The DECIDER trial was designed to address whether the add-on of VPA or ATRA would increase the overall response rate (ORR), overall (OS), and event-free survival (EFS). The results demonstrated a higher ORR and prolonged OS with ATRA but not VPA [2]. Prompted by the case described here, we analyzed all patients treated on the DECIDER trial who lived for more than 5 years from start of treatment. Of a total of 6 patients (last follow-up 04/2021), only one other patient had received continuous study treatment (39 cycles of DAC + VPA), the other patients had received an allogeneic stem cell transplantation (n = 3), or 7 + 3 salvage for early progressive disease (n = 1, ELN favorable risk). Conducting a PubMed-based literature search for the maximum number of HMA-cycles administered and reported in large phase II/III AML trials and a case series of HMA long-term responders, we could not identify a patient having received more than 49 treatment cycles. [1, 3,4,5,6,7] (Additional file 1: Table S1) These results confirm that the presented case with 52 cycles is indeed exceptional.

The continuous application of ATRA over 5 years, at the daily dose administered intermittently in acute promyelocytic leukemia (APL), led to a much greater cumulative drug exposure than that administered in APL. Notably, we observed a very good drug tolerability without ATRA-related toxicities. The DECIDER study demonstrated a good feasibility and safety of the combination DAC + ATRA in the clinical setting [7]. Furthermore, significantly improved survival across risk groups and higher objective response rates were observed for the combination of DAC + ATRA compared with the no-ATRA groups, without added toxicity [2]. The addition of ATRA is most likely impeding the development of secondary resistance to HMAs, possibly through reactivation of ATRA signaling. [2], [8] The currently recruiting DECIDER-2 phase III trial has the objective to compare the efficacy of ATRA versus placebo as add-on to DAC + VEN (DECIDER-2, AMLSG 32–21).

Regarding clonal evolution, apart from the initial del(5q), no further aberrations were detected by FISH at the time of transformation to AML; however, 2.7 years later a new clone, which harbored a trisomy 8, emerged. One year before the patient deceased, a new mutation in ETV6 (p.Y104Pfs*24) was detected. These findings led us to speculate that the combination of DAC + ATRA decelerated the acquisition of new mutations, i.e., “stabilized” the leukemic clone. At time of fully established secondary HMA resistance (5.3 years from AML diagnosis), a KRAS mutation had been newly acquired (see below). The acquisition of mutations in KRAS in a subset of patients at secondary resistance to HMA has been described previously [9]. Whether this mutation solely, or to what extent the remaining changes in the mutational profile contributed to the secondary resistance is unknown.

In addition to the aforementioned analyses, WES was conducted on blood samples of the patient collected at the time of diagnosis and shortly before she deceased. In total, the AML had gained or lost 1.45 variants/megabase [10]. In order to identify likely pathogenic variants, we focused on cancer genes as defined by OncoKB. The AML had overall gained 4 mutations in cancer genes: ETV1 (p.R405H, VAF 30.4%), KRAS (p.G12A, VAF 27.9%), PARP1 (c.2277 + 1G > C, VAF 7.5%), and ETV6 (p.I358M, VAF 5.3%). (Fig. 1C) Interestingly, the ETV6 mutation was not identical with the previously detected mutation in exon3 at 4.2 years, probably underlining the pressure on the clonal selection of an ETV6 mutant leukemic cell. ETV1 and PARP1 were not covered by the NGS at 4.2 years, while KRAS was in wild-type configuration. Thus, we cannot conclude the time of acquisition of ETV1 and PARP1 mutation during the disease course, but the AML had acquired a KRAS mutation toward resistance. The AML also lost mutations in cancer genes toward the end of treatment in comparison with initiation, e.g., in IL3 (p.P27S, VAF 9.3%) and NCOR2 (p.G1830delinsSSGG, VAF 19.6%).

In the decision-making process, we integrated the patient’s priorities and available therapy options, which resulted in more than 5 years OS, with a total of 43 days spent overnight in the hospital and 231 days of outpatient visits for therapy administration, transfusions, or ambulatory check-ups. This case is an example for successfully minimizing the treatment-associated time burden (“time toxicity”) resulting from hospital stays, which is a relevant factor defining quality-of-life for patients in a palliative setting [11]. Of note, this patient’s marked clinical benefit derived from the DAC + ATRA combination treatment (arm C of the DECIDER trial) over years is reflective of the two-year survival probability of all patients on this treatment arm of 25%, which compares favorably to the two-year survival rate of patients in arm A (decitabine-only, < 5%).

In summary, we report on a patient with several high-risk features (secondary AML, adverse genetics, older age) and an above-average survival treated with the combination therapy of HMA + ATRA, continuously administered over 52 cycles. The rate of side effects was kept to a minimum, and quality of life was maintained until weeks before the patient deceased. This case is important as older patients with AML—even in the era of HMA combination therapies—still have a dismal prognosis if allografting is not an option, so the stabilization of their quality of life is one of the central treatment goals.