Diagnosis and Treatment of Patients With Acute Myeloid Leukemia With Myelodysplasia-Related Changes (AML-MRC)

Daniel A. Arber, MD; Harry P. Erba, MD, PhD


Am J Clin Pathol. 2020;154(6):731-741. 

In This Article

Current Treatment Options for Patients With AML-MRC

The selection of treatment for patients with AML can be influenced by multiple factors, including age, cytogenetic risk, performance status, and others,[29] but there has been very limited evaluation of variables that might influence selection of therapy for patients with AML-MRC. Physicians must carefully consider the goals of therapy (curative vs palliative) prior to finalizing a treatment plan. Traditional combination chemotherapy and CPX-351 (Vyxeos; Jazz Pharmaceuticals; daunorubicin and cytarabine liposome for injection) are the most common intensive induction therapies for patients with AML-MRC, although patients who also have certain mutations and clinical features may benefit from targeted therapy, and patients who are frail may be appropriate for less-intensive treatment approaches.

Conventional Chemotherapy

Combination chemotherapy regimens are the historical standard of care for intensive induction in AML, including AML-MRC, and commonly consist of continuous cytarabine infusion for 7 days plus 3 days of an anthracycline ("7 + 3" regimen).[25] However, this approach has not provided satisfactory OS in patients with AML-MRC.[2,5–7] A retrospective analysis of results for 449 adults with AML-MRC (n = 115) or AML-NOS who were treated with conventional chemotherapy indicated a lower median OS of 10 months and CR rate of 52% among patients with AML-MRC, compared with 16 months and 77% for those with AML-NOS.[7]


CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine at a synergistic 1:5 molar drug ratio. The liposomal-based carrier system maintains the synergistic drug ratio for over 24 hours after administration, resulting in longer drug exposure; in vitro studies also demonstrated preferential uptake of CPX-351 by leukemic blasts compared with normal cells in the bone marrow. Together, these properties contribute to increased antileukemic activity.[31,32] CPX-351 is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of adults with newly diagnosed AML-MRC and therapy-related AML.[33,34] In addition, the National Cooperative Cancer Network guidelines for AML recommend CPX-351 for adults younger than 60 years (category 2B) and adults 60 years or older who are candidates for intensive therapy (category 1) who have antecedent MDS/CMML, cytogenetic changes consistent with MDS, or therapy-related AML (other than core binding factor/acute promyelocytic leukemia).[25]

The approval of CPX-351 for patients with AML-MRC was based on results from a multicenter, randomized, open-label, phase 3 clinical study of CPX-351 vs conventional 7 + 3 chemotherapy in 309 patients aged 60 to 75 years with newly diagnosed, high-risk, or secondary AML.[35,36] Of the 246 patients with AML-MRC enrolled in this study (n = 123 in each treatment arm), 59.0% had antecedent MDS, 9.3% had antecedent CMML, and 31.7% had de novo AML with MDS karyotype. Results of an exploratory subgroup analysis in patients with AML-MRC indicated prolonged median OS with CPX-351 vs 7 + 3 chemotherapy (9.07 vs 5.95 months; hazard ratio [HR], 0.70; 95% CI, 0.53–0.93);[36] prolonged median OS was observed with CPX-351 among patients with antecedent MDS/CMML (7.38 vs 5.95 months; HR, 0.70; 95% CI, 0.50–0.99) and de novo AML with MDS karyotype (10.09 vs 7.36 months; HR, 0.71; 95% CI, 0.42–1.20).[35] CPX-351 also demonstrated higher rates vs 7 + 3 of patients with AML-MRC who achieved CR (37.4% vs 24.4%; odds ratio [OR], 1.80; 95% CI, 1.02–3.17) and CR or CR with incomplete neutrophil or platelet recovery (CRi; 48.0% vs 32.5%; OR, 1.83; 95% CI, 1.09–3.09).[36] Hematopoietic cell transplantation (HCT) could be received at the discretion of the treating physician and was reported for 33.3% of patients in the CPX-351 arm vs 24.4% of patients in the 7 + 3 arm (OR, 1.53; 95% CI, 0.86–2.74). Median OS landmarked from the date of HCT was not reached for CPX-351 vs 10.68 months for 7 + 3 (HR, 0.48; 95% CI, 0.24–0.96). The safety profile of CPX-351 in patients with AML-MRC was generally consistent with that for conventional 7 + 3, except that the time to neutrophil and platelet count recovery was longer for patients achieving CR + CRi following CPX-351 compared with 7 + 3. However, the early mortality rates for CPX-351 and 7 + 3, respectively, were 5% and 9% within 30 days and 14% and 20% within 60 days. Grade 5 treatment-emergent adverse events occurring in more than one patient in a treatment arm included sepsis (2.4% and 0.8%), disease progression (1.6% and 3.4%), multiorgan failure (0.8% and 1.7%), and respiratory failure (0.8% and 1.7%).[36]

Targeted Agents

No targeted therapies are specifically approved or recommended for patients with AML-MRC, but some patients with AML-MRC may also have mutations or clinical features that make them candidates for treatment with these agents.

Gemtuzumab Ozogamicin

Studies showing a higher expression of CD33 on granulocytic cells from individuals with AML-MRC vs AML-NOS[37] and a high proportion (69%) of CD33-positive AML-MRC cases[38] suggest CD33 might be a therapeutic target for some patients with AML-MRC. Gemtuzumab ozogamicin (Mylotarg; Pfizer) is approved by the FDA for the treatment of adults with newly diagnosed CD33-positive AML and adults or pediatric patients 2 years or older with relapsed/refractory CD33-positive AML. Approval of gemtuzumab ozogamicin was based on the ALFA-0701 study, which was a multicenter, open-label, phase 3 study of 280 patients aged 50 to 70 years with newly diagnosed, de novo AML who were randomized to receive 7 + 3 with or without the addition of gemtuzumab ozogamicin.[39,40] However, at present there is no information regarding the efficacy or safety of gemtuzumab ozogamicin in patients with AML-MRC. The ALFA-0701 study excluded patients with prior MDS or MDS/MPN, and there has not been an analysis of the effect of multilineage dysplasia on outcomes in the ALFA-0701 study. However, patients with poor-risk karyotype (such as those seen in de novo AML-MRC) did not benefit from the addition of gemtuzumab ozogamicin.[40]

Midostaurin and Gilteritinib

FLT3–internal tandem duplication (ITD) mutations are relatively common in AML, reported in approximately 25% to 30% of AML cases overall[41,42] and in 13.5% of patients with AML-MRC.[7] Midostaurin (Rydapt; Novartis Pharmaceuticals) and gilteritinib (Xospata; Astellas Pharma) are small-molecule FLT3 inhibitors that are approved for the treatment of adults with newly diagnosed FLT3-mutated AML in combination with conventional cytarabine/daunorubicin or adults with relapsed/refractory FLT3-mutated AML, respectively. Although these agents are not approved specifically in patients with AML-MRC, they could be appropriate for some patients who have an FLT3 mutation. The approval of midostaurin was based on the results from the phase 3 RATIFY trial (CALGB 10603; n = 717), a randomized, placebo-controlled study carried out to determine whether the addition of midostaurin to standard 7 + 3 chemotherapy would improve the OS of patients (aged 18–59 years) with FLT3-mutated AML.[43] The approval of gilteritinib was based on an interim analysis of results from the ADMIRAL trial, which included 138 adults with relapsed/refractory AML who had an FLT3-ITD, FLT3-D835, or FLT3-I836 mutation.[44] Studies of both agents showed promising outcomes in their overall study populations;[43,45] however, no subanalyses of patients with AML-MRC have been reported.

Ivosidenib and Enasidenib

IDH1 and IDH2 mutations have been reported at frequencies of approximately 4% and 21%, respectively, among patients with AML-MRC.[14] Ivosidenib (Tibsovo; Agios Pharmaceuticals) and enasidenib (Idhifa; Celgene) are approved for the treatment of adults with relapsed/refractory AML with susceptible IDH1 and IDH2 mutations, respectively. Ivosidenib monotherapy (500 mg/d for ≥6 months) was assessed in a phase 1 study of patients with relapsed/refractory, IDH1-mutated AML (n = 125 evaluable).[46] The efficacy of enasidenib was assessed in an open-label, single-arm study that included 199 adult patients with relapsed/refractory IDH2-mutated AML.[47] Although promising efficacy was observed with both agents, neither of the studies evaluated outcomes in the subgroup of patients with AML-MRC.

Lower-intensity Therapies

AML-MRC is primarily diagnosed in older adults,[4] and some may not be considered healthy enough to receive intensive induction chemotherapy because of the presence of significant comorbidities. These patients may be appropriate candidates for lower-intensity therapies, including hypomethylating agents (HMAs; azacitidine or decitabine) with or without venetoclax, or low-dose cytarabine (LDAC) with or without either venetoclax or glasdegib.

A subanalysis of results from a phase 3 study that compared clinical outcomes for 262 patients with AML-MRC who were treated with azacitidine or conventional regimens (primarily LDAC) indicated that the median OS was significantly prolonged with azacitidine vs conventional care (8.9 vs 4.9 months; HR, 0.74; 95% CI, 0.57–0.97).[29]

Venetoclax has been approved in combination with either HMAs or LDAC for the treatment of newly diagnosed AML in patients who are 75 years or older or have comorbidities that preclude the use of intensive induction chemotherapy. A phase 1b study evaluated outcomes for venetoclax in combination with HMAs in 145 patients 65 years or older with untreated AML who were considered ineligible for intensive chemotherapy; the study included 36 (25%) patients with secondary AML (none with prior HMA therapy). The CR + CRi rate was 67% for patients with either de novo or secondary AML. Median OS was 12.5 months (95% CI, 10.3–24.4) for patients with de novo AML and was not reached (95% CI, 14.6 to not reached) for those with secondary AML.[48] A phase 1/2 study of venetoclax plus LDAC in 82 adults aged 60 years or older with untreated AML who were ineligible for intensive chemotherapy included 40 (49%) patients with secondary AML (24 with prior HMA exposure). CR and CR + CRi rates were lower for patients with secondary AML (CR, 5%; CR + CRi, 35%) vs de novo AML (CR, 45%; CR + CRi, 71%). Median OS was also shorter for patients with secondary AML (4.1 months; 95% CI, 2.9–10.1) vs de novo AML (13.5 months; 95% CI, 7.0–18.4). Outcomes for the 24 patients with prior HMA exposure were similar to those for the overall secondary AML subgroup, with a CR + CRi rate of 33%, including 4% who achieved CR, and a median OS of 4.1 months (95% CI, 2.9–10.1).[49] A subsequent randomized, phase 3 study in a similar population failed to meet its primary end point of improved median OS for venetoclax plus LDAC vs placebo plus LDAC (7.2 vs 4.1 months; HR, 0.75; 95% CI, 0.52–1.07) in the overall study population, which included 38% with secondary AML (primarily prior hematologic disorder) and 20% with prior HMA exposure.[50] Higher remission rates and longer median OS with the addition of venetoclax to LDAC were noted across patient subgroups, but specific data were not included with the online manuscript publication. However, a multivariable Cox regression analysis identified de novo vs secondary AML as significantly correlated with OS (HR, 0.59; 95% CI, 0.41–0.85).[50]

Glasdegib is also approved in combination with LDAC for the treatment of patients with newly diagnosed AML who are 75 years or older or have comorbidities that precluded the use of intensive induction chemotherapy. This approval was based on results from the BRIGHT AML 1003, a randomized trial of LDAC with or without glasdegib in 115 patients. The addition of glasdegib improved median OS in the overall study population,[51] but no analysis of patients with AML-MRC has been performed.