Syed Ali Abutalib, MD
Elizabeth J. Shpall, MD
To complement The ASCO Post’s continued comprehensive coverage of the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on the use of allogeneic hematopoietic cell transplantation (allo-HCT) in the treatment of patients with acute leukemias and myelodysplastic syndromes (MDS). For full details of these study abstracts, visit ashpublications.org.
Acute Myeloid Leukemia and MDS
ABSTRACT 189: Randomized study (n = 250) of myeloablative conditioning therapy with fludarabine and once daily intravenous busulfan with or without clofarabine for allo-HCT in patients with MDS (n = 69) and acute myeloid leukemia (AML; n = 181; ClinicalTrials.gov identifier NCT01471444)1
Methods: About 120 patients received fludarabine (40 mg/m2 × 4 days), busulfan × 4 days (AUC of 6,000 mM/min for patients aged ≤ 60 and 4,000 mM/min for patients aged 61–70) and clofarabine (10 mg/m2 × 4 days immediately prior to fludarabine; experimental arm) and 130 received fludarabine and busulfan (control arm). A total of 95 patients had a human leukocyte antigen (HLA)-matched sibling donor, 155 had an HLA-matched unrelated donor. About 92 patients (37%) had poor-risk cytogenetics. About 133 patients were in remission, and 117 had active disease at the time of transplantation. HCT Comorbidity Index score (HCT-CI2; a pre–allo-transplant comorbidity assessment tool) varied from 0 to 10, and scores were evenly distributed between the two groups. Performance status was at least 90% in 88% of patients. Graft-vs-host disease prophylaxis was tacrolimus and mini-methotrexate. In addition, the recipients of unrelated grafts received low-dose rabbit antithymocyte globulin, a total dose of 4 mg/kg (0.5 mg/kg on day –3, 1.5 mg/kg on day –2, and 2.0 mg/kg on day –1).
Key Results:
All evaluable patients (n = 249) in both arms achieved engraftment.There was a significantly lower risk of disease progression with the addition of clofarabine (P = .025), but this benefit was offset by a higher risk of nonrelapse mortality (P = .018).
There was no significant difference in progression-free-survival for patients in complete remission. Younger adults (≤ 60) not in remission had a median progression-free-survival of 28 months with the addition of clofarabine vs 8 months in the control arm. Older adults (> 60) not in remission had a median progression-free-survival of approximately 25 months with the addition of clofarabine vs 6 months in the control arm.
Additional analysis revealed that patients with an HCT-CI of 0 to 2 and active disease (not in remission) benefited more from the experimental therapy.
About 6% of patients developed grade 3 to 4 acute graft-vs-host disease, whereas the rate of chronic graft-vs-host disease was 39%.
Clinical Implications: Disease relapse remains the major cause of treatment failure following hematopoietic stem cell transplantation for AML/MDS, especially for patients undergoing transplant with active disease. A major goal is to develop more effective antileukemic/anti-MDS regimens without adding to nonrelapse morbidity and mortality.
In this trial, the investigators showed the safety and better efficacy of adding clofarabine to the backbone of myeloablative conditioning with fludarabine and busulfan in patients who underwent allo-HCT with active marrow disease. Also, of note, an HCT-CI score greater than 2, but not advanced age, dampened the benefit of the addition of clofarabine in patients with active disease. In summary, it is reasonable to consider adding clofarabine to fludarabine and busulfan–based myeloablative conditioning in patients with AML and MDS who are not in remission and have an HCT-CI score of up to 2.
Allo-HCT in Older Adults With MDS
ABSTRACT 75: A multicenter (34 centers) biologic assignment trial comparing reduced-intensity conditioning HLA-matched allo-HCT with hypomethylating therapy or best supportive care in patients between the ages of 50 and 75 with advanced MDS: Blood and Marrow Transplant Clinical Trials Network Study 1102 (BMT CTN 1102; NCT02016781)3
Methods: The primary analysis compared 3-year overall survival between arms using adjusted survival estimates to account for the potential bias resulting from biologic assignment. The sample size was selected to provide at least 80% power to detect a difference of 15% in 3-year overall survival. Between January 2014 and November 2018, 384 subjects (donor n = 260, no-donor n = 124) were enrolled. The median follow-up for surviving patients was 34.2 months (range, 2.3–38 months) in the donor arm and 26.9 months (range, 2.4–37.2 months) in the no-donor arm.
Key Results:
In an intent-to-treat analysis, adjusted overall survival at 3 years from study enrollment in the donor arm was 47.9% (95% confidence interval = 41.3%–54.1%) compared with 26.6% (95% CI = 18.4%–35.6%) in the no-donor arm (P = .0001, absolute difference of 21.3% [95% CI = 10.2%–31.8%]). A sensitivity analysis excluding subjects assigned to the no-donor arm who died or withdrew prior to the end of the 90-day search window showed no effect on outcome (adjusted overall survival: 48.0% vs 28.1%, P = .0004).
Leukemia-free-survival at 3 years was higher in the donor arm (35.8%, 95% CI = 29.8%–41.8%) compared with the no-donor arm (20.6%, 95% CI = 13.3%–29.1%, P = .003), with no changes in the sensitivity analysis.
“Allo-HCT, with an intent to cure, should be considered and offered to appropriately selected older individuals with de novo MDS who have an intermediate-2 or high IPSS score.”— Syed Ali Abutalib, MD, and Elizabeth J. Shpall, MD
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In an as-treated analysis, comparison of the allo-HCT and no–allo-HCT arms demonstrated a significant advantage in 3-year overall survival (47.4% vs 16.0%, P < .0001) and leukemia-free-survival (39.3% vs 10.9%, P < .0001) for subjects who underwent allo-HCT.
There were no clinically significant differences in quality-of-life parameters between the donor and no-donor arms, as measured by several methods.
Clinical Implications: The BMT CTN 1102 study shows a significant overall survival advantage for reduce-intensity conditioning HLA-matched allo-HCT in older adults with de novo MDS who have an intermediate-2 or higher International Prognostic Scoring System (IPSS) score compared with those without a donor. Allo-HCT, with an intent to cure, should be considered and offered to appropriately selected older individuals with de novo MDS who have an intermediate-2 or high IPSS score.
Haploidentical Transplantation in Acute Leukemias and MDS
ABSTRACT 76: Outcomes after HLA-haploidentical HCT (haplo-HCT) from a (biologic) relative and HLA-matched unrelated donor HCT with posttransplant cyclophosphamide–containing graft-vs-host disease prophylaxis regimens in adults with AML, MDS, and acute lymphoblastic leukemia (ALL)-A CIBMTR study4
Methods: Patients received myeloablative conditioning (n = 1,001) or reduced-intensity conditioning (n = 1,398) preparative regimens and were analyzed separately. Among recipients of myeloablative conditioning HLA-matched unrelated donor HCT, 55% received posttransplant cyclophosphamide plus a calcineurin inhibitor and mycophenolate mofetil and 45% received posttransplant cyclophosphamide plus a calcineurin inhibitor. All recipients of haplo-HCT and reduced-intensity conditioning HLA-matched unrelated donor HCT received posttransplant cyclophosphamide plus a calcineurin inhibitor and mycophenolate mofetil as graft-vs-host disease prophylaxis. As expected, haplo-HCT recipients were less likely to be White. Patients who received myeloablative conditioning were also more likely to have AML (55% vs 47%) and less likely to have MDS (13% vs 31%).
The predominant myeloablative conditioning regimen for haplo-HCT was total-body irradiation plus fludarabine (44%) and for HLA-matched unrelated donor–HCT, fludarabine plus busulfan with or without thiotepa (59%). Reduced-intensity conditioning haplo-HCT recipients were less likely to have MDS (19% vs 24%). The predominant conditioning regimen in the reduced-intensity conditioning group was total-body irradiation (200 cGy) plus fludarabine and cyclophosphamide (88%) for haplo-HCT and for HLA-matched unrelated donor–HCT, total-body irradiation (200 cGy) plus fludarabine and cyclophosphamide (37%) and fludarabine plus melphalan (33%).
Key Results:
Myeloablative Conditioning: Compared with haplo-HCT, grade 2 to 4 acute graft-vs-host disease was higher after HLA-matched unrelated donor–HCT with posttransplant cyclophosphamide plus a calcineurin inhibitor (59% vs 33%, hazard ratio [HR] = 1.97; P < .0001). There were no differences in grade 3 to 4 acute or chronic graft-vs-host disease between the treatment groups. Nonrelapse mortality, relapse, and disease-free and overall survival also did not differ between the treatment groups.
Reduced-Intensity Conditioning: Compared with haplo-HCT, the risks of acute and chronic graft-vs-host disease did not differ between the treatment groups. However, nonrelapse mortality was lower after HLA-matched unrelated donor–HCT (8% vs 16%, P = .0008), which led to higher disease-free (55% vs 41%, P = .008) and overall survival (67 vs 54%; P = .001).
Clinical Implications: Prevention of moderate to severe graft-vs-host disease without disease relapse (relapse-free survival) is the major goal of allo-HCT. In this CIBMTR analysis, adult patients with AML, MDS, and ALL who received myeloablative conditioning followed by posttransplant cyclophosphamide plus a calcineurin inhibitor and mycophenolate mofetil had comparable outcomes regardless of haplo-HCT or HLA-matched unrelated donor–HCT. However, the same was not true for patients who received a reduced-intensity conditioning regimen, where the disease-free and overall survival rates were superior after HLA-matched unrelated donor–HCT compared with haplo-HCT.
Adult ALL: Haploidentical Transplants
ABSTRACT 299: Comparison of haplo-HCT using posttransplant cyclophosphamide (n = 393) to matched-sibling donor (n = 1,627), HLA-matched unrelated donor (n = 1,646), 7/8 HLA-mismatched unrelated (n = 230), and cord blood donor (n = 230) transplantation in adults with ALL: A CIBMTR study5
Methods: Eligible patients were adults with ALL in complete remission undergoing first allo-HCT from 2013 to 2017. Key exclusion criteria included not receiving posttransplant cyclophosphamide for haplo-HCT and ex vivo T-cell–depleted or CD34-selected grafts. Compared with other groups, haplo-HCT was performed in the lowest percentage of non-Hispanic White patients (43% vs 49%–74%); non-Hispanic White patients were more likely to use reduced-intensity conditioning (42% vs 17%–25%) and more likely to use marrow grafts (41% vs 14%–29%).
Key Results From Multivariate Analysis:
Haplo-HCT vs Matched Sibling Donor–HCT: No differences were observed in overall survival, leukemia-free-survival, nonrelapse mortality, relapse, or acute graft-vs-host disease. Compared with haplo-HCT, the risk of chronic graft-vs-host disease was significantly higher with matched sibling donor–HCT (donor/recipient gender match female-to-male, HR = 2.59, P < .001, donor/recipient gender match, other, HR = 1.37, P = .003).
Haplo-HCT vs HLA-Matched Unrelated Donor–HCT: No differences were seen in overall survival, leukemia-free-survival, relapse, or grade 2 to 4 acute graft-vs-host disease, but HLA-matched unrelated donor–HCT was associated with increased incidences of nonrelapse mortality (HR = 1.42, P = .02), grade 3 to 4 acute graft-vs-host disease (HR = 1.59, P = .005), and chronic graft-vs-host disease (donor/recipient gender match female-to-male, HR = 2.91, P < .001, donor/recipient match, other, HR = 1.38, P = .001).
Haplo-HCT vs 7/8 HLA-Matched Unrelated Donor–HCT: No differences were seen in leukemia-free-survival or relapse, but 7/8 HLA-matched unrelated donor–HCT was associated with worse overall survival (HR = 1.38, P = .01) and increased incidences of nonrelapse mortality (HR = 2.13, P < .001), grade 2 to 4 acute graft-vs-host disease (HR = 1.33, P = .04), grade 3 to 4 acute graft-vs-host disease (HR = 1.86, P = .003), and chronic graft-vs-host disease (HR = 1.72, P < .001).
Haplo-HCT vs Cord Blood Transplantation: Cord blood transplantation was associated with worse early (≤ 18 months) overall survival (HR = 1.93, P < .001); worse early leukemia-free survival (HR = 1.40, P = .007); and increased incidences of nonrelapse mortality (HR = 2.08, P < .001), grade 2 to 4 acute graft-vs-host disease (HR = 1.83, P < .001), and grade 3 to 4 acute graft-vs-host disease (HR = 1.97, P < .001). There were no differences seen in late overall survival (> 18 months), late leukemia-free survival, relapse, or chronic graft-vs-host disease.
Similar outcomes were observed in sensitivity analyses restricted to one of two cohorts: myeloablative conditioning with peripheral blood grafts or a calcineurin inhibitor–based graft-vs-host disease prophylaxis for matched sibling donor, unrelated donor, and cord blood transplantation.
Clinical Implications: In this CIBMTR analysis, overall survival and leukemia-free survival with haplo-HCT using posttransplant cyclophosphamide in adult patients with ALL who were in complete remission were superior compared with those of 7/8 HLA-matched unrelated donor–HCT and cord blood transplantation recipients. However, overall survival and leukemia-free survival were equivalent in matched sibling donor and HLA-matched unrelated donor–HCT recipients. The haplo-HCT group, which had a higher incidence of marrow vs peripheral blood progenitor cell grafts, had a lower incidence of acute graft-vs-host disease compared with HLA-matched unrelated donor–HCT recipients, and a lower incidence of chronic graft-vs-host disease compared with both matched sibling donor and HLA-matched unrelated donor–HCT transplant recipients.
Practice Points:
The MD Anderson Cancer Center study suggested it may be reasonable to consider adding clofarabine to targeted busulfan and fludarabine myeloablative conditioning in patients with AML and MDS who are not in remission and have a HCT-CI score of up to 2.
The BMT CTN 1102 study showed the superiority of reduced-intensity conditioning HLA-matched allogeneic transplant compared with hypomethylating agent or best supportive care in appropriately selected older adults (50–75 years) with de novo MDS who have an intermediate-2 or high IPSS score.
The CIBMTR (retrospective) analysis showed that adult patients with AML, MDS, and ALL who received myeloablative conditioning (not reduced-intensity conditioning) followed by posttransplant cyclophosphamide plus a calcineurin inhibitor and mycophenolate mofetil, had comparable outcomes regardless of whether they received haploidentical or matched unrelated grafts.
The CIBMTR (retrospective) analysis demonstrated that in adult patients with ALL in complete remission, overall survival and leukemia-free-survival were superior using haploidentical graft with posttransplant cyclophosphamide graft-vs-host disease prophylaxis compared with using 7/8 matched unrelated donor or cord blood grafts.
DISCLOSURE: Dr. Abutalib has served on advisory boards for AstraZeneca and Partner Therapeutics. Dr. Shpall reported no conflicts of interest.
REFERENCES
1. Andersson BS, Thall P, Valdez BC, et al: A randomized study of pretransplant conditioning therapy for AML/MDS with fludarabine ± clofarabine and once daily IV busulfan with allogeneic hematopoietic transplantation for AML and MDS. 2020 ASH Annual Meeting & Exposition. Abstract 189. Presented December 5, 2020.
2. Sorror ML, Maris MB, Storb R, et al: Hematopoietic cell transplantation (HCT)-specific comorbidity index: A new tool for risk assessment before allogeneic HCT. Blood 106:2912-2919, 2005.
3. Nakamura R, Saber W, Martens MJ, et al: A multicenter 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. 2020 ASH Annual Meeting & Exposition. Abstract 75. Presented December 5, 2020.
4. Gooptu M, St. Martin A, Romee R, et al: Comparison of outcomes after haploidentical relative and HLA matched unrelated donor transplantation with post-transplant cyclophosphamide containing GVHD prophylaxis regimens. 2020 ASH Annual Meeting & Exposition. Abstract 76. Presented December 5, 2020.
5. Wieduwilt MJ, Metheny III L, Zhang MJ, et al: Comparison of haploidentical donor hematopoietic cell transplantation using post-transplant cyclophosphamide to matched-sibling, matched-unrelated, mismatched-unrelated, and umbilical cord blood donor transplantation in adults with acute lymphoblastic leukemia: A CIBMTR Study. 2020 ASH Annual Meeting & Exposition. Abstract 299. Presented December 5, 2020.
Dr. Abutalib is Associate Director of the Hematology and BMT/Cellular Therapy Programs and Director of the Clinical Apheresis Program at the Cancer Treatment Centers of America, Zion, Illinois; Associate Professor at Roseland Franklin University of Medicine and Science; and Founder and Co-Editor of Advances in Cell and Gene Therapy. Dr. Shpall is Professor of Medicine and Department Chair ad interim in the Department of Stem Cell Transplantation and Cellular Therapy at The University of Texas MD Anderson Cancer Center, Houston.
