A randomized phase III study of standard versus high-dose cytarabine with or without vorinostat for AML.

Prior experience indicated that use of higher doses of cytarabine during induction for acute myeloid leukemia (AML) with a histone deacetylase inhibitor resulted in high response rates. S1203 was a randomized multicenter trial for previously untreated patients aged 18-60 with AML which compared daunorubicin and cytarabine (DA), idarubicin with higher dose cytarabine (IA) and IA with vorinostat (IA + V). The primary endpoint was event free survival (EFS). 738 patients were randomized: 261 to each DA and IA arms and 216 to the IA + V arm. 96, 456, and 150 patients had favorable-, intermediate-, and unfavorable-risk cytogenetics, respectively. 152 were NPM1 and 158 FLT3 mutated. The overall remission rate was 77.5% including 62.5% CR and 15.0% CRi. No differences in remission, EFS, or overall survival were observed among the 3 arms except for the favorable cytogenetics subset who had improved outcomes with DA and postremission high dose cytarabine. A trend towards increased toxicity was observed with the IA and IA + V arms. The use of higher dose cytarabine during induction therapy in younger patients with AML, with or without vorinostat, does not result in improved outcomes. (Funded by the US National Institutes of Health and others, ClinicalTrials.gov number, NCT01802333.).

Canadian real-world experience of asciminib treatment in heavily pre-treated chronic myeloid leukemia (CML) patients who failed multiple lines of tyrosine kinase inhibitor (TKI) therapy.

BACKGROUND: Asciminib is a novel drug specifically targeting ABL myristoyl pocket in the ABL1 protein. METHODS: Forty one patients with chronic myeloid leukemia treated with asciminib from 2018 to 2022 were reviewed and analyzed for the efficacy and tolerability of asciminib using real-world experience data. RESULTS: The median age was 60 years (range 17-90) with a past history of a cardiovascular event in 21 patients (51%). Patients were pretreated with a median of 3 previous tyrosine kinase inhibitors (range 1-5). After a median of 12 months of asciminib (range 3-41), major molecular response (MMR) rate was 39% (n = 11/28) and 42% (n = 5/12) at 6 and 12 months, respectively. Molecular response with 2 log reduction (MR2) was noted in 54% (n = 15/28) and 50% (n = 6/12) at 6 and 12 months. The cumulative incidence of MMR and MR2 was 46.3% and 66% at 12 months. Five patients discontinued asciminib due to treatment failure (n = 3) or thrombocytopenia (n = 2). There were no cardiovascular events. Out of 7 patients treated with high dose asciminib for T315I mutation, 5 patients achieved MMR or deeper response. The event-free survival was 63% at 12 months. CONCLUSION: This study confirmed clinical efficacy and tolerability of asciminib with real-world experience.

Rapid Donor Identification Improves Survival in High-Risk First-Remission Patients With Acute Myeloid Leukemia.

PURPOSE: Patients with acute myeloid leukemia with high-risk cytogenetics in first complete remission (CR1) achieve better outcomes if they undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy alone. However, only approximately 40% of such patients typically proceed to HCT. METHODS: We used a prospective organized approach to rapidly identify donors to improve the allogeneic HCT rate in adults with high-risk acute myeloid leukemia in CR1. Newly diagnosed patients had cytogenetics obtained at enrollment, and those with high-risk cytogenetics underwent expedited HLA typing and were encouraged to be referred for consultation with a transplantation team with the goal of conducting an allogeneic HCT in CR1. RESULTS: Of 738 eligible patients (median age, 49 years; range, 18-60 years of age), 159 (22%) had high-risk cytogenetics and 107 of these patients (67%) achieved CR1. Seventy (65%) of the high-risk patients underwent transplantation in CR1 (P < .001 compared with the historical rate of 40%). Median time to HCT from CR1 was 77 days (range, 20-356 days). In landmark analysis, overall survival (OS) among patients who underwent transplantation was significantly better compared with that of patients who did not undergo transplantation (2-year OS, 48% v 35%, respectively [P = .031]). Median relapse-free survival after transplantation in the high-risk cohort who underwent transplantation in CR1 (n = 70) was 11.5 months (range, 4-47 months), and median OS after transplantation was 14 months (range, 4-44 months). CONCLUSION: Early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donor led to a CR1 transplantation rate of 65% in the high-risk group, which, in turn, led to an improvement in OS when compared with the OS of patients who did not undergo transplantation.

Impact of Donor and Recipient Cytomegalovirus Serostatus on Outcomes of Antithymocyte Globulin-Conditioned Hematopoietic Cell Transplantation.

Although previous studies involving allogeneic hematopoietic cell transplantation (HCT) without in vivo T cell depletion by rabbit antithymocyte globulin (ATG) have reported a substantial survival difference between D-R- and D+R- patients, but little to no survival difference between D-R+ and D+R+ patients (D, donor; R, recipient; +, cytomegalovirus [CMV] seropositive; -, CMV seronegative), whether this applies to HCT using ATG is unknown. We studied 928 patients who underwent myeloablative HCT for hematologic malignancies in Alberta between 1999 and 2014 who received graft-versus-host disease (GVHD) prophylaxis using ATG (Thymoglobulin, 4.5 mg/kg) in addition to methotrexate and cyclosporine. D-R- and D+R- patients had similar survival (no significant difference). D-R+ patients had a substantially lower survival than D+R+ patients (41% versus 59% at 5 years; P = .001). This difference was attributed to higher nonrelapse mortality, apparently due to higher GVHD-associated mortality. Survival rates were also lower for D-R+ HLA-matched sibling transplant recipients compared with D+R+ HLA-matched unrelated donor transplant recipients (44% versus 66% at 5 years; P = .009). In conclusion, when using ATG, choosing a seronegative donor for a seronegative patient is relatively unimportant, whereas choosing a seropositive donor for a seropositive patient is important, even if this requires the use of a seropositive matched unrelated donor graft.

Medication adherence among adults prescribed imatinib, dasatinib, or nilotinib for the treatment of chronic myeloid leukemia.

BACKGROUND: Oral tyrosine kinase inhibitors are the standard of care for chronic myeloid leukemia. Tyrosine kinase inhibitors are administered in an outpatient setting for an indefinite period which may negatively impact adherence. Non-adherence to tyrosine kinase inhibitors is associated with disease progression. OBJECTIVES: To evaluate the need for adherence-enhancing interventions, this study was designed to determine the proportion of chronic myeloid leukemia patients non-adherent to their tyrosine kinase inhibitor regimen. The secondary objective was to identify the influence of patient characteristics on tyrosine kinase inhibitor adherence. METHODS: Cross-sectional retrospective chart and dispensing record reviews were performed to identify patients receiving a tyrosine kinase inhibitor from 1 June 2010 to 31 January 2012. Adherence was evaluated using the medication possession ratio. RESULTS: A total of 124 patients were included. Thirty-eight (31%) patients were non-adherent to their tyrosine kinase inhibitor regimen. Patients not receiving concurrent medications were more likely to be non-adherent (odds ratio (OR) 2.33, 95% confidence interval (CI) 1.05-5.13, p=0.04). The median medication possession ratio was 0.95 (IQR=0.83-1.07). Median medication possession ratio was lower in patients receiving imatinib compared to dasatinib or nilotinib (0.95 vs. 1.00, p=0.01) and in those less than 50 years old compared to those greater than 50 years old (0.92 vs. 0.97, p=0.02). CONCLUSIONS: Optimal tyrosine kinase inhibitor adherence in chronic myeloid leukemia patients poses a significant obstacle in achieving best possible outcomes while reducing healthcare costs. In this study, one in three chronic myeloid leukemia patients treated with a tyrosine kinase inhibitor were non-adherent to their regimen. Those at higher risk of non-adherence were on no concurrent medications, less than 50 years old, and those treated with imatinib. Active intervention to improve tyrosine kinase inhibitor adherence should be developed, implemented, and evaluated to improve patient outcomes at our center.

Classifying cytogenetics in patients with acute myelogenous leukemia in complete remission undergoing allogeneic transplantation: a Center for International Blood and Marrow Transplant Research study.

Cytogenetics play a major role in determining the prognosis of patients with acute myelogenous leukemia (AML). However, existing cytogenetics classifications were developed in chemotherapy-treated patients and might not be optimal for patients undergoing allogeneic hematopoietic cell transplantation (HCT). We studied 821 adult patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) who underwent HCT for AML in first or second complete remission between 1999 and 2004. We compared the ability of the 6 existing classifications to stratify patients by overall survival. We then defined a new scheme specifically applicable to patients undergoing HCT using this patient cohort. Under this scheme, inv(16) is favorable, a complex karyotype (4 or more abnormalities) is adverse, and all other classified abnormalities are intermediate in predicting survival after HCT (5-year overall survival, 64%, 18%, and 50%, respectively; P = .0001). This scheme stratifies patients into 3 groups with similar nonrelapse mortality, but significantly different incidences of relapse, overall and leukemia-free survival. It applies to patients regardless of disease status (first or second complete remission), donor type (matched related or unrelated), or conditioning intensity (myeloablative or reduced intensity). This transplantation-specific classification could be adopted for prognostication purposes and to stratify patients with AML and karyotypic abnormalities entering HCT clinical trials.

High busulfan exposure is associated with worse outcomes in a daily i.v. busulfan and fludarabine allogeneic transplant regimen.

Low plasma busulfan (Bu) area under the concentration-time curve (AUC) is associated with graft failure and relapsed leukemias, and high AUC with toxicities when Bu is used orally or i.v. 4 times daily combined with cyclophosphamide in myeloablative hematopoietic stem cell transplantation (SCT) conditioning regimens. We report Bu AUC and its association with clinical outcomes in 130 patients with hematologic malignancies given a once-daily i.v. Bu (3.2 mg/kg days -5 to -2) and fludarabine (Flu, 50 mg/m(2) days -6 to -2) regimen. Total-body irradiation (TBI) 200 cGy x 2 was added for 51 patients with acute leukemias. Plasma AUC varied 3.6-fold (2184-7794 microM.min, median 4699 microM.min). Patients with an AUC >6000 microM.min had lower overall survival (OS) than those with AUC < or =6000 microM.min at 12 months (38% versus 74%) and 36 months (23% versus 68%, P < .001). This effect was apparent in patients with standard-risk and high-risk disease, and persisted when potential confounders were considered (hazard ratio 3.2, 95% confidence interval 1.7-6.3). Nonrelapse mortality (NRM) at 100 days (6% versus 19%) and progression free survival (PFS; 58% versus 16%) at 3 years were better with AUC < or =6000 microM.min. These data support a role for therapeutic dose monitoring and dose adjustment with daily i.v. busulfan.