Emerging drug profile: JAK inhibitors.

Dysregulated JAK/STAT hyperactivity is essential to the pathogenesis of myelofibrosis, and JAK inhibitors are the first-line treatment option for many patients. There are four FDA-approved JAK inhibitors for patients with myelofibrosis. Single-agent JAK inhibition can improve splenomegaly, symptom burden, cytopenias, and possibly survival in patients with myelofibrosis. Despite their efficacy, JAK inhibitors produce variable or short-lived responses, in part due to the large network of cooperating signaling pathways and downstream targets of JAK/STAT, which mediates upfront or acquired resistance to JAK inhibitors. Synergistic inhibition of JAK/STAT accessory pathways can increase the rates and duration of response for patients with myelofibrosis. Two recently reported, placebo-controlled phase III trials of novel agents added to JAK inhibition met their primary endpoint, and additional late-stage studies are ongoing. This paper will review role of dysregulated JAK/STAT signaling, biological plausible additional therapeutic targets and the recent advancements in combination strategies with JAK inhibitors for myelofibrosis.

Leukocytosis and MPNs: Where do we stand?

The Philadelphia-negative myeloproliferative neoplasms (MPNs)-essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF), are characterized by a propensity for thrombotic events and variable risks for transformation to MF (for ET and PV) and acute leukemia. Leukocytosis, which serves a minor criterion for the diagnosis of MF, is present in a significant portion of patients with MPNs. The relation and impact of leukocytosis on disease course and outcomes of patients with MPNs has been studied in multiple, large retrospective and prospective studies. Despite this, the association of leukocytosis and thrombosis, fibrosis and leukemic transformation remains unclear. This article details the published investigations regarding the impact of leukocytosis in MPNs and explores the changing role of leukocytosis in disease prognostication as increasing emphasis is placed on molecular and genetic studies.

Graded Cardiac Response Criteria for Patients With Systemic Light Chain Amyloidosis.

PURPOSE: Binary cardiac response assessment using cardiac biomarkers is prognostic in light chain amyloidosis. Previous studies suggested four-level cardiac responses using N-terminal prohormone of brain natiuretic peptide improves prognostic prediction. This study was designed to validate graded cardiac response criteria using N-terminal prohormone of brain natiuretic peptide/brain natiuretic peptide. PATIENTS AND METHODS: This retrospective, multicenter study included patients with light chain amyloidosis who achieved at least a hematologic partial response (PR) and were evaluable for cardiac response. Four response criteria were tested on the basis of natriuretic peptide response depth: cardiac complete response (CarCR), cardiac very good partial response (CarVGPR), cardiac PR (CarPR), and cardiac no response (CarNR). Response was classified as best response and at fixed time points (6, 12, and 24 months from therapy initiation). The study primary outcome was overall survival. RESULTS: 651 patients were included. Best CarCR, CarVGPR, CarPR, and CarNR were achieved in 16%, 26.4%, 22.9%, and 34.7% of patients, respectively. Patients in cardiac stage II were more likely to achieve CarCR than patients in cardiac stage IIIA and IIIB (22% v 13.5% v 3.2%; P < .001). A deeper cardiac response was associated with a longer survival (5-year overall survival 93%, 79%, 65%, and 33% for CarCR, CarVGPR, CarPR, and CarNR, respectively; P < .001). Fixed time-point analyses and time-varying covariates Cox regression analysis, to minimize survivorship bias, affirmed the independent survival advantage of deeper cardiac responses. Four-level response performed better than two-level response as early as 12 months from therapy initiation. CONCLUSION: Graded cardiac response criteria allow better assessment of cardiac improvement compared with the traditional binary response system. The study re-emphasizes the importance of early diagnosis, which increases the likelihood of deep cardiac responses.

Evaluating Race and Time to Transplantation in Multiple Myeloma: The Mount Sinai Hospital Experience.

BACKGROUND: Previous studies have found that Black patients with multiple myeloma undergo autologous stem-cell transplantation (ASCT) less frequently than their white counterparts, although the factors leading to decreased access and utilization have not been fully elucidated. PATIENTS AND METHODS: To identify whether racial differences in transplantation timing played a role in these disparities, we retrospectively analyzed 410 Black and white patients who received their first transplant at The Mount Sinai Hospital between 2011 and 2016 (260 white and 150 Black patients). We compared the time from initial diagnosis to stem-cell collection and the time from collection to transplantation between the 2 races while controlling for age, socioeconomic status, and functional status. RESULTS: Between Blacks and whites, time from diagnosis to collection was higher in Black patients (median 238, vs. 195 days, respectively, P = .051). Functional status, socioeconomic status, and age were also significantly associated with time to collection, and after controlling for these covariates, the effect of race was not significant (P = .0625). Conversely, time from collection to transplantation was increased in white patients compared to Black. CONCLUSION: Increased time from diagnosis to stem-cell collection for Black patients was driven in part by socioeconomic status and baseline functional status.

Real-World Outcomes of Ruxolitinib Treatment for Polycythemia Vera.

INTRODUCTION: Ruxolitinib is approved for the treatment of polycythemia vera (PV) with hydroxyurea resistance or intolerance. Approval was based on the phase III RESPONSE trial, which demonstrated efficacy in a highly selected patient population. MATERIALS AND METHODS: To characterize the tolerability and outcomes of ruxolitinib outside of a clinical trial, we performed a multi-center retrospective analysis of patients with PV treated with ruxolitinib at 11 participating sites across the United States. Outcomes of interest included change in phlebotomy requirements after starting ruxolitinib and spleen response, as these were included in the primary composite outcome in the RESPONSE trial. RESULTS: One hundred twenty-six patients met eligibility criteria, and the median duration of follow-up was 22.4 months (range, 0-63.0 months). At 32 weeks after starting ruxolitinib, the percentage of patients who received at least 1 phlebotomy was significantly decreased compared with before ruxolitinib (37% vs. 56%; relative risk [RR], 0.66; 95% confidence interval [CI], 0.52-0.84; P < .001). Phlebotomy requirements were similarly decreased in patients who had received at least 3 phlebotomies prior to ruxolitinib initiation (28% vs. 17%; RR, 1.65; 95% CI, 1.13-2.40; P < .01). Resolution of palpable splenomegaly was also documented (48% vs. 20%; RR, 2.45; 95% CI, 1.70-3.53; P < .0001). A total of 9.5% of patients discontinued ruxolitinib owing to treatment-emergent adverse events, and 81.7% of patients were receiving ruxolitinib at last known follow-up. CONCLUSION: These real-world results are similar to those reported from the RESPONSE trial, although additional follow-up is necessary to assess long-term outcomes and potential for late-onset toxicity.

Practicing Antimicrobial Stewardship: De-Escalating Antibiotics in Patients With Acute Myeloid Leukemia and Neutropenic Fever.

We compared risk of recurrent fever in patients with acute myeloid leukemia undergoing induction chemotherapy with febrile neutropenia without an infectious source in which antibacterials were de-escalated before neutrophil recovery versus continued. There was less recurrent fever when antibacterials were de-escalated early with no increased adverse events.

Romiplostim for thrombocytopenia following allogeneic stem cell transplantation: A case series.

Thrombocytopenia is a relatively common complication following allogeneic hematopoietic stem cell transplantation and is associated with increased bleeding, transfusion requirements, chronic graft-versus-host disease, and all-cause mortality. There are currently no approved treatments outside of supportive transfusions. We report on the outcomes of five patients at our institution who received romiplostim for either primary engraftment failure or secondary failure of platelet recovery following stem cell transplantation. In total, four out of the five patients demonstrated a response to romiplostim, which was defined as seven consecutive days of platelet count >50 × 109/L with transfusion independence, with two ongoing responses (>365 days each) at the conclusion of the study period. Responses to romiplostim were sustained in the absence of significant bone marrow disease, which was found to contribute to recurrent thrombocytopenia. Additionally, romiplostim was well-tolerated overall; one patient developed minimal fibrotic changes on bone marrow biopsy postromiplostim. Although these results are promising, data from randomized clinical trials are needed to fully understand the role of romiplostim after stem cell transplantation.

Risk factors for infections and secondary malignancies in patients with a myeloproliferative neoplasm treated with ruxolitinib: a dual-center, propensity score-matched analysis.

Ruxolitinib is a JAK1/2 inhibitor approved for the treatment of myelofibrosis (MF) and polycythemia vera (PV). Recent data have suggested the possibility of increased infectious and secondary malignancy rates in patients treated with ruxolitinib. We conducted a dual-center, retrospective study of 202 myeloproliferative neoplasm (MPN) patients receiving ruxolitinib and a control cohort of 73 ruxolitinib-naïve MPN patients. We utilized propensity score matching to analyze the primary outcome of development of any grade infection. Infections occurred in 38.4% of ruxolitinib-naïve patients and 42.6% of ruxolitinib-treated patients and were primarily grade 1/2. After propensity score weighting, there was no difference in risk of infection between ruxolitinib-treated and -naïve patients with MF (HR 1.15 [95% CI 0.80-1.65], p = .466) and non-MF MPNs (HR = 0.52 [95% CI 0.21-1.28, p = .152). These results suggest that there is not an increased risk of infection with ruxolitinib therapy.

Metabolic Effects of JAK1/2 Inhibition in Patients with Myeloproliferative Neoplasms.

Ruxolitinib is an FDA approved janus kinase (JAK)1/2 inhibitor used to treat myeloproliferative neoplasms (MPNs), including myelofibrosis and polycythemia vera. We aimed to determine the metabolic consequences of ruxolitinib treatment in patients with MPNs. We performed a retrospective single-center cohort study utilizing an electronic medical record based database of patients who began treatment with ruxolitinib for MPNs from January 2010 to March 2017. We also examined the effects of ruxolitinib on adipose tissue JAK/STAT signaling in a mouse model. 127 patients were identified, of which 69 had data available for weight, and at least one other parameter of interest before, and 72 weeks after starting ruxolitinib. Mean baseline weight was 73.9 ± 17.0 kg, and 78.54 ± 19.1 kg at 72 weeks (p < 0.001). 50% of patients gained >5% body weight. Baseline body mass index (BMI) was 25.8 ± 4.8 kg/m2, and 27.5 ± 5.5 kg/m2 at 72 weeks (p < 0.001). Patients treated with ruxolitinib had a higher systolic blood pressure, serum AST, and ALT at 72 weeks, compared with baseline (p = 0.03, p = 0.01, p = 0.04, respectively). In mice, ruxolitinib decreased basal and GH-stimulated STAT5 phosphorylation in adipose tissue. As pharmacological JAK1/2 inhibitors are being developed and used in clinical practice, it is important to understand their long-term metabolic consequences.

Relevant updates in systemic mastocytosis.

Systemic Mastocytosis (SM) is a rare myeloproliferative neoplasm (MPN) that is characterized by a clonal proliferation of mast cells (MCs). The symptoms and clinical presentation of SM are the result of both MC proliferation as well as activation and degranulation, causing hyperactive and over-exaggerated hypersensitivity responses, as well as organ infiltration by pathogenic MCs. The clinical presentation and course of SM is varied and organ involvement can lead to significant morbidity and mortality in some cases. The subtypes of SM include indolent SM (ISM), smoldering SM (SSM), aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL) and survival can range from normal in the case of ISM to months in MCL. The treatment of indolent forms of SM is largely focused on addressing symptom burden (B findings), while cytoreductive agents and more recently molecularly targeted agents are employed to reduce MC burden and reverse associated organ dysfunction (C findings). Although the pathogenesis of SM is multi-factorial, the acquisition of KIT D816 V is a relatively frequent mutational event and serves as the target of novel agents. The recent approval of midostaurin for the treatment of advanced SM has brought awareness to this disease and energized further drug development efforts. Expanding our understanding of the underlying molecular mechanisms of SM will continue to inform future therapeutic approaches.

Comparing the epidemiology, clinical characteristics and prognostic factors of acute myeloid leukemia with and without acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a particularly aggressive subtype of acute myeloid leukemia (AML), with high rates of early death. It is important to examine how epidemiological characteristics, clinical and treatment factors, cytogenetic and genetic data affect survival and differ between APL and non-APL AML patients. We analyzed population data from the New York State Cancer Registry to characterize AML including APL incidence rates by demographics. APL incidence rates were higher among Hispanics than non-Hispanics [incidence rate ratio = 1.22; 95% confidence interval (CI) = 1.02-1.43]; and among foreign-born than USA-born persons. APL incidence rates increased more rapidly through 1995-2014 than non-APL AML; and its frequency increased faster among foreign-born persons. In a hospital cohort of 390 AML patients, the risk of death was significantly higher among APL patients with FLT3-internal tandem duplications than those without [hazard ratio (HR) = 11.74; 95% CI = 1.03-134.5]; and among APL patients with secondary versus de novo disease (HR = 17.32; 95% CI = 1.56-192.1). Among non-APL AML patients, risk of death was significantly associated with prior chemotherapy with antitubulin agents after adjusting for age, gender and ethnicity (adjusted HR = 3.30; 95% CI = 1.49-7.32); and separately with older age, unfavorable cytogenetics and complex karyotype. This study highlights FLT3-internal tandem duplications as a prognostic factor in APL and proposes consideration of prior antitubulin therapy as a prognostic factor in non-APL AML.

A single-institution experience of performing bloodless transplant in Jehovah's Witness patients.

OBJECTIVE/BACKGROUND: Autologous stem cell transplant has been shown to prolong survival in multiple myeloma (MM). A common complication of the pre-transplant conditioning chemotherapy is severe multi-lineage cytopenias, resulting in significant transfusion requirements. Jehovah's Witnesses are members of a religious group that do not accept the transfusion of blood products. Many large transplant centers refuse to perform transplantation in Jehovah's Witnesses due to the complexity of treating cytopenic patients without blood product transfusions. However, some transplant centers that specialize in "bloodless" medicine and surgery have successfully transplanted in Jehovah's Witnesses without transfusion support. METHODS: In order to maximize successful outcomes in this population, potential transplant candidates are treated with a variety of agents to maximize baseline hemoglobin and platelet counts. In preparation for the first two "bloodless" transplants for MM at our institution, we conducted a retrospective study of patients with MM who underwent a transplant in the preceding year. RESULTS: Of the 60 patients reviewed, only six required packed red blood cell transfusion, whereas 39 required at least one platelet transfusion. These findings helped us to design a novel protocol for a "bloodless" autologous transplant. We administered romiplostim, a thrombopoietin (TPO) agonist, along with aminocaproic acid, desmopressin, and vitamin K post-transplant to two Jehovah's Witness patients to mitigate the risk of thrombocytopenia. Neither patient experienced significant bleeding nor qualified for platelet transfusion, and underwent successful and uncomplicated transplantation. CONCLUSION: We propose that the use of romiplostim or similar TPO agonists can be used to maximize the chance of a successful "bloodless" transplant for stem cell recipients.