In This Article
- Allogeneic Transplant Leads to Markedly Improved Survival in Older Patients with AML
- Effect of Cytarabine/Anthracycline/Crenolanib Induction on MRD in Newly Diagnosed AML with FLT3 Mutation
- Suboptimal Adherence to Guideline-Recommended Molecular Testing in Patients with Newly Diagnosed AML: Data from the Connect MDS/AML Disease Registry
- Improved Survival with Fludarabine and Timed Sequential Busulfan Regimen in Older Patients with AML or MDS
- Sorafenib plus 5-Azacytidine in Older, Untreated FLT3-ITD–Positive Patients with AML
- Nivolumab with Azacytidine in Patients with Relapsed AML
Allogeneic Transplant Leads to Markedly Improved Survival in Older Patients with AML
Allogeneic stem-cell transplant is curative for some patients with acute myeloid leukemia (AML); however, not all patients are eligible. To aid the clinician in making treatment decisions, the treatment pathway for older patients with AML should take into account their disease risk, comorbidities, and the effectiveness of treatment in improving survival.
Researchers conducted a retrospective analysis of 118 patients aged >65 years who were diagnosed with AML. Patients receiving therapy (N = 90) were categorized into 2 groups, including those receiving intensive induction therapy and those receiving induction therapy with a hypomethylating agent. Comorbidities were similar in the 2 groups. A total of 71 patients were categorized as poor risk; 25 (35%) of these patients underwent allogeneic stem-cell transplant (ASCT). All patients who underwent transplantation had achieved complete remission, whereas 8 patients in complete remission did not proceed to transplantation.
Across the pooled risk groups, the study results showed transplant was associated with improved median survival (34.6 months; P <.001) compared with induction therapy without transplant (6.5 months), regardless of induction regimen. The survival advantage was greatest in the poor-risk group (39.6 months with transplant vs 6.1 months without transplant). Patient age and chemotherapy regimen (including hypomethylating agents) did not affect median survival in this analysis.
The researchers concluded that ASCT can be safely performed in patients aged >70 years and that transplant confers a significant survival advantage compared with chemotherapy alone.
Source: Lachowiez CA, Cook, RJ, Meyers G, et al. Allogeneic transplant leads to markedly improved survival in older patients with AML. J Clin Oncol. 2017;35(15 suppl). Abstract 7048.
Effect of Cytarabine/Anthracycline/Crenolanib Induction on MRD in Newly Diagnosed AML with FLT3 Mutation
In acute myeloid leukemia (AML), patients who are positive for the FLT3-ITD mutation have a particularly poor prognosis. Elimination of FLT3-positive clones may lead to reduced relapse rates. Crenolanib, a type I FLT3 tyrosine kinase inhibitor, inhibits FLT3-ITD and TKD mutations. In this study, researchers found that a single induction cycle of crenolanib in combination with cytarabine/anthracycline leads to minimal residual disease (MRD) negativity and a low rate of early relapse in patients with newly diagnosed FLT3-positive AML.
A total of 32 evaluable patients with newly diagnosed, FLT3-positive AML received induction treatment with cytarabine 100 mg/m2 daily for 7 days and either daunorubicin (90 mg/m2 if aged <60 years; 60 mg/m2 if aged ≥60 years) or idarubicin 12 mg/m2 for 3 days. Crenolanib 100 mg 3 times daily was started on day 9 until 72 hours before the next chemotherapy.
MRD data were available in 24 patients, of whom 20 (80%) became MRD-negative after treatment. After a median follow-up of 8.2 months, 16 (80%) patients remain relapse-free. Patients aged ≥60 years were associated with higher MRD-negative complete remission and lower relapse rate.
The data suggest that crenolanib administered in combination with standard induction is associated with a high rate of achieving an MRD-negative state and a low rate of relapse in previously untreated adults with FLT3 mutation. Although these findings are promising, further research is needed to determine whether treatment with a crenolanib-containing regimen is superior to treatment with standard chemotherapy alone.
Source: Stone RM, Collins R, Tallman MS, et al. Effect of cytarabine/anthracycline/crenolanib induction on minimal residual disease (MRD) in newly diagnosed FLT3 mutant AML. J Clin Oncol. 2017;35(15 suppl). Abstract 7016.
Suboptimal Adherence to Guideline-Recommended Molecular Testing in Patients with Newly Diagnosed AML: Data from the Connect MDS/AML Disease Registry
Although the identification of recurrent mutations in acute myeloid leukemia (AML)-associated genes has prognostic value and may help guide treatment decisions, little is known about molecular genetic testing patterns for AML in clinical practice. Previous analyses of the Connect MDS/AML Disease Registry showed suboptimal adherence to World Health Organization 2008 recommendations for AML in a cohort of patients with newly diagnosed AML.
This analysis of the Connect MDS/AML Disease Registry evaluated patterns of molecular genetic testing in a similar patient population in community and academic settings. The current analysis evaluated the percentage of patients with AML with molecular genetic testing recommended by National Comprehensive Cancer Network (NCCN) guidelines, including for NPM1, FLT3-ITD, CEBPA, IDH1, IDH2, DNMT3A, and KIT.
Statistical analyses evaluated the effects of several variables, including site of care, karyotype, age, and type of insurance coverage, on the likelihood of molecular genetic testing.
During the 3-year study period, 259 patients with AML were enrolled at 86 sites. Overall, molecular genetic testing was reported in 173 of 259 (67%) patients. Younger patients, patients treated at academic versus community sites, patients with normal versus abnormal karyotype, and patients with non-Medicare versus Medicare insurance were all more likely to receive testing.
There was substantial variance in testing for specific mutations, with only 6% (N = 6) receiving all 4 NCCN-recommended molecular genetic tests in patients with normal karyotype. Of the NCCN-recommended tests, those for FLT3-ITD (81%) and NPM1 (80%) were most often reported, and TP53 (14%) was least often reported.
On a positive note, data from the Connect MDS/AML Disease Registry indicate that 66% of newly diagnosed patients with AML receive molecular testing for recurrent mutations; however, the majority does not receive guideline-recommended testing. Although further analysis of testing patterns is warranted, the data reveal an opportunity to educate providers about appropriate testing recommended by NCCN.
Source: Pollyea DA, George T, Foucar KM, et al. Molecular genetic testing patterns for patients with newly diagnosed acute myeloid leukemia (AML) enrolled in the CONNECT MDS/AML disease registry. J Clin Oncol. 2017;35(15 suppl). Abstract 7022.
Improved Survival with Fludarabine and Timed Sequential Busulfan Regimen in Older Patients with AML or MDS
In this study, researchers evaluated treatment with fludarabine and busulfan administered in a timed sequential regimen versus a reduced-intensity conditioning (RIC) regimen. Outcomes were assessed in an older patient population.
To be eligible for the study, patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) were required to have adequate organ function, a matched related or unrelated donor, and received treatment between January 2012 and September 2016.
Patients in the timed sequential cohort received intravenous (IV) busulfan 80 mg/m2 per day on days –13 and –12 and fludarabine 40 mg/m2 per day followed by IV busulfan on days –6 to –3. Patients in the RIC cohort received fludarabine 40 mg/m2 per day followed by IV busulfan daily for 4 days (days –6 to –3).
The study population comprised 162 patients, 50 with MDS and 112 with AML. Patient characteristics were well-balanced and without any significant difference in the 2 cohorts. The median age was 65 years in the timed sequential group and 66 years in the RIC group.
Two-year overall survival (51% vs 31%; P = .01) and progression-free survival (PFS; 45% vs 24%; P = .004) were significantly better in the timed sequential group. At 2 years, 59% of patients in the RIC group had progressed compared with 34% of patients in the timed sequential group (P = .003) The data indicate that there was a reduction in disease progression without any increase in nonrelapse mortality. The difference in PFS persisted after adjustment for other covariates. The researchers concluded that the timed sequential busulfan regimen improves survival and appears promising in older patients with AML and MDS.
Source: Popat UA, Sliba R, Oran B, et al. Better survival with fludarabine and timed sequential busulfan regimen in older patients with AML/MDS. J Clin Oncol. 2017;35(15 suppl). Abstract 7046.
Sorafenib plus 5-Azacytidine in Older, Untreated FLT3-ITD–Positive Patients with AML
Previously, the tyrosine kinase inhibitor sorafenib in combination with the demethylating agent 5-azacytidine was found to be safe and effective in patients with relapsed/refractory FLT3-ITD–positive acute myeloid leukemia (AML). Researchers sought to determine whether this combination is also safe and effective in older, untreated FLT3-ITD–positive patients with AML.
Inclusion criteria included FLT3-ITD–positive patients aged ≥60 years with Eastern Cooperative Oncology Group performance status ≤2. Patients were treated with azacytidine 75 mg/m2 daily for 7 days and sorafenib 400 mg twice daily for 28 days. A total of 28 patients with untreated AML were enrolled, the majority (64%) of whom had normal karyotype.
All 28 patients were evaluable; the overall response rate (ORR) was 79% (N = 22), of which 20 (71%) achieved complete remission (CR) or CR with incomplete platelet or blood count recovery, and 2 (7%) with partial response. The median number of cycles to achieve response was 2. After a median follow-up of 4.2 months, 5 patients are alive. The median overall survival (OS) for the entire group is 8.1 months compared with 9.1 months in the 22 responders.
Evaluable patients treated with azacytidine plus sorafenib were compared with a matched cohort of historical FLT3-ITD–positive patients aged ≥60 years who were treated with hypomethylator-based therapy without sorafenib (N = 14). In the 2 patient populations, ORR and median OS were found to be similar. However, the remission duration for the responding patients treated with azacytidine plus sorafenib was significantly longer (14.5 months) than those of other hypomethylating agent regimens without sorafenib (3.8 months; P = .01). The safety profiles were similar for the 2 cohorts.
The researchers concluded that the combination of azacytidine and sorafenib is well-tolerated and effective in older, untreated patients with FLT3-ITD–positive AML.
Source: Ohanian M, Garcia-Manero G, Levis MJ, et al. Sorafenib plus 5-azacytidine (AZA) in older untreated FLT3-ITD mutated AML. J Clin Oncol. 2017;35(15 suppl). Abstract 7029.
Nivolumab with Azacytidine in Patients with Relapsed AML
Previous research suggests that blocking PD-1/PD-L1 pathways may enhance antileukemic responses in patients with acute myeloid leukemia (AML). Because azacytidine upregulates PD-1 in AML, the combination of a PD-1 inhibitor with azacytidine is a rational choice for investigation. In this study, azacytidine 75 mg/m2 on days 1 to 7, with nivolumab 3 mg/kg on days 1 and 14, was established as the recommended phase 2 dose. Courses were repeated every 4 to 5 weeks indefinitely, and responses were evaluated at the end of 3 courses. In this single-arm study, the results were compared against a historical cohort of patients receiving hypomethylator combination salvage treatment.
To date, 70 patients have been enrolled; the baseline characteristics were a median age of 70 years, a median of 2 previous regimens, and secondary AML and poor-risk cytogenetics in 43% and 34% of enrolled patients, respectively. The common mutations included TP53 (N = 16), DNMT3A (N = 12), TET2 (N = 11), and ASXL1 (N = 11). The overall response rate was 32%, including 15 (21%) patients who achieved complete remission (CR) or CR with incomplete blood count recovery and 7 (14%) with hematologic improvement. In addition, 17 (24%) patients had ≥50% bone marrow blast reduction, and 26 (37%) had stable disease after 6 months or progressive disease. The median overall survival for evaluable patients was 6.2 months in patients receiving azacitidine and nivolumab versus 4.1 months for patients receiving historical hypomethylator combination salvage protocols. Immune toxicities occurred in 18 patients; all responded rapidly to steroids, and 16 of 18 patients were successfully rechallenged.
The patients who achieved CR or CR with incomplete blood count recovery had higher pretherapy total CD3 and CD8+ T-cell levels in the bone marrow. Responders also demonstrated progressive increases in CD8+ and CD4+ infiltrates in the bone marrow. However, responders and nonresponders had increases in CTLA-4+ CD8+ cells on therapy. The researchers concluded that full-dose azacitidine and nivolumab are tolerable and produces durable responses in first salvage AML. CTLA-4 was upregulated on therapy, suggesting the potential for dual checkpoint blockade.
Source: Daver NG, Basu S, Garcia-Manero G, et al. Phase IB/II study of nivolumab with azacytidine (AZA) in patients (pts) with relapsed AML. J Clin Oncol. 2017;35(15 suppl). Abstract 7026.