Cristina João

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

BACKGROUND Mantle-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. METHODS This 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). FINDINGS Between 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%]). INTERPRETATION Ibrutinib 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. FUNDING Janssen Research & Development, LLC.

Early lymphocyte recovery after autologous stem cell transplantation predicts superior survival in mantle-cell lymphoma

Autologous stem cell transplantation (ASCT) is an effective treatment strategy for mantle-cell lymphoma (MCL) demonstrating significantly prolonged progression-free survival (PFS) when compared to interferon-α maintenance therapy of patients in first remission. The study of absolute lymphocyte count at day 15 (ALC-15) after ASCT as a prognostic factor in non-Hodgkin lymphoma (NHL) included different lymphoma subtypes. The relationship of ALC-15 after ASCT in MCL has not been specifically addressed. We evaluated the impact of ALC-15 recovery on survival of MCL patients undergoing ASCT. We studied 42 consecutive MCL patients who underwent ASCT at the Mayo Clinic in Rochester from 1993 to 2005. ALC-15 threshold was set at 500 cells/μl. The median follow-up after ASCT was 25 months (range, 2–106 months). The median overall survival (OS) and PFS times were significantly better for the 24 patients who achieved an ALC-15 ⩾500 cells/μl compared with 18 patients with ALC-15 <500 cells/μl (not reached vs 30 months, P<0.01 and not reached vs 16 months, P<0.0006, respectively). Multivariate analysis demonstrated ALC-15 to be an independent prognostic factor for OS and PFS. The ALC-15 ⩾500 cells/μl is associated with a significantly improved clinical outcome following ASCT in MCL.

The Production Processes and Biological Effects of Intravenous Immunoglobulin

Immunoglobulin is a highly diverse autologous molecule able to influence immunity in different physiological and diseased situations. Its effect may be visible both in terms of development and function of B and T lymphocytes. Polyclonal immunoglobulin may be used as therapy in many diseases in different circumstances such as primary and secondary hypogammaglobulinemia, recurrent infections, polyneuropathies, cancer, after allogeneic transplantation in the presence of infections and/or GVHD. However, recent studies have broadened the possible uses of polyclonal immunoglobulin showing that it can stimulate certain sub-populations of T cells with effects on T cell proliferation, survival and function in situations of lymphopenia. These results present a novel and considerable impact of intravenous immunoglobulin (IVIg) treatment in situations of severe lymphopenia, a situation that can occur in cancer patients after chemo and radiotherapy treatments. In this review paper the established and experimental role of polyclonal immunoglobulin will be presented and discussed as well as the manufacturing processes involved in their production.

Treatment With Polyclonal Immunoglobulin During T-cell Reconstitution Promotes Naive T-cell Proliferation

Natural antibodies are unique self molecules endowed with both suppressive and activating functions on various cells of the immune system and are recognized as a fundamental link between the adaptive and innate immune system. Here, we examine the role of natural antibodies, using polyclonal immunoglobulins (Ig), as a promoter of T-cell reconstitution in a context of lymphopenia. We have established a mouse model to mimic immunologic recovery in adult patients with severe hypothymic function subjected to autologous hematopoietic precursor cell transplantation. Thymectomized mice were transplanted and treated with low doses of Ig or its Fab or Fc fragments. The animals displayed, during early phases of Ig treatment, a significant increase of T-cell reconstitution displaying a naive CD4+phenotype. In addition, the Ig-treated animals exhibited an increase dilution of single-joint T-cell receptor excision circles (sjTRECs) in peripheral blood, suggesting an early increase in proliferation of T cells stimulated by the natural antibodies. These results unveil a novel and considerable effect of intravenous Ig treatment in situations of severe lymphopenia as a stimulator of proliferation of peripheral naive T cells, possibly protecting diverse immune repertoires.

Adverse event management in patients with relapsed and refractory multiple myeloma taking pomalidomide plus low-dose dexamethasone: A pooled analysis

Heavily pretreated patients with relapsed and refractory multiple myeloma are susceptible to treatment‐related adverse events (AEs). Managing AEs are important to ensure patients continue therapy long enough to receive the best clinical benefit. Data from the MM‐002, MM‐003, and MM‐010 trials were pooled to further characterize the safety profile of pomalidomide plus low‐dose dexamethasone and AE management.

Long‐term survival in multiple myeloma

The survival of multiple myeloma patients has improved very significantly over the last decade. Still median overall survival is inferior to 5 years. A small proportion of patients survive longer than 10 years. In this paper we discuss four cases illustrating the nonhomogeneous clinical presentation and evolution of this subset of patients. Surprisingly, these long survivors do not always have deep responses and some require frequent treatments, which include autologous stem cell transplantation and novel drugs. The authors discuss several aspects of these clinical histories, including treatment options, raising hypothesis on their relation with long survivorship which may be important to have in consideration when studying this subject.

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.

Monoclonal Gammopathies of Indetermined Significance: Diagnosis and Clinical Follow-up Guidelines

The Portuguese group of multiple myeloma of the Portuguese Society of Hematology proposes a national protocol for diagnosis and clinical follow-up of monoclonal gammopathies. The proposed protocol aims to standardize clinical management of monoclonal gammopathies. Furthermore, it would also define the major risk factors for progression to Multiple Myeloma that require a precocious close articulation between general practitioners and a Hematology Clinic.