Iland, Harry

AbstractFrontline arsenic trioxide (ATO)–based treatment regimens achieve high rates of long-term relapse-free survival in treating acute promyelocytic leukemia (APL) and form the current standard of care. Refining prognostic estimates for newly diagnosed patients treated with ATO-containing regimens remains important in continuing to improve outcomes and identify patients who achieve suboptimal outcomes. We performed a pooled analysis of exclusively ATO-treated patients at a single academic institution and from the ALLG APML4 and Alliance C9710 studies to determine the prognostic importance of additional cytogenetic abnormalities and/or complex karyotype. We demonstrated inferior event-free survival for patients harboring complex karyotype (hazard ratio [HR], 3.74; 95% confidence interval [CI], 1.63-8.56; P = .002), but not for patients harboring additional cytogenetic abnormalities (HR, 2.13; 95% CI, 0.78-5.82; P = .142). These data support a role for full karyotypic analysis of all patients with APL and indicate a need for novel treatment strategies to overcome the adverse effect of APL harboring complex karyotype.

Abstract Background Acute promyelocytic leukemia (APL) is commonly complicated by complex coagulopathy. The early use of all-trans retinoic acid (ATRA) appears to have reduced induction mortality; however, with modern regimens the risk of early hemorrhagic death remains at about 5-10% in clinical trials and up to 30% in population-based studies. Previously identified as markers of bleeding risk in this setting are: white blood cell count (WBC), peripheral blood blast count, platelet count, fibrinogen, prothrombin time (PT), activated partial thromboplastin time (aPTT) and creatinine. Nonetheless, uncertainty remains as to which ones are independent predictors. Materials and Methods The database for study was from APL patients enrolled on three large clinical trials that used ATRA for induction: APML3 (single arm of ATRA + idarubicin ± prednisone), APML4 (single arm of ATRA + idarubicin + arsenic trioxide + prednisone) and ECOG 2491 (intergroup I0129, consisting of daunorubicin + cytarabine vs ATRA). Known determinants of bleeding were assessed at baseline and considered as potential predictors of hemorrhagic death in the first 30 days of induction. In univariate analysis, using Wilcoxon Rank Sum and Fisher’s exact test, we looked at the association of the parameters mentioned above with hemorrhagic death within 30 days of induction. Results A total of 619 patients were enrolled: ECOG 2491 (intergroup I0129) - 394, APML3 - 101, and APML4 -124. Among these, thirty (4.8%) deaths from bleeding during the first 30 days (early deaths, ED) following induction were recorded. Baseline characteristics of the patients are shown in Table 1 and Table 2. Initial coagulation parameters (PT, aPTT and fibrinogen) were not available for the ECOG trial. Parameters with significant differences between the ED cases and the remaining of the cohort included WBC (median: 7.4 vs 2.4 /Kmcl respectively, p<0.001), peripheral blood blast count (median: 1.0 vs 0.2 /Kmcl respectively, p=0.049) and platelet count (median: 20 vs 33 /Kmcl respectively, p=0.002). Conclusions In this large cohort of approximately 600 APL patients enrolled on 3 large clinical trials, higher WBC, peripheral blast count and lower platelet count emerged as univariate predictors of early hemorrhagic death. Surprisingly, age, PT, aPTT, fibrinogen and creatinine clearance did not differ between the patients who died from bleeding and the remaining of the cohort. Multivariate analysis will clarify the relative strength of the significant predictors in assessing ED, and will be available, along with coagulation parameters for ECOG, at the time of presentation. These data hopefully will allow us to build a clinical prediction rule to identify patients at the highest risk of early hemorrhagic death. Such a stratification tool could prove useful in future trials testing novel approaches to treat the coagulopathy associated with APL. : Abstract 948. Table 1 Baseline Characteristics of Patients, Continuous Variables Variable Total Death from Bleeding within 30 days No Yes N Median (IQR) N Median (IQR) N Median (IQR) p-value Age (years) 619 40.0 (26.0 - 54.0) 589 40.0 (26.0 - 54.0) 30 47.0 (26.0 - 63.0) 0.15 White Blood Cell Count (K/mcL) 611 2.5 (1.2 - 8.2) 582 2.4 (1.1 - 7.6) 29 7.4 (3.1 - 20.7) <0.001 Peripheral blood blast count (K/mcL) 581 0.2 (0.0 - 2.2) 552 0.2 (0.0 - 1.9) 29 1.0 (0.1 - 5.7) 0.049 Hemoglobin (g/dL) 615 9.3 (8.0 - 10.5) 585 9.3 (7.9 - 10.5) 30 9.4 (8.2 - 10.7) 0.75 Platelets (K/mcL) 615 31.0 (17.0 - 56.0) 585 33.0 (17.0 - 57.0) 30 20.0 (13.0 - 34.0) 0.002 Prothrombin time (s) 184 16.0 (13.3 - 18.2) 179 16.0 (13.3 - 18.1) 5 16.7 (16.5 - 144.3) 0.15 Activated partial thromboplastin time (s) 225 29.0 (26.0 - 32.0) 216 29.0 (26.0 - 32.0) 9 31.2 (29.0 - 38.0) 0.07 Fibrinogen (mg/dL) 217 1.8 (1.3 - 2.6) 208 1.8 (1.3 - 2.6) 9 2.3 (2.0 - 2.5) 0.36 Creatinine Clearance (mg/dL)* 225 389 (261.2 - 511.6) 216 392 (264.9 - 512.4) 9 262 (219.2 - 432.0) 0.15 *calculated using the Jelliffe formula : Table 2 Baseline Characteristics of Patients, Categorical Variables. Variable Total Death from Bleeding within 30 days No Yes N % N % N % p-value ECOG Performance Status 579 93.54 552 93.72 27 90.00 0.50 Good(0-2) Poor(3-4) 36 5.82 33 5.60 3 10.00 Missing 4 0.65 4 0.68 0 0 FAB Classification 248 40.06 239 40.58 9 30.00 >0.95 M3 M3v 67 10.82 65 11.04 2 6.67 Missing 304 49.11 285 48.39 19 63.33 Disclosures No relevant conflicts of interest to declare.

Key Points High WBC is an independent predictor of early HD in APL.