Houry Leblebjian

Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia

We examined the combination of the mammalian target of rapamycin inhibitor everolimus with bortezomib and rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM) in a phase I/II study. All patients received six cycles of the combination of everolimus/rituximab or everolimus/bortezomib/rituximab followed by maintenance with everolimus until progression. Forty-six patients were treated; 98% received prior rituximab and 57% received prior bortezomib. No dose-limiting toxicities were observed in the phase I. The most common treatment-related toxicities of all grades were fatigue (63%), anemia (54%), leucopenia (52%), neutropenia (48%) and diarrhea (43%). Thirty-six (78%) of the 46 patients received full dose therapy (FDT) of the three drugs. Of these 36, 2 (6%) had complete response (90% confidence interval (CI): 1–16). In all, 32/36 (89%) of patients experienced at least a minimal response (90% CI: 76–96%). The observed partial response or better response rate was 19/36 (53, 90 CI: 38–67%). For the 36 FDT patients, the median progression-free survival was 21 months (95% CI: 12–not estimable). In summary, this study demonstrates that the combination of everolimus, bortezomib and rituximab is well tolerated and achieved 89% response rate even in patients previously treated, making it a possible model of non-chemotherapeutic-based combination therapy in WM.

Waldenström macroglobulinemia: from biology to treatment

Waldenström macroglobulinemia (WM) is distinct B-cell lymphoproliferative disorder primarily characterized by bone marrow infiltration of lymphoplasmacytic cells along with production of a serum monoclonal (IgM). In this review, we describe the biology of WM, the diagnostic evaluation for WM with a discussion of other conditions that are in the differential diagnosis and clinical manifestations of the disease as well as current treatment options. Within the novel agents discussed are everolimus, perifosine, enzastaurin, panobinostat, bortezomib and carfilzomib, pomalidomide and ibrutinib. Many of the novel agents have shown good responses and have a better toxicity profile compared to traditional chemotherapeutic agents, which makes them good candidates to be used as primary therapies for WM in the future.

New insights into the pathogenesis and treatment of Waldenstrom macroglobulinemia

Purpose of reviewWaldenstrom macroglobulinemia is a distinct low-grade lymphoproliferative disease. There have been recent significant advances in understanding the underlying pathogenesis of this disease, including genetic and epigenetic regulators of tumor progression. Recent findingsCurrent studies have shown that the tumor microenvironment plays a critical role in cell proliferation, dissemination, and drug resistance. SummaryThis review provides an update of the advances in the pathogenesis of factors both intrinsic (in the tumor clone) and extrinsic (in the bone marrow microenvironment) that regulate tumor progression in Waldenstrom macroglobulinemia. We next discuss novel agents that have been recently tested in clinical trials based on the advances observed in the pathogenesis of Waldenstrom macroglobulinemia.

Predictive factors for all-trans retinoic acid-related differentiation syndrome in patients with acute promyelocytic leukemia

All-trans retinoic acid (ATRA) used for the treatment of APL can lead to the development of differentiation syndrome (DS), a potentially life threatening complication. Since ATRA is metabolized by cytochrome P450 (CYP) enzymes, we sought to identify drug interactions that might be associated with a higher risk for the development of DS in addition to other predictive factors related to the incidence of DS. We identified 60 consecutive patients with APL treated at our institution with ATRA from May 2004 until January 2010. Of the 60 patients identified, 29 (48%) developed DS within a median of 5 days (range 1-31) of ATRA initiation. We did not find any difference in overall incidence of DS whether patients were on concurrent CYP 2C8, 2C9 or 3A4 inhibitors, inducers or substrates. In multivariable analysis, higher peripheral blood blast counts on admission (p=0.04) as well as higher body mass index (p=0.003) were associated with developing DS. Out of the 29 patients with DS, there were 4 early deaths of which 2 were attributed to DS compared to no early deaths in the patients who did not develop DS (p=0.05). Regarding disease-related outcomes, only CR rate was different between patients developing DS versus those who did not develop DS.

Extramedullary Waldenström macroglobulinemia.

Disease assessment in Waldenstrom Macroglobulinemia (WM) is dependent on the percent involvement of B‐cell neoplasm in the bone marrow and IgM paraprotein in the serum. A subset of patients also demonstrates extramedullary involvement, which is infrequently examined. The role of extramedullary involvement in the diagnosis and prognosis of WM is poorly understood. The purpose of this study is to report the characteristics of WM patients with extramedullary disease (EMD). Nine hundred and eight‐five patients with WM were evaluated at one academic center and the presence of EMD was assessed in these patients. Forty‐three (4.4%) patients were identified to have EMD. Nine (21%) patients presented with involvement at WM diagnosis, while 34 (79%) developed EMD post‐therapy for WM. Most frequent EMD sites involved were pulmonary (30%), soft tissue (21%), cerebrospinal fluid (23%), renal (8%), and bone (9%). The median overall survival at 10 years was 79% (95% CI: 57–90%). This is the first study to describe the clinical characteristics, response and overall survival in patients with extramedullary WM. Further studies to define the molecular characteristics of this entity and mechanisms of its development are warranted. Am. J. Hematol. 90:100–104, 2015.

Novel treatment options for Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM), first described by Jan Waldenström in 1944, is a lymphoplasmacytic lymphoma characterized by the presence of an immunoglobulin M monoclonal gammopathy in the blood and monoclonal small lymphocytes and lymphoplasmacytoid cells in the bone marrow. WM is a rare and indolent disease but remains incurable. In this review we discuss the pathogenesis of WM and focus on novel treatment options that target pathways deregulated in this disease. Recent studies have helped us identify specific genetic mutations that are commonly seen in WM and might prove to be important therapeutic targets in the future. We discuss the role of epigenetics and the changes in the bone marrow microenvironment that are important in the pathogenesis of WM. The commonly used drugs are discussed with a focus on novel agents that are currently being used as single agents or in combination to treat WM. We finally focus on some agents that have shown preclinical efficacy and might be available in the near future.

Cyclophosphamide, bortezomib, and dexamethasone combination in waldenstrom macroglobulinemia

Age, years Median 63 Range 45–76 Sex, male 9 60% International scoring system for WM Low 1 6 Intermediate 7 47 High 7 47 Baseline IgM prior to CyBorD Median 3,540 Range 1,530–7,700 Baseline M-spike prior to CyBorD Median 2.06 Range 0.07–4.54 Baseline hemoglobin, g/dL Median 8.7 Range 6.7–13.4 Baseline platelet count, 10/L Median 145 Range 30–468 B2-microglobulin >3 mg/dL 14 93 Bone marrow percent involvement* Median 70 Range 40–90 No. of prior therapies No prior therapy 4 27 Prior therapy 11 73 Median number of prior therapy 4 range (1–8) 1–3 4/11 36 4–6 5/11 45 >6 2/11 18 Prior therapy (no. of patients) Rituximab 11 73 Bortezomib 7 47 Alkylators 5 33 Purine nucleoside analogue 4 27 Thalidomide, lenalidomide 2 13 Interferon 1 7 Clinical trial based therapy Panobinostat 4 27 Enzastaurin 2 13 Perifosine 2 13 Everolimus 3 20 No. of patients with concurrent rituximab with CyborD 7 47

Safety of live-attenuated measles-mumps-rubella and herpes zoster vaccination in multiple myeloma patients on maintenance lenalidomide or bortezomib after autologous hematopoietic cell transplantation.

Attenuated live virus vaccinations are generally recommended 24 months following hematopoietic cell transplantation (HCT) in patients not receiving immunosuppressive therapy. To date, there are no data regarding the safety of live-attenuated herpes zoster or measles-mumps-rubella (MMR) vaccinations in multiple myeloma patients on maintenance lenalidomide or bortezomib following autologous HCT. One hundred thirty-seven multiple myeloma patients on maintenance lenalidomide or bortezomib post-auto-HCT who received either MMR or herpes zoster vaccine were analyzed and any adverse events documented in the medical record in the 42 days following vaccination were recorded. Patients were vaccinated a median of 25 months (range, 18–62) post transplant. The most common post-vaccination adverse event was upper respiratory tract infection (18/137 patients); no rash attributed to vaccine strains or other adverse outcomes potentially related to the vaccines were identified. MMR and herpes zoster vaccination were safe and well-tolerated in this cohort.

A single center experience with romiplostim for the management of chemotherapy-induced thrombocytopenia

e Angers, UFR Sant e, Angers, France CHU d’Angers, Laboratoire d’H ematologie, Angers, France CRCINA, INSERM, Universit e d’Angers, Angers, France F ed eration Hospitalo-Universitaire ‘Grand Ouest Against Leukemia’ (FHU GOAL), Angers, France CHU de Brest, Service d’H ematologie Clinique, Brest, France CHU de Nantes, Laboratoire d’H ematologie, Nantes, France CHU de Brest, Laboratoire d’H ematologie, Brest, France INSERM U1078, CHRU Brest, Brest, France Universit e de Bretagne Occidentale, UFR M edecine, Brest, France CHU d’Angers, Service des Maladies du Sang, Angers, France AP-HP, CHU Henri Mondor, Laboratoire d’H ematologie, Cr eteil, France Polyclinique Bordeaux Nord Aquitaine, Service d’h emato-oncologie, Bordeaux, France INSERM 1066 MINT, Universit e d’Angers, Angers, France Service de M edecine-H ematologie, CH Robert Boulin, Libourne, France CHU de Limoges, Service d’H ematologie, Limoges, France CHU de Limoges, Laboratoire d’H ematologie, CRBS, Limoges, France UMR CNRS 7276, Limoges, France Service de M edecine Interne-Maladies Infectieuses, CHU de Bordeaux, Pessac, France