We have previously shown that complete response (CR) rates and overall survival of patients with acute myeloid leukemia have improved since the 1980s. However, we have not previously evaluated how the length of first CR (CR1) has changed over this time period. To address this, we analyzed 1,247 patients aged 65 or younger randomized to "7+3" arms from five SWOG studies: S8600 (n=530), S9031 (n=98), S9333 (n=57), S0106 (n=301), and S1203 (n=261). We evaluated length of CR1 and survival after relapse from CR1 over the four decades that these studies represent. Both length of CR1 and survival after relapse from CR1 have improved over the last four decades. The relative benefit associated with CR1 and the relative detriment associated with relapse have decreased over this period; while achieving CR1 and relapse from CR1 still have strong prognostic associations with outcomes, the magnitude of the association has decreased over time. Possible explanations for these patterns include higher CR rates with salvage therapies after relapse, more frequent use of hematopoietic cell transplant, and better supportive care.
We have previously shown that the early mortality, complete remission (CR) rates, and overall survival of patients with acute myeloid leukemia (AML) treated with cytarabine (ara-C) and an anthracycline (“7+3” regimen) have improved since the 1980s.1 However, we have not previously evaluated how much of the increase in overall survival is due to longer duration of first complete remission (CR1) and how much is due to improved salvage therapies after first relapse, including allogeneic hematopoietic cell transplantation (HCT). Understanding the relative contributions of these two effects should provide insight into the interpretation of past and current studies. This prompted us to evaluate AML clinical trials from the 1980s, 1990s, 2000s, and 2010s to examine whether the length of CR1 and survival after relapse from CR1 have changed over time.
We analyzed 1,247 patients randomized to “7+3” arms in five National Cancer Institute National Clinical Trials Network clinical trials conducted by the SWOG Cancer Research Network. We analyzed patients who were aged 65 and younger from SWOG studies (number of cases; enrollment decade): S8600 (n=530; 1980s), S9031 (n=98; 1990s), S9333 (n=57; 1990s), S0106 (n=301; 2000s), and S1203 (n=261; 2010s).2-6 S9031 and S9333 were analyzed together. In each trial, the “7+3” regimen was given per contemporary standard, which changed over time. In S8600, S9031, and S9333, the ara-C and daunorubicin doses were 200 mg/m2 and 45 mg/m2 respectively, in S0106 the doses were 100 mg/m2 and 60 mg/m2, and in S1203 the doses were 100 mg/m2 and 90 mg/m2. Consolidation chemotherapy varied over time per contemporary practice, with protocols S9031 and S9333 specifying two cycles of consolidation therapy with ara-C and daunorubicin doses of 200 mg/m2 and 45 mg/m2, respectively; protocols S0106 and S1203 specified three and four cycles, respectively, of 3,000 mg/m2 of ara-C and no daunorubicin; protocol S8600 included a consolidation randomization between up to two cycles of the contemporary standard ara-C and daunorubicin doses of 200 mg/m2 and 45 mg/m2 versus 2,000 mg/m2 and 30 mg/m2. HCT was not specified as a component of protocol therapy (with associated data collected) except in the most recent trial S1203. The institutional review boards of the participating institutions approved all protocols, and patients were treated according to the Declaration of Helsinki.
CR was defined morphologically and required full recovery of absolute neutrophil counts and platelets (>1x109/L and >100x109/L, respectively).4 Overall survival was measured from the date of study registration/randomization to date of death due to any cause; patients last known to be alive were censored at the date of last contact. Relapse-free survival was measured for patients who achieved CR from the date of CR to the first of relapse from CR or death from any cause, with patients last known to be alive censored at the date of last contact. Time to relapse was measured for patients who achieved CR1 from the date of CR1 to relapse, with death without relapse considered a competing risk. Endpoints were not censored at the time of a transplant. Overall and relapse-free survival were estimated using the Kaplan-Meier method. Time to relapse was estimated by cumulative incidence curves and multivariable associations were evaluated by Fine and Gray subdistribution hazard models.7 Among patients who achieved CR1, the percent in CR1 without relapse was summarized at landmark times in 6-month increments between 6 months and 3 years after CR1. Time-dependent Cox regression models for overall survival and relapse-free survival were fitted with CR1 and relapse from CR1 as time-dependent covariates. Multivariable regression models included the following covariates (modeled quantitatively unless otherwise specified): age at study registration, gender (male vs. female), cytogenetic risk (favorable vs. intermediate vs. high vs. missing), prestudy white blood cell counts, pre-study platelet counts, pre-study marrow blast percentages, secondary AML (vs. de novo AML), indicator of receiving reinduction, and decade/study.
Characteristics of the cohorts
Table 1 summarizes the patients’ characteristics from the studies as analyzed by decade. Trials S9031 and S9333 (completed in the 1990s) were restricted to patients aged 55 and older; the other studies included patients aged 18 and older. The proportion of patients with performance status 2 and higher has decreased over time, particularly comparing studies conducted in the 1980s and 1990s (S8600, S9031/S9333) with those conducted in the 2000s and 2010s (S0106, S1203). Patients with secondary AML were not eligible for S0106, which compared “7+3” to “7+3” plus gemtuzumab ozogamicin.
Outcome paterns over time
Overall survival after CR1 increased over the time period analyzed here (Figure 1), as demonstrated also by multivariable regression models (Table 2), with a multivariable hazard ratio (HR) of 0.43 (95% confidence interval [95% CI]: 0.34-0.53, P<0.0001) for patients treated since year 2000 compared to patients treated before year 2000. Among patients who achieved CR1, there were fewer relapses and a longer time to relapse among patients treated since 2000 (Figure 2), also in multivariable regression models (Table 2), with a multivariable HR of 0.40 (95% CI: 0.31-0.51, P<0.0001) taking before year 2000 as the reference. Among patients who relapsed after CR1, those treated since year 2000 had a significantly longer overall survival after relapse compared to those treated before year 2000 (Figure 3), also in multivariable modeling (Table 2): HR=0.43, 95% CI: 0.34-0.52, P<0.0001.
Figure 4 and Table 3 summarize the percentage of patients, from among the patients who achieved CR1, who were in continuous CR1 at the landmark times. In multivariable models (data not shown), the probability of being alive without relapse was higher at all landmark times for patients treated since year 2000 compared to patients treated before year 2000.
Relative benefit of complete remission and relative detriment of relapse over time
Over the four decades analyzed, achieving CR1 was associated with a large benefit in overall survival (HR=0.06, 95% CI: 0.04-0.10 before year 2000; HR=0.16, 95% CI: 0.11-0.23 since year 2000), although the magnitude of benefit was less extreme for patients treated since 2000 (in other words the HR for since year 2000 was significantly closer to 1 than the HR for before year 2000, interaction P=0.001). Similarly, relapsing from CR1 was associated with a large decrement in overall survival across all the decades analyzed (HR=16.6, 95% CI: 11.0-24.1 for before year 2000; HR=10.1, 95% CI: 7.0-14.7 for since year 2000), although there was some evidence that the magnitude of decrement was less for patients treated since 2000 (in other words the HR for after 2000 was significantly closer to 1 than the HR for before 2000, interaction P=0.079).
In the cohorts of patients studied here, overall survival for AML improved drastically over the last four decades, and this improvement was observed in all the intermediate endpoints we evaluated: early death rates, CR1 rates, length of CR1/time to relapse, relapse rates, and overall survival after relapse from CR1.
Reasons for improved outcomes are plausibly related to higher chemotherapy doses,8-10 improved antibiotics, more use of allogeneic HCT,11,12 and incorporation of novel agents (including gemtuzumab ozogamicin and FLT3 inhibitors) in the upfront, refractory, and salvage settings. These same reasons for improved survival may also explain why the relative benefit of achieving CR1 and the relative decrement from relapse from CR1 are less extreme among patients who were treated after year 2000 compared to patients treated before year 2000. We recognize that the lack of HCT data from older studies confounds these analyses, in particular the length of CR1. Without HCT data we cannot separate out the specific role of HCT in these changing trends over time.
The characteristics of patients treated with the “7+3” regimen on these trials changed over time, even though eligibility criteria were stable across time with the exception of age (as noted above in the Methods section) and secondary AML patients being ineligible for S0106. On average the proportion of lower-risk patients increased, possibly reflecting the availability of less intense therapies, in particular azacitidine and decitibine after year 2000 and introducing the possibility of increased selection bias in later years. Although we present regression results from multivariable models, these models can only account for the covariates that are available in the datasets analyzed. Notably, HCT rates increased over the period analyzed and this post-remission therapy could not be analyzed statistically because rates of HCT were so low in the trials before year 2000 and data on HCT were not collected in the established trial forms. It should also be noted that “7+3” therapy changed over time; doses of both drugs changed over time as noted in the Methods section. The multivariable analysis cannot adjust for factors perfectly confounded with study/decade, such as changes in doses of therapy, to tease out individual contributions.-
Only since the 2000s have response criteria such as CR with incomplete platelet recovery, CR with incomplete hematologic recovery, morphological leukemia-free state, and CR with partial hematologic recovery been introduced and it will be interesting to examine their effects on survival relative to that of CR as contemporary trials mature and longer-term analysis of their outcomes becomes feasible.13
- Received January 27, 2022
- Accepted July 6, 2022
No conflicts of interest to disclose.
MO designed research, analyzed the data, and wrote the paper. GGM, JEG, JKW, FRA, HPE, and EHE designed research and wrote the paper.
The analyzed dataset can be requested following SWOG data-sharing procedures: https://www.swog.org/sites/default/files/docs/2019-12/Policy43_0.pdf. Questions may be directed to the author for correspondence.
This investigation was supported in part by the following PHS/DHHS grants awarded by the National Cancer Institute, National Clinical Trials Network to SWOG: U10CA180888 (Principal Investigator, C.D. Blanke) and U10CA180819 (Principal Investigator, M. Leblanc).
The authors gratefully acknowledge the important contributions of the late Dr. Stephen H. Petersdorf to SWOG and to study S0106.
- Othus M, Kantarjian H, Petersdorf S. Declining rates of treatment-related mortality in patients with newly diagnosed AML given ‘intense’ induction regimens: a report from SWOG and MD Anderson. Leukemia. 2014; 28(2):289-292. https://doi.org/10.1038/leu.2013.176PubMedPubMed CentralGoogle Scholar
- Weick JK, Kopecky KJ, Appelbaum FR. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood. 1996; 88(8):2841-2851. https://doi.org/10.1182/blood.V88.8.2841.bloodjournal8882841Google Scholar
- Godwin JE, Kopecky KJ, Head DR. A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study (9031). Blood. 1998; 91(10):3607-3615. https://doi.org/10.1182/blood.V91.10.3607.3607_3607_3615Google Scholar
- Cheson BD, Bennett JM, Kopecky KJ. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003; 21(24):4642-4649. https://doi.org/10.1200/JCO.2003.04.036PubMedGoogle Scholar
- Petersdorf SH, Kopecky KJ, Slovak M. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013; 121(24):4854-4860. https://doi.org/10.1182/blood-2013-01-466706PubMedPubMed CentralGoogle Scholar
- Garcia-Manero G, Othus M, Pagel JM. SWOG S1203: a randomized phase III study of standard cytarabine plus daunorubicin (7+3) therapy versus idarubicin with high dose cytarabine (IA) with or without vorinostat (IA+V) in younger patients with previously untreated acute myeloid leukemia (AML). Blood. 2016; 128(22):901. https://doi.org/10.1182/blood.V128.22.901.901Google Scholar
- Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999; 94(446):496-509. https://doi.org/10.1080/01621459.1999.10474144Google Scholar
- Fernandez HF, Sun Z, Yao X. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009; 361(26):1249-1259. https://doi.org/10.1056/NEJMoa0904544PubMedPubMed CentralGoogle Scholar
- Rowe JM, Tallman MS. Intensifying induction therapy in acute myeloid leukemia: has a new standard of care emerged?. Blood. 1997; 90(6):2121-2126. https://doi.org/10.1182/blood.V90.6.2121Google Scholar
- Büchner T, Urbanitz D, Hiddemann W. Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): two multicenter studies of the German AML Cooperative Group. J Clin Oncol. 1985; 3(12):1583-1589. https://doi.org/10.1200/JCO.19188.8.131.523PubMedGoogle Scholar
- McDonald GB, Sandmaier BM, Mielcarek M. Survival, nonrelapse mortality, and relapse-related mortality after allogeneic hematopoietic cell transplantation: comparing 2003–2007 versus 2013–2017 cohorts. Ann Intern Med. 2020; 172(4):229-239. https://doi.org/10.7326/M19-2936PubMedPubMed CentralGoogle Scholar
- Gooley TA, Chien JW, Pergam SA. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010; 363(22):2091-2101. https://doi.org/10.1056/NEJMoa1004383PubMedPubMed CentralGoogle Scholar
- Döhner H, Estey E, Grimwade D. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017; 129(4):424-447. https://doi.org/10.1182/blood-2016-08-733196PubMedPubMed CentralGoogle Scholar
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