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Editorials
historically poor outcome data of single agent azacitidine treatment (CR rates approx. 20%; OS not exceeding 12 months in AML patients3), it becomes clear that this novel targeted combined strategy will potentially dominate the future treatment landscape in HR-MDS and AML patients not eligible for intensive induction therapy. Nevertheless, previous clinical trials in AML demonstrated a toxicity profile that represents cause for concern. Over 50% of included patients developed grade ≥3 neutropenia, leading to a high incidence of treatment interruption and subse- quent study discontinuation due to progressive disease (PD).9,11 Recruitment is currently underway for a clinical study evaluating the combination of venetoclax with azacitidine in patients with HR-MDS after HMA failure (clinicaltrials.gov identifier: 02966782).
It is known that HMA can reduce immune response by upregulation of inhibitory immune checkpoint molecule expression. Therefore, preventing resistance to HMA by combining HMA and checkpoint inhibition is another possible new treatment strategy which is currently under investigation in several clinical trials. We reported on a patient with sAML undergoing single agent pem- brolizumab (anti-PD-1) treatment.12 After two months of therapy, platelet count increased in line with a response according to International Working Group (IWG) 2018 criteria, together with clearance of IDH1 mutation.12 Recently Daver et al. reported on a phase II study evalu- ating response to azacitidine and nivolumab in relapsed/refractory AML patients. In HMA pretreated patients, ORR was 22% and median OS for the 70 includ- ed patients was 6.3 months.13
Gemtuzumab ozogamicin (GO), a humanized anti- CD33 antibody conjugate, is currently licensed by both the US Food and Drug Administration and the European Medicines Agency in combination with daunorubicin and cytarabine for the treatment of de novo CD33-positive AML patients. Moreover, available data suggest activity of GO in combination with HMA. The maturation of AML blasts increases CD33 expression after HMA thera- py, resulting in an enhanced uptake of GO by blast cells.14 A phase II clinical trial in older AML patients evaluated the combination of hydroxyurea followed by azacitidine for seven days and GO on day eight. Results demonstrat- ed CR in 44% of patients in the good risk group (age 60- 69 years or performance status 0-1) and 35% (19 of 59 patients) CR rate in the poor risk group (age ≥70 years and performance status 2 or 3).14 In a phase II study in newly diagnosed or relapsed HR-MDS and AML patients, the combination of decitabine with GO achieved CR/CRi in 35% of patients (39 of 110 patients).15
Rigosertib (ON-01910), a multikinase inhibitor, is cur- rently undergoing evaluation in a randomized phase III trial (clinicaltrials.gov identifier: 02562443) in HR-MDS patients after HMA failure. Results of a previous phase III study demonstrated that patients treated with rigosertib had longer (8.6 vs. 5.3 months) median OS compared to patients receiving best supportive care after HMA fail- ure.16 The combination of rigosertib with azacitidine after HMA failure was recently evaluated in a phase II trial, showing an ORR of 54%, including 8% CR in this patient population; the safety profile was similar to those described for azacitidine alone.17
One interesting new therapeutic target in patients fail- ing HMA is the selective inhibition of AXL, a surface membrane protein kinase receptor on blast cells. Signaling through AXL seems to stimulate a number of pro-survival pathways and enables malignant cells to develop resistance to conventional chemotherapies.18 Pre- clinical studies with bemcentinib, an orally selective small molecule AXL inhibitor, demonstrated in vitro and in mouse models that leukemic proliferation was blocked by interference with AXL signaling.18 Thus, AXL repre- sents a promising target and bemcentinib a possible new treatment option for HR-MDS or AML patients.18 The efficacy and safety of bemcentinib is currently being eval- uated in a phase II study (BERGAMO trial; clinicaltrials.gov identifier: 03824080) within the European Myelodysplastic Syndromes Cooperative Group (EMSCO) in patients with HR-MDS or AML after HMA failure. Other poten- tially available therapeutic approaches after failing HMA include the use of targeted molecular therapies, e.g. with IDH or FLT3-inhibitors. IDH mutations are quite com- mon in MDS (10-15% of patients) and data in relapsed AML have so far proved promising.19 FLT3-inhibitors have already been approved in the US for second-line treatment of patients with AML and may, therefore, offer a therapeutic option in rare FLT3 mutated cases with dis- ease progression.20
In conclusion, patients with HR-MDS or AML failing HMA remain a population with a dismal outcome and limited therapeutic options. In the future, a personalized targeted treatment strategy on the basis of the patient’s molecular profile, cytogenetics, and previous therapies may be the best approach. Until then, translational stud- ies based on a variety of prospective clinical trials are urgently required to overcome the enormous unmet med- ical need for additional treatment options.
References
1. Platzbecker U. Treatment of MDS. Blood. 2019;133(10):1096-1107. 2. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azaciti- dine compared with that of conventional care regimens in the treat- ment of higher-risk myelodysplastic syndromes: a randomised,
open-label, phase III study. Lancet Oncol. 2009;10(3):223-232.
3. DombretH,SeymourJF,ButrymA,etal.Internationalphase3study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126(3):291-
299.
4. Itzykson R, Thepot S, Quesnel B, et al. Prognostic factors for
response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood. 2011;117(2):403-411.
5. Craddock CF, Houlton AE, Quek LS, et al. Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature. Clin Cancer Res. 2017;23(21):6430-6440.
6. Komrokji RS. Treatment of Higher-Risk Myelodysplastic Syndromes After Failure of Hypomethylating Agents. Clin Lymphoma Myeloma Leuk. 2015;15 Suppl:S56-59.
7. Sebert M, Renneville A, Bally C, et al. A phase II study of guadecitabine in higher-risk myelodysplastic syndrome and low blast count acute myeloid leukemia after azacitidine failure. Haematologica. 2019, 104(8):1565-1571.
8. Dinardo CD, Pratz KW, Potluri J, et al. Durable response with vene- toclax in combination with decitabine or azacitadine in elderly patients with acute myeloid leukemia (AML). J Clin Oncol. 2018;36(15_suppl): 7010-7010.
9. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17.
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