Prediction Of CR On Reinduction In Patients With Newly Diagnosed Acute Myeloid Leukemia Given Intensive Induction Regimens: A Report From SWOG and Cleveland Clinic
Authors: Othus Megan , Sudipto Mukherjee , Sekeres Mikkael A. , Godwin John , Anderson Jeanne E. , Petersdorf Stephen , Appelbaum Frederick R. , Erba Harry P , Estey Elihu H. 
Published: October 2019

Abstract
3+7” (3 days of daunorubicin or idarubicin + 7 of cytarabine) is the most frequently used intensive induction regimen for newly diagnosed AML. While it is common practice to reinduce patients (pts) who do not achieve marrow ablation by day 14 with the same agents, it remains unclear whether any particular disease or treatment-related factors can predict for CR with such a strategy, or can identify pts who should more appropriately be considered to have primary refractory disease at day 14 and treated with different agents.
This analysis was designed to address this question.

Methods
We analyzed 1505 pts given 3+7 on SWOG studies S8600 (n = 534), S9031 (n= 215), S9333 (n = 161), and S0106 (n = 595) and 235 treated at Cleveland Clinic from 2006-2010 of whom 54 were reinduced with anthracycline-based therapy. In the SWOG cohort, 49% of pts achieved CR on course 1. Of the 734 patients who were alive at day 28 but did not achieve CR on course 1, 336 (53%) had received a reinduction course of 3+7. We used multivariate logistic regression to identify covariates associated with achievement of CR to reinduction in these 336 pts. The area under receiver operating characteristic curves (AUC) were used to quantify the effectiveness of the multivariate models at predicting CR in reinduction (AUC 1.0 = perfect prediction, AUC 0.5 = “coin flip”). Numerical covariates examined were [median (range)]: age (51, 15-83), day the first post-induction marrow was examined (hereafter “day 14”, 15, 7-48), day 14 blasts % (20, 0-95), day 14 % cellularity (37, 1-85), and their product (infiltrate, 5, 0-74), change in % blasts from day 1 (-44, -96,50), change in cellularity from day 1 (-5, -99-80), change in infiltrate from day 1 (-2, 93-41), and days from start of course 1 to start of course 2 (21, 13-67). Categorical covariates examined were: pre-treatment performance status (PS, ECOG scale) and pre-treatment cytogenetics (SWOG criteria).

Results
40% of the 336 SWOG pts achieved CR to 3+7 reinduction, while 14% died during the first 28 days following reinduction, and 45% neither died during this time nor achieved CR (resistant). Age was associated with reinduction CR rate (median 47 for CR, 56 for no CR, p<0.001), as was day of reinduction (median 24 for CR, 20 for no CR, p=0.005), cytogenetics (CR rates 75% for favorable, 35% for intermediate, 18% for unfavorable, and 9% for unknown, p=0.04), and AML status (CR rate 42% for de novo and 16% for secondary AML). However, the AUC for age was 0.63, day of second induction was 0.59, cytogenetics was 0.60, and AML status was 0.53. Day 14 marrow blast % was similar in pts who did and did not achieve CR to reinduction (medians 20% and 22% respectively, p = 0.8). Similarly, day 14 cellularity, day 14 infiltrate, change in blast %, cellularity, infiltrate from pretreatment, and day when course 2 began were not associated with reinduction CR rate. On multivariate analysis, none of these covariates nor SWOG protocol was associated with second course CR rate, and the AUC for this multivariate model was only 0.70. There was no evidence that the effects of covariates differed in the different protocols. In the Cleveland Clinic cohort, 53% of pts achieved a CR on their reinduction or 3rd induction course, 11% died during the first 28 days of reinduction, and 33% were resistant. In this cohort, no covariates were associated with CR on reinduction or 3rd induction and AUC values were uniformly low and similar to the SWOG cohort.

Conclusion
In AML pts treated with 3+7 regimens, our findings indicate that bone marrow parameters, specifically day 14 blasts %, marrow cellularity, and treatment-related changes do not predict for subsequent CR with a reinduction Perhaps too few patients not in CR after a first course of 3+7 receive reinduction with 3+7.
ClinicalTrials.gov Identifier: NCT00085709 (others precede registry reporting)

Funding
This work was supported by PHS Cooperative Agreement grants awarded by the National Cancer Institute, CA32102 and CA38926

Disclosures:
No relevant conflicts of interest to declare.