Maria Badillo

Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial

BACKGROUND The combination of rituximab and lenalidomide has shown promise for the treatment of mantle-cell lymphoma (MCL) in preclinical studies. We aimed to identify the maximum tolerated dose (MTD) of lenalidomide when combined with rituximab in a phase 1 trial and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL. METHODS Patients with relapsed or refractory MCL who had received one to four previous lines of treatment were enrolled in this single-arm, open-label, phase 1/2 trial at MD Anderson Cancer Center. In phase 1, to identify the MTD of lenalidomide, four patient cohorts received escalating doses (10, 15, 20, and 25 mg) of daily oral lenalidomide on days 1-21 of each 28-day cycle. 375 mg/m(2) intravenous rituximab was also administered in four weekly doses during cycle 1 only. In phase 2, patients received rituximab plus the MTD of lenalidomide, following the same cycles as for phase 1. Treatment in both phases continued until disease progression, stem-cell transplantation, or severe toxicity. The primary efficacy endpoint was overall response (complete or partial response). The secondary efficacy endpoint was survival. We used the Kaplan-Meier method to estimate response duration, progression-free survival, and overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00294632. FINDINGS 52 patients were enrolled between Feb 10, 2006 and July 30, 2009, 14 in phase 1 and 44 (including six patients who received the MTD of lenalidomide in the phase 1 portion) in phase 2. The MTD was 20 mg lenalidomide. One patient who was treated with 25 mg lenalidomide developed a grade 4 non-neutropenic infection and died. In the phase 2 portion of the study, grade 3-4 haematological toxicities included neutropenia (29 patients), lymphopenia (16 patients), leucopenia (13 patients), and thrombocytopenia (ten patients). There were only two episodes of febrile neutropenia. Among 44 patients in phase 2, 25 (57%) had an overall response: 16 (36%) had a complete response and nine (20%) had a partial response. The median response duration was 18·9 months (95% CI 17·0 months to not reached [NR]). The median progression-free survival was 11·1 months (95% CI 8·3 to 24·9 months), and the median overall survival was 24·3 months (19·8 months to NR). Five of 14 patients who had received bortezomib treatment before enrolment achieved an overall response. INTERPRETATION Oral lenalidomide plus rituximab is well tolerated and effective for patients with relapsed or refractory MCL. FUNDING Celgene.

Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial

Lenalidomide–rituximab therapy is effective in grade 1–2 follicular and mantle cell lymphoma, but its efficacy in diffuse large B-cell lymphoma (DLBCL), transformed large cell lymphoma (TL) and grade 3 follicular lymphoma (FLG3) is unknown. In this phase II trial, 45 patients with relapsed or refractory DLBCL (n=32), TL (n=9) or FLG3 (n=4) who had received 1–4 prior lines of treatment were given 20 mg oral lenalidomide on days 1–21 of each 28-day cycle, and intravenous rituximab (375 mg/m2) weekly during cycle 1. Grade 3/4 hematological toxicities included neutropenia (53%), lymphopenia (40%), thrombocytopenia (33%), leukopenia (27%) and anemia (18%), with a median follow-up time of 29.1 months (range 14.7–52.0 months). Overall response (OR) rate was 33%; median response duration was 10.2 months. Median progression-free survival (PFS) and overall survival (OS) were 3.7 and 10.7 months, respectively. Nine of the 15 responding patients (three partial response (PR), six complete response (CR)) proceeded with stem cell transplantation (SCT) and were censored at the time of transplantation. When data were analyzed without censoring, median PFS remained 3.7 months and response duration increased to 30.9 months. Rituximab plus oral lenalidomide is well tolerated and effective for patients with relapsed/refractory DLBCL and TL. SCT after lenalidomide–rituximab is associated with prolonged response duration.

Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial

BACKGROUND Ibrutinib is approved in the EU, USA, and other countries for patients with mantle cell lymphoma who received one previous therapy. In a previous phase 2 study with single-agent ibrutinib, the proportion of patients who achieved an objective response was 68%; 38 (34%) of 111 patients had transient lymphocytosis. We hypothesised that adding rituximab could target mantle cell lymphoma cells associated with redistribution lymphocytosis, leading to more potent antitumour activity. METHODS Patients with a confirmed mantle cell lymphoma diagnosis (based on CD20-positive and cyclin D1-positive cells in tissue biopsy specimens), no upper limit on the number of previous treatments received, and an Eastern Cooperative Oncology Group performance status score of 2 or less were enrolled in this single-centre, open-label, phase 2 study. Patients received continuous oral ibrutinib (560 mg) daily until progressive disease or unacceptable toxic effects. Rituximab 375 mg/m(2) was given intravenously once per week for 4 weeks during cycle 1, then on day 1 of cycles 3-8, and thereafter once every other cycle up to 2 years. The primary endpoint was the proportion of patients who achieved an objective response in the intention-to-treat population and safety assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT01880567, and is still ongoing, but no longer accruing patients. FINDINGS Between July 15, 2013, and June 30, 2014, 50 patients were enrolled. Median age was 67 years (range 45-86), and the median number of previous regimens was three (range 1-9). At a median follow-up of 16·5 months (IQR 12·09-19·28), 44 (88%, 95% CI 75·7-95·5) patients achieved an objective response, with 22 (44%, 30·0-58·7) patients achieving a complete response, and 22 (44%, 30·0-58·7) a partial response. The only grade 3 adverse event in >=10% of patients was atrial fibrillation, which was noted in six (12%) patients. Grade 4 diarrhoea and neutropenia occurred in one patient each. Adverse events led to discontinuation of therapy in five (10%) patients (atrial fibrillation in three [6%] patients, liver infection in one [2%], and bleeding in one [2%]). Two patients died while on-study from cardiac arrest and septic shock; the latter was deemed possibly related to treatment. INTERPRETATION Ibrutinib combined with rituximab is active and well tolerated in patients with relapsed or refractory mantle cell lymphoma. Our results provide preliminary evidence for the activity of this combination in clinical practice. A phase 3 trial is warranted for more definitive data. FUNDING Pharmacyclics LLC, an AbbVie Company.

B-Cell Lymphoma Patient-Derived Xenograft Models Enable Drug Discovery and Are a Platform for Personalized Therapy

Purpose: Patients with B-cell lymphomas often relapse after frontline therapy, and novel therapies are urgently needed to provide long-term remission. We established B-cell lymphoma patient-derived xenograft (PDX) models to assess their ability to mimic tumor biology and to identify B-cell lymphoma patient treatment options. Experimental Design: We established the PDX models from 16 patients with diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, or Burkitt lymphoma by inoculating the patient tumor cells into a human bone chip implanted into mice. We subjected the PDX models to histopathologic and phenotypical examination, sequencing, and drug efficacy analysis. Primary and acquired resistance to ibrutinib, an oral covalent inhibitor of Bruton tyrosine kinase, were investigated to elucidate the mechanisms underlying ibrutinib resistance and to identify drug treatments to overcome resistance. Results: The PDXs maintained the same biological, histopathologic, and immunophenotypical features, retained similar genetic mutations, and produced comparable drug responses with the original patient tumors. In the acquired ibrutinib-resistant PDXs, PLC-γ2, p65, and Src were downregulated; however, a PI3K signaling pathway member was upregulated. Inactivation of the PI3K pathway with the inhibitor idelalisib in combination with ibrutinib significantly inhibited the growth of the ibrutinib-resistant tumors. Furthermore, we used a PDX model derived from a clinically ibrutinib-relapsed patient to evaluate various therapeutic choices, ultimately eliminating the tumor cells in the patients peripheral blood. Conclusions: Our results demonstrate that the B-cell lymphoma PDX model is an effective system to predict and personalize therapies and address therapeutic resistance in B-cell lymphoma patients. Clin Cancer Res; 23(15); 4212–23. ©2017 AACR.

Four-year follow-up of a single arm, phase II clinical trial of ibrutinib with rituximab (IR) in patients with relapsed/refractory mantle cell lymphoma (MCL).

Ibrutinib has shown significant activity in patients with relapsed or refractory mantle cell lymphoma (RR‐MCL). We report the long‐term outcome and safety profile of a single‐centre, single arm, open‐label, phase 2 study of RR‐MCL treated with IR. Overall, the median follow‐up time was 47 months (range 1–52 months), median duration on treatment was 16 months (range 1–53 months) and median number of treatment cycles was 17 (range 1–56). Twenty‐nine patients (58%) achieved complete remission and of these, 12 patients continue on study. Thirty‐eight patients discontinued treatment, 14 due to disease progression (2 transformed). Patients with blastoid morphology, high risk MCL International Prognostic Index score and high Ki67% had inferior survival. The commonest grade 1–2 toxicities were fatigue, diarrhoea, nausea, arthralgias and myalgias. None had long term toxicities. Median progression‐free survival was 43 months. Eighteen patients (36%) died (14 deaths were MCL‐related). The median overall survival has not been reached. Treatment with IR can provide durable remissions in a subset of patients with RR‐MCL, especially those with low Ki67%. The possible benefit of adding other therapies in combination with IR in RR‐MCL is under exploration.

A phase II study of carfilzomib in the treatment of relapsed/refractory mantle cell lymphoma

Velden, V.H., Brooimans, R.A., Pabst, T., Maertens, J., Boeckx, N., de Greef, G.E., Valk, P.J., Preijers, F.W., Huijgens, P.C., Dr€ager, A.M., Schanz, U., Jongen-Lavrecic, M., Biemond, B.J., Passweg, J.R., van Gelder, M., Wijermans, P., Graux, C., Bargetzi, M., Legdeur, M.C., Kuball, J., de Weerdt, O., Chalandon, Y., Hess, U., Verdonck, L.F., Gratama, J.W., Oussoren, Y.J., Scholten, W.J., Slomp, J., Snel, A.N., Vekemans, M.C., L€ owenberg, B., Ossenkoppele, G.J. & Schuurhuis, G.J. (2013) High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 42A study. Journal of Clinical Oncology, 31, 3889–3897. Venditti, A., Piciocchi, A., Candoni, A., Melillo, L., Calafiore, V., Cairoli, R., De Fabritiis, P., Storti, G., Salutari, P., Lanza, F., Martinelli, G., Luppi, M., Mazza, P., Falini, B., Cuneo, A., Specchia, G., Fabbiano, F., Tafuri, A., Ronci, B., Tieghi, A., Fracchiolla, N. S., Capelli, D., Fo a, R., Ronco, F., La Sala, E., Fazi, P., Maurillo, L., Buccisano, F., Del Principe, M.I., Lo Coco, F., Arcese, W. & Amadori, S. (2017) Risk-adapted, MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia: results of the AML 1310 trial of the GIMEMA group. Haematologica, 102(s2), 6–7. (abstract s111).

Integrated stress response and immune cell infiltration in an ibrutinib-refractory mantle cell lymphoma patient following ONC201 treatment

Mantle cell lymphoma (MCL) is an incurable subtype of non-Hodgkin lymphoma (NHL). The Bruton tyrosine kinase (BTK) inhibitor ibrutinib achieves a 68% overall response rate in relapsed/refractory MCL patients, but 69% will progress within 2 years and their median survival is only 5 8 months (Cheah et al, 2015). ONC201, a first-in-class small molecule that selectively antagonizes the G protein-coupled receptor (GPCR) dopamine receptor D2 (DRD2) (Madhukar et al, 2017a), activates the integrated stress response (ISR) that attenuates protein translation and induces activating transcription factor 4 (ATF4) and C/EBP homology protein (CHOP), which transcriptionally regulate genes involved in apoptosis that include TNFRSF10B (also termed death receptor 5, DR5) and TNFSF10 (also termed tumour necrosis factor-related apoptosis-inducing ligand, TRAIL) (Allen et al, 2016). Preclinical evidence suggests that ONC201 lacks cross-resistance with other endoplasmic reticulum stress-inducing agents, such as bortezomib, and exhibits pro-apoptotic activity in refractory cancer models, including ibrutinib-refractory MCL (Ishizawa et al,

Long-term outcomes and mutation profiling of patients with mantle cell lymphoma (MCL) who discontinued ibrutinib

Long term outcomes and mutations in patients with mantle cell lymphoma (MCL) who discontinued ibrutinib have not been described. Using deep targeted next generation sequencing, we performed somatic mutation profiling from 15 MCL patients (including 5 patients with paired samples; before and after progression on ibrutinib). We identified 80 patients with MCL who discontinued ibrutinib therapy for various reasons. Median follow‐up after ibrutinib discontinuation was 38 months. The median duration on ibrutinib was 7·6 months. Forty‐one (51%) patients discontinued ibrutinib due to disease progression/transformation, 20 (25%) for intolerance, 7 (9%) due to patient choice, 5 (6%) for stem cell transplant, 4 (5%) due to second cancers and 3 (4%) other causes. The median survival after ibrutinib was 10 and 6 months for disease progression and transformation, respectively, and 25 months for patients with ibrutinib intolerance. Overall, BTK mutations were observed in 17% patients after progression on ibrutinib. Notably, TP53 alterations were observed after progression in 75% patients. Among the 4 patients with blastoid transformation, 3 (75%) had NSD2 mutations (co‐existing with TP53). Ibrutinib‐refractory MCL patients had a short survival. Demonstration of TP53 and NSD2 mutations in patients who developed blastoid transformation and ATM and TP53 mutations in patients who progressed, opens the door for future investigations in ibrutinib‐refractory MCL.

Phase II Study of Bortezomib in Combination with Cyclophosphamide and Rituximab for Relapsed or Refractory Mantle Cell Lymphoma

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 36.4 months, respectively. The regimens 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. The Oncologist 2017;22:549-553 IMPLICATIONS FOR PRACTICE: The combination of bortezomib with cyclophosphamide and rituximab represents an additional effective novel salvage regimen for mantle cell lymphoma. This combination adds to the growing list of treatment options available for patients with mantle cell lymphoma.

Improved outcome for patients with relapsed/refractory mantle cell lymphoma (MCL) who stop ibrutinib +/− rituximab for reasons other than progression of disease

Background: Ibrutinib produces a high rate of response in patients with previously treated mantle cell lymphoma (MCL). However, patients who discontinue therapy due to disease progression have a poor overall survival rate (OS; median 8.4 months). The outcome of patients who discontinue ibrutinib due to reasons other than progression has not been well described. Methods: Retrospective review of single institutional patients who received ibrutinib with or without rituximab both on and off protocol for relapsed/refractory MCL. Results: Between 2011 and 2017, 24 patients who received ibrutinib ± rituximab had their treatment discontinued for reasons other than progression after a median of 14 months of therapy (range 2‐57 months), the most common reason being due to infection (see table), and have since been observed without therapy. After a median follow‐up of 13 months from discontinuation of ibrutinib therapy, the median OS is 13 months and likely to improve, since 14 patients are still in CR/PR, with all of them alive except for one. Ten patients have relapsed/progressed and of these, 6 have died (4 from disease). The patients who have not progressed had a mean duration of ibrutinib ± rituximab treatment of 22 months compared to 13 months for those who progressed. Among the 10 patients with progressive disease, the median time to progression was 11 months. Patients who received ibrutinib alone had more frequency of relapse (8/15) than patients who received ibrutinib with rituximab (2/9). Conclusion: Patients who discontinue ibrutinib while responding have better outcomes than patients who discontinue ibrutinib due to disease progression. A longer duration of ibrutinib therapy appears to prolong response duration. Further exploration of outcomes and correlation with pre‐treatment variables will be explored and presented at the symposium. Reasons for Discontinuation of Therapy