Piyanuch Kongtim

Complement-Binding Donor-Specific Anti-HLA Antibodies and Risk of Primary Graft Failure in Hematopoietic Stem Cell Transplantation

Detection of donor-specific anti-HLA antibodies (DSA) has been associated with graft rejection in all forms of transplantation. The mechanism by which DSA increase the risk of graft failure remains unclear. We hypothesized that complement-binding DSA are associated with engraftment failure in hematopoietic stem cell transplantation (HSCT) and analyzed 122 haploidentical transplant recipients tested prospectively for DSA. Retrospective analysis to detect C1q binding DSA (C1q+DSA) was performed on 22 allosensitized recipients. Twenty-two of 122 patients (18%) had DSA, 19 of which were women (86%). Seven patients with DSA (32%) rejected the graft. Median DSA level at transplant for patients who failed to engraft was 10,055 mean fluorescence intensity (MFI) versus 2065 MFI for those who engrafted (P = .007). Nine patients with DSA were C1q positive in the initial samples with median DSA levels of 15,279 MFI (range, 1554 to 28,615), compared with 7 C1q-negative patients with median DSA levels of 2471 MFI (range, 665 to 12,254) (P = .016). Of 9 patients who were C1q positive in the initial samples, 5 patients remained C1q positive at time of transplant (all with high DSA levels [median, 15,279; range, 6487 to 22,944]) and experienced engraftment failure, whereas 4 patients became C1q negative pretransplant and all engrafted the donor cells (P = .008). In conclusion, patients with high DSA levels (>5000 MFI) and complement-binding DSA antibodies (C1q positive) appear to be at much higher risk of primary graft failure. The presence of C1q+DSA should be assessed in allosensitized patients before HSCT. Reduction of C1q+DSA levels might prevent engraftment failure in HSCT.

Results of a 2-arm, phase 2 clinical trial using post-transplantation cyclophosphamide for the prevention of graft-versus-host disease in haploidentical donor and mismatched unrelated donor hematopoietic stem cell transplantation

High‐dose, post‐transplantation cyclophosphamide (PTCy) to prevent graft‐versus‐host disease (GVHD) has improved outcomes in haploidentical (HAPLO) stem cell transplantation (SCT). However, it remains unclear whether this strategy is effective in SCT from 1‐antigen human leukocyte antigen (HLA)‐mismatched unrelated donors (9/10 MUD) and how the outcomes of these patients compare with those of haploidentical transplantation recipients.

Donor Specific Anti-HLA Antibody and Risk of Graft Failure in Haploidentical Stem Cell Transplantation

Outcomes of allogeneic hematopoietic stem cell transplantation (AHSCT) using HLA-half matched related donors (haploidentical) have recently improved due to better control of alloreactive reactions in both graft-versus-host and host-versus-graft directions. The recognition of the role of humoral rejection in the development of primary graft failure in this setting has broadened our understanding about causes of engraftment failure in these patients, helped us better select donors for patients in need of AHSCT, and developed rational therapeutic measures for HLA sensitized patients to prevent this unfortunate event, which is usually associated with a very high mortality rate. With these recent advances the rate of graft failure in haploidentical transplantation has decreased to less than 5%.

Can a female donor for a male recipient decrease the relapse rate for patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation

The mismatched minor histocompatibility antigens present on Y chromosome (H-Y) in male recipients receiving stem cells from female donors may contribute to the graft-versus-leukemia effect and results in a reduced relapse rate, especially in patients with high-risk disease. We retrospectively compared the outcomes of male patients with acute myeloid leukemia who received an allogeneic hematopoietic stem cell transplant (HSCT) from female donors (F-M) (174 patients) versus other gender combinations (667 patients). Median age was 50 years (range, 18 to 74 years). For the whole group, the 1-year cumulative incidence of relapse was significantly lower in F-M group (34.1% versus 41.3%, P = .044), whereas nonrelapse mortality (NRM) was higher (23.2% versus 15.7%, P = .004). For patients younger than 50 years beyond first complete remission, the F-M group was associated with lower relapse rate (42.5% versus 55.2%, P = .045) whereas NRM was not significantly different (35.8% versus 25.5%, P = .141). Although survival was not significantly improved, transplantation from a female donor for male recipient was associated with a lower relapse rate. When relapse is the most common concern for treatment failure, especially for younger patients, a female donor for a male recipient might be beneficial to decrease relapse rate after transplantation. Future studies are needed to explore how the H-Y mismatch may improve survival after transplantation.

Auto-SCT improves survival in systemic light chain amyloidosis: a retrospective analysis with 14-year follow-up

Optimal treatment approach continues to remain a challenge for systemic light chain amyloidosis (AL). So far, Auto-SCT is the only modality associated with long-term survival. However, failure to show survival benefit in randomized study raises questions regarding its efficacy. We present a comparative outcome analysis of Auto-SCT to conventional therapies (CTR) in AL patients treated over a 14-year period at our institution. Out of the 145 AL amyloidosis patients, Auto-SCT was performed in 80 patients with 1-year non-relapse mortality rate of 12.5%. Novel agents were used as part of induction therapy in 56% of transplant recipients vs 46% of CTR patients. Hematological and organ responses were seen in 74.6% and 39% in the Auto-SCT arm vs 53% and 12% in the CTR arm, respectively. The projected 5-year survival for Auto-SCT vs CTR was 63% vs 38%, respectively. Landmark analysis of patients alive at 1-year after diagnosis showed improved 5-year OS of 72% with Auto-SCT vs 65% in the CTR arm. In the multivariate analysis, age <60 years, induction therapy with novel agents, kidney only involvement and Auto-SCT were associated with improved survival. In conclusion, Auto-SCT is associated with long-term survival for patients with AL amyloidosis.

Haploidentical Transplantation for Older Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome

Allogeneic stem cell transplantation with HLA-matched donors is increasingly used for older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). It remains unclear if haploidentical stem cell transplantation (haploSCT) is a suitable option for older patients with this disease. We analyzed 43 patients with AML/MDS (median age, 61 years) who underwent a haploSCT at our institution. All patients received a fludarabine-melphalan-based reduced-intensity conditioning regimen and post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis. Except for 1 patient who had early death, the remaining 42 patients (98%) engrafted donor cells. The cumulative incidences of grades II to IV and III to IV acute GVHD at 6 months were 35% and 5%, respectively, and chronic GVHD at 2 years was 9%. After a median follow-up of 19 months, 2-year overall survival, progression-free survival (PFS), and relapse incidence were 42%, 42%, and 24%, respectively. Best PFS (74% at 2 years) was seen in patients with intermediate-/good-risk cytogenetics, in first or second remission (hazard ratio, .4; P = .05), and with a younger donor (≤40 years; hazard ratio, .2; P = .01). In conclusion, these data suggest that haploidentical transplantation is safe and effective for older AML/MDS patients. Disease status, cytogenetics, and younger donor age are predictors for improved survival in older patients receiving a haploidentical transplant.

Should a More Personalized Approach be Applied to Hematopoietic Stem-Cell Transplantation?

Background: Allogeneic stem cell transplantation for older patients with hematological malignancies has generally been performed with reduced-intensity conditioning, as regimen-related toxicity prohibits a fully myeloablative conditioning regimen. We hypothesized that differences in intensity of conditioning are needed for different disease status. Patients and Methods: We analyzed 115 older patients with AML (55 years or older) who received conditioning with fludarabine and melphalan, with a melphalan dose of 140 mg/m2 (FM140) (N=73) or 100 mg/m2 (FM100) (N=42). Results: Overall, FM100 was associated with less TRM (18.1% versus 43.5%, p=0.007), and acute GVHD (aGVHD) (28.2% versus 36.7%, p=0.021) while relapse was similar (21.5% versus 25.5%, p=0.489). The lower TRM with comparable relapse rate resulted in higher survival for FM100 as compared with FM140 conditioning regimen, 3-year PFS was 60.2% and 28.6% (p=0.014). Conversely, patients with high-risk SWOG cytogenetics and adverse ELN risk had better survival outcomes with FM140 regimen due to lower relapse, while TRM was not different. In multivariable analysis, high-risk SWOG cytogenetics, adverse ELN risk and the development of grade 2-4 aGVHD predicted for worse PFS whereas using FM140 conditioning and aGVHD were an independent factor for TRM. Conclusion: These results suggest as a proof-of-principle that a differential approach should be applied for patients receiving an allogeneic hematopoietic stem cell transplant, not only based on age, but also on disease characteristics impacting the risk of relapse. Further studies are needed to develop a more personalized approach to hematopoietic stem cell transplant recipients.

High-dose therapy with auto-SCT is feasible in high-risk cardiac amyloidosis

Cardiac involvement in light-chain amyloidosis (AL) predicts poor prognosis and is associated with higher TRM and morbidity during high-dose therapy and auto-SCT (HDT–ASCT). We studied the outcomes of 30 patients with cardiac amyloidosis undergoing HDT–ASCT at our center between January 1998 and March 2012. The median age of the patients was 53 years (range, 36–74) with a median follow-up of 35 months (range, 0.4–97 months). Twenty-seven patients (90%) had more than one organ involved besides the heart with 37% with cardiac stage ⩾3. Melphalan-based conditioning regimen (140–200 mg/m2) was used for HDT–ASCT. One-year TRM is 10%. Three-year OS and EFS from HDT–ASCT was 83% and 56.8%, respectively. Cumulative incidence of relapse at 3 years was 38.5%. Negative factors affecting survival included age >60 years, lack of novel induction therapy and BM plasmacytosis >10%. We conclude that HDT–ASCT is well tolerated in patients with high-risk cardiac amyloidosis and can lead to improved overall outcomes.

Donor type, in addition to transplantation in chronic phase and myeloablative conditioning, influence transplant survival for patients with advanced chronic myeloid leukemia in the era of tyrosine kinase inhibitors

Donor type, in addition to transplantation in chronic phase and myeloablative conditioning, influence transplant survival for patients with advanced chronic myeloid leukemia in the era of tyrosine kinase inhibitors

Predictive model for survival in patients with AML/MDS receiving haploidentical stem cell transplantation

To the editor: Allogeneic hematopoietic stem cell transplantation (ASCT) is an effective consolidative strategy to decrease relapse for patients with acute myeloid leukemia (AML) and can cure ∼30% to 50% of patients with AML.[1][1],[2][2] It has been recognized that survival can vary widely after