Hematocrit control and thrombotic risk in patients with polycythemia vera treated with ruxolitinib in clinical practice.

Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by unregulated red blood cell production resulting in elevated hemoglobin and/or hematocrit levels. Patients often have symptoms such as fatigue, pruritus, and painful splenomegaly, but are also at risk of thrombosis, both venous and arterial. Ruxolitinib, a selective Janus kinase inhibitor, is approved by the US Food and Drug Administration as second-line cytoreductive treatment after intolerance or inadequate response to hydroxyurea. Although ruxolitinib has been widely used in this setting, limited data exist in the literature on ruxolitinib treatment patterns and outcomes among patients with PV in routine clinical practice. We report a retrospective, observational, cohort study of patients treated for PV with ruxolitinib across three US centers (academic and regional practice) from December 2014-December 2019. The study included 69 patients, with a median follow-up duration of 3.7 years (95% CI, 2.9-4.4). Our data demonstrate very high rates of hematocrit control (88% of patients by three months and 89% by six months); few patients required dose adjustments or suspension. No arterial thromboses were observed; however, the follow-up duration does not allow for the generation of meaningful conclusions from this. Three patients had thrombotic events; one was in the setting of a second malignancy, one post-operative, and a third related to prolonged immobility. We also found that 28% of patients initiated ruxolitinib as a result of poorly controlled platelet counts, second only to hydroxyurea intolerance (46%) as a reason to start therapy. In clinical practice, ruxolitinib continues to be effective in controlling hematocrit levels after three and six months of treatment in patients and is associated with low thrombotic risk.

Evaluation of pentamidine tolerability and efficacy between CYP2C19 phenotypes.

Intravenous pentamidine is used for prophylaxis against Pneumocystis jirovecii pneumonia, an infection seen in hematopoietic stem cell transplant recipients. Pentamidine is partially metabolized by CYP2C19, which is vulnerable to pharmacogenetic variation. This retrospective study evaluated allogeneic hematopoietic stem cell transplant patients who received intravenous pentamidine as P. jirovecii pneumonia prophylaxis. The primary objective was the association between CYP2C19 phenotype and discontinuation of pentamidine due to drug-related side effects based on univariate logistic regression (N = 81). Ten patients (12.3%) discontinued pentamidine because of side effects. There was no difference in discontinuation between phenotype groups (p = 0.18) or discontinuation due to side effects (p = 0.76). Overall, no association was seen between phenotypes and pentamidine-related side effects (p = 0.475). Drug discontinuation rates and P. jirovecii pneumonia infection rates were low.

Allogeneic hematopoietic cell transplantation in acute myeloid leukemia.

Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment modality for select patients with acute myeloid leukemia (AML), functioning as a restorative agent following intensified chemo- and/or radiotherapy and also engendering the disease-directed immunologic threat of graft-versus-leukemia effect. Advancements in conditioning regimen intensity, donor availability, and supportive care have broadened the eligibility for allogeneic HCT, reduced rates of transplant related mortality, and improved outcomes over time. There are still obstacles to transplant in AML, offering opportunities for ongoing discovery, including poor recipient fitness, insufficient donor availability for certain populations, and limited access to care. Relapse remains the most common cause of treatment failure and a high priority area of investigative efforts. Post-transplant maintenance and novel applications of cellular therapeutics are expected to usher in a new era of promise for successful HCT in AML and will aim to overcome the remaining barriers impeding favorable outcomes for these patients.

COVID-19 vaccine uptake trends in SARS-CoV-2 previously infected cancer patients.

Purpose: Cancer patients are at high risk of developing severe illness from SARS-CoV-2 infection, but risk is lowered with receipt of COVID-19 vaccine. COVID-19 vaccination uptake among previously infected cancer patients may be influenced by an assumption of natural immunity, predicted weak immune response, or concerns about vaccine safety. The objective of this study was to evaluate COVID-19 vaccine uptake trends in cancer patients previously infected with SARS-CoV-2. Materials and Methods: Medical records of 579 sequential cancer patients undergoing active treatment at Levine Cancer Institute who tested positive for COVID-19 between January 2020 and January 2021 were evaluated. Patients who died prior to vaccine eligibility were excluded from the analysis. Demographic, clinical, and COVID-19 related characteristics were analyzed to identify prognostic factors for COVID-19 vaccine uptake as this information could be important for health policy design for future pandemics. Results: Eighty-one patients died prior to the availability of COVID-19 vaccines. The acceptance rate of COVID-19 vaccination among 498 previously infected cancer patients was 54.6%. Of the patients with known vaccination dates, 76.8% received their first vaccine by April 17th, 2021. As of November 30, 2021, 23.7.% of eligible patients were boosted. In univariate models, older age, female sex, higher income, solid tumor cancer type, and hormone therapy were significantly associated with higher vaccine uptake, while Hispanic/Latino ethnicity was significantly associated with lower vaccine uptake. In a multivariable model, age (OR 1.18, 95% CI 1.10-1.28; p < 0.001), female sex (OR 1.80, 95% CI 1.22-2.66; p = 0.003), and higher income (OR 1.11, 95% CI 1.01-1.22; p = 0.032), were predictive of COVID-19 vaccine uptake. Conclusions: Overall, vaccine uptake was low among our cohort of previously infected cancer patients. Older age, female sex, and higher income were the only variables associated with COVID-19 vaccine uptake within this vulnerable patient population.

Retrospective Review of Outcomes of Multiple Myeloma (MM) Patients With COVID-19 Infection (Two-Center Study).

INTRODUCTION: COVID-19 has profound effects on patients with multiple myeloma (MM) mainly due to underlying immune dysfunction and associated therapies leading to increased susceptibility to infections. The overall risk of morbidity and mortality (M&M) in MM patients due to COVID-19 infection is unclear with various studies suggesting case fatality rate of 22% to 29%. Additionally, most of these studies did not stratify patients by their molecular risk profile. METHODS: Here, we aim to investigate the effects of COVID-19 infection with associated risk factors in MM patients and the effectiveness of newly implemented screening and treatment protocols on outcomes. After obtaining institutional review board approvals from each participating institution, we collected data from MM patients diagnosed with SARS-CoV-2 infection from March 1, 2020, to October 30, 2020, at 2 myeloma centers (Levine Cancer Institute & University of Kansas medical center). RESULTS: We identified a total of 162 MM patients who had COVID-19 infection. The majority of patients were males (57%) with a median age of 64 years. Most patients had an associated comorbid condition. Their myeloma disease status and prior autologous stem cell transplant at the time of infection had no impact on hospitalization or mortality. In univariate analysis, chronic kidney disease, hepatic dysfunction, diabetes, and hypertension were associated with an increased risk of hospitalization. In multivariate analysis regarding survival, increased age and lymphopenia were associated with increased COVID-19-related mortality. CONCLUSION: Our study supports the use of infection mitigation measures in all MM patients, and adjustment of treatment pathways in MM patients diagnosed with COVID-19.

Impact of second primary malignancy post-autologous transplantation on outcomes of multiple myeloma: a CIBMTR analysis.

The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P < .001 and HR 5.01, P < .001, respectively) and OS (HR 3.85, P < .001 and HR 8.13, P < .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post-auto-HSCT.

Financial Toxicity Intervention Improves Outcomes in Patients With Hematologic Malignancy.

PURPOSE: Patients with hematologic malignancies are extremely vulnerable to financial toxicity (FT) because of the high costs of treatment and health care utilization. This pilot study identified patients at high risk because of FT and attempted to improve clinical outcomes with comprehensive intervention. METHODS: All patients who presented to the Levine Cancer Institute's Leukemia Clinic between May 26, 2019, and March 10, 2020, were screened for inclusion by standardized two question previsit survey. Patients screening positive were enrolled in the comprehensive intervention that used nurse navigators, clinical pharmacists, and community pro bono financial planners. Primary outcomes were defined as improvement in mental and physical quality of life in all patients and improvement in overall survival in the high-risk disease group. RESULTS: One hundred seven patients completed comprehensive intervention. Patients experiencing FT had increased rates of noncompliance including to prescription (16.8%) and over-the-counter medications (15.9%). The intervention resulted in statistically significantly higher quality of life when measured by using Patient-Reported Outcomes Measurement Information System physical (12.5 ± 2.2 v 13.7 ± 1.8) and mental health scores (11.4 ± 2.2 v 12.4 ± 2.2; all P < .001). In patients with high-risk disease (as determined by using disease-specific scoring systems), risk of death in those receiving the intervention was 0.44 times the risk of death in those without the intervention after adjusting for race, and treatment with stem-cell transplant, oral chemotherapy, or immunotherapy (95% CI, 0.21 to 0.94; P = .034). CONCLUSION: Screening and intervention on FT for patients with hematologic malignancies is associated with increased quality of life and survival.

Oral MEK 1/2 Inhibitor Trametinib in Combination With AKT Inhibitor GSK2141795 in Patients With Acute Myeloid Leukemia With RAS Mutations: A Phase II Study.

BACKGROUND: With proven single-agent activity and favorable toxicity profile of MEK-1/2 inhibition in advanced leukemia, investigation into combination strategies to overcome proposed resistance pathways is warranted. Resistance to MEK inhibition is secondary to upstream hyperactivation of RAS/RAF or activation of the PI3K/PTEN/AKT/mTOR pathway. This phase II multi-institution Cancer Therapy Evaluation Program-sponsored study was conducted to determine efficacy and safety of the combination of the ATP-competitive pan-AKT inhibitor GSK2141795, targeting the PI3K/AKT pathway, and the MEK inhibitor trametinib in RAS-mutated relapsed/refractory acute myeloid leukemia (AML). PATIENTS AND METHODS: The primary objective was to determine the proportion of patients achieving a complete remission. Secondary objectives included assessment of toxicity profile and biologic effects of this combination. Twenty-three patients with RAS-mutated AML received the combination. Two dose levels were explored (dose level 1: 2 mg trametinib, 25 mg GSK2141795 and dose level 2: 1.5 mg trametinib, 50 mg GSK2141795). RESULTS: Dose level 1 was identified as the recommended phase II dose. No complete remissions were identified in either cohort. Minor responses were recognized in 5 (22%) patients. The most common drug-related toxicities included rash and diarrhea, with dose-limiting toxicities of mucositis and colitis. Longitudinal correlative assessment of the modulation of MEK and AKT pathways using reverse phase protein array and phospho-flow analysis revealed significant and near significant down-modulation of pERK and pS6, respectively. Combined MEK and AKT inhibition had no clinical activity in patients with RAS-mutated AML. CONCLUSION: Further investigation is required to explore the discrepancy between the activity of this combination on leukemia cells and the lack of clinical efficacy.

The Art of Transplantation: Conditioning Intensity for Allogeneic Hematopoietic Stem Cell Transplantation.

The search for the optimal conditioning regimen before allogeneic hematopoietic stem cell transplantation (HCT) for acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) has been ongoing for decades. In this issue, Solh et al present an original analysis evaluating the impact of conditioning intensity on different disease risk index (DRI) groups of patients with AML and MDS. An impressive difference was observed in outcomes between reduced-intensity conditioning and myeloablative conditioning (MAC) regimens in the low/intermediate-risk disease groups, supporting the use of MAC in this population. Further prospective trials in this population are encouraged.

Higher Incidence of Hemorrhagic Cystitis Following Haploidentical Related Donor Transplantation Compared with Matched Related Donor Transplantation.

Hemorrhagic cystitis (HC) is a common and important complication of allogeneic hematopoietic cell transplantation (HCT). Reactivation of BK virus is its most common cause. The more intense immunosuppressive regimens administered to recipients of grafts from alternative donors have been reported to account for the increased susceptibility to HC in this population. This study compares patients undergoing HCT with either a haploidentical donor or a matched related donor, all of whom received identical immunosuppression with a post-transplantation cyclophosphamide-based regimen. The incidence of HC was significantly higher in the patients receiving a haploidentical graft (P = .01). The higher incidence of HC in haploidentical graft recipients is therefore directly related to the inherent immune deficiency that follows HLA-mismatched transplantation, independent of the intensity of pharmacologic immunosuppression. This finding carries significant clinical impact for the prevention and treatment of HC in haploidentical graft recipients.

Pentostatin therapy for steroid-refractory acute graft versus host disease: identifying those who may benefit.

We report outcomes of 60 patients with steroid-refractory (SR)-aGVHD treated with pentostatin. Almost half (47%) of patients had grade 4 GVHD-22% had stage 3-4 liver GVHD and 51% had stage 3-4 lower gastrointestinal tract (LGI) GVHD. Patients received a median of 3 courses (range, 1-9) of pentostatin. Day 28 overall response rate (ORR) was 33% (n = 20) (complete response 18% (n = 11), partial response 15% (n = 9)). Non-relapse mortality was 72% (95% confidence interval (CI) 61-84%) and overall survival (OS) was 21% (95% CI 12-32%) at 18 months. On univariate analysis, age >60 years (HR 1.9, 95% CI 1.01-3.7, p = 0.045) and presence of liver GVHD (HR 1.9, 95% CI 1.9, 95% CI 1.5-3.3, p = 0.03) were significant predictors of poor OS while patients with LGI GVHD had superior OS than those without (HR 0.4, 95% CI 0.2-0.8, p = 0.01). On stratified analysis, patients <60 years with isolated LGI GVHD had the best outcomes with an ORR of 48% and OS of 42% at 18 months. Among older patients, OS was 14% in those with isolated LGI aGVHD and 0% in others. Pentostatin remains a viable treatment option for SR-aGVHD, especially in patients 60 years or younger with isolated LGI involvement.

Targeting IDH1 and IDH2 Mutations in Acute Myeloid Leukemia.

PURPOSE OF REVIEW: Over the past decade, the pathogenic role of mutations in isocitrate dehydrogenases (IDH) 1 and 2, affecting approximately 20% of patients with AML, has been defined, allowing for the development of specific therapeutic strategies for IDH-mutant AML. In this review, the landscape and progress of targeted therapeutics aimed at IDH mutations in AML and related myeloid malignancies will be described. RECENT FINDINGS: Since 2013, several mutant IDH-targeted inhibitors have been developed, and nearly a dozen clinical trials have opened specifically for IDH-mutant hematologic malignancies. Preliminary results for several of these investigations have shown evidence of safety, tolerability, and encouraging evidence of efficacy. Targeting IDH mutations in AML is a biologically informed and rational strategy to promote clinical responses, primarily through differentiation and maturation of the malignant clone. The use of IDH targeted therapy is expected to soon become part of a genomically defined and individualized AML treatment strategy.

The Challenge of Treating Myelodysplastic Syndromes/Myeloproliferative Neoplasms.

Myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) comprise a spectrum of myeloid disorders with both dysplastic and proliferative features, arising from hematopoietic stem cells. MDS/MPN are neither MDS nor MPN but a distinct World Health Organization-defined subclassification of diseases that, by definition, do not arise from a pre-existing MDS or MPN, inherently creating diagnostic and therapeutic challenges. Appropriately recognizing and classifying MDS/MPN is paramount for appropriately formulating treatment strategies and accurate prognostication. Highlighting the unique molecular, morphologic, and clinical characteristics among the subclassifications of MDS/MPN can assist in the appropriate diagnosis and aid in choice of therapeutic strategies. We describe the challenges of the appropriate diagnosis and treatment of MDS/MPN.

Minimal residual disease eradication with epigenetic therapy in core binding factor acute myeloid leukemia.

Recurrent translocations, t(8;21) or inv(16), in core binding factor acute myeloid leukemia (CBF-AML) are amenable to monitoring for minimal residual disease (MRD) with reverse transcriptase polymerase chain reaction (RTPCR). Despite a favorable prognosis, disease relapse remains the single cause of treatment failure in CBF-AML. Fusion products of these translocations recruit epigenetic silencing complexes resulting in hematopoietic maturation arrest. We hypothesized that maintenance therapy with hypomethylating agents (HMA), including decitabine (DAC) and azacitidine (AZA) after induction/consolidation, can be used for MRD elimination to ultimately prolong relapse free survival. Real-time quantitative (RTPCR) trends were reviewed in 23 patients (median age 53 years) with CBF-AML that received HMA therapy following induction/consolidation with fludarabine, cytarabine, and G-CSF (FLAG) with low dose gemtuzumab or idarubicin (NCT00801489). Of the 23 patients evaluated, 17 had a detectable RTPCR at HMA initiation. Five patients had progressive disease and a notable increase in RTPCR values over 1-2 cycles of HMA therapy. Twelve patients did not fail HMA and had a median RTPCR at HMA initiation of 0.06 (range, 0.01-0.91). Unlike the HMA failure subset, 11 of these patients had a reduction in RTPCR after the first or second cycle of HMA. Our data suggests that CBF-AML patients with low levels of RTPCR (between 0.01 and 0.05) at the conclusion of induction/consolidation chemotherapy benefit most from maintenance HMA, particularly those that have a reduction in the RTPCR within the first two cycles of HMA therapy.

Focal Adhesion Kinase as a Potential Target in AML and MDS.

Although overexpression/activation of focal adhesion kinase (FAK) is widely known in solid tumors to control cell growth, survival, invasion, metastasis, gene expression, and stem cell self-renewal, its expression and function in myeloid leukemia are not well investigated. Using reverse-phase protein arrays in large cohorts of newly diagnosed acute myeloid leukemia (AML) and myeloid dysplastic syndrome (MDS) samples, we found that high FAK expression was associated with unfavorable cytogenetics (P = 2 × 10-4) and relapse (P = 0.02) in AML. FAK expression was significantly lower in patients with FLT3-ITD (P = 0.0024) or RAS (P = 0.05) mutations and strongly correlated with p-SRC and integrinß3 levels. FAK protein levels were significantly higher in CD34+ (P = 5.42 × 10-20) and CD34+CD38- MDS (P = 7.62 × 10-9) cells compared with normal CD34+ cells. MDS patients with higher FAK in CD34+ cells tended to have better overall survival (P = 0.05). FAK expression was significantly higher in MDS patients who later transformed to compared with those who did not transform to AML and in AML patients who transformed from MDS compared with those with de novo AML. Coculture with mesenchymal stromal cells (MSC) increased FAK expression in AML cells. Inhibition of FAK decreased MSC-mediated adhesion/migration and viability of AML cells and prolonged survival in an AML xenograft murine model. Our results suggest that FAK regulates leukemia-stromal interactions and supports leukemia cell survival; hence, FAK is a potential therapeutic target in myeloid leukemia. Mol Cancer Ther; 16(6); 1133-44. ©2017 AACR.

Buparlisib, a PI3K inhibitor, demonstrates acceptable tolerability and preliminary activity in a phase I trial of patients with advanced leukemias.

Phosphatidylinositol-3-kinase (PI3K) signaling plays a crucial role in oncogene-mediated tumor growth and proliferation. Buparlisib (BKM120) is an oral pan-class I PI3K inhibitor. This phase I study was conducted to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of BKM120 in patients (pts) with relapsed/refractory acute leukemias. Fourteen pts (12 acute myeloid leukemia, 1 acute lymphoblastic leukemia, and 1 mixed phenotype leukemia) were enrolled. Twelve pts received BKM-120 80 mg/day and two 100 mg/day. The MTD was 80 mg/day. Of the 14 patients treated, the best response was stable disease in one patient that lasted 82 days. The median survival for all patients was 75 days (range 10-568). Three patients with a 3q26 chromosome abnormality had a significantly improved median survival of 360 days (range 278-568) as compared to a median survival of 57 days (range, 10-125) among the 11 other patients. The most frequent drug-related toxicities included confusion, mucositis, dysphagia, and fatigue. Western blot profiling revealed a decrease in p-pS6K/total pS6K in 5/7 (71%) available patient samples with a mean quantitative inhibition of 65% (range, 32-100%) and a decrease in p-FOXO3/total FOXO3 in 4/6 (67%) samples with a mean quantitative inhibition of 93% (range, 89-100%). BKM120 administered at 80 mg/day showed modest efficacy and was tolerable in advanced acute leukemias. Am. J. Hematol. 92:7-11, 2017. © 2016 Wiley Periodicals, Inc.

Penetrance of Hemochromatosis in HFE Genotypes Resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network.

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder associated with pathogenic HFE variants, most commonly those resulting in p.Cys282Tyr and p.His63Asp. Recommendations on returning incidental findings of HFE variants in individuals undergoing genome-scale sequencing should be informed by penetrance estimates of HH in unselected samples. We used the eMERGE Network, a multicenter cohort with genotype data linked to electronic medical records, to estimate the diagnostic rate and clinical penetrance of HH in 98 individuals homozygous for the variant coding for HFE p.Cys282Tyr and 397 compound heterozygotes with variants resulting in p.[His63Asp];[Cys282Tyr]. The diagnostic rate of HH in males was 24.4% for p.Cys282Tyr homozygotes and 3.5% for compound heterozygotes (p < 0.001); in females, it was 14.0% for p.Cys282Tyr homozygotes and 2.3% for compound heterozygotes (p < 0.001). Only males showed differences across genotypes in transferrin saturation levels (100% of homozygotes versus 37.5% of compound heterozygotes with transferrin saturation > 50%; p = 0.003), serum ferritin levels (77.8% versus 33.3% with serum ferritin > 300 ng/ml; p = 0.006), and diabetes (44.7% versus 28.0%; p = 0.03). No differences were found in the prevalence of heart disease, arthritis, or liver disease, except for the rate of liver biopsy (10.9% versus 1.8% [p = 0.013] in males; 9.1% versus 2% [p = 0.035] in females). Given the higher rate of HH diagnosis than in prior studies, the high penetrance of iron overload, and the frequency of at-risk genotypes, in addition to other suggested actionable adult-onset genetic conditions, opportunistic screening should be considered for p.[Cys282Tyr];[Cys282Tyr] individuals with existing genomic data.