Fabio P S Santos

Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis

Few treatment options exist for patients with myelofibrosis (MF), and their survival is significantly shortened. Activating mutation of the JAK2 tyrosine kinase (JAK2(V617F)) is found in approximately 50% of MF patients. CEP-701 is a tyrosine kinase inhibitor that inhibits JAK2 in in vitro and in vivo experiments. We conducted a phase 2 clinical study of CEP-701 in 22 JAK2(V617F)-positive MF patients (80 mg orally twice daily), and 6 (27%) responded by International Working Group criteria (clinical improvement in all cases): reduction in spleen size only (n = 3), transfusion independency (n = 2), and reduction in spleen size with improvement in cytopenias (n = 1). Median time to response was 3 months, and duration of response was more than or equal to 14 months. No improvement was seen in bone marrow fibrosis or JAK2(V617F) allele burden. Phosphorylated STAT3 levels decreased from baseline in responders while on therapy. Eight patients (36%) experienced grade 3 or 4 toxicity, and 6 (27%) required dose reduction. Main side effects were myelosuppression (grade 3 or 4 anemia, 14%; and thrombocytopenia, 23%) and gastrointestinal disturbances (diarrhea, any grade, 72%; grade 3 or 4, 9%; nausea, grade 1 or 2 only, 50%; vomiting, grade 1 or 2 only, 27%). In conclusion, CEP-701 resulted in modest efficacy and mild but frequent gastrointestinal toxicity in MF patients. The study was registered at http://clinicaltrials.gov as NCT00494585.

Histone deacetylase inhibitors for the treatment of myelodysplastic syndrome and acute myeloid leukemia

Epigenetic changes have been identified in recent years as important factors in the pathogenesis of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Histone deacetylase inhibitors (HDACIs) regulate the acetylation of histones as well as other non-histone protein targets. Treatment with HDACIs results in chromatin remodeling that permits re-expression of silenced tumor suppressor genes in cancer cells, which, in turn, can potentially result in cellular differentiation, inhibition of proliferation and/or apoptosis. Several classes of HDACIs are currently under development for the treatment of patients with MDS and AML. Although modest clinical activity has been reported with the use of HDACIs as single-agent therapy, marked responses have been observed in selected subsets of patients. More importantly, HDACIs appear to be synergistic in vitro and improve response rates in vivo when combined with other agents, such as hypomethylating agents. Furthermore, HDACIs are also being investigated in combination with non-epigenetic therapies. This article synthesizes the most recent results reported with HDACIs in clinical trials conducted in patients with MDS and other myeloid malignancies.

Characteristics and outcome of patients with acute myeloid leukemia refractory to 1 cycle of high-dose cytarabine-based induction chemotherapy

Pretreatment characteristics and outcome of patients treated with induction regimens containing high-dose ara-C (HiDAC) at M. D. Anderson Cancer Center refractory to 1 cycle of induction were compared with similar patients achieving a complete response (CR). Among 1597 patients treated with HiDAC-based induction from 1995 to 2009, 285 were refractory to 1 cycle. Median age was 59 years (range, 18-85 years). Induction regimens included HiDAC with anthracyclines (n = 181; 64%) or HiDAC with nonanthracycline chemotherapy (n = 104; 36%). Refractory patients were older (median age, 59 vs 56 years; P < .001), more likely with unfavorable cytogenetics (P < .001) and antecedent hematologic disorder (P < .001), and had a higher presentation white blood cell count (P = .04), but not a higher incidence of FLT3 mutations (P = .85), than those achieving CR. Forty-three patients (22%) responded to salvage (35 CR and 8 CR without platelet recovery). With a median follow-up of 72 months (range, 27-118 months) in responders, 11 are alive. Nineteen patients (7%) were alive and in CR for at least 6 months, including 9 who underwent allogeneic stem cell transplantation. On multivariate analysis, severe thrombocytopenia, leukocytosis, increasing marrow blast percentage, unfavorable cytogenetics, and salvage not including allogeneic stem cell transplantation were associated with a worse survival. Alternative strategies are needed for these patients.

Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia

The impact of FMS‐like tyrosine kinase 3 (FLT3) mutations and mutation burden among cytogenetic subgroups of patients with acute myeloid leukemia (AML) other than normal karyotype (NK) AML is unclear.

JAK2 inhibitors: What's the true therapeutic potential?

Physicians treating patients with the classic Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs) (polycythemia vera [PV], essential thrombocythemia [ET] and primary myelofibrosis [PMF]) traditionally had few therapeutic drugs available. Spurred by the discovery of activating mutation of the JAK2 tyrosine kinase (JAK2 V617F mutation) in patients with Ph-negative MPNs several years ago, several JAK2 inhibitors were synthesized and are currently undergoing clinical trials in patients with PMF, PV and ET. Initial results from these studies have shown that these drugs can markedly reduce spleen size and alleviate constitutional symptoms, increase weight and improve exercise capacity in MF patients, thus improve quality of their life, which is significant clinical benefit. In ET and PV JAK2 inhibitor therapy may efficiently control blood cell count, as well as improve splenomegaly and control disease related symptoms. JAK2 inhibitors are a novel class of agents with promising results for treating patients with MF, PV and ET. In this article we will review the current evidence regarding the role of JAK2 mutations in the pathogenesis of Ph-negative MPNs and summarize results from the most recent clinical trials with JAK2 inhibitors in these disorders. JAK2 inhibitors are a novel class of agents with promising results for treating patients with MF, PV and ET.

Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib

Although most patients with myelofibrosis (MF) derive benefit from ruxolitinib, some are refractory, have a suboptimal response, or quickly lose their response. To identify genes that may predict response to ruxolitinib, we performed targeted next-generation sequencing (NGS) of a panel of 28 genes recurrently mutated in hematologic malignancies in a cohort of patients with MF who were treated with ruxolitinib in a phase 1/2 study. We also tested for CALR deletions by standard polymerase chain reaction methods. Ninety-eight percent of patients had a mutation in ≥1 gene. Seventy-nine (82.1%) patients had the JAK2(V617F) mutation, 9 (9.5%) had CALR mutations (7 type 1, 2 type 2), 3 (3.1%) had MPL mutations, and 4 (4.2%) were negative for all 3. ASXL1/JAK2 and TET2/JAK2 were the most frequently comutated genes. Mutations in NRAS, KRAS, PTPN11, GATA2, TP53, and RUNX1 were found in <5% of patients. Spleen response (≥50% reduction in palpable spleen size) was inversely correlated with the number of mutations; patients with ≤2 mutations had ninefold higher odds of a spleen response than those with ≥3 mutations (odds ratio = 9.37; 95% confidence interval, 1.86-47.2). Patients with ≥3 mutations also had a shorter time to treatment discontinuation and shorter overall survival than those with fewer mutations. In multivariable analysis, only number of mutations and spleen response remained associated with time to treatment discontinuation. Patients with ≥3 mutations had the worst outcomes, suggesting that multigene profiling may be useful for therapeutic planning for MF.

Therapy with azanucleosides for myelodysplastic syndromes

Azanucleosides constitute the core therapy in the management of myelodysplastic syndromes (MDS), and have altered the treatment paradigm of MDS, previously dominated by supportive care strategies. DNA methylation regulates gene transcription in MDS, and it is hypothesized that azanucleoside therapy induces DNA hypomethylation and re-expression of aberrantly silenced genes in patients with these disorders. A series of clinical trials conducted over the past 5 years has demonstrated the activity of these therapies. Two agents, 5-azacitidine and decitabine, have been approved by the FDA for treatment of MDS. Recently, 5-azacitidine therapy has been shown, for the first time, to prolong survival in patients with MDS. Because the targeting of biologic pathways in MDS is best accomplished by combining agents with complementary mechanisms of action, combinations of azanucleosides with other drugs are being investigated. In this article, we critically appraise the most relevant clinical data reported on the use of azanucleosides for the treatment of patients with MDS.

Adult acute erythroleukemia: an analysis of 91 patients treated at a single institution

Acute erythroleukemia (AML-M6) is an uncommon subtype of acute myeloid leukemia (AML); it is considered to have a poor prognosis. From 1 January 1980 to 21 May 2008, 91 patients with newly diagnosed AML-M6 were seen at the University of Texas–M.D. Anderson Cancer Center (UT–MDACC). Forty-five patients (50%) had a history of myelodysplatic syndrome (MDS), compared with 41% in our control group (patients with other AML subtypes) (P=0.08). Poor-risk cytogenetics were more common in patients with AML-M6 (61% versus 38%, P=0.001). Complete remission rates were 62% for patients with AML-M6, comparing with 58% for the control group (P=0.35). Median disease free survival (DFS) for patients with AML-M6 was 32 weeks, versus 49 weeks for the control group (P=0.05). Median overall survival (OS) of patients with AML-M6 was 36 weeks, compared with 43 weeks for the control group (P=0.60). On multivariate analysis for DFS and OS, AML-M6 was not an independent risk factor. AML-M6 is commonly associated with a previous diagnosis of MDS and poor-risk karyotype. The diagnosis of AML-M6 does not impart by itself a worse prognosis, and treatment decisions on this disease should be guided by well known AML prognostic factors.

Results of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia patients who failed tyrosine kinase inhibitors after developing BCR-ABL1 kinase domain mutations

Hematopoietic stem cell transplantation (HSCT) is effective therapy for patients with chronic myelogenous leukemia (CML) but is now mostly indicated for patients who develop resistance to tyrosine kinase inhibitors (TKIs), which can be associated with point mutations in BCR-ABL1. We reviewed the outcomes of imatinib-resistant CML patients (chronic phase, n = 34; accelerated phase [AP], n = 9; and blast phase [BP], n = 4) who underwent HSCT and had BCR-ABL1 sequencing. Mutations were found in 19 patients (40%); 15 of 19 had advanced CML (AP + BP + second chronic phase). Patients with mutations were more likely to transform to AP/BP at time of imatinib failure (69% vs 35%, P = .03). Forty-two patients (89%) responded to HSCT: 32 (68%) had at least a major molecular response. The 2-year event-free survival was 36% and 58% (P = .05) for the mutant and nonmutant groups, respectively; and the 2-year overall survival was 44% and 76% (P = .02), respectively. HSCT is an important salvage option for TKI-resistant patients with or without BCR-ABL1 mutations. Patients with mutations were more likely to develop advanced disease and had worse outcomes after HSCT. HSCT should be considered early for patients deemed to have a low probability of responding to second-generation TKI.

Decitabine in the treatment of myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias and a propensity to transform into acute myeloid leukemia. There are few treatment options available for patients with MDS. Studies into the molecular biology of MDS have demonstrated abnormal patterns of DNA methylation that lead to silencing of tumor-suppressor genes. Hypomethylating agents are compounds that have the potential to reverse the aberrant DNA methylation and increase the expression of silenced genes, leading to cellular differentiation and/or apoptosis. Decitabine is a cytidine analogue that has activity as a hypomethylating agent and has been evaluated in the therapy of patients with high-risk MDS. Several studies have confirmed the clinical activity of low-dose decitabine in patients with high-risk MDS, leading to responses in approximately 50% of patients, with low treatment-related mortality. Responses have even been seen in patients with high-risk cytogenetic abnormalities, and some studies have demonstrated increased re-expression of genes that were previously silenced by hypermethylation, such as CDKN2B/p15INK4B. There are still some issues concerning the ideal dose and schedule of decitabine for treating patients with MDS. This article focuses on the most recent clinical studies of decitabine for therapy of MDS.