Chetasi Talati

The Treatment Landscape of Myelofibrosis Before and After Ruxolitinib Approval

Micro‐Abstract The US Food and Drug Administration approval of ruxolitinib for intermediate‐ and high‐risk myelofibrosis (MF) in 2011 changed the therapeutic landscape of the disease. We investigated the first‐line treatment choices for MF patients in the pre‐ and post‐ruxolitinib eras and found that the increased use of ruxolitinib has come at the expense of several agents, but has not significantly affected the utilization of hydroxyurea in the first‐line setting. Introduction/Background: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm that presents with a heterogeneous clinical phenotype and prognosis. Before the US Food and Drug Administration approval of ruxolitinib, treatment options were varied and had limited effect. The increased use of ruxolitinib has drastically altered the MF treatment landscape. In this study, we aimed to clarify the clinical situations in which ruxolitinib is being used and analyze its effect on this landscape. Patients and Methods: We retrospectively assessed treatment choices for MF patients treated at our institution (n = 309). This population was divided into 2 cohorts on the basis of a diagnosis before (cohort BR: n = 174) or after (cohort AR: n = 135) ruxolitinib approval. Cohorts were further stratified for comparison according to presenting clinical factors. Results: Expectedly, the first‐line use of ruxolitinib markedly increased after its approval. AR patients were less likely to receive erythropoiesis‐stimulating agents (ESAs; P = .0003) and thalidomide (P = .003) than BR patients. In patients with MF‐related symptoms and/or splenomegaly, increased use of ruxolitinib was associated with decreased use of first‐line ESA (P = .03) or thalidomide (P = .03). In anemic patients, increased use of first‐line ruxolitinib was associated with a decreased use of thalidomide (P = .007). In patients with severe leukocytosis, ruxolitinib use did not significantly increase and hydroxyurea was the preferred first‐line agent. Conclusion: Overall, the increased use of ruxolitinib appears to have come predominantly at the expense of thalidomide and ESAs, while not having a large effect on the first‐line use of hydroxyurea.

An Exercise in Extrapolation: Clinical Management of Atypical CML, MDS/MPN-Unclassifiable, and MDS/MPN-RS-T

According to the recently published 2016 World Health Organization (WHO) classification of myeloid malignancies, myelodysplastic/myeloproliferative neoplasms (MDS/MPN) include atypical chronic myeloid leukemia (aCML), MDS/MPN-unclassifiable (MDS/MPN-U), chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), and MDS/MPN ring sideroblasts with thrombocytosis (MDS/MPN-RS-T). MDS/MPN-RS-T was previously a provisional category known as refractory anemia with ring sideroblasts with thrombocytosis (RARS-T) which has now attained a distinct designation in the 2016 WHO classification. In this review, we focus on biology and management of aCML, MDS/MPN-U, and MDS/MPN-RS-T. There is considerable overlap between these entities which we attempt to further elucidate in this review. We also discuss recent advances in the field of molecular landscape that further defines and characterizes this heterogeneous group of disorders. The paucity of clinical trials available secondary to unclear pathogenesis and rarity of these diseases makes the management of these entities clinically challenging. This review summarizes some of the current knowledge of the molecular pathogenesis and suggested treatment guidelines based on the available data.

Association between immunoglobulin heavy-chain variable region mutational status and isolated favorable baseline genomic aberrations in chronic lymphocytic leukemia

Abstract Immunoglobulin heavy-chain variable region (IGHV) mutational status and karyotype abnormalities are important prognostic factors in chronic lymphocytic leukemia (CLL). The goal was to assess the impact of IGHV in CLL patients with isolated favorable genetic aberrations (del13q, trisomy 12, or negative fluorescence in situ hybridization [FISH]). We studied 273 CLL patients with both IGHV mutational status and cytogenetic information: 145 with isolated del13q 49 with sole trisomy 12 and 79 with negative FISH. After a median follow-up of 7.8 years, patients with del13q-unmutated IGHV had a shorter time to first treatment (TFT) (2.98 vs. 17.44 years; p < .001) and shorter overall survival (10.45 years vs. not reached; p = .0026). Patients with negative FISH-unmutated IGHV had shorter TFT (p = .02) (3.10 vs. 9.75 years, p = .053). IGHV status did not influence clinical outcomes in trisomy 12 CLL. In conclusion, IGHV mutational status shows prognostic impact in CLL patients with good prognosis genomic features.

Lenalidomide: Myelodysplastic syndromes with del(5q) and beyond

Myelodysplastic syndrome (MDS) with deletion 5q (del(5q)) is a distinct clinical and pathological disease subset that is exquisitely sensitive to lenalidomide for the treatment of red blood cell transfusion-dependent anemia. Although lenalidomide has erythropoeitic promoting activity in MDS without del(5q) (non-del(5q) MDS), the frequency of response to treatment is lower and relates to biologically separate drug effects. In del(5q) MDS, lenalidomide suppresses the malignant clone to restore effective erythropoiesis by virtue of synthetic lethality, arising from cereblon-dependent degradation of haplodeficient proteins encoded within the commonly deleted region of the chromosome 5q deletion. In contrast, in non-del(5q) MDS, lenalidomide restores effective erythropoiesis via enhancement of erythropoietin (EPO) receptor-initiated transcriptional response arising from the assembly of signaling-competent receptor complexes within membrane lipid raft domains. Recently, large phase III clinical studies have explored the role of lenalidomide, alone and in combination with, erythropoiesis-stimulating agents showing additive improvement in erythroid responses. Herein, we will describe the mechanisms of lenalidomide action in MDS and pivotal clinical studies testing the benefit of lenalidomide in both del(5q) and non-del(5q) MDS. Furthermore, we discuss evidence-based strategies to incorporate lenalidomide into the treatment algorithm for patients with MDS.

Recently approved therapies in acute myeloid leukemia: A complex treatment landscape

Acute myeloid leukemia (AML) is a heterogeneous disease. Until recently, treatment for patients with AML was limited to induction chemotherapy with cytarabine and anthracycline or hypomethylating agents, and, in some instances, allogeneic hematopoietic stem cell transplant. With the recent approval of new therapies-i.e., CPX-351, enasidenib, ivosidenib, gemtuzumab ozogamicin, and midostaurin-a new era in AML treatment has emerged. Comprehensive diagnostic testing, such as cytogenetic and molecular testing, is necessary for establishing patient eligibility for these new agents and should be performed in a timely manner. However, choosing a therapy for patients who are eligible for multiple treatments may be a complex process, particularly for patients with newly diagnosed AML. This review discusses data, including associated safety profiles that supported these recent approvals, and provides insights to help clinicians navigate new therapy options for this devastating disease. Given the heterogeneity of AML, the treatment landscape will likely continue to grow and evolve as additional agents (and their combinations) are approved for the treatment of subpopulations of patients with AML. Physicians will need to remain abreast of the ever-changing treatment landscape.

Nuclear transport inhibition in acute myeloid leukemia: recent advances and future perspectives

Selective inhibitors of nuclear export (SINE) are emerging as a potentially efficacious therapeutic strategy for overcoming resistance to conventional chemotherapy for acute myeloid leukemia. SINE specifically block the protein Exportin 1, also known as chromosomal region maintenance 1, leading to nuclear retention of cargo proteins, including several tumor suppressor proteins. Selinexor, a first generation SINE, is currently in early phase clinical studies in various combinations with promising antileukemic and pro-apoptotic activity. Here we discuss the mechanism of action of SINEs and further elaborate on the clinical data available from the various trials in acute myeloid leukemia.

Ponatinib in the treatment of chronic myeloid leukemia and philadelphia chromosome positive acute lymphoblastic leukemia

Philadelphia chromosome, reciprocal translocation between chromosome 9 and 22, leading to a constitutively active fusion protein BCR-ABL1 is the common feature among Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML). The discovery of tyrosine kinase inhibitors (TKIs) has led to significant improvement in the treatment of CML and Ph+ ALL. Ponatinib is a third-generation TKI that is currently approved as per label when no other TKIs are indicated for the treatment of patients with CML and Ph+ ALL after failing treatment with second-generation TKIs or if presence of T315I mutation is discovered. This review summarizes the ponatinib development, approved indications as well as ongoing clinical studies in CML and Ph+ ALL.

CPX-351: changing the landscape of treatment for patients with secondary acute myeloid leukemia

Multiple novel therapeutic agents against acute myeloid leukemia (AML) have been evaluated in the past several decades without meaningful clinical improvement in outcomes, especially for AML patients age ≥60, where the overall incidence of AML is highest. Therapeutic options mainly consist of hypomethylating agents, ongoing clinical trials and, less commonly, intensive cytotoxic chemotherapy. CPX-351, a novel liposomal formulation which encapsulates cytarabine and daunorubicin in 5:1 molar ratio, has shown promising efficacy, leading to recent US FDA approval for front-line therapy for patients with therapy-related AML and AML with myelodysplasia-related changes based on a large multicenter Phase III clinical trial. This review summarizes the clinical development of CPX-351 as induction therapy.

Hypomethylating Agents Versus Intensive Chemotherapy in Older Patients (Age ≥ 70) with Acute Myeloid Leukemia with High White Blood Cell Count

patients who achieved CR significantly decreased at the time of response compared to that at the diagnosis (P 1⁄4 0.02), whereas those who achieved PR or mR did not (P 1⁄4 0.06). Conclusions: Our data showed the clinical efficacy and tolerability of decitabine for patients with eAML in real-word setting. In addition, the possible role of WT-1 as a surrogate marker to predict outcomes or estimate the response by decitabine is suggested.

SOHO State of the Art and Next Questions: Management of Myelodysplastic Syndromes With Deletion 5q

Abstract Myelodysplastic syndrome (MDS) with deletion 5q [del(5q)] is a distinct clinical and pathologic disease subset that is exquisitely sensitive to lenalidomide for the treatment of red blood cell transfusion‐dependent anemia. Lenalidomide resistance, including primary resistance, occurs by clonal evolution, which is frequently attributable to the presence of somatic mutations in the DNA‐binding domain of the TP53 gene. The treatment options after development of resistance to lenalidomide are limited and consist of hypomethylating agents, clinical trials, and allogeneic hematopoietic stem cell transplantation. We discuss evidence‐based strategies to devise a treatment algorithm for patients with MDS with del(5q).