Three trials supported the use of 25 mg oral lenalidomide daily every 28 days from days 1 to 21 until disease progression or intolerance developed.[14,15,16] A phase II randomized controlled trial (RCT) conducted by Trněný et al examined PFS of lenalidomide versus investigator's choice, and found that lenalidomide demonstrated a statistically significant increase in PFS to 8.7 months compared with an average of 5.2 months in the control group. Goy et al conducted a subgroup analysis including only patients with prior ASCT and the results were similar to the overall study population. Overall, PFS in patient groups treated with lenalidomide ranged from 4 to 8.7 months. However, 2 of the 3 trials included lacked a comparator group, while only 1 (Trněný et al) compared lenalidomide to a control drug of the investigator's choice.
Temsirolimus administered 175 mg weekly for 3 weeks followed by 75 mg weekly intravenously was found to significantly improve the PFS and objective response rate (ORR) in MCL patients post-ASCT (median PFS of 4.8 months vs. 1.9 months). The authors of this study also compared the adverse effects profile of the 75 mg continuation dose and a 25 mg continuation dose, and ultimately recommended a 75 mg dose as similar rates of adverse effects were observed.
Bortezomib in combination with rituximab and dexamethasone was identified as a potential therapy in relapsed or refractory MCL. Out of 5 patients studied who had a prior ASCT, 3 had a complete response, 1 had a partial response, and 1 did not respond to therapy. Toxicities of therapy included thrombocytopenia, peripheral neuropathy, and fatigue, with two patients discontinuing therapy due to grade III neuropathy.
Allogeneic hematopoietic transplantation (alloHSCT) as a therapeutic regimen was explored by Maris et al AlloHSCT demonstrated a high response rate, especially in those previously treated with less than 4 treatment regimens. However, the investigators also reported a high non-relapse associated mortality rate (24%)—potentially limiting the usefulness of alloHSCT as a therapy for relapsed or refractory MCL.
Conventional chemotherapy consisting of gemcitabine, dexamethasone with or without cisplatin was evaluated in terms of efficacy and safety. All ASCT patients who received this regimen with the addition of cisplatin showed improved response rate and duration of response, with median PFS reported as 8.5 months. The authors suggested that convention chemotherapy be considered before high-dose therapy or alloHSCT in younger patients who are able to tolerate the regimen.
Everolimus administered orally was given daily for 4 weeks to evaluate response rates and safety. Unfortunately, disease progression was a persistent problem as the median time to treatment discontinuation was 2 months. The cause of this poor response is thought to be attributed to the resistance of mTORC1 inhibition in these patients’ cancer.
A phase I trial of venetoclax in patients with relapsed or refractory NHL, including 7 patients (25%) with MCL and prior ASCT, was conducted by Davids et al The dose associated with a ORR in MCL of 75% was less than 800 mg. Compared to the other NHL subtypes, the MCL cohort had the highest response rate with a median PFS of 14 months. The authors cautioned that future studies, including ones with combination therapy, are required to evaluate the efficacy and safety of venetoclax in this patient population.
Overall, our results indicate that treatment with ibrutinib and venetoclax appear to achieve the highest response rates and median PFS lengths in patients with relapsed/refractory MCL post-ASCT. The evidence is stronger for ibrutinib where 72 patients with prior ASCT were included while the trial looking at venetoclax had just 7 patients with prior ASCT. This finding supports the European Society for Medical Oncology guidelines, which recommends ibrutinib as first-line therapy in relapsed/refractory disease post-ASCT. ESMO guidelines also recommend consideration of lenalidomide where contraindications exist for ibrutinib. However, study design and outcomes reported across the trials identified were highly variable, and as a result, it is difficult to draw any meaningful conclusions regarding how the efficacy of each treatment regimen compared with every other. High response rates were also seen with alloHSCT, with high mortality rates likely limiting the applicability of this approach.
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