Ehab Atallah, MD
CPX-351 is a liposomal cytarabine and daunorubicin. It was FDA approved in 2017 for the treatment of patients with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). The approval was based on the results from a randomized trial comparing CPX-351 vs standard 7 +3 chemotherapy in patients older that 65 with t-AML or AML-MRC. The 5-year results from that study were recently published by Lancet et al . At 5 years of follow-up, CPX-351 continued to show benefit in older patients with t-AML or AML-MRC vs standard chemotherapy with cytarabine for 7 days and daunorubicin for 3 days ( 7+3) . The median OS in favor of CPX-351 vs 7+3 group was maintained (hazard ratio, 0.70; 95% confidence interval [CI], 0.55-0.91). At 5 years, survival estimates were higher for CPX-351 vs 7+3 (18% [95% CI, 12%-25%] vs 8% [95% CI, 4%-13%]). Overall, 5% of deaths in both groups were considered related to the study treatment. Overall, more patients treated with CPX-351 were able to proceed to stem cell transplantation (SCT) compared to those treated with 7 + 3 (35% vs 25%).
The 3-year overall survival from SCT was 56% vs 23% for patients treated with CPX-351 vs 7 +3. Of the responding patients who did not proceed to SCT, only 3 patients were alive at 5 years. Although this data is encouraging, it demonstrates that we have a long way to go to improve the outcome of these patients. In addition, more patients who achieve remission should proceed to SCT in order to improve the survival of this patient population ( Lancet JE et al ). In terms of supportive care during induction chemotherapy, two published studies this month evaluated two approaches to aiming to decrease the morbidity from infections: prospective monitoring for fungal infections and the use of romyelocel with G-CSF. Prospectively monitoring for fungal infections was performed as an observation study imbedded within a phase 3 Children’s Oncology Group trial ( ACCL0933). The study included 471 patients with AML (age, 3 months-30 years) receiving fluconazole (n=235) or caspofungin (n=236).
Twice-weekly surveillance with galactomannan enzyme immunoassay (GM-EIA) and b-D-glucan (BDG) assay were performed in all patients. The negative predictive value was greater than 99% for an individual or combination of GM-EIA and BDG assays. However, true positive results were not observed in any sample collected within 7 days of an invasive aspergillosis/candidiasis diagnosis, resulting in sensitivity and positive predictive value for each test of 0%. This approach was ineffective at detecting invasive fungal diseases (IFDs) in children, adolescents, and young adults with acute myeloid leukemia (AML) receiving antifungal prophylaxis ( Fisher BT et al ).
A different approach to reduce infection morbidity and mortality during induction chemotherapy is the administration of romyelocel. Myeloid progenitor cells are cells that can produce granulocytes but have no long-term reconstitution capability. Romyelocel is a cryopreserved product, of MPC manufactured by ex vivo expansion of CD34 + hematopoietic stem cells. Romyelocel is capable of producing granulocytes, and thereby may reduce the severity or duration of neutropenic fevers. This phase 2 study included 163 patients with de novo AML receiving induction chemotherapy. Evaluable patients (n=120) were randomly assigned to receive either romyelocel-L plus G-CSF (n=59) or G-CSF monotherapy (n=61). From days 15 to 28, romyelocel-L plus G-CSF vs G-CSF monotherapy significantly reduced the mean duration of febrile episodes (2.36 days vs 3.90 days; P = .02) and incidence of infections (6.8% vs 27.9%; P = .0013). Length of hospitalization was significantly shorter in the romyelocel-L plus G-CSF vs G-CSF monotherapy group (25.5 days vs 28.7 days; P = .002). These results are encouraging, and a phase III trial is suggested by the authors. ( Desai PM et al ).
Finally, a study by MDACC reported disappointing results with the use of venetoclax in patients with tp53 mutation. Findings are from a retrospective analysis of 238 patients with newly diagnosed TP53-mutated AML treated with either VEN-based (n=58) or non-VEN-based (n=180) therapies. The addition of venetoclax to standard treatment regimens (VEN-based) did not improve clinical outcomes in patients with TP53-mutated acute myeloid leukemia (AML), highlighting the need for novel therapies in this patient population. Overall, there was no significant differences in overall survival (median, 5.7 months vs 6.6 months; P = .4), relapse-free survival (median, 3.5 months vs 4.7 months; P = .43), 4-week mortality (7% vs 10%; P = .5), and 8-week mortality (22% vs 17%; P = .4) in patients receiving VEN-based vs non-VEN-based therapies ( Venugopal S et al ). Clearly, better therapies are needed for this patient population.