. Bortezomib is indicated in the frontline setting and in patients with R/R MCL in combination with rituximab, cyclophosphamide, doxorubicin (Adriamycin), and prednisone (VR-CAP).

Bortezomib has demonstrated modest single-agent activity in MCL. In the single-arm phase II PINNACLE trial, Richard Fisher, MD, and colleagues³⁹investigated the safety and efficacy of bortezomib monotherapy in 155 patients with R/R MCL. Initial results showed an ORR of 33% (8% CR/CRu), median time to treatment progression of 6.2 months, and median DOR of 9.2 months; median OS was not reached after a median follow-up of 13.4 months. Updated trial results after extended follow-up (median, 26.4 months) indicated an ORR of 32% (8% CR/CRu), median TTP of 6.7 months, median DOR of 9.2 months, and median OS of 35.4 months.

The addition of bortezomib appears useful in combination with CIT for the treatment of MCL in the frontline setting. In the phase

III LYM-3002 trial, Tadeusz Robak, MD, and colleagues40 investigated the efficacy and safety of R-CHOP versus combination therapy with bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) in 487 patients with newly diagnosed MCL who were transplant ineligible. After a median follow-up of 40 months, the median PFS was 14.4 months in the R-CHOP group versus 24.7 months in the VR-CAP group (P <.001). Similar ORRs were observed in the treatment groups; however, the CR rate was signi cantly higher in the VR-CAP group versus the R-CHOP group (53% vs 42%; P = .007). Increased hematologic toxicity was observed in the VR-CAP group, which had higher rates of neutropenia and thrombocytopenia than the R-CHOP group.

IMMUNOMODULATORY AGENTS

Lenalidomide, an immunomodulatory agent that inhibits the BCR-signaling pathway, was approved in 2013 for patients with MCL who have relapsed or whose disease has progressed after 2 prior therapies, including &ge;1 prior treatment with bortezomib.

Lenalidomide has demonstrated durable responses in a heavily pretreated MCL population. In the open-label phase II MCL-001 (EMERGE) trial, Andre Goy, MD, and colleagues⁴¹explored the safety and efficacy of lenalidomide in heavily pretreated patients with MCL who had relapsed or were refractory to bortezomib. A total of 134 patients were enrolled with a median age of 67 years and 4 prior therapies. After a median follow-up of 9.9 months, the median PFS was 4.0 months, median DOR was 16.6 months, and median OS was 19.0 months; ORR was 28% (7.5% CR/CRu).

Lenalidomide has also shown clinical activity in patients with MCL who relapsed, progressed, or were refractory or intolerant to ibrutinib. In the observational MCL-004 study, Wang and colleagues⁴²evaluated outcomes in 58 patients with R/R MCL who received lenalidomide-based therapy after ibrutinib failure or intolerance. The MCL-004 study included patients who had a high number of previous therapy regimens and were considered to be high risk. After a median of 2 cycles of lenalidomide-based treatment, an ORR of 29% was observed, with similar ORRs in those after relapsed or progressive disease on ibrutinib and in those refractory to ibrutinib. The most common treatment-emergent AEs were fatigue and cough (38% each) and dizziness, dyspnea, nausea, and peripheral edema (19% each).

STEM CELL TRANSPLANTATION

Even with the addition of novel agents to the evolving MCL paradigm, the European Society for Blood and Marrow Transplantation and the European MCL Network have given consensus support of ASCT as standard frontline consolidation therapy.⁴³Both ASCT and allo-SCT remain initial treatment approaches for aggressive MCL in younger and fit patients following induction chemotherapy regimens.^44,45Consolidative ASCT has shown benefit in clinical outcomes versus maintenance treatment with IFN&alpha;. In a prospective randomized trial of the European MCL Network, Martin Dreyling, MD, and colleagues⁴⁶compared myeloablative radiochemotherapy followed by ASCT consolidation in first remission versus IFN&alpha; maintenance in 269 patients &le;65 years after a CHOP-like induction regimen. After a median follow-up of 25 months, the median PFS was 39 months in the ASCT arm versus 17 months in the maintenance IFN&alpha; arm (P = .0108).

In the setting of relapsed disease, allo-SCT is considered to be the only curative treatment.⁴⁵As most patients with MCL present at ˃60 years and with multiple comorbidities, allo-SCT is frequently not an option. Currently, allo-SCT is not recommended outside of a clinical trial in frontline therapy, but is suggested in R/R disease for those patients who are young and t, even after ASCT.⁸

Moreover, in a retrospective study, Constantine Tam, MD, and colleagues⁴⁷reported on the use of reduced-intensity conditioning (RIC) allo-SCT in patients with R/R MCL. The study included 121 patients who underwent ASCT in first remission, ASCT for R/R MCL, or nonmyeloablative allo-SCT. After a median follow-up of 56 months, the median PFS was 60 months and median OS was not reached. At 6 years, the PFS rate was 46% and the OS rate was 53%.

Jennifer Vaughn, MD, and colleagues⁴⁸conducted a retrospective study on the use of a total body irradiation (TBI)-based nonmyeloablative regimen comprising 3 doses of udarabine and low-dose TBI as a conditioning regimen for patients with MCL.⁴⁸At 5 years, the nonrelapse mortality incidence was 28%, OS rate was 55%, and PFS rate was 46%. At 10 years, the OS rate was 44% and PFS rate was 41%. Although RIC allo-SCT can induce long-term remissions in patients with R/R MCL, potential complications that need to be considered include chronic graft-versus-host disease, which occurred in 64% of patients at 2 years, and infection.

With the availability of new treatment options incorporating biologic agents, there is the potential to optimize therapy to further improve outcomes, including in patients with high Mantle Cell Lymphoma International Prognostic Index (MIPI) scores and those in patient subsets identi ed by prognostic markers, p53, or microRNAs.⁴⁹Combining biologic agents with current standard regimens as part of strategies for induction, ASCT consolidation, and maintenance may deepen response. Dreyling and Simone Ferrero, MD, commented, &ldquo;Only after tailoring treatment according to the clinical and biological heterogeneity of the disease, the role of transplantation and modern therapeutic options will be rede ned in mantle cell lymphoma.&rdquo;⁵⁰

As the treatment landscape of MCL evolves, the role of SCT is being reexamined.⁵¹Evidence supporting the benefit of SCT is generally from clinical trials of young healthy patients with low-risk MIPI.⁴⁶Stem cell transplantation consolidation does not overcome high-risk MIPI. Additionally, consolidation with rituximab (or RIT) prolongs PFS, and low-risk MIPI patients do well with intense or nonintense therapy.²⁹Researchers are hoping with the availability of novel agents allowing for combinations and sequencing of treatments in patients with R/R disease, that patients can be treated more effectively and safely without SCT.

SEQUENCING STRATEGIES

The number of agents now available in the treatment landscape may provide some questions for physicians when determining the optimal sequence for their patients with MCL. Highlighting the importance of sequencing strategies, Andre Goy, MD, stated, &ldquo;[We are developing] combinations of novel therapies in the frontline setting without chemotherapy that will allow us to hopefully reach a high level of CR and minimal residual disease—negative status that will have an impact on outcomes. As much enthusiasm as there is for these novel therapies, we must refocus on sequencing.&rdquo;⁵²

Current and future research endeavors thus will need to focus on finding the optimal sequencing and combination of available novel agents for the treatment of MCL.⁵³

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