CLINICAL NEWS
in a Different Vein
Research from ASH’s online peer-reviewed
journal, Blood Advances
Weighing Conditioning Regimens for Patients With CML
Undergoing Transplant
Conditioning with a reduced-intensity, nonmyeloabla-
tive 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 dif-
ference is not to be taken as an argument in favor of
selecting reduced-intensity over myeloablative condition-
ing,” 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/m 2 , 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 condi-
tioning regimen versus the other, Dr. Chhabra said, based
on these results, “we can speculate that patients with
higher relapse risk (such as those with 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.
“While reduced-intensity
conditioning afforded
similar survival, it
was associated with
increased early post-
transplant relapse risk.”
–SAURABH CHHABRA, MD
“TKIs used as maintenance might have resulted in
lower relapse and/or improved OS in relapsed CML
patients in the reduced-intensity-conditioning co-
hort,” Dr. Chhabra explained, citing the lack of data on
conditioning-intensity selection criteria and the indica-
tion 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.
Dr. Chhabra reports financial relationships with Boston
Biomedical and Incyte. ●
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.
PERSPECTIVES
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
ASHClinicalNews.org
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
ASH Clinical News
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