James E. Hoffman

Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma

Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade ≥ 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.

Phase II study of (90)Y Ibritumomab tiuxetan (Zevalin) in patients with previously untreated marginal zone lymphoma.

Abstract The best upfront therapy for patients with non-gastric extranodal marginal zone lymphomas (MZLs) is not defined. We assessed the safety and efficacy of radioimmunotherapy with 90yttrium (90Y) ibritumomab tiuxetan as upfront therapy in MZL (NCT00453102). A total of 16 patients were enrolled, 81% with advanced-stage disease and 44% with bulky disease. The overall response rate (ORR) at 12 weeks post-therapy was 87.5% (90% confidence interval [CI]: 65.6–97.7%), including a complete response in eight (50%), complete response unconfirmed in one (6%) and partial response in five (31%) patients. With a median follow-up of 65.6 months (range 4.0–96.5), the median progression-free survival (PFS) was 47.6 months (range 4.0–93.3) and median overall survival (OS) was not reached. The 5-year PFS was 40% (90% CI: 19.9–59.5%) and 5-year OS was 71.8% (90% CI: 46.8–86.5%). Overall, 90Y ibritumomab tiuxetan was well tolerated and led to long-term responses and PFS rates.

Updated survival analysis of two sequential prospective trials of R-MACLO-IVAM followed by maintenance for newly diagnosed mantle cell lymphoma

A phase II trial of R‐MACLO‐IVAM followed by thalidomide maintenance for mantle cell lymphoma (MCL) demonstrated promising progression‐free survival (PFS) and overall survival (OS) rates. Thalidomide maintenance was associated with significant toxicity and was subsequently modified to rituximab maintenance. Herein, we present updated results and follow‐up. Two sequential phase II trials included chemotherapy‐naïve patients with MCL up to 75 years old. Four cycles of R‐MACLO‐IVAM chemotherapy were delivered as previously described. Patients who achieved complete responses (CR) were eligible for thalidomide or rituximab maintenance therapy. Among 36 patients enrolled, the MCL International Prognostic Index (MIPI) was low in 53%, intermediate in 36% and high in 11%. Thirty‐five patients completed at least 2 cycles of chemotherapy; 34 (94%) achieved a CR. After a median follow‐up of 74.4 months, the 5‐year PFS was 51% (95% CI 33–68%) and the 5‐year OS was 85% (95% CI 73–97%). Two deaths occurred during the chemotherapy phase due to disease progression and neutropenic sepsis, respectively. One patient developed secondary acute myeloid leukemia after 7 years. R‐MACLO‐IVAM chemotherapy is effective for patients with newly diagnosed MCL. Am. J. Hematol. 90:E111–E116, 2015.

Severe mononeuritis multiplex after rituximab in IgM-κ monoclonal gammopathy

Gammopathies are disorders associated with B-cell proliferation. Monoclonal gammopathy of uncertain significance (MGUS), in which this proliferation is nonneoplastic, is observed in up to 7.5% of the elderly population. Immunoglobulin M (IgM)-MGUS may evolve into the B-cell malignancy Waldenstr€ om macroglobulinemia (WM), potentially requiring more aggressive treatment. The prevalence of neuropathy in gammopathies is about 10%, which can increase to 30% in patients with j light chain of immunoglobulin M (IgM-j)-MGUS. Distal acquired demyelinating symmetric neuropathy is associated with IgM-j-MGUS and myelin-associated glycoprotein (MAG) antibodies in > 50% of cases. Although MAG antibodies are considered a causative factor, the pathogenic significance of anti–MAG-negative IgM is less clear in patients with neuropathy. Rituximab is a chimeric murine-human monoclonal antibody against CD20 that results in sustained B-cell depletion. Plasma cells, which retain the ability to produce antibodies, are not targeted by rituximab. Although rituximab was found safe and possibly effective for anti–MAG-positive IgM-associated demyelinating neuropathy in 2 clinical trials, worsening neuropathy of unclear mechanism has been reported. The safety and efficacy of rituximab in anti–MAG-negative IgM neuropathy is even less clear. We report a case of mild axonal sensory neuropathy associated with anti–MAG-negative IgM-j-MGUS that progressed to severe mononeuritis multiplex in the setting of accelerated immune complex deposition after rituximab.

Lymphoma associated hemophagocytic syndrome: it's going viral

Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome of immune overactivation, particularly of lymphocytes and histiocytes, with resultant hypercytokinemia. HLH represents a spectrum of inherited (familiar) and acquired (secondary) conditions with common abnormalities in immune regulation. Th is persistent hyperinfl ammatory state classically manifests as fever, cytopenias and splenomegaly, with accompanying hyperferritinemia, hypofi brinogenemia, hypertriglyceridemia, low or absent natural killer (NK)-cell activity and elevated levels of soluble CD25. Mechanisms underlying the presenting signs and symptoms have been elucidated in recent years, and it appears that fever is caused by interleukins and tumor necrosis factor- α (TNF- α ), ferritinemia results from direct secretion by activated macrophages, and cytokines have been shown to suppress hematopoiesis – a process already strained by destruction of cells by hemophagocytosis [1]. Historically, the association between Epstein – Barr virus (EBV) and “ malignant histiocytosis ” was initially illustrated in the childhood benign form of hemophagocytic syndrome. Ultimately, it became clear that EBV played a role in the development in lymphoma associated hemophagocytic syndrome (LAHS) [2]. LAHS is a well described syndrome associated with a constellation of defi ned symptoms and signs, and a uniformly poor prognosis. Remissions are usually observed only when the underlying malignant lymphoma is successfully controlled with therapy. In an eff ort to prognosticate and manage such patients more eff ectively, eff orts have been made to better delineate its pathogenesis, and to defi ne sub-entities. In this respect, clinical diff erences between B cell LAHS and T or NK/T LAHS have been previously reported [3]. In this issue of Leukemia and Lymphoma , there are two interesting articles related to LAHS that advance the fi eld in distinct ways. Chen et al . evaluate whether EBV localizing to malignant T cells (T-EBV) versus bystander B cells (B-EBV) aff ects the risk for development of hemophagocytic syndrome (HPS) and poor outcome in patients with angioimmunoblastic T cell lymphoma (AITL) and/or peripheral T cell lymphoma not otherwise specifi ed (PTCL-NOS) [4]. Th is issue is very much at the core of the hemophagocytic disorder, and relates to the dual role of EBV as both source of direct malignant transformation and promoter of permissive immune suppression. Th e development of HPS is an important clinical feature that often drives outcome. In this regard, the authors clearly provide evidence for an association between T-EBV and HPS, and link them with poor outcome in PTCL-NOS. In contrast in AITL, where B-EBV clearly predominates, absence of EBV was associated with a trend toward development of more HPS. A mechanism in PTCL whereby EBV latent membrane protein 1 (LMP1) provokes cytokine release, which in turns provokes hemophagocytosis, is suggested but needs further experimental confi rmation. In turn, in AITL, the authors theorize that bystander B cell EBV positivity may impair the immune response inherent in HPS pathobiology, thereby diminishing the risk. While these observations are novel and intriguing, they need to be confi rmed in independent studies. Th e role of EBV within and around the tumor cells is left better defi ned. More important than histologic diff erentiation within the umbrella category of non-Hodgkin lymphoma is the appreciation of a unique molecular environment and associated disease behavior. Th e clear diff erence between PTCL-NOS and AITL relating to EBV localization and its relationship to the pathobiology of HPS is a novel fi