Isabelle Bence-Bruckler

Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study

BACKGROUNDnMantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma.nnnMETHODSnThis randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74).nnnFINDINGSnBetween Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0·0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0·43 [95% CI 0·32-0·58]; median progression-free survival 14·6 months [95% CI 10·4-not estimable] vs 6·2 months [4·2-7·9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]).nnnINTERPRETATIONnIbrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma.nnnFUNDINGnJanssen Research & Development, LLC.

Autologous Stem Cell Transplantation for Stiff Person Syndrome: Two Cases From the Ottawa Blood and Marrow Transplant Program

IMPORTANCEnStiff person syndrome (SPS) is a rare neurological disease causing significant functional disability for patients and presenting a therapeutic challenge for clinicians. Autologous hematopoietic stem cell transplantation (auto-HSCT) has been used successfully to remit autoimmune-mediated neurological diseases. We report 2 cases of severe SPS treated with auto-HSCT, a novel therapy for this disease.nnnOBSERVATIONSnTwo anti-glutamic acid decarboxylase antibody-positive patients with SPS had an autologous hematopoietic stem cell graft collected and stored. Subsequently, the patients underwent auto-HSCT. Both patients achieved clinical remission with sustained, marked improvement in symptoms and a return to premorbid functioning, now more than 2.5 and 4.5 years after the procedure.nnnCONCLUSIONS AND RELEVANCEnStiff person syndrome represents a novel indication for auto-HSCT. The resolution of clinical manifestations of SPS despite the persistence of anti-glutamic acid decarboxylase antibodies following auto-HSCT suggests that the antibody does not play a direct role in pathogenesis of SPS.

Advances in the treatment of relapsed/refractory chronic lymphocytic leukemia

Treatment of chronic lymphocytic leukemia (CLL) has advanced with the introduction of chemoimmunotherapy (CIT) agents that have improved the outcomes of frontline therapy. However, most treated patients will relapse and require subsequent therapy. This review focuses on recent advances in the treatment of relapsed or refractory CLL. Until recently, treatment options for relapsed CLL were of limited efficacy. Retreatment with fludarabine, cyclophosphamide, and rituximab (FCR) was recommended for patients with a durable response to first-line FCR, although acquired genetic aberrations, impaired marrow reserve, and comorbidities often made this suboptimal therapy for many patients. New options include two agents targeting B cell receptor (BCR) signaling pathways (ibrutinib and idelalisib) and a B cell lymphoma-2 (BCL-2) inhibitor (venetoclax). Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative option for younger patients with a suitable donor.

Health-related quality of life data from a phase 3, international, randomized, open-label, multicenter study in patients with previously treated mantle cell lymphoma treated with ibrutinib versus temsirolimus

Abstract Mantle cell lymphoma (MCL) is a rare, aggressive, incurable B-cell malignancy. Ibrutinib has been shown to be highly active for patients with relapsed/refractory (R/R) MCL. The RAY trial (MCL3001) was a phase 3, randomized, open-label, multicenter study that compared ibrutinib with temsirolimus in patients with R/R MCL. Active disease is frequently associated with impaired functional status and reduced well-being. Therefore, the current study employed two patient-reported outcome instruments, the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the EQ-5D-5L, to assess symptoms, well-being, health status, and health-related quality of life of patients on treatment within the RAY trial. We found that patients on ibrutinib had substantial improvement in FACT-Lym subscale and total scores, and had improvement in EQ-5D-5L utility and VAS scores compared with temsirolimus patients, indicating a superior well-being. These improvements in well-being correlated with clinical response, indicating that better health-related quality of life was associated with decreased disease burden.

Ibrutinib versus temsirolimus: 3-year follow-up of patients with previously treated mantle cell lymphoma from the phase 3, international, randomized, open-label RAY study

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a reported median overall survival (OS) of 3–5 years [1]. Most patients relapse after first-line therapy and have a poor prognosis [1]. Regulatory approval of ibrutinib has provided a much needed therapeutic option for patients with relapsed or refractory (R/R) MCL [2], with ibrutinib becoming a preferred standard of care in current guidelines [3, 4]. The randomized, open-label phase 3 RAY study (NCT01646021) was key in confirming the efficacy and safety of ibrutinib, with ibrutinib (N= 139) showing significantly improved progression-free survival (PFS) versus temsirolimus (N= 141) (primary analysis [20-month follow-up]: 14.6 vs. 6.2 months, hazard ratio [HR] 0.43, 95% confidence interval [CI]: 0.32–0.58) [5]. Here, we report extended follow-up data from the final analysis of the RAY study. At this final analysis, after an almost doubled median study follow-up of 38.7 months, 33 patients (24%) in the ibrutinib group and no patients in the temsirolimus group remained on initially randomized treatment. Crossover to ibrutinib from the temsirolimus group was permitted for patients who had confirmed disease progression. Fifty-five patients in the temsirolimus group (39%) received subsequent ibrutinib (42 were included in the formal study crossover; 13 received ibrutinib outside of the study). Disease progression or relapse was the most common reason for discontinuing treatment for both groups (ibrutinib, 78 patients [56%]; temsirolimus, 66 patients [47%]). Fewer patients in the ibrutinib group (12 [9%]) than in the temsirolimus group (39 [28%]) discontinued treatment due to adverse events (AEs); eight patients in each arm discontinued due to death. Other reasons for discontinuation included refusing further treatment. Median duration of

IBRUTINIB VS TEMSIROLIMUS: THREE‐YEAR FOLLOW‐UP OF PATIENTS WITH PREVIOUSLY TREATED MANTLE CELL LYMPHOMA FROM THE PHASE 3, INTERNATIONAL, RANDOMIZED, OPEN‐LABEL RAY STUDY

Introduction: The ibrutinib–rituximab combination produced durable responses in 88% of relapsed/refractory mantle cell lymphoma (MCL) patients, providing a “Window” of opportunity to use chemotherapy‐ free induction with ibrutinib‐rituximab followed by fewer cycles of chemo‐immunotherapy in young, fit patients with newly diagnosed MCL. Methods: Enrollment began in June 2015 for a Phase II single‐center clinical trial consisting of a chemotherapy‐free phase of ibrutinib‐rituximab treatment (Part 1) until best response, followed by a shortened intense chemo‐immunotherapy course (Part 2) among newly diagnosed MCL patients of ≤65 years. We previously presented the initial results of this trial with ibrutinib‐rituximab and consolidation (Wang et al., ASH 2016). Here, we report updated data with a longer follow‐ up duration. The primary objective was to evaluate the response rate. Ibrutinib is dosed at 560 mg orally, daily, continuously. Rituximab is dosed at 375 mg/m IV weekly x 4 during cycle 1 (28 days cycle), then day 1 of cycles 3‐12. Intense chemo‐immunotherapy consists of rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper‐CVAD); alternating every 28 days with rituximab plus high‐dose methotrexate‐Ara C. If in complete remission (CR) after ibrutinib‐rituximab treatment, only 4 cycles of intense chemo‐immunotherapy are given. If the patient is in partial response or progression, and if responding to intensive chemo‐immunotherapy, a total of 2 cycles of chemo‐immunotherapy therapy are administered beyond achievement of CR. Results: As of March 3, 2017, 50 patients were evaluable for response. Of the evaluable patients, overall response rate (ORR) to chemotherapy‐free therapy alone was 100% (50), with CR in 80% (40) and PR in 20% (10). Thirty‐three (33) patients have completed both Parts 1 and 2 and all have achieved CR (i.e., ORR =100%). In Part 1, the most common grade 1‐2 non‐haematological (non‐heme) adverse effects (AEs) were fatigue (50), diarrhea (28), rash (29), myalgia (41), oral mucositis (52), peripheral neuropathy (19), nausea (25), blurred vision (19), edema (23), constipation (18), dry eyes (18), and dizziness (22). Grade 3 non‐heme AEs included fatigue (4), nausea (2), infection (3) and dyspnea (2). No grade 4‐5 non‐heme toxicities were observed in Part 1. Grade 3‐4 heme AEs included lymphocytosis (22), thrombocytopenia (13) and leukopenia (15). Conclusions: These updated data indicate that ibrutinib‐rituximab induction in newly diagnosed, young MCL patients was efficacious and well‐tolerated, providing a window of opportunity for less chemo‐immunotherapy needed for consolidation.

Disseminated histoplasmosis associated with acquired hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a potentially life‐threatening clinical syndrome caused by uncontrolled activation of lymphocytes and histiocytes resulting in high levels of cytokines. Acquired HLH occurs in autoimmune, inflammatory, infectious, and immunosuppressive disorders. Prompt identification and treatment of an underlying triggering cause improves clinical outcome.

Outcomes of both abbreviated hyper-CVAD induction followed by autologous hematopoietic cell transplantation and conventional chemotherapy for mantle cell lymphoma: a 10-year single-centre experience with literature review.

We retrospectively evaluated consecutive patients diagnosed with Mantle cell lymphoma (MCL) between 01 January 2000 and 31 December 2009. Eighty eight patients with MCL were included in the analysis of whom 46 (52%) received abbreviated Hyper‐CVAD (a total of two cycles; with addition of Rituximab since 2005) with an intention of proceeding to autologous hematopoietic cell transplantation (auto‐HCT), with a median age of 58 years. Response rate to induction at auto‐HCT time was 89% and complete response was 61%. Forty four patients received an auto‐HCT with a 5‐year progression‐free survival (PFS) and overall survival (OS) were 31.2% and 62.5%, respectively. There were 42 nontransplant eligible patients with a median age of 72 years, and 5‐year PFS and OS were 0.0% and 39.9%, respectively. The median survival and PFS in the auto‐HCT eligible group were 68 and 33 months, compared to 32 and 12 months in nontransplant eligible group, without a plateauing of the survival curves in either group. Treatment‐related mortality in the auto‐HCT eligible group was 10.9% (n = 5); two patients died during R‐Hyper‐CVAD and 3 (6.8%) experienced transplant‐related mortality. An abbreviated R‐Hyper‐CVAD‐based induction strategy followed by consolidative auto‐HCT is feasible and provides moderate potential of long‐term survival. Further research to define risk‐adapted strategies; to optimize disease control, is required.

A Canadian Perspective on the First-Line Treatment of Chronic Lymphocytic Leukemia

Despite important advances in the treatment of first-line chronic lymphocytic leukemia (CLL) over the past decade, CLL remains an incurable disease with significant unmet needs. The combination of rituximab with fludarabine and cyclophosphamide (FCR) significantly improved overall survival and progression-free survival compared with fludarabine and cyclophosphamide alone in first-line treatment of CLL. However, because of its high toxicity, FCR is only recommended for younger, fit patients who can tolerate the treatment. This excludes a large fraction of CLL patients who are elderly and/or who have comorbidities. Thus, determining the appropriate treatment choices for this group of patients who are unfit for FCR treatment is a significant challenge in CLL. Current treatment choices in Canadian practice include bendamustine with rituximab, fludarabine with rituximab, and chlorambucil with rituximab. Two novel monoclonal antibodies, ofatumumab and obinutuzumab, have also recently received Health Canada approval for the first-line treatment of CLL patients in combination with chlorambucil. In addition, the Bruton tyrosine kinase inhibitor, ibrutinib, has recently been approved by Health Canada for the first-line treatment of CLL patients with deletion 17p. In the coming years, several other novel agents that are being developed are likely to change the CLL treatment landscape dramatically, however, because these novel agents are currently unavailable, the purpose of this review is to recommend the best treatment approaches in Canada using currently available therapies.