Unsatisfactory efficacy in randomized study of reduced-dose CPX-351 for medically less fit adults with newly diagnosed acute myeloid leukemia or other high-grade myeloid neoplasm

Abstract

. Unsatisfactory efficacy in randomized study of reduced-dose CPX-351 for medically less fit adults with newly diagnosed acute myeloid leukemia or other high-grade myeloid neoplasm. Haematologica. 2017; 102:xxx doi:10.3324/haematol.2017.182642 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process. LETTER TO THE EDITORThe need for new therapies for medically less-fit adults with acute myeloid leukemia (AML) is unquestioned. 1 CPX-351, a liposomal formulation of cytarabine and daunorubicin, 2 may be an attractive option. In patients with relapsed/refractory leukemia, in whom CPX-351 was administered on days 1, 3, and 5 of a treatment cycle, a maximum tolerated dose (MTD) of 101 units/m 2 was identified, but responses were seen with doses as low as 32 units/m 2 . 3 In a subsequent study in fit adults age 60-75 years with newly diagnosed AML who were randomized 2:1 between CPX-351 (100 units/m 2 ) and 7+3, 60-day mortality was lower with CPX-351 (4.7% vs. 14.6%, p=0.053) while response rates were higher (66.7% vs. 51.2%, p=0.07). 4 Pre-planned subset analyses indicated improved survival in patients with secondary leukemias. 4 These observations prompted us to conduct a randomized phase 2 trial (ClinicalTrials.gov: Because of the small sample size, randomization was stratified using a dynamic allocation scheme 11 based on: 1) TRM score (13.1-22.8 vs. >22.8); 2) cytogenetic risk (monosomal karyotype vs. other unfavorable vs. intermediate/favorable); and 3) presence/absence of secondary disease. For each dose, we used a Bayesian design that adaptively monitored response (CR achievement) and toxicity (death by day 28, excluding deaths due to progressive disease and no treatment-related toxicity). 12 Prior probabilities of response and toxicity for standard (historical) treatment and the experimental (CPX-351) treatment were defined using a beta distribution. For standard, we used β(30, 70) for response and toxicity, corresponding to CR and TRM rates of 30% in 100 patients. For CPX-351, we used β(0.6, 1.4) for response and toxicity, corresponding to CR and TRM rates of 30% in 2 patients. This non-informative distribution allows the current ("posterior") probability distributions to be dominated by the trial data. In each arm of this trial, patients were treated in cohorts of size 5. A minimum number of 20 patients were randomized before an arm was considered for ea...

A comparison of patients with acute myeloid leukemia and high-risk myelodysplastic syndrome treated on versus off study

“…We performed a trial with reduced doses of CPX-351 for patients with a high TRM score (≥13.1, which corresponds roughly to a 13% chance of dying in the first 28 days after induction), which showed minimal efficacy without adequate improvement in toxicity. [22] An ongoing study at our center randomizes patients with a similarly high TRM score to full-dose G-CLAM or reduced-dose G-CLAM (NCT03012672). Additionally, a recent provocative study from MD Anderson Cancer Center specifically enrolled patients who did not meet eligibility criteria for other trials, demonstrating that treatment of such "ineligible" patients was feasible.…”

Low-intensity regimens versus standard-intensity induction strategies in acute myeloid leukemia

“…Walter and colleagues evaluated the use of reduced doses of CPX-351 (32 or 64 units/m 2 ) in patients with comorbidities and found that a reduction of treatment-related mortality could not be achieved while maintaining the CR rate. 22 For patients who achieve CR, the administration of additional chemotherapy is generally deemed necessary, although no standard postremission therapy has been established thus far. The ALFA-9803 trial compared the administration of one course of intensive consolidation (daunorubicin 45 mg/m 2 /day or idarubicin 9 mg/m 2 for 4 days in combination with cytarabine 200 mg/m 2 IV for 7 days) with repeated cycles of less-intensive consolidation courses (either 45 mg/m 2 daunorubicin or 9 mg/m 2 idarubicin for 1 day in combination with 60 mg/m 2 /12 h cytarabine for 5 days), in elderly patients (age > 50 years) in first CR.…”

“…Walter and colleagues evaluated the use of reduced doses of CPX-351 (32 or 64 units/m 2 ) in patients with comorbidities and found that a reduction of treatment-related mortality could not be achieved while maintaining the CR rate. 22…”

Determination of fitness and therapeutic options in older patients with acute myeloid leukemia

“…Although CPX‐351 has primarily been studied as intensive chemotherapy, a phase 2 study evaluated lower‐intensity doses of CPX‐351 in adults with newly diagnosed AML who were considered less fit and had a composite treatment‐related mortality score of >13.1 (corresponding to a >13.1% probability of death within 28 days of receiving intensive chemotherapy) 64 . Among patients who received CPX‐351 32 units/m 2 /dose (n = 38) and 64 units/m 2 /dose (n = 10), respectively, the CR + CRi rates were 29% and 20%, 12‐month OS rates were 17% and 20%, and early mortality rates within 28 days were 29% and 40% 64 . An ongoing clinical trial is also evaluating lower‐intensity CPX‐351 plus venetoclax in adults considered unfit for intensive therapy (http://clinicaltrials.gov Identifier NCT04038437).…”