General AML

ESH 2018 | Salvage therapy for R/R AML

An oral session took place at the European School of Hematology (ESH) Clinical Updates on Acute Leukemias Meeting on 4–6 May 2018, in Budapest, Hungary. During this session, an educational talk was presented by Professor Arnold Ganser, Director of the Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation of Hannover Medical School, on salvage therapy for relapsed/refractory (R/R) acute myeloid leukemia (AML) patients.1

Induction failure

Failure to respond to intensive induction chemotherapy is a major unfavorable prognostic factor for outcome in AML.  At present, there is no universally agreed definition for induction failure. Professor Ganser began his talk by discussing the variable definitions of primary refractory disease. The National Comprehensive Cancer Network (NCCN) guidelines define induction failure as the persistence of a significant leukemic blasts population in a patient alive seven days or more following high-dose cytarabine therapy.2 However, other studies investigating refractory AML to second induction therapy have defined refractoriness as a failure to achieve complete remission (CR) after two courses of chemotherapy or the presence of < 50% blast reduction in bone marrow (BM) and > 25% at blood count recovery between day 21 and 35 following induction cycle 1. Furthermore, the European LeukemiaNet (ELN) guidelines define primary refractory disease after two courses of induction therapy as persistent leukemic blasts in either the peripheral blood or the BM of a patient alive after seven days of treatment excluding patients with death due to aplasia or indeterminate cause. It also defines primary refractory disease as CR without measurable residual disease (MRD)3

Salvage therapy approaches

Currently, there is no collectively accepted standard treatment for R/R AML. Therefore, Professor Arnold Ganser discussed a range of studies investigating salvage therapy approaches for R/R AML. In a systemic review published in the Annals of Hematology in April 2018 by Juan Eduardo Megías-Vericat and colleagues, the clinical outcomes of adult R/R AML patients treated with conventional salvage chemotherapy regimens were analyzed. In this study, it was demonstrated that several intensive regimens (cytarabine + mitoxantrone + etoposide or gemtuzumab, and cytarabine + purine analogue ± antracycline) achieve relatively high CR rates (44–59.4%). However, most of these regimens did not obtain substantial CR duration (4.9–9.8 months) or overall survival (6.2–8.7 months).4 Furthermore, in a study presented at the 2016 American Society of Hematology Meeting, which evaluated the impact of experimental drugs in R/R AML via a comprehensive analysis of all phase II and III randomized clinical trials (RCTs) in the past three decades. The study demonstrated a lack of significant or clinically meaningful improvement in disease outcomes, including OS, in R/R AML patients treated within RCTs over the past 3 decades.5

The speaker then discussed a study by Wattad et al., which evaluated the impact of salvage regimens and allogeneic hematopoietic cell transplantation (allo-HCT) in AML patients with induction failure. In total, 3,324 patients with newly diagnosed AML who were enrolled in five prospective treatment trials. Of these, 1,025 patients with induction failure, 875 (median age = 55 years) received intensive salvage therapy: 7+3-based (n = 59), high-dose cytarabine combined with mitoxantrone (HAM; n = 150), with all-trans retinoic acid (n = 247), with gemtuzumab ozogamicin and A (GO; GO-A-HAM) (n = 140), other intensive regimens (n = 165), experimental treatment (n = 27) and direct allo-HCT (n = 87). GO-A-HAM regimen was associated with a response rate of 50% (OR = 1.93, P = 0.002). Findings from this study suggest that in patients with primary refractory AML, direct allo-HCT and GO-A-HAM are associated with a high probability of achieving a response.6

Recommendations

Finally, the speaker discussed an algorithm for patients with early R/R AML published in Blood by Felicitas Thol and colleagues. In this “How I treat” series, it was suggested that patients with primary refractory/early relapse AML should be evaluated for allogeneic HSCT. If the patient is a candidate, then allogeneic HSCT from a matched related or unrelated donor is the treatment approach with the highest probability of cure. However, if the patient is not a candidate for allogeneic HSCT, other treatment modalities including novel agents and/or palliative therapy with the aim to prolong the patient’s life with a meaningful quality of life should be considered.7

Professor Arnold Ganser concluded his talk by recommending the enrolment of R/R AML patients in clinical trials, whenever possible because currently there is no standard therapy option for this group of patients. He further highlighted that novel therapies should be used as a bridge to HSCT and in frail, older patients who are not candidates for transplantation.

References
  1. Ganser A. Salvage therapy for refractory and relapsed AML. ESH Clinical Updates in Acute Leukemias. May 4–6 2018, Budapest, Hungary.
  2. National Comprehensive Cancer Network (NCCN) Guidelines: Acute Myeloid Leukemia. 2016.
  3. Döhner H. et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017 Jan 26;129(4):424-447. DOI: 10.1182/blood-2016-08-733196. [Epub 2016 Nov 28]
  4. Megías-Vericat J E. et al. Salvage regimens using conventional chemotherapy agents for relapsed/refractory adult AML patients: a systematic literature review. Ann Hematol. 2018 Apr 21. DOI: 10.1007/s00277-018-3304-y. [Epub ahead of print].
  5. Tchekmedyian R. et al. Analysis of Outcomes of Patients with Relapsed/Refractory Acute Myeloid Leukemia Treated in Randomized Clinical Trials. Blood. 2016; 128: 4000.
  6. Wattad M. et al. Impact of salvage regimens on response and overall survival in acute myeloid leukemia with induction failure. Leukemia. 2017 Jun;31(6):1306-1313. DOI: 10.1038/leu.2017.23. Epub 2017 Jan 19.
  7. Thol F. et al. How I treat refractory and early relapsed acute myeloid leukemia. Blood. 2015 Jul 16;126(3):319-27. DOI: 10.1182/blood-2014-10-551911. [Epub 2015 Apr 7.]
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