Phase 2 studies of lenalidomide, subcutaneous bortezomib, and dexamethasone as induction therapy in patients with newly diagnosed multiple myeloma.

There are limited prospective data on lenalidomide, subcutaneous bortezomib, and dexamethasone (RsqVd) in transplant-eligible/transplant-ineligible patients with newly diagnosed multiple myeloma. Reliable biomarkers for efficacy and toxicity are required to better tailor therapy. Two parallel studies were conducted by Cancer Trials Ireland (CTI; NCT02219178) and the Dana-Farber Cancer Institute (DFCI; NCT02441686). Patients received four 21-day cycles of RsqVd and could then receive either another 4 cycles of RsqVd or undergo autologous stem cell transplant. Postinduction/posttransplant, patients received lenalidomide maintenance, with bortezomib included for high-risk patients. The primary endpoint was overall response rate (ORR) after 4 cycles of RsqVd. Eighty-eight patients were enrolled and 84 treated across the two studies; median age was 64.7 (CTI study) and 60.0 years (DFCI study), and 59% and 57% had stage II-III disease. Pooled ORR after 4 cycles in evaluable patients was 93.5%, including 48.1% complete or very good partial responses (CTI study: 91.9%, 59.5%; DFCI study: 95.0%, 37.5%), and in the all-treated population was 85.7% (44.0%). Patients received a median of 4 (CTI study) and 8 (DFCI study) RsqVd cycles; 60% and 31% of patients (CTI study) and 33% and 51% of patients (DFCI study) underwent transplant or received further RsqVd induction, respectively. The most common toxicity was peripheral neuropathy (pooled: 68%, 7% grade 3-4; CTI study: 57%, 7%; DFCI study: 79%, 7%). Proteomics analyses indicated elevated kallikrein-6 in good versus poor responders, decreased midkine in good responders, and elevated macrophage inflammatory protein 1-alpha in patients who stopped treatment from neurotoxicity, suggesting predictive biomarkers warranting further investigation.

A multi-centre retrospective study of rituximab use in the treatment of relapsed or resistant warm autoimmune haemolytic anaemia.

This retrospective analysis assessed the response, safety and duration of response to standard dose rituximab 375 mg/m(2) weekly for four weeks as therapy for patients with primary or secondary warm autoimmune haemolytic anaemia (WAIHA), who had failed initial treatment. Thirty-four patients received rituximab for WAIHA in seven centres in the Republic of Ireland. The overall response rate was 70·6% (24/34) with 26·5% (9/34) achieving a complete response (CR). The time to response was 1 month post-initiation of rituximab in 87·5% (21/24) and 3 months in 12·5% (3/24) of patients. The median duration of follow-up was 36 months (range 6-90 months). Of the patients who responded, 50% (12/24) relapsed during follow up with a median time to next treatment of 16·5 months (range 6-60 months). Three patients were re-treated with rituximab 375 mg/m2 weekly for four weeks at relapse and responded. There was a single episode of neutropenic sepsis. Rituximab is an effective and safe treatment for WAIHA but a significant number of patients will relapse in the first two years post treatment. Re-treatment was effective in a small number of patients, suggesting that intermittent pulse treatment or maintenance treatment may improve long-term response.

Biclonal lymphoproliferative disorders: another association with NOTCH1-mutated chronic lymphocytic leukaemias.

INTRODUCTION: Biclonal lymphoid disorders, when two distinct lymphoproliferative disorders (LPD) co-exist, are rare (incidence of 1.4%) and associated with a poor prognosis. NOTCH1 mutations occur in 10% of CLL at diagnosis, associated with a short disease-free interval and increased risk of Richter's transformation. We hypothesised that the incidence of NOTCH1 mutations in CLL with a second LPD may be increased, because the mutation occurs early in leukaemogenesis, permitting clonal divergence. METHODS: We identified 19 patients with biclonal LPD at diagnosis: 11 with CLL and a second LPD (group A) and 8 with a second distinct CLL (group B). NOTCH1 mutation analysis was performed and clinical outcome investigated. RESULTS: Ten of 19 (52%) were NOTCH1 mutated: 5 in group A (45%) and 5 in group B (62.5%) with a favourable clinical outcome observed among this cohort with 28.7 (range 1-99) months of follow-up. CONCLUSION: In conclusion, we identified a significant (52%) incidence of NOTCH1 mutations in CLL in the context of biclonal LPD, associated with an indolent clinical course.

The spectrum of peripheral T-cell lymphomas.

PURPOSE OF REVIEW: This review summarizes recent progress that has advanced our understanding of the pathobiology and prognosis of peripheral T-cell lymphomas including the changes introduced to the updated World Health Organization classification of lymphoid neoplasms. RECENT FINDINGS: The International Peripheral T-Cell Lymphoma Project was a large collaborative project, highlighting the clinico-pathologic and geographic differences of this diverse group of diseases. Peripheral T-cell lymphoma, not otherwise specified, is a biologically heterogeneous subtype, and a number of studies including investigations using molecular profiling have explored whether meaningful prognostic or biologic subgroups can be identified. Angioimmunoblastic T-cell lymphoma demonstrates overlapping immunophenotypical and molecular features with normal follicular T-helper cells, giving some insight into the cell of origin. Systemic anaplastic large cell lymphoma is composed of two disease groups based on the presence or absence of anaplastic lymphoma kinase overexpression. Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma has a significantly better prognosis than anaplastic lymphoma kinase-negative anaplastic large cell lymphoma and molecular studies have illustrated that each entity has a distinct molecular profile. Anaplastic lymphoma kinase-negative anaplastic large cell lymphoma has been recently shown to have a more favourable, but still unsatisfactory, prognosis than peripheral T-cell lymphoma, not otherwise specified, and biological and molecular distinctions confirm that they are separate entities. SUMMARY: Advances are being made in understanding the unique pathobiology of the peripheral T-cell lymphoma subtypes that will help to refine diagnoses, identify potential prognostic markers, elucidate the molecular mechanisms critical in disease pathogenesis and define new therapeutic targets in the poor-risk population.

Prefibrotic Myelofibrosis Presenting with Multiple Cerebral Embolic Infarcts and the Rare MPL W515S Mutation.

Acquired, activating mutations of MPL W515 are recognised driver mutations of the myeloproliferative neoplasms (MPN), namely, essential thrombocythemia and primary myelofibrosis. The most common mutation at this codon is W515L with several other mutations also described at a lower frequency. Of these less common mutations, MPL W515S has only been reported sporadically with limited information on clinicopathological associations. We describe the case of an elderly man with persistent thrombocytosis presenting with an ischemic cerebral event. Bone marrow biopsy showed evidence of prefibrotic myelofibrosis with targeted sequencing demonstrating the presence of the rare MPL W515S mutation. Thrombolytic and cytoreductive therapies resulted in a favorable outcome and follow-up. This case provides additional, necessary, and phenotypic data for the rare MPN-associated MPL W515S mutation.

Novel therapies in peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of disorders associated with a very poor prognosis. Historically, treatment protocols have been largely based on regimens used to treat aggressive B-cell lymphomas; unfortunately, the efficacy of these regimens has been suboptimal, with most patients experiencing relapse after initial therapy. An improved understanding of the molecular biology, pathogenesis, and progression of these disorders has led to the development of a variety of novel targeted agents that may improve outcomes in patients with PTCLs. The purpose of this review is to focus on these novel agents and the various treatment approaches that are currently being evaluated in PTCLs.

Risk adjusted therapy in chronic lymphocytic leukemia: a phase II cancer trials Ireland (CTRIAL-IE [ICORG 07-01]) study of fludarabine, cyclophosphamide, and rituximab therapy evaluating response adapted, abbreviated frontline therapy with FCR in non-del(17p) CLL.

Minimal residual disease negative complete response (MRD-negative CR) provides an early marker for time to treatment failure (TTF) in CLL treated with fludarabine, cyclophosphamide, and rituximab (FCR). MRD was assessed after four FCR cycles (FCR4); MRD-negative CR patients discontinued treatment. Fifty-two patients (35M; 17F) were enrolled. Eighteen (18/52; 34.6%) patients reached MRD-negative CR after FCR4 and 29/52 (55.8%) were MRD-negative CR at end of treatment (EOT). Median TTF was 71.1 months (95% CI 61.3-84.1 months), with median overall survival not reached. Mutated immunoglobulin heavy chain gene rearrangements (IGHV) were associated with early MRD-negative remissions, translating into prolonged TTF. Unmutated-IGHV, mutated-SF3B1 and mutated-NOTCH1 were associated with shortened TTF. No TTF difference was observed between patients in MRD-negative CR after four versus six cycles (82.2 versus 85.3 months, p = .6306). Abbreviated FCR therapy is effective for patients achieving early MRD-negative remissions. Interim MRD assessment assists in personalizing therapy and reducing chemotherapy-associated toxicity.

Pneumocystis jiroveci prophylaxis in patients undergoing Bendamustine treatment: the need for a standardized protocol.

The decision for PJP prophylaxis depends on a physician's evaluation of multiple variables. The high rate of PJP infection described in this article combined with the known impaired T-cell function post Bendamustine treatment justifies considering all patients for PJP prophylaxis when they receive Bendamustine treatment.

T-lymphoblastic leukemia/lymphoma: a single center retrospective study of outcome.

T-lymphoblastic leukemia/lymphoma (LBL and ALL) is a rare lymphoid malignancy typically presenting in adolescent and young adult males. Patients are traditionally treated with ALL-type protocols, with no consensus on the role of maintenance therapy, or allogeneic or autologous transplant. Outcome results are thus difficult to interpret. The successful use of intensified ALL protocols in patients <25 years with lymphoblastic malignancies without transplant prompted the Haematology Unit at St James's Hospital (SJH) to change practice in 2005 from transplanting in first complete remission (CR1) to treating patients <25 years with chemotherapy alone. We reviewed the outcome of patients treated before 2005 in order to compare the pre- and post-2005 management approaches in the future. This retrospective study included 31 patients with T-LBL treated from 1980 to 2004. The patients were divided into group A (16-25 years) and group B (>25 years). Twenty-one patients had an allograft in CR1 (group A, n = 12 and group B, n = 9). For the allografted patients the 5-year EFS and OS was 57%, with a treatment related mortality of 10%. In conclusion, this series confirms that allograft in CR1 has an acceptable cure rate, and we will use these results to benchmark outcomes using pediatric-type protocols in the future.

Update on the World Health Organization classification of peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of lymphoproliferative disorders of postthymic origin. Progress in elucidating the pathobiology and appropriate therapy of these neoplasms has been slow, primarily because of their rarity, but also because until the early 1990s, they were generally grouped together and combined with B-cell lymphomas. It is now understood that most PTCLs are highly aggressive and respond poorly to standard chemo therapy, and thus they have a significantly poorer prognosis than their B-cell counterparts. In 1994, the Revised European and American Lymphoma classification provided the first uniform system to classify lymphoproliferative disorders on the basis of morphology, phenotype, genetics, and clinical features. Since then, the World Health Organization (WHO) has refined this system as additional information has evolved to further elucidate the origin of these neoplasms. More recently, several new distinct and provisional categories in the updated WHO classification have been defined. This review summarizes the changes in the fourth edition of the WHO classification of lymphoid tumors, with particular focus on the aggressive subtypes.

Novel therapies in peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of disorders associated with a very poor prognosis. Historically, treatment protocols have been largely based on regimens used to treat aggressive B-cell lymphomas; unfortunately, the efficacy of these regimens has been suboptimal, with most patients experiencing relapse after initial therapy. An improved understanding of the molecular biology, pathogenesis, and progression of these disorders has led to the development of a variety of novel targeted agents that may improve outcomes in patients with PTCLs. The purpose of this review is to focus on these novel agents and the various treatment approaches that are currently being evaluated in PTCLs.