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High rates of durable remission were achieved in transplant-eligible (TE) patients with untreated mantle cell lymphoma (uMCL) in two phase 2 clinical trials of induction therapy followed by autologous stem cell transplant (ASCT), according to a poster abstract presented at the 2018 American Society of Hematology (ASH) Annual Meeting and Exposition.
Standard-of-care therapy for TE patients with uMCL is induction chemotherapy followed by ASCT; however, no consensus is established for an optimal induction regimen. Rituximab plus high-dose cytarabine (RC) added to an RCHOP-like regimen has been shown to be associated with better outcomes; however, rituximab/bendamustine (RB) was shown to have superior efficacy and tolerability that RCHOP in this patient population.
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Therefore, Reid W. Merryman, MD, Dana-Farber Cancer Institute (DFCI) in Boston, and colleagues conducted a phase 2 trial to determine progression-free survival (PFS) and overall survival (OS) with sequential cycles of RB and RC in patients with uMCL. In a separate trial, occurring simultaneously, researchers at Washington University School of Medicine (WUSTL), St Louis, Missouri, were investigating rituximab with bendamustine in alternating cycles with rituximab plus high-dose cytarabine in patients with uMCL.
In the DFCI trial, 23 TE patients with uMCL received 3 cycles of RB (rituximab 375 mg/m2 on day 1 and bendamustine 90 mg/m2 on days 1 to 2) followed by 3 cycles of RC (rituximab 375 mg/m2 on day 1 and cytarabine 3 gm/m2 on days 1 to 2 with dose reductions for age, renal dysfunction, or pre-existing neurotoxicity). In addition, 49 patients, retrospectively identified from clinical and pharmacy databases, were treated off-trial at DFCI or a community practice. Response assessments were made using CT scans in the trial patients and PET/CT in the off-trial patients.
In the WUSTL trial, 14 TE patients received the same doses as in the DFCI trial but in alternating cycles: RB in cycles 1, 3, and 5; and RC in cycles 2, 4, and 6. Patients in this trial were more likely to be male, have a high MIPI score, and have blastoid variant. Response assessments were made using PET/CT.
Of the 86 patients in total, 94% completed 6 cycles of RB/RC therapy. Off-trial patients (76%) were more likely to receive a lower starting dose (2 gm/m2 or less) of cytarabine compared with trial patients (38%). Overall response rate and complete response rate were 98% and 92%, respectively, at the end of infusion.
Seventy-three patients (85%) subsequently underwent ASCT and 4 additional patients (5%) have ASCTs planned. Three patients did not undergo ASCT due to persistent or PD; 3 did not undergo ASCT due to prolonged cytopenias; and one patient each due to an incidentally identified ASXL1 mutation without cytopenias, patient preference, and inadequate stem cell collection.
Delayed platelet engraftment after ASCT was seen for patients receiving alternating cycles of RB/RC compared with sequential RB/RC at day 30 (platelets <50: 70% vs 16%, P =.001) and at day 100 (platelets <100: 60% vs 21%, P =.017). An initial cytarabine dose of more than 2 gm/m2 was also associated with reduced 30-day platelet count (platelets <50: 41% vs 8%, P =.004). One treatment-related death occurred, due to respiratory failure and RSV infection, on day 56 after ASCT.
Progression-free survival (PFS) for the entire cohort at 24 months and 48 months, respectively, were 88% (95 CI, 77-93) and 80% (95 CI, 66-89); overall survival (OS) were 96% (95 CI, 89-99) and 92% (95 CI, 81-97). PFS and OS were similar across cohorts with a trend toward inferior PFS in the higher-risk WUSTL cohort.
PFS was similar among off-trial patients treated at DFCI (32 patients) and in community centers (17 patients). In univariate analyses, PFS was not improved with a higher cytarabine dose (more than 2 gm/m2), whereas both blastoid or pleomorphic variant (HR 4.5, P =.016) and high-risk MIPI score (HR 4.0, I =.034) were associated with inferior PFS.
Outcomes with RB/RC induction therapy were similar across both trials as well as in a cohort of off-trial patients treated at DFCI and in community practices. In conclusion, however, the investigators state that “sequential, rather than alternating, RB/RC cycles and lower dose cytarabine may reduce the risk of prolonged thrombocytopenia post-ASCT.
Disclosures: Multiple authors declare affiliations with the pharmaceutical industry. For a complete list of disclosures, please refer to the original abstract.
Reference
Merryman RW, Kahl BS, Redd RA, et al. Rituximab/bendamustine and rituximab/cytarabine (RB/RC) induction chemotherapy for transplant-eligible patients with mantle cell lymphoma: a pooled analysis of two phase 2 clinical trials and off-trial experience. Poster presentation at: American Society of Hematology 60th Annual Meeting and Exposition; December 1-4, 2018; San Diego, CA. Abstract 145.
