Summary
Purpose
To review data on acute myeloid leukemia (AML) presented at the 2017 meeting of the American Society of Hematology (ASH) and to discuss these data within the framework of future developments for the disease.
Results and conclusion
Data generated by next generation sequencing (NGS) may be used for primary diagnosis, therapy selection and monitoring as well as characterization of persons at risk for AML development. After validation, this method will need to be implemented in general practice in the future. For treatment more targeted therapies—single agent or in combination with standard chemotherapy or low-dose treatment approaches—will become available and complement our armamentarium against AML. Among others interesting targets discussed are FLT-3, IDH1 and 2, BCL-2, MEK, E‑selectin, MDM2 and JAK1. Furthermore, maintenance after induction chemotherapy is again being considered for the management of AML.
Introduction
The development of new substances for the treatment of AML has recently gained momentum; some drugs have already received at least FDA approval or fast track designation which means hope to provide alternative treatment approaches away from the standard “3 + 7” therapy scheme in the future. Therefore, many presentations were devoted to these new substances at the 2017 ASH meeting. In addition, it is hoped to further exploit the data generated using next generation sequencing with the aim to translate knowledge on AML biology into clinical practice.
Next generation sequencing
The method of next generation sequencing (NGS) which is increasingly entering daily routine in many blood diseases allows the examination of the detailed genetic background of diseases in individual patients. As biology and genetics of AML are known to be heterogeneous, this is of particular interest. In addition, AML typical changes were demonstrated in several studies to occur also in (yet) healthy individuals with increasing age [1]. Although much must remain open at this time point, according to data presented from cohort studies at ASH, there are already clear indications that different genetic patterns are associated with a higher risk of progression, and that various AML-inducing factors may have typical NGS signatures at the onset of the disease [2, 3].
A further application for NGS could be anticipated in the prediction of response to specific therapies in the future: preliminary data on response to classical chemotherapy, hypomethylating agents and stem cell transplantation were presented [4,5,6].
Special interest received a late breaking abstract (LBA 5) reporting a HOVON SAKK trial, which dealt with the application of NGS for diagnosis of minimal residual disease [7]. Overall, 51.4% of 482 AML patients under 65 years of age in morphological complete remission after induction chemotherapy had one or more detectable persistent mutations in NGS analysis. In contrast to the persistent clonal hematopoieses (characterized by DNMT3, TET2 or ASXL1 mutations) residual leukemia marked by other mutations was associated with relapse.
Treatment with targeted therapies
FLT3
Midostaurin targeting FLT3, meanwhile also approved in Europe, was the subject of multiple abstracts: a subgroup analysis of the pivotal RATIFY study on the different FLT3 genotypes showed favorable outcome for ELN 2017 very good risk patients (NPM1/FLT3-ITDlow) [8]. In long-term results, these patients are likely to remain in remission without allogeneic transplant and may therefore not benefit from such an approach. In addition the bad prognosis of high-risk genetic variants could at least partly be overcome by using midostaurin in combination with allogeneic transplantation.
A further subgroup analysis of the RATIFY trial could not convincingly show a possible benefit of maintenance treatment with midostaurin for methodological reasons because allogeneically transplanted patients did not receive maintenance and went off study [9]. Generally, there is the impression that the effect of additional midostaurin as a supplement to classic AML therapy is largest in early stages of therapy.
Data on alternative FLT 3 inhibitors such as sorafenib, crenolanib, gilteritinib, and quizartinib were also reported at ASH [10,11,12,13]. Currently, it remains open whether a possible greater potency of more selective inhibitors is clinically relevant—i. e., whether higher response rates reported can be translated into survival advantage. On the other hand, the less selective multikinase inhibitors such as sorafenib or midostaurin may have also a role in FLT3-wild-type AML, a hypothesis which still remains to be tested.
IDH
The IDH-2 inhibitor enasidenib (formerly AG-221) is now approved by the FDA, while for IDH-1 mutant patients ivosidenib (formerly AG-120) is being developed. Experience as monotherapy in relapsed or refractory patients updated at ASH confirms clinical activity for this setting: total response rates around 40%, complete remission (CR) rates around 20%, long-running remissions in cases of “only” hematologic improvement and acceptable toxicity with the particularity of a well-controllable differentiation syndrome [14]. Ongoing studies presented at ASH dealt with first-line treatment with enasidenib in the monotherapy setting [15] and the two inhibitors in combination with induction chemotherapy or azacytidine [16, 17]. Combinations seem to be feasible, but at this time point no reliable efficacy results are available. Specific open questions that remain are which backbone in the combination is actually clinically useful, or specifically which for which patient. For the monotherapy predictive markers would be desirable as responses may occur only after longer treatment periods.
BCL-2
The specific BCL-2 inhibitor venetoclax approved for lymphoma is also being investigated in AML.
Very encouraging data in first line treatment in elderly patients not suitable for chemotherapy in combination with hypomethylating agents or low dose cytarabine had already been presented at the 2017 European hematologogy association (EHA) meeting [18, 19]. The ASH updates (1 year data) confirmed high response rates, long overall survival and acceptable toxicity: in combination with low dose cytarabine the CR + CR with incomplete blood count recovery (CRi) rate was 62% and the median survival 11.4 months, in combination with hypomethylating agents, the CR + CRi rate was 67%, and the median overall survival was not reached at the 400 mg dose level and was 17.5 months at 800 mg [20, 21].
Subgroup analyses on the genetic background were of specific interest. In combination with low dose cytarabine differences were noticeable: the median overall survival was not reached in cases with CEBPa or NPM1 mutations compared to 11.4 months with spliceosome mutations and 6.5 months with a p53 mutation. For cytogenetic risk groups the median survival of 15.7 months with intermediate risk compared to only 5.8 months at high risk [20]. In contrast, no risk factors predicting response were identified for the combination with azacytidine. In addition, data with hypomethylating agents show that MRD may be achieved with this combination [21].
In summary the robust activity of the venetoclax combinations with lower intensity therapies such as low dose cytarabine or hypomethylating agents was confirmed and also favorably compares with results with outcome with chemotherapy in older patients or the current standard azacitidine monotherapy. Genetic data may be essential for future treatment decisions and selection of the suitable backbone.
Further targets and agents
A number of small early clinical trials are ongoing exploring new drugs targeting many promising targets that may be of importance in AML. The clinical relevance is presently still pending, the presentations show the ways of present research and future developments in AML therapy. Although some modest single agent activities are shown, most studies address combination therapies either with standard treatment or with other targeted agents such as venetoclax. A list of selected targets and agents reported at ASH is given in Table 1.
Maintenance treatment in AML with hypomethylating agents
Two clinical trials completed in 2017 at the ASH dealt with azacytidine as a maintenance therapy or pre-emptive therapy after induction chemotherapy.
In the HOVON97 study, 117 patients older than 60 years after standard chemotherapy received 50 mg/m2 azacytidine, subcutaneously, for 5 days of 28 day cycles, as maintenance therapy until relapse or for maximum of 12 cycles [22]. The therapy is feasible, there was no additional toxicity described, and great adherence was achieved. While the disease free survival (DFS) in the arm with maintenance therapy was statistically significantly better (after 12 months 63% compared to 39%), overall survival was not significantly different in the intent to treat (ITT) analysis; only after censoring the patients receiving an allogeneic transplant was a significant advantage for the maintenance arm found: overall survival (OS) at 12 months was 83% compared to 64%.
Maintenance with azacytidine is therefore an option at least for patients who cannot be consolidated in the classical sense (chemotherapy in cytogenetically low risk or allogeneic transplantation in high risk). In this context, data from the ongoing placebo-controlled study using oral azacytidine as maintenance in a similar setting are eagerly awaited (CC-486, AML001-Quazar study).
In the RELAZA-2 study impending relapse was defined in morphologically CR patients by either chimarism analysis after allogeneic transplantation or rising molecular markers in patients treated with chemotherapy only [23]. Pre-emptively azacytidine (75 mg/m2, subcutaneously for 7 days of 28 day cycle) was administered for up to 18 additional months. Screening 205 patients in CR after chemotherapy and allogeneic transplantation identified 53 patients at impending relapse that were subsequently treated: 58% have responded, i. e., they still remained in morphologically CR, 62% of these could again reach MRD negativity.
Conclusions
The studies presented at the 2017 ASH meeting show that the landscape of AML treatment is changing and the many decades old treatment concept of “3 + 7” chemotherapy is becoming less important. The era of biological treatment approaches seen in so many fields of hematology is finally also arriving in AML. There are still many unmet medical needs. Hypomethylating agents have changed the treatment of elderly patients but despite this progress OS still needs to be improved, either by combinations or by alternative treatments. Add on treatments to “3 + 7” may improve results for younger patients but will not benefit those who cannot tolerate induction chemotherapy per se. Again combinations of biologicals or alternative backbones will be needed. All these problems are addressed in ongoing trials. Recent approvals of new substances show the way to a future with possibly better therapies that can provide a survival benefit with acceptable toxicity.
How to select the right individual therapy for each patient will be the challenge for the future.
Take-home messages
In diagnostics NGS will gain importance in general diagnosis, therapy selection, and monitoring of AML.
In treatment, more new substances are entering the AML arena possibly replacing classical chemotherapy. Maintenance therapy is again being discussed.
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M. Pfeilstöcker has received speaker honoraria and served on advisory boards from Celgene, Janssen, and Novartis.
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Pfeilstöcker, M. Acute myeloid leukemia—current data from the 2017 American Society of Hematology meeting. memo 11, 97–100 (2018). https://doi.org/10.1007/s12254-018-0410-4
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DOI: https://doi.org/10.1007/s12254-018-0410-4