The PI3K pathway is another survival pathway that is dysfunctional in several hematologic disorders, including MCL. Overexpression of PI3K and its downstream targets contributes to MCL pathogenesis.53 Idelalisib is an oral small molecule inhibitor of the delta isoform of PI3K that is dosed daily; it was approved by the FDA for the treatment of relapsed and refractory follicular lymphoma, small lymphocytic lymphoma, and chronic lymphocytic leukemia. It is being further evaluated in MCL. A dose-escalation phase 1 study in heavily pre-treated MCL patients established safety and tolerability.54 Efficacy analysis showed an ORR of 40%, CR of 5%, and 1-year OS of 22%. Further phase 2 studies testing idelalisib as a single agent and in combination for MCL are ongoing. Side effects of idelalisib include elevated liver enzymes, pneumonitis, and diarrhea.
The BCL family of proteins is involved in both pro-and anti-apoptotic functions. BCL2 is an intracellular protein that blocks apoptosis. ABT-199 is an oral BCL2 inhibitor that in early clinical trials has shown very promising activity in MCL. In a phase 1 study of 31 relapsed and refractory NHL patients, all 8 MCL patients (100% ORR) responded to ABT-199 therapy.55 Given these promising initial results, multiple studies evaluating ABT-199 are ongoing in MCL as part of first-line treatment as well as for relapsed disease. ABT-199 has been implicated in tumor lysis syndrome, and in early studies of chronic lymphocytic leukemia, fatal tumor lysis was observed.
The mammalian target of rapamycin (mTOR) inhibitor temsirolimus has been evaluated in relapsed MCL. It is given weekly at 250 mg intravenously. Response rates to single-agent temsirolimus are approximately 20% to 35%, and are higher when combined with rituximab.56,57 The phase 2 study evaluating temsirolimus as a single agent enrolled 35 heavily pre-treated patients. ORR was 38% with only 1 CR. The duration of response was 7 months. Temsirolimus is approved for relapsed MCL in Europe but not in the United States. Similar to the other targeted agents, temsirolimus is actively being studied in combination with other active agents in MCL. Adverse effects noted with temsirolimus include diarrhea, stomatitis, and rash. Thrombocytopenia requiring dose reductions is another frequently observed complication.
Radioimmunotherapy
Radioimmunotherapy (RIT) has been studied extensively in MCL. RIT consists of anti-CD 20 antibodies coupled to radioactive particles that deliver radiation to targeted cells, minimizing toxicity to surrounding tissues. RIT is not used as frequently in the modern era as it had been in the past. At this time, only yttrium-90-ibritumomab tiuxetan is available.
RIT has been evaluated in MCL both at the time of relapse58 and more recently, as part of a conditioning regimen prior to autoSCT, with good tolerability.65–67 Averse events noted with RIT include hematologic toxicity (can be prolonged), hypothyroidism, and in rare cases, myelodysplastic syndrome and acute leukemia. The bone marrow must have less than 25% involvement with disease prior to administration. Wang and colleagues evaluated yttrium-90-ibritumomab tiuxetan in 34 heavily pretreated patients with MCL.58 They observed an ORR of 31%. The median event-free survival (EFS) was 6 months, but in patients achieving either CR or PR, EFS was 28 months. A 21-month OS was noted.
In the upfront setting, RIT has been added as a mechanism of intensification. A recent Nordic group study of RIT with autoSCT did not find benefit with the addition of RIT.59 An ECOG study recently added yttrium-90-ibritumomab tiuxetan after CHOP chemotherapy in the upfront treatment of MCL, with good tolerability.55 However, when added to R-hyper-CVAD, the combination had unexpected high rates of hematologic toxicity, including grade 3/4 cytopenias and an unacceptably high rate of secondary malignancies.68
AutoSCT or Allogeneic Transplant
While many studies noted above have established the beneficial role of autoSCT in MCL in first remission, the role of allogeneic transplant (alloSCT) in MCL remains controversial. A recent large retrospective study conducted by the Center for International Blood and Marrow Transplant Research (CIBMTR) evaluated 519 patients with MCL who underwent both autoSCT and alloSCT.60 Patients were grouped into an early cohort (transplant in first PR or CR, and 2 or fewer treatments) and late cohort (all other patients). The analysis had mature follow up. A multivariate analysis demonstrated that early autoSCT was associated with superior outcomes compared to autoSCT performed later. While it was not possible to demonstrate a survival benefit favoring autoSCT over reduced intensity (RIC) alloSCT, patients transplanted later in their disease course had shorter OS. For patients receiving autoSCT in CR 1 following only 1 prior line of therapy, OS at 5 years was 75% and PFS was 70%. Patients undergoing RIC followed by alloSCT had fewer relapses, but this was negated by higher nonrelapse mortality (25%), resulting in a PFS similar to autoSCT.