General AML

A comparison of reduced-intensity and myeloablative before Hematopoietic Cell Transplantation in MDS and AML patients

Hematopoietic Cell Transplantation (HCT) has been shown to offer a chance of cure for patients with Acute Myeloid Leukemia (AML) by introducing a potent immunologic effect termed Graft Versus Leukemia (GVL). The intensity of chemotherapy before HCT varies between patients due to several factors including age, performance status, and pre-existing conditions.1 Furthermore, the ideal conditioning regimen before HCT is not yet elucidated, hence the rationale for this study. Myeloablative Conditioning (MAC) is associated with increased toxicity and Treatment Related Mortality (TRM). Reduced Intensity Conditioning (RIC), usually used in old and less fit patients, depends on GVL effect and it is associated with less toxicity.2

In an article recently published ahead of print in the Journal of Clinical Oncology, Bart L. Scott from the Fred Hutchinson Cancer Research Center and colleagues discuss their results from their phase III randomized trial, where they compared the intensity of conditioning regimens, MAC and RIC, in AML and Myelodysplastic Syndrome (MDS) patients.2

In this study, 272 patients (AML = 218, MDS = 54 [age between 18–65 years, median age = 54.8 years]) with comorbidity index ≤ 4 and < 5% marrow myeloblasts pre-HCT were enrolled. Patients were randomly assigned to receive either MAC (n = 135) or RIC (n = 137) followed by HCT. The primary endpoint of this study was Overall Survival (OS) at 18 months post-random assignment. The secondary endpoints of the study include Relapse Free Survival (RFS) and TRM.

The key results of the study were:
  • 18-month OS in patients that received MAC and RIC; 77.5% vs 67.7%, P = 0.07
  • 18-month RFS in patients that received MAC and RIC; 67.8% vs 47.3%, P < 0.001
  • 18-month cumulative incidence of relapse in patients receiving MAC (n = 13) and RIC (n = 66); 13.5% vs 48.3%, P < 0.001
  • 18-month incidence of TRM in patients receiving MAC and RIC; 15.8% vs 4.4%, P = 0.002
  • In patients assigned to receive MAC (n = 35) death occurred mostly due to GVHD (50%) and relapse (33.3%)
  • In patients assigned to receive RIC (n = 35) death occurred mostly due to relapse (86.4%)

In summary, RIC resulted in lower TRM and higher risk of relapse compared to MAC. However, MAC had a higher OS and a significantly higher RFS compared to RIC. The authors noted that the relapse rates observed in their study exceeded expectations, which led to early termination of the study due to ethical reasons.

The authors concluded by stating that their data support the use of MAC as the standard care for fit AML and MDS patients.

Abstract
Purpose

The optimal regimen intensity before allogeneic hematopoietic cell transplantation (HCT) is unknown. We hypothesized that lower treatment-related mortality (TRM) with reduced-intensity conditioning (RIC) would result in improved overall survival (OS) compared with myeloablative conditioning (MAC). To test this hypothesis, we performed a phase III randomized trial comparing MAC with RIC in patients with acute myeloid leukemia or myelodysplastic syndromes.

Patients and Methods

Patients age 18 to 65 years with HCT comorbidity index ≤ 4 and < 5% marrow myeloblasts pre-HCT were randomly assigned to receive MAC (n = 135) or RIC (n = 137) followed by HCT from HLA-matched related or unrelated donors. The primary end point was OS 18 months post–random assignment based on an intent-to-treat analysis. Secondary end points included relapse-free survival (RFS) and TRM.

Results

Planned enrollment was 356 patients; accrual ceased at 272 because of high relapse incidence with RIC versus MAC (48.3%; 95% CI, 39.6% to 56.4% and 13.5%; 95% CI, 8.3% to 19.8%, respectively; P < .001). At 18 months, OS for patients in the RIC arm was 67.7% (95% CI, 59.1% to 74.9%) versus 77.5% (95% CI, 69.4% to 83.7%) for those in the MAC arm (difference, 9.8%; 95% CI, −0.8% to 20.3%; P = .07). TRM with RIC was 4.4% (95% CI, 1.8% to 8.9%) versus 15.8% (95% CI, 10.2% to 22.5%) with MAC (P = .002). RFS with RIC was 47.3% (95% CI, 38.7% to 55.4%) versus 67.8% (95% CI, 59.1% to 75%) with MAC (P < .01).

Conclusion

OS was higher with MAC, but this was not statistically significant. RIC resulted in lower TRM but higher relapse rates compared with MAC, with a statistically significant advantage in RFS with MAC. These data support the use of MAC as the standard of care for fit patients with acute myeloid leukemia or myelodysplastic syndromes.

References
  1. Sarmiento M.M. et al. Intensity adjustment of hematopoietic allogeneic transplantation in acute leukemia. Rev Med Chil. 2016 Sep; 144(9):1112–1118. DOI: 4067/S0034-98872016000900003.
  2. Scott B.L. et al. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol. 2017 Feb 13. DOI: 1200/JCO.2016.70.7091. [Epub ahead of print].