Genetic Predictors of Ibrutinib-related Cardiovascular Side Effects in Patients with Chronic Lymphocytic Leukemia.

PURPOSE: Patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib are at risk of developing cardiovascular side effects (CVSE). The molecular determinants of CVSEs have not been fully elucidated. We interrogated genetic polymorphisms in the Bruton tyrosine kinase (BTK) signaling pathway for their association with ibrutinib-related CVSEs. EXPERIMENTAL DESIGN: We conducted a retrospective/prospective observational pharmacogenetic study of 50 patients with newly diagnosed or relapsed CLL who received ibrutinib at a starting daily dose of 420 mg for at least 6 months. CVSEs, primarily atrial fibrillation and hypertension, occurred in 10 patients (20%), of whom 4 discontinued therapy. DNA was isolated from buccal swabs of all 50 patients and genotyped for 40 SNPs in GATA4, SGK1, KCNQ1, KCNA4, NPPA, and SCN5A using a customized next-generation sequencing panel. Univariate and multivariate logistic regression analysis were performed to determine genetic and clinical factors associated with the incidence of ibrutinib-related CVSEs. RESULTS: GATA4 rs804280 AA (P = 0.043), KCNQ1 rs163182 GG (P = 0.036), and KCNQ1 rs2237895 AA (P = 0.023) genotypes were univariately associated with ibrutinib-related CVSEs. On the basis of multivariate analysis, a high genetic risk score, defined as the presence of at least two of these genotypes, was associated with 11.5-fold increased odds of CVSEs (P = 0.019; 95% confidence interval, 1.79-119.73). CONCLUSIONS: Our findings suggest possible genetic determinants of ibrutinib-related CVSEs in CLL. If replicated in a larger study, pretreatment pharmacogenetic testing for GATA4 and KCNQ1 polymorphisms may be a useful clinical tool for personalizing treatment selection for CLL and/or instituting early risk mitigation strategies.

Peripheral blood progenitor cell mobilization for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation.

Peripheral blood progenitor cell mobilization practices vary significantly among institutions. Effective mobilization regimens include growth factor alone, chemotherapy and growth factor combined, and, more recently, incorporation of plerixafor with either approach. Many institutions have developed algorithms to improve stem cell mobilization success rates and cost-effectiveness. However, an optimal stem cell mobilization regimen has not been defined. Practical guidelines are needed to address important clinical questions, including which growth factor is optimal, what chemotherapy and dose is most effective, and when to initiate leukapheresis. We present recommendations, based on a comprehensive review of the literature, from the American Society of Blood and Marrow Transplantation.

Allogeneic hematopoietic cell transplantation for advanced polycythemia vera and essential thrombocythemia.

Allogeneic hematopoietic cell transplantation (HCT) is curative for selected patients with advanced essential thrombocythemia (ET) or polycythemia vera (PV). From 1990 to 2007, 75 patients with ET (median age 49 years) and 42 patients with PV (median age 53 years) underwent transplantations at the Fred Hutchinson Cancer Research Center (FHCRC; n = 43) or at other Center for International Blood and Marrow Transplant Research (CIBMTR) centers (n = 74). Thirty-eight percent of the patients had splenomegaly and 28% had a prior splenectomy. Most patients (69% for ET and 67% for PV) received a myeloablative (MA) conditioning regimen. Cumulative incidence of neutrophil engraftment at 28 days was 88% for ET patients and 90% for PV patients. Acute graft-versus-host disease (aGVHD) grades II to IV occurred in 57% and 50% of ET and PV patients, respectively. The 1-year treatment-related mortality (TRM) was 27% for ET and 22% for PV. The 5-year cumulative incidence of relapse was 13% for ET and 30% for PV. Five-year survival/progression-free survival (PFS) was 55%/47% and 71%/48% for ET and PV, respectively. Patients without splenomegaly had faster neutrophil and platelet engraftment, but there were no differences in TRM, survival, or PFS. Presence of myelofibrosis (MF) did not affect engraftment or TRM. Over 45% of the patients who undergo transplantations for ET and PV experience long-term PFS.

p53-Independent, normal stem cell sparing epigenetic differentiation therapy for myeloid and other malignancies.

Cytotoxic chemotherapy for acute myeloid leukemia (AML) usually produces only temporary remissions, at the cost of significant toxicity and risk for death. One fundamental reason for treatment failure is that it is designed to activate apoptosis genes (eg, TP53) that may be unavailable because of mutation or deletion. Unlike deletion of apoptosis genes, genes that mediate cell cycle exit by differentiation are present in myelodysplastic syndrome (MDS) and AML cells but are epigenetically repressed: MDS/AML cells express high levels of key lineage-specifying transcription factors. Mutations in these transcription factors (eg, CEBPA) or their cofactors (eg., RUNX1) affect transactivation function and produce epigenetic repression of late-differentiation genes that antagonize MYC. Importantly, this aberrant epigenetic repression can be redressed clinically by depleting DNA methyltransferase 1 (DNMT1, a central component of the epigenetic network that mediates transcription repression) using the deoxycytidine analogue decitabine at non-cytotoxic concentrations. The DNMT1 depletion is sufficient to trigger upregulation of late-differentiation genes and irreversible cell cycle exit by p53-independent differentiation mechanisms. Fortuitously, the same treatment maintains or increases self-renewal of normal hematopoietic stem cells, which do not express high levels of lineage-specifying transcription factors. The biological rationale for this approach to therapy appears to apply to cancers other than MDS/AML also. Decitabine or 5-azacytidine dose and schedule can be rationalized to emphasize this mechanism of action, as an alternative or complement to conventional apoptosis-based oncotherapy.

Histone H4 acetylation by immunohistochemistry and prognosis in relapsed acute lymphocytic leukaemia (ALL).

Histone H4 acetylation was examined by immunohistochemistry in patients with acute lymphocytic leukaemia (ALL) in first relapse. Univariate and multivariate models identified correlates of complete remission (CR) and overall survival (OS). No variables were associated with achievement of CR. In multivariate analysis, weak histone H4 acetylation [Hazard Ratio (HR) 2·20, 95% confidence interval (CI) 0·93-5·23, P=0·07], shorter interval from diagnosis to relapse (<9 vs. 9-24 vs. >24 months) (HR 1·82, 95% CI 1·20-2·75, P= 0·005), and central nervous system involvement (HR 3·43, 95% CI 1·31-8·99, P=0·01) were independent poor prognostic factors for OS. These data provide a rationale for the use of histone deacetylase inhibitors in the treatment of relapsed ALL.

A Phase II trial of gemcitabine and mitoxantrone for patients with acute myeloid leukemia in first relapse.

INTRODUCTION: We evaluated the complete remission (CR) rate in patients with acute myeloid leukemia (AML) in first relapse treated with fixed-dose-rate gemcitabine and mitoxantrone. In addition, we measured multidrug resistance (MDR) proteins on pretreatment bone marrows and correlated expression with outcome. PATIENTS AND METHODS: The study was performed in a 2-stage design. Pretreatment bone marrows were assayed for the MDR proteins (LRP, MDR1, MRP1, SLC28-29A1/A2, ABCC4/C5, and GSTP1) by immunohistochemistry and reverse-transcriptase polymerase chain reaction (RT-PCR). RESULTS: Only 5 of the first 24 patients (21%) achieved CR; therefore, the study was terminated. Eleven patients (46%) had poor-risk cytogenetics and the median duration of first CR was 7.3 months. Patients had significant expression of the various MDR genes, with 70% of patients expressing moderate to high levels of GSTP1 by immunohistochemistry. Higher sum total of ABCC4 and SLC29A2 expression measured by RT-PCR was associated with not achieving CR (20.6 vs. 12.1; P = .006). In addition, there was a trend for higher expression of the sum total of the 10 MDR genes (measured by RT-PCR) and not achieving CR (P = .06). CONCLUSION: The CR rate in this study was comparable to other regimens used in poor-risk patients. Of interest, ABCC4 and SLC29A2 expression were predictive of achieving CR. The high expression of GSTP1 suggests that this may be a therapeutic target for relapsed AML. Finally, the rapidity and ease of using RT-PCR to quantify MDR in this study may have clinical utility in future trials.

Histone H4 acetylation by immunohistochemistry and prognosis in newly diagnosed adult acute lymphoblastic leukemia (ALL) patients.

BACKGROUND: Histone deacetylase (HDAC) inhibitors are a novel anti-tumor therapy. To determine whether HDAC inhibitors may be useful in the treatment of adult acute lymphoblastic leukemia (ALL), we examined the acetylation of histone H4 by immunohistochemistry in newly diagnosed ALL patients and evaluated the impact of acetylation on complete remission (CR) rate, relapse-free survival (RFS), and overall survival (OS). METHODS: Patients > or = 18 years of age and an available diagnostic bone marrow biopsy were evaluated. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of CR, RFS, and OS. The variables histone H4 acetylation (positive or negative), white blood count, cytogenetic (CG) risk group (CALGB criteria), and age were used in multivariate analysis. RESULTS: On multivariate analysis, histone acetylation was associated with a trend towards an improved OS (for all CG risk groups) (HR = 0.51, p = 0.09). In patients without poor risk CG, there was an impressive association between the presence of histone acetylation and an improved CR rate (OR 3.43, p = 0.035), RFS (HR 0.07, p = 0.005), and OS (HR 0.24, p = 0.007). This association remained statistically significant in multivariate analysis. CONCLUSIONS: These data provide a rationale for the design of novel regimens incorporating HDAC inhibitors in ALL.

OCT-2 expression and OCT-2/BOB.1 co-expression predict prognosis in patients with newly diagnosed acute myeloid leukemia.

OCT-2 and its co-activator, BOB.1, are B-cell associated transcription factors expressed in a subset of patients with acute myeloid leukemia (AML). We evaluated OCT-2 and BOB.1 expression by immunohistochemistry in patients with newly diagnosed AML. The median overall survival (OS) for patients with varying levels of OCT-2 expression was statistically different (p = 0.03) (OCT-2 <10%: 21.7 months; OCT-2 10-50%: 18.4 months; OCT-2 >50%: 11.6 months). On multivariate analysis, co-expression of OCT-2/BOB.1 remained predictive for achievement of complete remission (HR 0.44, p = 0.010) and increased risk of relapse (HR 2.30, p = 0.047). OCT-2 (per 10% increase) was associated with a decreased progression-free survival (HR 1.10, p = 0.036) and a trend toward a worse OS (HR 1.10, p = 0.063). OCT-2 may act as a cell survival factor in AML by mediating expression of downstream targets, such as BCL-2. These results will need to be validated prospectively.

Time to post-remission therapy is an independent prognostic factor in adults with acute lymphoblastic leukemia.

We evaluated patients with newly diagnosed ALL treated at the Cleveland Clinic during the years 1996 through 2005. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of complete remission, overall survival and progression-free survival. On univariate analysis, significant prognostic factors included: age at diagnosis (per 10-year increase), poor risk cytogenetics, time to white blood count recovery, and time from induction chemotherapy (IC) to post-remission therapy (PRT). In patients age <60 years without poor risk cytogenetics, time from IC to PRT (per week increase) was a significant prognostic factor by multivariate analysis and was associated with a decreased progression-free survival [HR 1.27, CI (1.04-1.55), p = 0.019] and decreased overall survival [HR 1.34, CI (1.08-1.67), p = 0.009]. Delayed time from IC to PRT (> or =6.6 weeks) was associated with a statistically worse progression-free and overall survival.