Uma Borate

A cautionary tale for probiotic use in hematopoietic SCT patients-Lactobacillus acidophilus sepsis in a patient with mantle cell lymphoma undergoing hematopoietic SCT.

A cautionary tale for probiotic use in hematopoietic SCT patients– Lactobacillus acidophilus sepsis in a patient with mantle cell lymphoma undergoing hematopoietic SCT

Treatment of CD30-positive systemic mastocytosis with brentuximab vedotin.

Systemic mastocytosis is a myeloproliferative neoplasm with varying presentation that is caused by infiltration of neoplastic mast cells into extracutaneous tissues. Cytoreductive therapy is used to control organ dysfunction in aggressive systemic mastocytosis and is sometimes needed for control of severe refractory symptoms in patients with indolent disease. However, current standard cytoreductive agents are limited by their suboptimal degree and duration of response and associated significant toxicities, highlighting the need for novel treatments for systemic mastocytosis. Recent studies have identified CD30 as a therapeutic target in systemic mastocytosis, as CD30 is expressed on a majority of neoplastic mast cells. In this case series, the clinical outcomes of 4 patients with aggressive or indolent systemic mastocytosis treated with the anti-CD30 antibody-drug conjugate brentuximab vedotin are reported. Two patients showed evidence of a response to treatment with a reduction in disease burden, 1 of which has demonstrated a durable response with ongoing benefit for more than 3 years. Treatment with brentuximab vedotin was well-tolerated with side effects that were effectively managed by dose modifications. The results presented suggest that brentuximab vedotin is active in systemic mastocytosis and can induce durable responses with a manageable toxicity profile.

US intergroup study of chemotherapy plus dasatinib and allogeneic stem cell transplant in Philadelphia chromosome positive ALL

This multicenter trial was conducted to determine whether the addition of dasatinib to chemotherapy followed by an allogeneic hematopoietic cell transplant (HCT) in patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) was feasible. Patients ≥ 18 and ≤ 60 years of age with newly diagnosed Ph+ ALL received up to 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate with dasatinib. Patients with an available matched sibling or unrelated donor underwent an allogeneic HCT in first complete remission (CR1) followed by daily dasatinib starting from day 100. Others received maintenance therapy with vincristine and prednisone for 2 years and dasatinib indefinitely. 97 patients (94 evaluable) with median age of 44 years (range, 20 - 60) and median WBC at presentation of 10 × 109/L (range, 1 - 410 × 109/L) were accrued. 83 (88%) patients achieved CR or CR with incomplete count recovery (CRi) and 41 underwent ASCT in CR1. Median follow-up is 36 months (range, 9 - 63). For the overall population, overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) at 3 years were 69%, 55%, and 62%, respectively. The 12-month RFS and OS after transplant were 71% and 87%, respectively. Landmark analysis at 175 days from the time of CR/CRi (longest time to HCT), showed statistically superior advantages for RFS and OS (p=0.038 and 0.037, respectively) for the transplanted patients. Addition of dasatinib to chemotherapy and HCT for younger patients with Ph+ ALL is feasible and warrants further testing.

Potential of whole-genome sequencing for determining risk and personalizing therapy: focus on AML

In spite of recent advances in molecular diagnostic techniques and expanded indications for allogeneic hematopoietic stem cell transplantation, treatment of acute myeloid leukemia (AML) remains a major challenge. In the last decade, several recurrent genetic abnormalities and gene mutations with prognostic implications have been identified. This has led to improved informed treatment decisions. However, there has been limited change in the use of nonspecific cytotoxic chemotherapy and mortality rates continue to be unacceptably high, with 5 year overall survival rates of older AML patients at 30% or less. Whole-genome sequencing offers hope for greater diagnostic accuracy and is likely to lead to further characterization of disease subsets with differential outcome and response to treatment. The holy grail of personalized targeted therapy for the individual AML patient, while minimizing toxicity and prolonging survival, appears closer than ever.

Clinicopathological and molecular features of myeloid sarcoma as initial presentation of therapy-related myeloid neoplasms: a single institution experience

Therapy-related myeloid neoplasms (t-MN) have a common origin in prior cytotoxic therapy and/or radiation. These neoplasms include therapy-related acute myeloid leukemia, myelodysplastic syndrome (t-MDS), and myelodysplastic/myeloproliferative neoplasms (t-MDS/MPN). Myeloid sarcoma (MS), on the other hand, is a rare disease manifesting as an extramedullary collection of immature cells of myeloid lineage. Rarer still is therapy-related MS (t-MS), which has not been adequately studied due to its rarity and its lack of recognition as a unique entity among other t-MN. Here, we report what is to our knowledge the first case series of t-MS, with the aim of investigating and establishing salient clinicopathological and molecular features of this entity.

How we diagnose and treat systemic mastocytosis in adults

Rapid advances in the understanding of the molecular biology, data from translational and clinical trials, and retrospective analyses has influenced the diagnosis and treatment of systemic mastocytosis (SM). Many options have existed for the symptomatic management of SM patients, but recent evolution in regards to the molecular underpinnings of this disease and our ability to distinguish clonal mastocytosis from mast cell activation syndrome has changed our treatment paradigm and opened new opportunities for understanding genetic risk, transformation to mast cell leukaemia, and treatment choices. Key to this change has been the discovery of the KIT mutation and the use of next generation sequencing to evaluate for co‐existing molecular mutations that may define the disease course. Careful diagnosis, judicious symptom management and close surveillance of those who may have yet undiagnosed disease is paramount in providing optimal management. In this article, we review the diagnosis and provide a paradigm for the management of SM patients.

Therapy-related B-lymphoblastic leukemia associated with Philadelphia chromosome and MLL rearrangement: Single institution experience and the review of the literature.

Therapy related acute lymphoblastic leukemia (t‐ALL) of B cell origin is rare and constitutes approximately 2% of all ALL. Previously compiled data on the complete cytogenetic analysis of 48 t‐B‐ALL cases suggested that MLL rearrangement at 11q23 gene locus is the most common abnormality. Philadelphia chromosome (Ph) and a normal karyotype were reported as the second and third most common karyotypes, respectively. We investigated cytogenetic karyotypes of six t‐B‐ALL cases with a pre‐B cell immunophenotype. Ph + t‐B‐ALL was noted in four of six patients previously treated with radiation and/or chemotherapy. In addition, one case demonstrated MLL rearrangement at 11q23 locus while one case demonstrated normal cytogenetic karyotype. Five of the six t‐B‐ALL patients had persistent leukemia following initiation of chemotherapy for secondary leukemia with survival ranging from 10 to 21 months. To our knowledge, only fourteen patients with Ph + t‐B‐ALL have been described in the literature. In the current study, three of four cases with Ph + t‐B‐ALL were associated with treated breast carcinoma while one patient was treated for Hodgkin lymphoma. All four patients had undergone radiation therapy. The results may indicate a plausible association between Ph+t‐B‐ALL and prior radiation exposure.

Functional genomic landscape of acute myeloid leukaemia.

The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset—accessible through the Beat AML data viewer (Vizome)—that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.Analyses of samples from patients with acute myeloid leukaemia reveal that drug response is associated with mutational status and gene expression; the generated dataset provides a basis for future clinical and functional studies of this disease.

Dual inhibition of JAK1/2 kinases and BCL2: a promising therapeutic strategy for acute myeloid leukemia

Acute myeloid leukemia (AML) is a blood cancer resulting from the enhanced proliferation and impaired differentiation of hematopoietic stem and progenitor cells. Chemotherapy consisting of cytarabine and anthracyclines has been the standard of AML care for decades, with a 5-year overall survival rate of 25% [1]. Outcomes in older patients, who represent the majority of patients with this disease, are poor with a median survival of 5 to 10 months. Owing to their inability to tolerate intensive chemotherapy, many older patients do not receive any anti-leukemic therapy [2]. Although the development of drugs targeted to specific pathways offers the promise of improved treatment options, resistance to individual inhibitors has limited their effectiveness. This is in part the result of the substantial disease heterogeneity and clonality underlying AML and underscores the need for combinations of targeted therapies to achieve durable responses. Our group and others have previously established the utility of ex vivo screening platforms to identify effective targeted treatments for leukemia patients [3]. We adapted this approach to test combinations of targeted drugs in a fixed molar concentration series of seven dose points. This work identified several candidate combinations with enhanced efficacy in myeloid leukemia samples, many of which included the BCL2 inhibitor venetoclax [4]. Given the many complex subtypes of AML, we performed expanded studies on the combination of ruxolitinib plus venetoclax (Rux+Ven) because of its broad effectiveness on a majority of AML samples tested. A total of 195 unique AML patients were screened ex vivo for sensitivity to the Rux+Ven combination. Briefly, freshly isolated mononuclear cells were cultured in presence of inhibitors alone or in combination for 3 days before assessing viability as a measure of sensitivity. Under these assay conditions, the cells are viable but not proliferating. The cohort included patients with newly diagnosed AML (n= 137) or relapsed/refractory AML (n= 58). While relapsed/refractory patients surveyed were slightly older than those with newly diagnosed disease (median [range] age of 55.5 (2–87) yrs vs. 62.5 (12–86) yrs, respectively; Mann–Whitney test, p= 0.0371), no significant differences were observed between newly diagnosed and relapsed/refractory patients with respect to sex, WBC count, bone marrow blasts, or ELN prognostic risk (Supplemental Table S1). Among all AML patient specimens tested, the Rux+Ven combination is significantly more effective than either respective single agent by two different effect measures (IC50 and AUC; Fig. 1a, b). For example, median IC50 for Rux+Ven across all patient specimens was 0.014 μM, compared with 10 and 1.45 μM for ruxolitinib and venetoclax, respectively (Friedman test with Dunn’s multiple comparisons test; adjusted p < 0.0001). Furthermore, 80% (156/195) of samples tested demonstrate IC50 values for Rux+Ven <0.5 μM. Previously reported levels of each drug in plasma (ruxolitinib Cmax for 10 mg BID: 0.562 μM [5]; venetoclax Cmax for 400 mg QD: 2.51 μM [6]) suggest * Jeffrey W. Tyner tynerj@ohsu.edu

Applicability of the AML knowledge bank approach

In this issue of Blood, Huet et al analyze the real-life applicability of “knowledge banks“ (see figure); large databases of patients with acute myeloid leukemia (AML) treated with high-dose chemotherapy in a tertiary care center, containing genomic data matched to clinical variables, treatments, and outcomes.1,2