t(8;21) Acute Myeloid Leukemia (AML) Differs from inv(16) AML in Pretreatment Characteristics, Outcome and Prognostic Factors Predicting Outcome: A Cancer and Leukemia Group B (CALGB) Study.
Authors: Marcucci Guido , Mrózek K. , Ruppert A. S. , Maharry K. , Kolitz J. E. , Mayer R. J. , Pettenati M. J. , Powell B. L. , Edwards C. G. , Sterling L. J. , Vardiman J. W. , Schiffer C. A. , Carroll A. J. , Larson R. A. , Bloomfield C. D. 
Published: October 2019

Since t(8;21) and inv(16) disrupt core binding factor in AML and confer a favorable prognosis, these cytogenetic groups are often treated similarly, but hitherto have not been compared in a large study. We compared 144 adult AML patients (pts) with t(8;21) with 168 with inv(16) enrolled on the cytogenetic study CALGB 8461. t(8;21) pts were less frequently white (P=.01), had lower hemoglobin levels (P=.03), WBC (P<.001) and % blood (P<.001) and BM blasts (P=.005), and had more frequently secondary chromosome aberrations (P<.001) than inv(16) pts, who more often had extramedullary disease (P<.001). Pts were induced with cytarabine/daunorubicin (AD) or cytarabine/daunorubicin/etoposide ±PSC833(ADE±P). Complete remission (CR) was achieved by 89% of t(8;21) and 87% of inv(16) pts. Upon multivariable analysis (MVA), non-white race (P=.006), lower platelets (P=.01) and higher BM blasts (P=.004) predicted negatively for CR in t(8;21), and lower platelets (P=.009) and hepatomegaly (P=.04) in inv(16) pts. Non-whites with t(8;21) had 5.7 times the odds of not achieving CR as whites. For the entire group (median follow-up 6.4 yrs), the estimated 5-yr overall survival (OS) and cumulative incidence of relapse (CIR) were 51% and 53%, respectively. Pts with t(8;21) showed a trend for shorter OS (46% vs 54%; P=.17) but no difference in CIR compared with inv(16) pts. Upon MVA, t(8;21) pts had worse OS than inv(16) pts (HR 1.5; P=.04), once adjusting for age, platelets, and WBC. Following first relapse, the 5-yr survival of t(8;21) pts (n=58) was shorter than that of inv(16) pts (n=74) (14% vs 36%; P=.01); in an age-adjusted model, the risk of death was 1.8 times higher for t(8;21) pts (P=.005). In a subanalysis of pts <60 yrs, consolidation therapy with multi-course high-dose cytarabine (HDAC x3 or 4) significantly decreased CIR compared to single-course HDAC (x1) in t(8;21) (5-yr CIR, 35% vs 64%; P=.005) and inv(16) (5-yr CIR, 44% vs 70%; P =.03) pts. Upon MVA, consolidation with multi-course HDAC reduced CIR for both t(8;21) and inv(16), but other prognostic factors differed (see Table). For t(8;21), induction with ADE±P and higher platelets increased risk of relapse. However, relatively few pts received ADE±P so its prognostic impact requires confirmation. For inv(16), +22 and other secondary cytogenetic aberrations, and male sex were favorable prognostic factors.

Multivariable analysis (MVA) for CIR in pts <60 yrs achieving CR on CALGB 8221, 8525, 9022, 9222, 9621

Variable t(8;21) HR (95% CI); P inv(16) HR (95% CI); P HR=Hazard Ratio, CI=confidence intervals —, not included in final model Consolidation:Single vs multi-course HDAC 4.5 (2.1-9.4); <.001 3.4 (1.7-6.6); <.001 Induction:ADE±P vs AD 2.6 (1.1-5.9); .02 1.4 (0.6-3.2); .41 log(platelets) 1.8 (1.2-2.9); .007 — Secondary cytogenetics — 0.2 (<0.1-0.5); .002 Male vs Female — 0.5 (0.3-0.9); .03

In summary, once pretreatment factors and therapy are considered, the outcome of t(8;21) AML appears inferior to that of inv(16). Although these data should be confirmed prospectively, our analysis suggests that future studies should report the outcomes of pts with t(8;21) and inv(16) separately, and seek to identify and target therapeutically leukemogenic mechanisms accountable for these clinical differences.