Weighing Conditioning Regimens for Patients With CML Undergoing Transplant

Conditioning with a reduced-intensity, nonmyeloablative regimen was associated with similar post-transplant survival but a lower risk of chronic graft-versus-host disease (cGVHD), compared with a standard myeloablative conditioning, according to a study of patients with chronic myeloid leukemia (CML) published in Blood Advances.

“Our findings suggest that overall survival in patients with CML who are ineligible for myeloablative conditioning based on clinical grounds is similar, should these patients receive reduced-intensity conditioning instead,” lead study author Saurabh Chhabra, MD, from the Medical College of Wisconsin, told ASH Clinical News.

However, “the absence of an overall survival difference is not to be taken as an argument in favor of selecting reduced-intensity over myeloablative conditioning,” he added. “On the contrary, while reduced-intensity conditioning afforded similar survival, it was associated with increased early post-transplant relapse risk.”

In this study, the authors analyzed outcomes among 1,395 patients with CML (age range = 18-60 years) who received allogeneic hematopoietic cell transplantation (alloHCT) with either a sibling donor or unrelated donor and were enrolled in the Center for International Blood and Marrow Transplant Research (CIBMTR) registry between 2007 and 2014.

Recipients and donors in this study were matched at the allele level (HLA-A, HLA-B, HLA-C, and HLA- DRB1 loci) or mismatched at a single HLA locus. Consensus CIBMTR criteria determined conditioning intensity, with:

  • 1,204 patients receiving a myeloablative regimen, consisting of total body irradiation (TBI) ≥5 Gy single dose or ≥8 Gy fractionated dose, or busulfan >8 mg/kg orally or >6.4 mg/kg intravenously
  • 191 patients receiving reduced-intensity conditioning (RIC): busulfan ≤8 mg/kg oral or intravenous equivalent, melphalan ≤150 mg/m2, or TBI ≤2 Gy

In the multivariable analysis for overall survival (OS; primary endpoint), there was no significant difference between the myeloablative and RIC cohorts (hazard ratio [HR] = 0.99; p=0.95). In addition, the investigators found no difference in five-year OS between the cohorts: 53 percent for myeloablative versus 53 percent for RIC regimens (p=0.98).

The following variables were associated with a higher risk of post-alloHCT mortality:

  • alloHCT with a well-matched unrelated donor (HR=1.32; 95% CI 1.09-1.60; p=0.004) or partially matched unrelated donor (HR=1.45; 95% CI 1.10-1.89; p=0.007)
  • peripheral blood graft (HR=1.36; 95% CI 1.10-1.66; p=0.004)
  • accelerated-phase CML (vs. chronic phase 1 CML; HR=1.59; 95% CI 1.13-2.24; p<0.001)
  • chronic-phase 2+ CML (vs. chronic phase 1 CML; HR=1.18; 95% CI 0.85-1.63; p<0.001)

The authors also observed no differences between the myeloablative and RIC groups in leukemia-free survival (HR=1.13; p=0.29) or five-year probability of leukemia-free survival (44% vs. 43%; p=0.81).

However, in secondary analyses, patients in the RIC cohort had a higher risk of relapse within the first five months post-transplant, compared with those in the myeloablative conditioning group (HR=1.85; 95% CI 1.27-2.70; p=0.001). There were no differences in the cumulative incidence of late, five-year relapse (26% for myeloablative vs. 25% for RIC; p=0.96).

One year after transplant, the risk of cGVHD was higher in the myeloablative group, compared with the RIC group (50% vs. 41%; p=0.02). This association was also observed at five years post-transplant: 59 percent versus 51 percent, although it did not reach statistical significance (p=0.07).

With the lack of any OS advantage with one conditioning regimen versus the other, Dr. Chhabra said, based on these results, “we can speculate that patients with higher relapse risk (such as those with  in chronic-phase 2 [or more advanced] disease or those in accelerated phase at transplant) may be better suited for myeloablative conditioning, if eligible.”

According to the researchers, limitations of the study included the missing data on frequency, timing, and indications for CML therapies, including tyrosine kinase inhibitors (TKIs) and donor leukocyte infusion used after alloHCT.

“TKIs used as maintenance might have resulted in lower relapse and/or improved OS in relapsed CML patients in the reduced-intensity-conditioning cohort,” Dr. Chhabra explained, citing the lack of data on conditioning-intensity selection criteria and the indication for alloHCT in the entire cohort as inherent study limitations. Residual confounding also was possible in this analysis, “despite the multivariable analysis to control for the differences in various clinical variables between myeloablative and RIC cohorts,” he stated.

Co-author Amer Assal, MD, reports financial relationships with Boston Biomedical and Incyte. The other authors report no relevant financial relationships.


Reference

Chhabra S, Ahn KW, Hu ZH, et al. Myeloablative vs reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chronic myeloid leukemia. Blood Adv. 2018;2:2922-36.

Although it is encouraging that, overall, the results with both types of preparative regimens were similar, the outcome of the group undergoing myeloablative conditioning turned out to be much better than one would have thought given the skew toward patients with more advanced disease in that group.

In this study, the choice of preparative conditioning regimen was made by the treating physician, likely in consultation with the patient and according to standard operating procedure at the transplant site. This explains the differences in the patient populations included in the study; there also were more patients in an advanced state of chronic-phase CML in the group undergoing myeloablative conditioning, which suggests that more advanced disease biology was associated with the choice of regimen.

However, the risk of early relapse was still lower in those who were treated with the myeloablative regimen, suggesting that initial disease control, even among patients with higher-risk disease, was better with the myeloablative regimen.

Clinicians should be reassured that, for the right patient, a reduced-intensity regimen has the significant potential to induce long-term disease control – not inferior and perhaps equivalent to what can be achieved with a fully myeloablative regimen.

For patients with more advanced disease, that may not be the case, and a more updated assessment might look at secondary cytogenetic or molecular features that might confer added risk and may predict for more rapid relapse after a reduced-intensity regimen.

Gary Schiller, MD
David Geffen School of Medicine
University of California, Los Angeles

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