Effect of haematological improvement on survival in patients given targeted therapy as initial treatment of acute myeloid leukaemia or high‐risk myelodysplastic syndrome

The limited effectiveness and excess toxicity of standard chemotherapy in older patients with untreated acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS) have prompted the use of agents thought to specifically target malignant blasts (Tallman et al, 2005; Kolitz, 2006). New response categories for such targeted therapy (TT) have been promulgated, for example ‘haematological improvement (HI)’ (Cheson et al, 2006), the criteria, for which are less stringent than those for traditional complete remission (CR). However, whereas the ability of CR to prolong survival is well-known (Freireich et al, 1961), the effect of HI on survival is uncertain. Here, we compare subsequent survival in patients with newly diagnosed AML or high-risk MDS according to whether, TT produced HI but not CR, or produced neither HI nor CR. In our study, 180 patients with AML or high-risk MDS (10–19% blasts) (Greenberg et al, 1997) received TT as initial treatment at the M.D. Anderson Cancer Center between 2000 and 2006, generally, because they were aged 60 years or older. Treatment-related death occurred in 11%, CR in 28%, CR with incomplete platelet recovery (CRp) in 6%, and the remaining 55% (99 patients) were judged ‘resistant’. Given the overlap between AML and high-risk MDS (Harris et al, 1999), we examined, survival in these 99 patients according to whether TT produced HI, as defined by the International Working Group (IWG) for MDS (Cheson et al, 2006). The 99 patients had a median age of 74 years, 55% had MDS and 25% had a documented abnormality in blood count for ‡1 month before M.D. Anderson presentation (antecedent haematological disorder, AHD), and 35% had abnormalities involving chromosomes 5 and/or 7 ()5/)7); only eight were under 75 years of age without an AHD or )5/)7. Thirty-one patients received decitabine as initial treatment, 14 received PKC412 (a FLT3 inhibitor), eight received 5-azacytidine/valproic acid/all-trans retinoic acid, eight received AG-013736 (a multiple-receptor tyrosine kinase inhibitor), five received imatinib/cytarabine, four received tipifarnib (a farnesyl transferase inhibitor), four received avandia (a peroxisome proliferators-activated receptor gamma agonist)/targretin (a selective retinoic acid X receptor agonist) and 11 agents each given to less than four patients. Targeted therapy produced HI in 32 of the 99 patients. In our initial analysis, we, unlike the IWG, did not require a minimum duration of HI; in subsequent analyses, we required minimum durations of 8 weeks (according to the IWG), and of 4 weeks. Using the 8-week criterion, HI occurred in 13 of the 32 patients, and using the 4-week criterion, HI occurred in 14 patients: erythroid response in seven, platelet response in four, erythroid and platelet response in two and erythroid and neutrophil response in one. The log-rank test was used to compare survival from start of TT in the HI and non-HI groups. However, because time is required to achieve and maintain HI, this approach gives an inherent survival advantage to the HI patients. To reduce this bias we, in addition to comparing survival in all patients, compared survival (1) only in those patients alive at 67 d after starting TT, with 67 d corresponding to the median time needed to observe HI, and (2) only in those patients alive 138 d after starting TT, by that time 75% of the patients achieving HI had performed so. Any effect of HI on survival may have reflected its association with other covariates that themselves influence survival, e.g. age or cytogenetics (Tallman et al, 2005; Estey & Dohner, 2006). Such potential confounding led us to fit a Cox model considering age (as a numerical variable), cytogenetics ()5/)7 versus other), diagnosis (AML versus MDS), haemoglobin, white blood cell count, platelet count, and percentage of blood and marrow blasts (each as a numerical variable), as well as HI versus no HI as potential predictors of survival time. SAS software (SAS Institute, Cary, NC, USA) was used for statistical analyses. The M.D. Anderson Institutional Review Board approved the work, and patients were treated in accordance with the Declaration of Helsinki. Achievement of HI without any requirement for duration (32 patients) was without effect on survival (P 1⁄4 0Æ46). The same was true (P 1⁄4 0Æ71) when the above-noted covariates were included in the Cox model. However, the 13 patients who had HI lasting ‡8-weeks (HI ‡ 8) lived longer (P 1⁄4 0Æ01) than those who did not. To our knowledge, this is the first demonstration that HI, as defined by the IWG (Cheson et al, 2006), is of clinical benefit, as opposed to merely indicating that the treatment producing HI is ‘active’. As there also appeared to be a survival benefit from HI lasting ‡4 weeks (HI ‡ 4) (P 1⁄4 0Æ01, Fig 1), we fitted a Cox model including the covariates noted above in patients who survived at least 67 d. The covariate most associated with longer survival time was HI ‡ 4 [Relative risk (RR) 0Æ34; 95% confidence interval (CI), 0Æ13–0Æ86; P 1⁄4 0Æ02). When HI was ignored, older age (P 1⁄4 0Æ04) and unfavourable cytogenetics (P 1⁄4 0Æ02) were more predictive, suggesting that the population we correspondence