Nadia Khan

Central nervous system prophylaxis in diffuse large B-cell lymphoma.

Central nervous system (CNS) involvement with diffuse large B‐cell lymphoma (DLBCL) is a relatively uncommon manifestation; with most cases of CNS involvement occuring during relapse after primary therapy. CNS dissemination typically occurs early in the disease course and is most likely present subclinically at the time of diagnosis in many patients who later relapse in the CNS. CNS relapse in these patients is associated with poor outcomes. Based on a CNS relapse rate of 5% in DLBCL and weighing the benefits against the toxicities, universal application of CNS prophylaxis is not justified. The introduction of rituximab has significantly reduced the incidence of CNS relapse in DLBCL. Different studies have employed other agents for CNS prophylaxis, such as intrathecal chemotherapy and high‐dose systemic agents with sufficient CNS penetration. If CNS prophylaxis is to be given, it should be preferably administered during primary chemotherapy. However, there is no strong evidence that supports any single approach for CNS prophylaxis. In this review, we outline different strategies of administering CNS prophylaxis in DLBCL patients reported in literature and discuss their advantages and drawbacks.

Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies

ABSTRACT ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1–8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitts lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkins lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitts lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitts lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkins lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.

A phase 1 study of lenalidomide and ibrutinib in combination with rituximab in relapsed and refractory CLL

Attempts to improve upon the activity of ibrutinib in chronic lymphocytic leukemia (CLL) include the addition of targeted therapies. The combination of lenalidomide and rituximab demonstrated an overall response rate (ORR) of 66% with a complete response (CR) of 12% in the relapsed/refractory setting. Based on these data, we conducted a phase 1 study of rituximab (R), lenalidomide (L), and ibrutinib (I) in relapsed/refractory CLL. Patients received R 375 mg/m2 cycles 1 to 6 day 1, L on cycles 1 to 12 days 1 to 21, and I until disease progression. Dose escalation used a standard 3+3 design from a dose level (DL) of L 5 mg (DL1) and increasing to 15 mg (DL3) for a total of 3 dose levels. Twelve patients were enrolled; there were 2 dose-limiting toxicities of grade 4 neutropenia at DL3; thus, DL2 was the recommended phase 2 dose. A high incidence of sustained grade 4 neutropenia occurred at all dose levels, prompting study withdrawal in 5 patients, despite growth factor support. The ORR was 67%; ORR at the RP2D was 100% (1 CR). The 12-month progression-free survival at the RP2D was 83%. Preliminary efficacy data with the triplet did not appear superior to prior reports of the rituximab-lenalidomide doublet or single-agent ibrutinib. Given these findings and the sustained neutropenia, this regimen was not pursued. The study was registered at www.clinicaltrials.gov as #NCT02200848.

Genomic imbalances in peripheral blood confirm the diagnosis of myelodysplastic syndrome in a patient presenting with non-immune hemolytic anemia

Myelodysplastic syndrome (MDS) is a clonal stem-cell disorder characterized by dyshematopoiesis. We report a patient who presented with cytopenias and microangiopathic hemolytic anemia. Chromosome microarray analysis (CMA), using single nucleotide polymorphism arrays, on peripheral blood revealed genomic imbalances indicative of MDS, which was confirmed by bone marrow examination. This report highlights the importance of suspecting MDS in patients with cytopenias and microangiopathic hemolytic anemia. CMA of peripheral blood may assist in the preliminary diagnosis of MDS, representing a comparatively less invasive diagnostic procedure and may aid bone marrow evaluation when an aspirate sample is insufficient for conventional cytogenetic analysis.

Subtype-specific therapy for DLBCL: are we there yet?

In this issue of Blood, Offner et al report the results of LYM-2034, a phase 2 multinational trial in which 164 patients with nongerminal center B-cell–like diffuse large B-cell lymphoma (non-GCB DLBCL) were randomized to receive rituximab, cyclophosphamide, adriamycin, prednisone, and either vincristine (R-CHOP) or bortezomib (VR-CAP). DLBCL, previously recognized as a single disease entity, represents a heterogeneous group of diseases.

Hairy cell Leukemia, Version 2.2018: Clinical practice guidelines in oncology

Hairy cell leukemia (HCL) is a rare type of indolent B-cell leukemia, characterized by symptoms of fatigue and weakness, organomegaly, pancytopenia, and recurrent opportunistic infections. Classic HCL should be considered a distinct clinical entity separate from HCLvariant (HCLv), which is associated with a more aggressive disease course and may not respond to standard HCL therapies. Somatic hypermutation in the IGHV gene is present in most patients with HCL. The BRAF V600E mutation has been reported in most patients with classic HCL but not in those with other B-cell leukemias or lymphomas. Therefore, it is necessary to distinguish HCLv from classic HCL. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of classic HCL.

PTCL therapies: a review of treatment and outline of novel therapies.

Peripheral T-cell lymphomas (PTCLs) are relatively uncommon lymphomas, compared with B-cell malignancies, and given short-lived responses to therapies and an aggressive clinical course provide a therapeutic challenge for the clinician. Although anthracycline-based regimens have been a mainstay of therapy, inferior outcomes with these regimens have called attention to the need for the development of novel agents and effective combination therapies. Recently, new agents with activity in PTCL have emerged with evidence of improved efficacy. This review summarizes novel, investigational, and standard treatment options in the management of treatment naive and relapsed refractory PTCL.