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However, patients who fail ibrutinib therapy have demonstrated poor survival outcomes, and there has been an urgent need to develop treatment options to tackle ibrutinib resistance (Martin I et al. i , [8]). The higher number of side-effects among patients in dose level one when compared with dose levels two and three could not be explained on the basis of patient risk characteristics in the three cohorts. It is interesting to note that four of eight patients achieved a partial response, including four of five patients with prior BTK inhibitor exposure and two of three patients with prior bortezomib exposure. [Extracted from the article]

Background: Although the outcomes of patients with mantle cell lymphoma (MCL) have improved, there is still no cure. Bortezomib has a 33% response rate in relapsed/refractory MCL and has shown additive and/or synergistic effects in preclinical trials with known effective agents.Methods: This is a report of a prospective phase 2 trial of bortezomib added to rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (BzR-hyperCVAD)/rituximab, high-dose methotrexate, and high-dose cytarabine (BzR-MA) for 95 patients with newly diagnosed MCL.Results: The overall and complete response rates were 100% and 82%, respectively. Hematologic toxicity was high but expected and did not lead to an increased incidence of neutropenic fever or dose reductions in comparison with a similar reported regimen without bortezomib. After a median follow-up of 44 months, the median overall survival had not been reached, and the time to treatment failure (TTF) was 55 months, which is not different from that of historical controls.Conclusions: BzR-hyperCVAD/BzR-MA at the dose and schedule studied produced high rates of response and a TTF similar to that of historical reports without bortezomib. Cancer 2018;124:2561-9. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background. Relapsed or refractory mantle cell lymphoma (MCL) has a poor prognosis. The best outcome is achieved in patients who have a partial or complete response to salvage treatment and proceed to allogeneic stem cell transplant. Patients and Methods. Twenty-one patients were given a combination regimen of bortezomib, cyclophosphamide, and rituximab at MD Anderson Cancer Center as part of a single-arm, prospective, open-label phase II clinical trial. The median age was 66 years, with a median number of prior treatments of three. Sixty-seven percent had failed intensive chemoimmunotherapy and 43% were intermediate/high risk according to the MCL international prognostic index score, with a median Ki-67 proliferation index of 45% in those who were tested. Results. The rates of overall and complete response achieved were 74% and 42%, respectively, with median progression-free and overall survivals of 9 months and 36.4months, respectively. The regimen's toxicity profile was acceptable; only 25% of the cycles resulted in grade 3 or 4 neutropenia or thrombocytopenia, and only 3% of cycles produced grade 3-4 fatigue. There were no episodes of grade 3-4 neuropathy. Conclusion. The combination of bortezomib with cyclophosphamide and rituximab is an effective and well-tolerated regimen in patients with relapsed/refractory MCL. Because of its low toxicity, future combinations of this regimen with other promising drugs that have different mechanisms of action offer a realistic possibility that may improve outcomes for patients who have MCL. [ABSTRACT FROM AUTHOR]

Intensive chemotherapy regimens containing cytarabine have substantially improved remission durability and overall survival in younger adults with mantle cell lymphoma (MCL). However, there have been no long-term follow-up results for patients treated with these regimens. We present long-term survival outcomes from a pivotal phase II trial of rituximab, hyper-fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine (R-HCVAD/MA). At 15 years of follow-up (median: 13·4 years), the median failure-free survival (FFS) and overall survival (OS) for all patients was 4·8 years and 10·7 years, respectively. The FFS seems to have plateaued after 10 years, with an estimated 15-year FFS of 30% in younger patients (≤65 years). Patients who achieved complete response (CR) after 2 cycles had a favourable median FFS of 8·8 years. Six patients developed myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) whilst in first CR. The 10-year cumulative incidence of MDS/AML of patients in first remission was 6·2% (95% confidence interval: 2·5-12·2%). In patients with newly diagnosed MCL, R-HCVAD/MA showed sustained efficacy, with a median OS exceeding 10 years in all patients and freedom from disease recurrence of nearly 15 years in almost one-third of the younger patients (≤65 years). [ABSTRACT FROM AUTHOR]

We evaluated the role of flow cytometric immunophenotyping (FCI) in the assessment of bone marrow (BM) specimens in 104 patients with mantle cell lymphoma (MCL) following treatment with aggressive combination chemotherapy. Of the patients, 77 had no morphologic or FCI evidence of MCL, 13 had morphologic and FCI evidence of MCL, and 14 patients were morphologically negative but FCI showed CD5+ clonal B-cells (M-/FCI+). Retrospective cyclin D1 immunostaining was positive in 3 of 12 M-/FCI+ cases. Clinical staging and follow-up showed that 4 of 12 patients had concurrent extramedullary involvement by MCL, 5 patients subsequently became M+ for MCL in BM (within 2-24 months), and 3 patients had no recurrent MCL on follow-up. We conclude that FCI is more sensitive than morphologic examination of BM at the time of restaging in patients with MCL and that positivity by only FCI in BM often correlates with concurrent disease or subsequent relapse. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) outcomes have improved over the last two decades; however, late relapses occur. Bortezomib has shown single agent activity of 33% in relapsed MCL and has an additive/synergistic effect in vitro when combined with drugs currently used to treat MCL. We hypothesized that a combination of bortezomib with current intense non-transplant chemoimmunotherapy might prevent late relapses. The toxicity of bortezomib when combined with methotrexate and cytarabine is unknown. Patients aged 18–79 years with untreated aggressive MCL were treated with R-HyperCVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with rituximab-methotrexate/cytarabine (R-M/A). Bortezomib was added to the R-Hyper-CVAD combination as a fixed dose of 1·3 mg/m2 IV on days 2 and 5 and was added to the R-M/A regimen after rituximab, in increasing doses of 0·7, 1, and 1·3 mg/m2 in cohorts of three patients. Twenty patients were assessed for toxicity of the regimen. The principal toxicity was haematological and did not differ from that observed with a similar regimen without the bortezomib. In particular, there was no pulmonary or neurological dose-limiting toxicity, showing that bortezomib can be safely combined with R-HyperCVAD and R-M/A. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) has a poor overall survival after treatment with conventional chemotherapy. Intense chemoimmunotherapy without consolidation stem cell transplantation is a potential therapeutic option. We report on a prospective Phase II study with rituximab in combination with fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (R-Hyper-CVAD) alternating with rituximab in combination with high-dose methotrexate-cytarabine (R-MA) in untreated patients with diffuse and nodular MCL and their blastoid variants. Ninety-seven patients were treated, of whom 97% responded and 87% achieved a complete remission. At 10 years of follow up (median 8 years), the median overall survival (OS) for all patients had not been reached and the median time to failure (TTF) for all patients was 4.6 years, without a plateau in the curves. For the group of patients aged 65 years or younger, the median OS had not been reached and the median TTF was 5.9 years. Multivariate analysis revealed pre-treatment serum levels of β2 microglobulin, International Prognostic Index (IPI) score and mantle cell IPI (MIPI) score, as predictive of both OS and TTF. We conclude that intense chemoimmunotherapy without stem cell transplantation is effective for untreated aggressive MCL. [ABSTRACT FROM AUTHOR]

The article informs that eukaryotic initiation factor 4E (elF4E) predicts clinical outcome in patients with mantle cell lymphoma (MCL) treated with hyper-CVAD and rituximab, alternating with rituximab, high-dose methotrexate, and cytarabine. It is stated that the authors investigated the prognostic significance of elF4E expression in 70 MCL patients.

The article discusses the use of tumor proliferation index (PI) to predict prognosis of patients with mantle cell lymphoma (MCL) treated with an aggressive chemotherapy regimen. The chemotherapy regimen used rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethsone alternating with rituximab plus high-dose methotrexate and cytarabine (R-hyper-CVAD). The results show that PI has prognostic significance in patients with MCL taking R-hyper-CVAD therapy regimen.

Ibrutinib, an oral inhibitor of Bruton tyrosine kinase, is approved for patients with mantle cell lymphoma (MCL) who have received one prior therapy. We report the updated safety and efficacy results from the multicenter, open-label phase 2 registration trial of ibrutinib (median 26.7-month follow-up). Patients (N = 111) received oral ibrutinib 560 mg once daily, and those with stable disease or better could enter a long-term extension study. The primary end point was overall response rate (ORR). The median patient age was 68 years (range, 40-84), with a median of 3 prior therapies (range, 1-5). The median treatment duration was 8.3 months; 46% of patients were treated for >12 months, and 22% were treated for ≥2 years. The ORR was 67% (23% complete response), with a median duration of response of 17.5 months. The 24-month progression-free survival and overall survival rates were 31% (95% confidence interval [CI], 22.3-40.4) and 47% (95% CI, 37.1-56.9), respectively. The most common adverse events (AEs) in >30% of patients included diarrhea (54%), fatigue (50%), nausea (33%), and dyspnea (32%). The most frequent grade ≥3 infections included pneumonia (8%), urinary tract infection (4%), and cellulitis (3%). Grade ≥3 bleeding events in ≥2% of patients were hematuria (2%) and subdural hematoma (2%). Common all-grade hematologic AEs were thrombocytopenia (22%), neutropenia (19%), and anemia (18%). The prevalence of infection, diarrhea, and bleeding was highest for the first 6 months of therapy and less thereafter. With longer follow-up, ibrutinib continues to demonstrate durable responses and favorable safety in relapsed/refractory MCL. [ABSTRACT FROM AUTHOR]