Vamsi Kota

Consensus Opinion on Allogeneic Hematopoietic Cell Transplantation in Advanced Systemic Mastocytosis

Advanced systemic mastocytosis (advanced SM), a rare disease closely associated with KIT mutations (most commonly KIT D816V), encompasses three variants: systemic mastocytosis (SM) with an associated hematologic clonal non-mast cell disorder, aggressive SM, and mast cell leukemia. All variants are associated with shortened survival. Although interferon-alpha or cladribine exhibit efficacy in selected patients, they do not result in cure. Imatinib is approved for the minority of aggressive SM patients with negative or unknown KIT D816V status. The multikinase/KIT inhibitor midostaurin is a promising agent for patients with advanced SM and is currently available on an investigational basis. We recently reported the largest retrospective study of allogeneic hematopoietic stem cell transplantation (alloHSCT) in patients with advanced SM (n=57). The evidence from this study and a few case reports indicate that it can cure some patients and lead to long-term survival. However, there is still a significant gap of knowledge regarding the use of this high-intensity therapy in advanced SM. The present paper provides a consensus opinion on methods to optimize decision-making regarding the use of alloHCT in this patient population in light of currently available data. In addition, we outline strategies that combine midostaurin in the peritransplant setting. Such protocols should generate useful outcome data regarding the safety and efficacy of KIT inhibition in conjunction with high-intensity therapy in the treatment of advanced SM.

Predicting early blast transformation in chronic-phase chronic myeloid leukemia: is immunophenotyping the missing link?

Flow cytometry (FC) is a commonly requested test in the workup of leukocytosis in community practices. The role of FC in chronic‐phase chronic myeloid leukemia (CP‐CML) is unknown. We hypothesized that finding aberrant cells with FC in CP‐CML may predict early blast‐phase (BP) transformation.

Momelotinib in myelofibrosis: JAK1/2 inhibitor with a role in treating and understanding the anemia

Myelofibrosis (MF) is a chronic malignancy of the blood-forming system caused by hyperactivation of JAK2/STAT signaling pathway. Small-molecule inhibitors of JAK2 can variably ameliorate MF-related symptoms caused by chronic inflammation and hepatosplenomegaly. Anemia is a significant problem and adverse prognostic factor in over a third of MF patients and is often worsened by JAK2 inhibitors. The JAK1/2 inhibitor momelotinib unexpectedly resulted in reduction of anemia in MF patients during Phase I/II trials. Current Phase III trials will be the basis for seeking regulatory approval of momelotinib during 2017. Studies to determine how momelotinib improves anemia are underway, potentially leading to expanded momelotinib use and/or development of other targeted therapies for treating anemia in MF and related diseases.

Acute leukemia with PICALM–MLLT10 fusion gene: diagnostic and treatment struggle

Patients with various hematologic malignancies, including acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), diffuse histiocytic lymphoma, and granulocytic sarcoma, have sometimes been shown to carry the PICALM-MLLT10 fusion gene (alias CALM-AF10) by various cytogenetic methodologies. Cases with the PICALM-MLLT10 fusion gene can involve a diagnostic dilemma for the following reasons: (1) the fusion gene occurs very rarely, (2) the cases do not have a distinct myeloid or lymphoid morphology and cells often appear immature, (3) cases usually have a mixed T-cell and myeloid phenotype, and (4) cases often have a mixed clinical presentation (e.g., mediastinal mass in a patient with AML). A 27-year-old woman was diagnosed with AML with the PICALM-MLLT10 fusion gene. The patient was treated on an AML regimen and achieved a complete remission. Although the reported treatment of these patients varies greatly, outcome remains very poor in the vast majority. Furthermore, central nervous system involvement at diagnosis and relapse are reported in pediatric populations. Routine acute leukemia fluorescence in situ hybridization panels do not include a probe for the PICALM-MLLT10 fusion gene, and therefore diagnosis can be made only when karyotyping is available; that delay can result in initial misdiagnosis and mistreatment. The case report and literature review here (including discussion of the poor prognosis and of management, including CNS prophylaxis) are intended to raise awareness and to inform about PICALM-MLLT10 in acute leukemia.

Bosutinib: a third generation tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia

Bosutinib is an oral tyrosine kinase inhibitor (TKI) with very potent dual inhibitory activity against SRC and abelson gene. Bosutinib was approved in 2012 for the treatment of resistant Philadelphia chromosome positive chronic myeloid leukemia (CML). Bosutinib is a very effective TKI against all phases of intolerant or resistant CML regardless of the presence or absence of an abelson gene domain mutation, except for cases with detectable T315I or V299L. Bosutinib is overall well tolerated and associated with a unique, but manageable toxicity profile. Factors that influence the prescribing pattern of this drug are complex and include physicians’, and increasingly patients and families’ preference, patients’ comorbid conditions, schedule of administration, as well as financial factors. This paper provides an overview of CML, the TKI market, pharmacokinetics, pharmacodynamics, clinical efficacy, safety and tolerability of bosutinib.

Evaluation of romiplostim for the treatment of secondary failure of platelet recovery among allogeneic hematopoietic stem cell transplant patients

Secondary failure of platelet recovery (SFPR) is a serious complication observed in approximately 20% of allogeneic hematopoietic stem cell transplant (HSCT) recipients. Although the standard therapeutic approach has been frequent platelet transfusions, romiplostim, a thrombopoietin receptor agonist, may have utility in treating SFPR. The primary objective of this single-center retrospective analysis was to assess effectiveness of romiplostim for SFPR and to evaluate patient factors which may influence clinical outcomes. The primary outcome measure of response was defined as achievement of platelet count ≥ 50 × 109/L without transfusions for ≥ 7 consecutive days. During the study period, 93 patients underwent HSCT and 13 (13.9%) received romiplostim for SFPR. Seven patients (53.8%) responded to romiplostim, requiring a median of three doses (range 1–6) to achieve independence from platelet transfusions. Disease relapse occurred in 38.5% of all patients, two responders and three nonresponders. Median survival post-HSCT was 753 days among responders and 266 days among nonresponders (p = 0.0375). No serious adverse events were reported, and rates of graft-versus-host disease did not increase following administration of romiplostim. Thrombopoietin receptor agonists including romiplostim offer a treatment option for persistent thrombocytopenia following HSCT. Positive clinical response to romiplostim post-HSCT is associated with improved outcomes.

A novel immunohistochemical score to predict early mortality in acute myeloid leukemia patients based on indoleamine 2,3 dioxygenase expression

Indoleamine 2,3 dioxygenase-1 (IDO-1) is an enzyme in the kynurenine pathway which augments tumor-induced immune tolerance. Previous studies in childhood acute myeloid leukemia (AML) have shown a negative correlation of IDO-1 mRNA expression with outcomes. The aim of our study was to develop a practical and objective immunohistochemical technique to quantify IDO-1 expression on diagnostic bone marrow biopsies of AML patients in order to facilitate its use in routine clinical practice. IDO-1 mRNA was extracted from diagnostic bone marrow specimens from 29 AML patients. IDO-1 protein expression was assessed in 40 cases via immunohistochemistry and quantified by a novel ‘composite IDO-1 score’. In a univariate analysis, higher age (p = 0.0018), male gender (p = 0.019), high risk cytogenetics (p = 0.002), higher IDO-1 mRNA (p = 0.005), higher composite IDO-1 score (p < 0.0001) and not undergoing allogeneic stem cell transplant (SCT, p = 0.0005) predicted poor overall survival. In a multivariate model that included the aforementioned variables, higher composite IDO-1 score (p = 0.007) and not undergoing allogeneic SCT (p = 0.007) was found to significantly predict poor outcomes. Further, patients who failed induction had higher composite IDO-1 score (p = 0.01). In conclusion, ‘composite IDO-1 score’ is a prognostic tool that can help identify a certain subset of AML patients with ‘early mortality’. This unique subset of patients can potentially benefit from specific IDO-1 inhibitor therapy, currently in clinical trials.

Volasertib for AML: clinical use and patient consideration

Acute myeloid leukemia (AML) is a disease diagnosed mostly in patients >65 years of age. Despite its heterogeneous nature, the different types of AMLs are still managed by standard induction chemotherapy for those who can tolerate it in the beginning. For the elderly and infirm patients, however, this approach leads to unacceptably high induction mortality rate. This article reviews past and current efforts searching for low-intensiveness treatments for the elderly and infirm patients who cannot tolerate the standard induction regimen. Volasertib, currently in Phase III clinical trials in combination with cytarabine, is reviewed as a promising agent for this patient population with AML, from the viewpoints of potential compliance and efficacy.

The safety of Bosutinib for the treatment of chronic myeloid leukemia

ABSTRACT Introduction: Tyrosine kinase inhibitors (TKIs) are a potentially lifelong treatment for patients with chronic myeloid leukemia (CML). Adverse events (AEs) associated with TKIs are significant impediments in the daily life of patients that can impact compliance, and efficacy. Areas covered: This is a review on safety of bosutinib in the treatment of chronic phase CML. Data is extracted from the latest updates of bosutinib phase I/II and III trials. Expert opinion: Bosutinib is an effective agent against all phases of CML presently approved for the treatment in patients with resistance or intolerance to prior TKI therapy. Bosutinib has a unique toxicity profile characterized by early and transient diarrhea. Otherwise, the AE profile of bosutinib is comparable to other TKIs, with the exception of cardiovascular AEs that are infrequent in bosutinib-treated patients. Similar to other TKIs, the minimum effective dose of bosutinib remains unknown. Better definition of the optimal effective dose may spare, for those patients otherwise benefitting from treatment, unnecessary AEs.

Outcomes of Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia Following an Elective Switch From Second-Generation Tyrosine Kinase Inhibitor to Imatinib

Abstract The second‐generation tyrosine kinase inhibitors (TKIs) (2G‐TKIs) dasatinib (DAS) and nilotinib (NIL) yield faster responses in newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) as compared with imatinib (IM); however, long‐term safety of these agents is a growing concern. We identified 20 patients with CP‐CML diagnosed between August 2013 and October 2016 who initiated 2G‐TKIs and were then switched after optimal response at 3 months to IM. Second‐generation TKIs initiated were DAS (n = 15), NIL (n = 3), or both sequentially due to intolerance (n = 1). One other patient initiated therapy with ponatinib on trial. Response was assessed by quantitative reverse‐transcriptase polymerase chain reaction (qRT‐PCR) for BCR‐ABL1 levels every 3 months and in patients with qRT‐PCR values less than 10% at 3 months, IM was started at 400 mg/d. IM was well tolerated except in 2 patients who required dose‐reduction and discontinuation due to grade 2 skin rash (1) and grade 2 anxiety (1). After initiation of IM therapy, the BCR‐ABL1 qRT‐PCR levels trended down as expected. At 12 months 16 (84.2%) of 19 evaluable patients showed a 3 log (major molecular remission) or better reduction in their PCR levels. In conclusion, this retrospective analysis shows that IM can be safely and effectively administered following optimal response to 2G‐TKIs. A prospective trial exploring this approach is currently enrolling and will be needed to confirm the safety and efficacy of this therapeutic approach.