The future of AML sees us aggressively treating this disease in induction and consolidation. Molecular targets are being discovered, and directed therapy will hopefully improve upon remission rates and overall survival in this deadly disease.
—Hugo F. Fernandez, MD
With the emergence of molecular diagnostics and new therapeutics, the treatment of acute myeloid leukemia (AML) is entering a new era. Hugo F. Fernandez, MD, Associate Chief of Blood and Marrow Transplantation at Moffitt Cancer Center in Tampa, Florida, spoke with The ASCO Post about how he approaches these patients.
Cytogenetics and Molecular Studies
Can you offer a few major requirements in treating AML today?
In 2014, we need to know the results of cytogenetics and molecular studies, which should be done on all patients with AML. Cytogenetics has long been a standard diagnostic test, and we classify cytogenetic profiles as conveying a “good (favorable), bad (intermediate), or ugly (unfavorable)” profile. Ten-year overall survival rates have been shown to be 55% to 81% for patients with favorable profiles, 22% to 39% for those with intermediate-risk profiles, and 10% or less for those with unfavorable profiles.1
But now we know about a variety of mutations that also confer prognosis. Molecular studies are allowing us to reclassify our patients, which will be important down the road when we can more precisely select optimal treatments. These new molecular assays are important and readily available at academic centers and in commercial laboratories.
An important mutational analysis of 18 genes, performed by Patel et al on the Eastern Cooperative Oncology Group (ECOG) E1900 patient population, found that more extensive mutational analysis can better discriminate patients with AML into various prognostic groups.2 The analysis separated patients with AML into three subgroups with very different outcomes: those with a favorable mutational risk profile (3-year overall survival rate, 85%), a subgroup with an unfavorable mutational risk profile (3-year overall survival rate, 13%), and a subgroup remaining at intermediate risk (3-year overall survival rate, 42%).
The integration of mutational and cytogenetic analyses reduced the proportion of patient with intermediate-risk disease from 63% to 35%. The favorable-risk subgroup increased from 19% to 26%, and the proportion deemed unfavorable increased from 18% to 39%.
What are the key mutations associated with prognosis?
In cytogenetically normal patients, there are two abnormalities that generally tell us the patient will probably do well: mutations in NPM1 only or isolated biallelic CEBPA. Intermediate-risk disease, on the other hand, is conferred by the c-KIT mutation in core-binding factor leukemia.
Poor prognosis is associated with the FLT3-ITD mutation, which we see in about one-third of patients. FLT3 is normally expressed on hematopoietic cells, and regulates the proliferation of early progenitor cells. When mutated, FLT3 constitutively activates leukemia cells so that they never stop growing.
The impact of FLT3 is obvious from the study by Patel et al.2 They showed that in patients with intermediate-risk AML, the mutant FLT3-ITD was associated with an adverse outcome regardless of other mutations. In patients with wild-type FLT3, the presence of several additional mutations—DNMT3A, PHF6, ASXL1, MLL, RAS, WT1 and TP53—conferred a worse prognosis. However, these mutations are less frequent and need more study.
What is your initial approach to treatment?
AML needs aggressive treatment. Most patients will relapse with conventional therapies, so just getting them through induction is not enough; they also need consolidation. The attainment of a complete response will impact their disease course.
Patients with favorable-risk disease generally have excellent outcomes and can be treated with standard chemotherapy. Other genotypes that fall into the intermediate-risk and high-risk groups need more aggressive treatment.
It is very important for FLT3-positive patients to receive better therapy, and while we have no real options now, we believe this will change in the near future. A phase II study with sorafenib (Nexavar) was encouraging for patients with FLT3-ITD, and this is the only agent we have available for this purpose. A randomized phase III trial adding the investigational tyrosine kinase inhibitor midostaurin to conventional therapy has been completed and is awaiting maturation.
There may be other tyrosine kinase inhibitors that more directly target FLT3, but whether this will be a good thing or not remains to be seen. At least now, we have proof of principle that FLT3 inhibition can positively impact outcomes in these patients.
What is your induction approach?
High-dose anthracyclines must be given to these patients. No patient with AML has benefited from low-dose therapy. Idarubicin and daunorubicin are equivalent at higher doses. If the patient is too ill for this approach, find an alternative, but you still must be aggressive.
We also see gemtuzumab ozogamicin (Mylotarg) making a comeback. Early trials were encouraging, but the randomized phase III SWOG trial was negative, partly due to a high incidence of side effects.3 This led to the drug’s voluntary withdrawal from the market, but gentuzumab ozogamicin has not completely disappeared from our armamentarium.
A recent meta-analysis showed that the addition of gemtuzumab ozogamicin to treatment improved relapse-free survival (hazard ratio [HR] = 0.84) and event-free survival (HR = 0.59) but not overall survival (HR = 0.95).4 While the addition of the drug resulted in a 60% higher rate of early mortality in the meta-analysis, improved overall survival was observed in studies using a lower cumulative dose (< 6 mg/m2).
So gemtuzumab ozogamicin can be beneficial, especially in patients with favorable- and intermediate-risk disease, but with the issue of side effects, we still have questions. By reducing the dose, we see less treatment-related morbidity and mortality. We are still not sure whether the drug will come back on the market, and in the future we may be seeing more targeted trials stratified by risk. In the meantime, patients who have core-binding factor leukemia may get some benefit by adding this drug at the lower dose.
Moving to consolidation therapy, we can say that prognostic factors and performance status drive treatment. For favorable-risk patients, standard chemotherapy with or without gemtuzumab ozogamicin is the way to go.
Can you effectively delay stem cell transplantation to second remission?
Although the majority of adult patients with AML will achieve remission with upfront chemotherapy, many patients still relapse. Often, the strategy proposed is to delay transplant until a patient relapses and achieves a second remission. We should not let the “second remission fallacy”—that is, thinking that we can take patients to transplant in their second remission—guide our treatment.
Remember that most patients will relapse, and obtaining a second remission is not guaranteed. If the patient relapses within 12 months, the chance of a second remission is only about 15%. Beyond 12 months, it improves to 30% or 40%, but these are still not great numbers. Taking the patient to transplant while in first remission, especially those with intermediate- or high-risk disease, is often beneficial.
Allogeneic transplant is preferred for patients with FLT3 mutations. Neither chemotherapy nor autologous transplants helps these patients. Allogeneic transplant is the only treatment that will level the playing field.
What emerging treatments for AML look promising?
The cooperative group trials are evaluating a number of new agents in high-risk patients. In patients with core-binding factor leukemia, we are evaluating dasatinib (Sprycel) given with high-dose daunorubicin. For FLT3-positive disease, we are looking at sorafenib plus 7+3 chemotherapy (continuous intravenous [IV] cytarabine infusion for 7 days with an anthracycline given by IV push for 3 days). Another trial is comparing high-dose daunorubicin to high-dose idarubicin with or without vorinostat (Zolinza). We are also evaluating early allogeneic transplant in high-risk patients.
The future of AML sees us aggressively treating this disease in induction and consolidation. Molecular targets are being discovered, and directed therapy will hopefully improve upon remission rates and overall survival in this deadly disease. ■
Disclosure: Dr. Fernandez reported no potential conflicts of interest.
1. Grimwade D, Hills RK, Moorman AV, et al: Refinement of cytogenetic classification in acute myeloid leukemia: Determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 116:354-365, 2010.
2. Patel JP, Gönen M, Figueroa MET, et al: Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 366:1079-1089, 2012.
3. Petersdorf SH, Kopecky KJ, Slovak M, et al: A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood 121:4854-4850, 2013.
4. Kharfan-Dabaja MA, Hamadani M, Reljic T, et al: Gemtuzumab ozogamicin for treatment of newly diagnosed acute myeloid leukaemia: A systematic review and meta-analysis. Br J Haematol 163:315-325, 2013.