Patients with acute myeloid leukemia whose mutations persisted a month after starting treatment were three times more likely to relapse and die as those who cleared the mutations, according to a new study (JAMA 2015;314:811–22; doi:10.1001/jama.2015.9643). Designed to determine whether mutations in the genome detected at the beginning of treatment were associated with outcomes, the research revealed that patients who cleared mutations at 30 days had a median survival of 42 months, compared with 10.5 months for the others. “In addition to helping determine whose disease is higher risk early in treatment without having to wait for a recurrence, our study points to the importance of clearing the driver mutations, not simply subsets of mutations,” said primary investigator Timothy Ley, M.D., Lewis T. and Rosalind B. Apple Chair in oncology and professor of medicine and genetics at Washington University in
Using whole-genome sequencing, Ley’s team showed that genetic mutations that were initiators of early blood cell transformation, such as TET2, DNMT3A, IDH1, and IDH2, were rarely eradicated by using conventional chemotherapy. By contrast, other mutations, such as FLT3, KRAS, NRAS, and NPM1, were commonly cleared and often absent at relapse. “This suggests that they [the latter] are relatively late mutations,” Ley said. His study may help explain why 20% of adults with acute myeloid leukemia (AML) do not achieve remission with initial, or induction, chemotherapy, and why about 50% patients relapse after complete remission. “Our research suggests that to cure patients with AML, it may be necessary to direct therapy to eradicate disease-initiating mutations,” Ley said. Until recently, most sequencing did not look at clonality, that is, which clones had evolved from the original mutations and which occurred subsequently, he said. It is the noninitiating clones that most treatments eliminate, and why the disease returns, with the earliest mutations remaining. “AML is an oligoclonal disease, not polyclonal,” said Ross Levine, M.D., Laurence Joseph Dineen Chair in leukemia research at Memorial Sloan–Kettering Cancer Center in New York. This means that there is a small number of genetic mutations that lead to AML.
AML is the most lethal of blood cancers, with only 10%–25% of patients surviving 5 years. Each year, 20,800 are diagnosed in the U.S., and 10,400 die. Over the last decades, relatively small improvements have been made in lengthening life expectancy of patients with AML. The disease is characterized by the production of immature blood cells that do not differentiate into mature, functioning blood cells. Although standard induction chemotherapy puts many into remission, these remissions are usually not durable. A major issue is relapse, with many other mutations, such as FLT-3, rendering afflicted patients resistant to treatment, said Guillermo Garcia-Manero, M.D., professor in the Department of Leukemia, Division of Cancer Medicine, at the University of Texas M. D. Anderson Cancer Center in Houston. The only cure is stem cell transplantation, which is very risky and not recommended for most older or frail patients, which constitute the bulk of AML patients.
New research indicates that lower-intensity stem cell transplantation is a new option for the older, frail population, and there are now a group of new molecular targets for and pathways with which to attack AML (Lancet Haematol. 2015, vol. 2; doi:10.1016/S2352-3026(15)00148-9). Promising approaches include treating initiating mutations, the tumor microenvironment, leukemic stem cells, and focusing on apoptosis, adhesion molecules, epigenetic mechanisms, and immune response.
Driver Mutations
“Researchers have long recognized the importance for AML and myelodysplastic syndrome, which often precedes AML, of epigenetic pathways and mutations, but only recently, with deep sequencing has there been a new recognition that some epigenetic mutations are key to AML initiation and development,” said Jean-Pierre Issa, M.D., professor of medicine and director of the Fels Institute for Cancer Research and Molecular Biology at Temple University in Philadelphia. The Cancer Genome Atlas and other research confirm that 44% of patients with AML have mutations in genes that regulate genomic DNA methylation. But whereas epigenetic-targeting drugs for myelodysplastic syndrome and AML have been used with some efficacy to date, they have not produced cures or long-term survival, Issa said. “In particular, histone deacetylase inhibitors have been fairly disappointing,” he said.
New sequencing, however, indicates that mutations in the IDH1, IDH2, and DNMTA3a genes are drivers, and new drugs targeting these mutations are in early-stage testing, whereas older epigenetic drugs such as azacytidine and decitabine are in later-stage combination trials.
One of most exciting new targets is a mitochondrial gene mutation of the isocitrate dehydrogenase enzyme, which has two isoforms, IDH1 and IDH2, according to Issa and others. “First discovered in patients with glioma in 2009, and subsequently in those with AML, mutated IDH1 and -2 affects cellular differentiation and metabolism and is a very early mutation,” said Eytan Stein, M.D., hematologic oncologist at Memorial Sloan–Kettering Cancer Center. IDH1 and IDH2 mutations lead to the accumulation of an oncometabolite, hydroxyglutarate, 2-HG, and hypermethylation, which blocks normal differentiation of stem cells. At the December American Society of Hematology meeting in Orlando, Fla., Stein presented “extraordinarily robust” results from a first-in-class oral IDH1 inhibitor, AG-120, in an ongoing phase I study in 66 IDH22–positive patients. The overall response rate was 36%, which he said was remarkable in advanced AML, with some partial responses lasting as long as the complete responses. The median duration of response was 5.6 months (abstr. 1306; https://ash.confex.com/ash/2015/webprogram/Paper82957.html). One unusual finding was that although some patients showed only partial reduction of blasts, or immature cells, they had good recovery of blood counts, which appeared to take them from an acute to chro nic leukemic state, Stein said. In May, the U.S. Food and Drug Adm inistration granted AG-120 Fast Track designation for IDH1-–mutant AML.
Timothy Ley, M.D.
Stein also reported on an oral IDH2 inhibitor, AG-221, in an ongoing phase I/II study in 198 IDH2-postive patients, most with relapsed/refractory disease. AG-221 is a small-molecule inhibitor of mutant IDH2 that enables immature, cancerous blood cells to differentiate into normal cells. About 15% of AML patients have mutations in that gene. Patients in this trial had a response rate of 41%, with 56% experiencing changes in absolute neutrophil count from the first treatment, indicating that immature cells differentiated into mature neutrophils (abstr. 323; https://ash.confex.com/ash/2015/webprogram/Paper81999.html). The median response lasted 6.9 months, and eight patients proceeded to transplant. Those who had increases in absolute neutrophil count had lower rates of infection and febrile neutropenia, and the drug was well tolerated. A phase III study for relapsed/refractory patients, and combination trials for frontline treatment, should begin by year’s end, and phase 1/2 trials with either drug plus azacytidine are planned for the first quarter of 2016. Other research, presented by scientists at the Cleveland Clinic in Ohio, showed that IDH 1/2 inhibitors may be useful as adjuvants to chemotherapy without increased toxicity (abstr. 3788; https://ash.confex.com/ash/2015/webprogram/Paper86972.html).
The DNA methyltransferase 3A, or DNMT3A, gene is another important target. Mutations are found in 4%–22% of AML patients, but less is known about its effect than for IDH1 and -2. Decitabine, a hypomethylating drug that induces differentiation and apoptosis of leukemic cells, is widely used in myelodysplastic syndrome, and off-label for AML, in elderly patients who cannot tolerate induction chemotherapy, targets this gene. “A next-generation hypomethylator, guadecitabine, or SGI-110, has a longer half-life and has shown activity in AML in a phase III study, and in phase I and II studies has shown activity that compares favorably to decitabine, based on historical controls,” Issa said. An 800-patient phase III recently began in treatment-naïve patients who cannot induction chemotherapy, and earlier-stage studies are ongoing.
Mutations Denoting Poor Prognosis
Many later-stage mutations, such as those in the FLT-3 gene, and the presence of the WT-1 gene, are of great concern because they signal particularly poor prognoses. In a phase III study of the multikinase inhibitor midostaurin with chemotherapy versus chemotherapy and placebo in 717 newly diagnosed patients, patients took the combination for induction and then for 1 year as maintenance therapy. Primary investigator Richard M. Stone, M.D., chief of staff and program director of the Adult Acute Leukemia Program at the Dana–Farber Cancer Institute in Boston reported at a plenary session at ASH that patients taking the combination had better overall and event-free survival (EFS): 74.7 months compared with 26 months, and 8 versus 3 months, respectively (abstr. 6, plenary; https://ash.confex.com/ash/2015/webprogram/Paper86972.html). Stone explained that EFS was less dramatic than OS because the trial’s EFS cutoff was 60 days, so if a patient was not in remission at 60 days, but later, it was counted as an “event.” Remarkably, however, there was a 70% complete response rate at any time.
WT-1 is expressed on myeloid progenitor and myeloid leukemia cells, but not on healthy adult cells, said David Scheinberg, M.D., Ph.D., chair of the molecular pharmacology program, and director of the Center for Experimental Therapeutics at Memorial Sloan–Kettering Cancer Center. At the 8th International Congress on WT-1 in Kyoto, Japan, in late November, Scheinberg presented results of a phase II study of a WT-1 vaccine with 31 patients in remission, with overall median survival rates ranging from of 52.2 months. In a previous phase I study, the vaccine produced a median overall survival of more than 5 years. Together, both trials yielded a 2-year overall survival of 79%, compared with an historical rate of 30–45% Consisting of four modified peptide chains plus an adjuvant and immunomodulator, the vaccine induced strong CD4 and CD8 T-cell responses against the WT-1 antigen and destroyed residual cancer cells. A phase III randomized trial will begin in early 2016 with 300 patients.
Although researchers are looking to cure AML, many also hope that more and longer durable remissions like these may enable conversion of AML to a chronic disease that patients can live with long term, Issa said.
