Allogeneic HSCT Recommended Early for Older Patients With Higher-Risk MDS

Allogeneic hematopoietic stem cell transplant with a donor leads to significant improvements in outcomes, even for patients up to age 75, in patients with higher-risk myelodysplastic syndrome.

Allogeneic hematopoietic stem cell transplant (HSCT) with a donor leads to significant improvements in outcomes, even for patients up to age 75, in patients with higher-risk myelodysplastic syndrome (MDS), according to the results of a study from the Blood and Marrow Transplant Clinical Trials Network.

The role of allogeneic HSCT as treatment of patients with higher-risk MDS is the enhancement of outcomes like survival compared with hypomethylating therapy alone.

During a presentation for the 2020 American Society of Hematology (ASH) Annual Meeting, Corey S. Cutler, MD, MPH, FRCPC, explained that multiple clinical trials have hinted that having a donor for allogeneic HSCT could be imperative for achieving better outcomes in patients with higher-risk MDS who are aged 50 to 75 years. Improvements can be seen in overall survival (OS) and leukemia-free survival (LFS) with maintained quality of life (QoL) compared with no-donor controls.

“Despite this evidence, allogeneic transplantation is not offered to a large proportion of older individuals with high-risk MDS and is not a covered service by Medicare in the United States,” said Cutler, who is medical director, Adult Stem Cell Transplantation Program, director of clinical research, Stem Cell Transplantation, director, Stem Cell Transplantation Survivorship Program, institute physician, Dana-Farber Cancer Institute, and an associate professor of medicine, Harvard Medical School.

Cutler’s statement highlighted the need to further study the use of allogeneic HSCT in patients with higher-risk MDS aged 50 to 75. The overall goal of the open-label, multi-center, biologic assignment study (NCT02016781) was to assess whether allogeneic HSCT was beneficial for this patient population.

Patients enrolled in the study were assigned to either the donor or no-donor arm based on high-resolution human leukocyte antigens (HLA) typing of family matches, as well as a 90-day search through a database of non-relative matches. All patients enrolled were initially assigned to the no-donor arm then transferred to the donor arm once a match was identified. The study protocol was set up so that any patient who did not have a donor after 90 days remained in the no-donor arm for the remainder of the study. Data for patients who died within 90 days of the study’s initiation were evaluated as part of the no-donor arm.

The study enrolled patients aged 50 to 75 who were diagnosed with primary MDS with intermediate-2 to high risk according to the International Prognostic Scoring System (IPSS), per the eligibility criteria. Patients were also required to be eligible for traditional reduced-intensity transplantation. Whether patients received a transplant or non-transplant therapy was at the discretion of the center where they received treatment.

Adjusted 3-year OS rate was the primary end point explored in the study and LFS was the main secondary end point. To prevent bias based on biologics, adjustments were made for age, ethnicity, performance status, and disease status, Cutler stated. The investigators also factored in comorbidities, IPSS, MDS duration, and response to hypomethylating therapy. The study was 80% powered to detect a difference of 15% in the 3-year OS rate. Patients who died or withdrew from the study within the 90-day donor search window were not included in sensitivity analyses. A prespecified as-treated analysis was conducted and QoL and cost-effective data were also collected.

The study was actively monitored by a data and safety monitoring board assigned by the National Heart, Lung, and Blood Institute.

Overall, the patient population included 384 older patients with MDS. A total of 260 patients were included in the donor arm and 124 were in the no-donor arm, including 7 who died during the 90-day period. These patients made up the intent-to-treat population of the study.

At baseline, it was shown that the overall patient population had a median age of 66.7 years with 61.2% of patients being 65 years of age or older. The population was 62.8% male. The baseline Karnofsky performance score was 90 to 100 for 50.8% of patients and was <90 for 49.2%. The MDS duration from the time of diagnosis to enrollment in the study was a mean of 9.2 months. The median MDS duration from the time of diagnosis to study enrollment was 2.3 months (range, 0.2 -211.6). The majority of the patients had an intermediate-2 IPSS risk score, and the remaining 33.9% had a high-risk IPSS score.

Prior treatment with a hypomethylating agent and donor status were also assessed at baseline. Most patients (31.5% each) had no response to prior hypomethylating therapy or never received a hypomethylating agent. Of the patients who did receive a hypomethylating agent and responded, complete responses (CRs) were achieved in 4.4% of patients and partial responses for 18.0%. Response to hypomethylating agents was unknown for 14.6% of patients. A matched unrelated donor was identified for 69.2% of patients at baseline.

Only 15.8% of the patient population did not have any comorbidities at enrollment. Comorbidities found at baseline were sorted per the Hematopoietic Cell Transplantation–specific Comorbidity Index (HCT-CI). It was shown that 11.9% of patients had 1 comorbidity, 13.5% had 2, and 37.7% had 3. Information was missing for 21.2% of patients.

The 3-year OS rate was estimated to be 47.9% (95% CI, 41.3%-54.1%) in the donor arm compared with 26.6% (95% CI, 18.4%-35.6%) for an absolute improvement of 21.3 percentage points (P = .0001). Based on this result, Cutler noted that patients with a donor had significantly higher 3-year OS when compared with patients who did not have a donor. No effect on outcome was noted in the sensitivity analysis, Cutler explained.

Subgroup analyses of 3-year OS rate based on stratification factors showed no significant difference in the treatment outcomes for any subgroup of patients based on donor status. This was especially true for the subgroup of patients above (odds ratio, 2.962) or below (odds ratio, 2.436) the age of 65.

Patients in the donor arm achieved an LFS rate of 35.8% (95% CI, 29.8%-41.8%), according to the 3-year estimate. In comparison, the no-donor arm had an estimated 3-year LFS rate of 20.6% (95% CI, 13.3%-29.1%). The absolute improvement in LFS was 15.2 percentage points (P = .003). Cutler made a note that significant improvement in this outcome was observed in the donor group demonstrating similarity to the OS analysis. There was also no impact on outcomes according to the sensitivity analysis. No major differences in LFS were seen in the patients above (odds ratio, 2.206) or below (odds ratio, 2.398) the age of 65, or for the other subgroups investigated.

In explanation of the as-treated analysis, Cutler said: “The non-compliance rate in this trial was 26%. Forty-four subjects in the donor arm did not undergo transplant because of disease progression, subject preference, progressive comorbidity, or donor or insurance issues. In addition, 26 subjects in the donor arm underwent myeloablative transplantation due to physician or subject preference or disease-related issues. In the no-donor arm, 31 subjects underwent transplantation, including 9 who found a donor after the 90-day search window. All others received alternative donor transplants, including 6 who received myeloablative conditioning. The as-treated analysis subjects who died during the search window were excluded. This as-treated analysis, therefore, compares reduced-intensity transplantation to best supportive care in subjects with MDS.”

An even greater improvement in OS and LFS were observed in the as-treated analysis. The estimated absolute improvement in the 3-year OS rate in the donor arm compared with the no-donor arm was 31.4 percentage points (P = .0001). LFS also favored the donor arm versus the no-donor arm with an absolute improvement of 28.4 percentage points (P = .0001).

“For the 25 subjects in the no-donor arm who subsequently underwent alternative donor reduced-intensity transplant, 3-year overall survival and leukemia-free survival were both 58.5%, similar to outcomes in the donor arm, underscoring the potential value of alternative donor transplant in this high-risk patient population,” Cutler stated during his presentation.

Finally, the QoL analysis assessed general QoL status using the Functional Assessment of Chronic Illness Therapy General (FACT-G) scoring system. The physical and mental impact of transplantation was also evaluated using 2 separate SF-36 questionnaires. An overall QoL was measured using the EQ-5D score. Cutler et al found that QoL scores at any time during the study were not significantly different between the 2 study arms. Cutler stated that the factors that were found to be significant were not clinically meaningful and further analysis of the QoL data will ensue once data collection is complete.

Based on the findings from this study, Cutler et al recommended that allogeneic HSCT become an integral component of managing higher-risk disease in patients with MDS who are aged 50 to 75. It was also recommended that patients be referred early to centers for transplantation and that Medicare insurance covers the cost of treatment, based on this research.


Cutler C, Horowitz M, Logan B, et al; Blood and Marrow Transplant Clinical Trials Network. A multi-center biologic assignment trial comparing reduced intensity allogeneic hematopoietic cell transplantation to hypomethylating therapy or best supportive care in patients aged 50-75 with advanced myelodysplastic syndrome: blood and marrow transplant clinical trials network study 1102. Presented at: 2020 ASH Annual Meeting; December 5-8, 2020; Virtual. Abstract 75.