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Azacitidine Post-transplant Maintenance Improves Disease Progression in High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome
Pasvolsky, O., Saliba, R. M., Popat, U. R., Alousi, A., Mehta, R., Yeh, J., Al-Atrash, G., Adeel, M., Ramdial, J., Marin, D., et al
Clinical lymphoma, myeloma & leukemia. 2024
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Editor's Choice
Abstract
BACKGROUND Maintenance after allogeneic hematopoietic cell transplantation (alloHCT) with hypomethylating agents has yielded conflicting results. MATERIALS AND METHODS We conducted a single center retrospective matched-control analysis with the study group (5-azacitidine [AZA] group) including adults with FLT3-negative acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received post-transplant AZA maintenance off clinical trial (n = 93). A matched control group was comprised of contemporaneous AML/MDS patients who did not receive any maintenance (n = 357). Primary endpoint was disease progression. RESULTS The AZA and control groups had comparable patient and disease characteristics except for older age (median: 61 vs. 57 years, P = .01) and lower hematopoietic comorbidity index (median: 2 vs. 3, P = .04) in the AZA group. The 3-year cumulative incidence of progression in the AZA and control groups was 29% vs. 33% (P = .09). The protective effect of AZA on progression was limited to patients with high-risk AML/MDS (HR = 0.4, 95% CI = 0.2-0.8, P = .009). This led to improved progression-free survival both in high-risk AML and MDS patients with maintenance (HR = 0.2, 95% CI = 0.1-0.6, P = .004 and HR = 0.4, 95% CI = 0.2-0.9, P = .04). CONCLUSION AZA maintenance was associated with a lower progression rate in patients with high-risk FLT3-negative AML or MDS, and AZA maintenance should be considered for post-alloHCT maintenance in this subset.
PICO Summary
Population
Adults with FLT3-negative acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)
Intervention
Post-transplant 5-azacitidine (AZA) maintenance off clinical trial (n = 93).
Comparison
Contemporaneous AML/MDS patients who did not receive any maintenance (n = 357)
Outcome
The AZA and control groups had comparable patient and disease characteristics except for older age (median: 61 vs. 57 years) and lower hematopoietic comorbidity index (median: 2 vs. 3) in the AZA group. The 3-year cumulative incidence of progression in the AZA and control groups was 29% vs. 33%. The protective effect of AZA on progression was limited to patients with high-risk AML/MDS (HR = 0.4, 95% CI = 0.2-0.8). This led to improved progression-free survival both in high-risk AML and MDS patients with maintenance (HR = 0.2, 95% CI = 0.1-0.6, and HR = 0.4, 95% CI = 0.2-0.9).
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2.
HLA Factors Versus Non-HLA Factors for Haploidentical Donor Selection
Mehta, R. S., Cao, K., Saliba, R. M., Al-Atrash, G., Alousi, A. M., Lontos, K., Marcoux, C., Carmazzi, Y., Rondon, G., Bashir, Q., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
When multiple haploidentical donors are available for transplantation, those of younger generations are generally selected over those of older generations. However, it is unclear who is the optimal donor when selecting candidates from within a generation, such as a father vs mother, son vs daughter, or brother vs sister. Although traditionally, male donors are favored over female donors, particularly for male recipients and significant associations of individual HLA mis(matches) on outcomes are being recognized, the hierarchy of factors for donor selection is indeterminate. To assess whether HLA factors take precedence over non-HLA factors and to isolate the influence of specific characteristics on outcomes, we analyzed 412 patients stratified by donor relationship: child donor [son (n=202) vs daughter (n=96)]; parent [(father: n=28 vs mother: n=29)] and sibling [non-inherited maternal (NIMA, n=29) vs paternal (NIPA, n=28)-mismatched]. Among siblings, NIMA-mismatch was associated with a lower risk of acute graft-versus-host disease (aGVHD); B-leader mismatch was associated with high non-relapse mortality (NRM), poor progression-free survival, and a trend towards poor overall survival (OS); A-mismatch was associated with lower aGVHD. Among parent donors, the relationship did not impact any outcome; B-leader mismatch was associated with higher NRM and a trend towards poor OS; A-mismatch was associated with lower NRM and improved PFS and OS. Among child donors, no individual HLA mismatch predicted any outcome, and daughter donors were not associated with any adverse outcomes in multivariate analyses. Our data suggest that certain HLA factors may be more significant in some cases and should be given priority than simply selecting a donor based on relationship/gender.
PICO Summary
Population
Adults with haematological malignancy who underwent haploidentical transplantation at a single centre in USA (n=412
Intervention
Sibling donor: non-inherited maternal mismatched (NIMA, n=29); non-inherited paternal mismatch (NIPA, n=28)
Comparison
Child donor: son (n=202), daughter (n=96); Parent donor: father, (n=28), mother, (n=29)
Outcome
Among siblings, NIMA-mismatch was associated with a lower risk of acute graft-versus-host disease (aGVHD); B-leader mismatch was associated with high non-relapse mortality (NRM), poor progression-free survival (PFS), and a trend towards poor overall survival (OS); A-mismatch was associated with lower aGVHD. Among parent donors, the relationship did not impact any outcome; B-leader mismatch was associated with higher NRM and a trend towards poor OS; A-mismatch was associated with lower NRM and improved PFS and OS. Among child donors, no individual HLA mismatch predicted any outcome, and daughter donors were not associated with any adverse outcomes in multivariate analyses.
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3.
Haploidentical vs Matched Unrelated vs Matched Sibling Donor HCT with Post-Transplantation Cyclophosphamide
Mehta, R. S., Saliba, R. M., Ghanem, S., Alousi, A. M., Rondon, G., Anderlini, P., Al-Atrash, G., Bashir, Q., Hosing, C. M., Im, J. S., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
With the use of post-transplantation cyclophosphamide (PTCy), the outcomes of mismatched related donor hematopoietic cell transplantation (HCT) are now approaching that of matched donors. We compared haploidentical versus HLA-matched (MUD) versus HLA-identical sibling (MSD) donors, where all patients received PTCy for graft-versus-host disease (GVHD) prophylaxis. We included 661 patients (275 haploidentical, 246 MUD, and 140 MSD). The most common diagnoses were acute myeloid leukemia or myelodysplastic syndrome. In multivariate analysis, the haploidentical group was associated with a significantly higher non-relapse mortality (NRM; Hazard Ratio [HR] 3.2, 95% confidence interval [CI] 2-4.9, p<0.001), inferior progression-free survival (HR 1.8, 95% CI 1.4-2.4, p<0.001) and overall survival (HR 2.2, 95% CI 1.6-3, p<0.001) than the MUD group. Relapse was the most common cause of death in all groups. Among NRM causes, the haploidentical group had more infection-related deaths and fewer GVHD-related deaths than other groups. The haploidentical group had a higher risk of viral and fungal infections, grade ≥3 hemorrhagic cystitis and cardiovascular toxicities, and slower reconstitution of CD4, CD8, and regulatory T cells but faster reconstitution of NK cells. In an exploratory analysis, older patients with older donors (>50 years for both) appeared to be associated with particularly high NRM and lower OS in haploidentical than the other groups. Our data suggest that even with the use of PTCy, the outcomes of haploidentical HCT are inferior as compared to HLA-matched donor HCT.
PICO Summary
Population
Adults with acute myeloid leukaemia or myelodysplastic syndromes requiring hematopoietic cell transplantation in single centre in the USA (HCT, n=661)
Intervention
HCT from haploidentical donors (n=275)
Comparison
HCT from HLA-matched donors (MUD, n=246) or HLA-identical sibling donors (MSD, n=140)
Outcome
In multivariate analysis, the haploidentical group was associated with a significantly higher non-relapse mortality (NRM; Hazard Ratio [HR] 3.2, 95% confidence interval [CI] 2-4.9), inferior progression-free survival (HR 1.8, 95% CI 1.4-2.4) and overall survival (HR 2.2, 95% CI 1.6-3) than the MUD group. Relapse was the most common cause of death in all groups. Among NRM causes, the haploidentical group had more infection-related deaths and fewer GVHD-related deaths than other groups. The haploidentical group had a higher risk of viral and fungal infections, grade ≥3 hemorrhagic cystitis and cardiovascular toxicities, and slower reconstitution of CD4, CD8, and regulatory T cells but faster reconstitution of NK cells. In an exploratory analysis, older patients with older donors (>50 years for both) appeared to be associated with particularly high NRM and lower OS in haploidentical than the other groups.
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Mycophenolate Mofetil: A Friend or a Foe with PTCy and Tacrolimus Prophylaxis in HLA-Matched donors?
Mehta, R. S., Saliba, R. M., Hayase, E., Jenq, R. R., Abraham, S., Rashid, A., Rondon, G., Al-Atrash, G., Bashir, Q., Hosing, C. M., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
Adapted from the haploidentical literature, post-transplantation cyclophosphamide (PTCy) is increasingly being used with HLA-matched donors, generally with a calcineurin inhibitor, such as tacrolimus (Tac) with or without mycophenolate mofetil (MMF). Owing to its immunosuppressive, potentially antitumor, and antimicrobial properties, MMF is an attractive drug; however, it remains unclear how much benefit is gained when used with PTCy/Tac. To assess that, we compared PTCy/Tac (n=242) to PTCy/Tac/MMF (n= 144) in recipients of HLA-matched donors. In multivariate analysis, the PTCy/Tac/MMF group had a significantly higher risk of grade II-IV acute graft-versus-host disease (GVHD; hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.6-2.8, p<0.001), and steroid-refractory/dependent acute GVHD (HR 4.8, 95% CI 2.4-9.6, p<0.001), yet a significantly lower risk of relapse (HR 0.5, 95% CI, 0.3-0.9, p=0.009) and better progression-free survival (PFS; HR 0.7, 95% CI 0.5-0.9, p=0.04). There was no difference in the risk of grade III-IV acute GVHD, chronic GVHD, non-relapse mortality, or overall survival. MMF was associated with prolonged neutrophil engraftment by 2 days, and a higher risk of bacterial infections. In an exploratory stool microbiome analysis (n=16), we noted a higher relative abundance of β-glucuronidase-producing bacteria in the MMF group, which may have a role in the pathogenesis of MMF-related GVHD. Our data suggest that the addition of MMF to PTCy/Tac for HLA-matched donor HCT does not provide any advantage for GVHD prevention. Further studies are needed to decipher this mechanism, and understand its role with PTCy-based prophylaxis.
PICO Summary
Population
Adults with haematological malignancy who had first transplant with HLA-matched donor (n=386)
Intervention
Post-transplant cyclophosphamide with tacrolimus and mycophenalate mofetil (PTCy/Tac/MMF, n= 144)
Comparison
Post-transplant cyclophosphamide with tacrolimus only (PTCy/Tac, n=242)
Outcome
In multivariate analysis, the PTCy/Tac/MMF group had a significantly higher risk of grade II-IV acute graft-versus-host disease (GVHD; hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.6-2.8), and steroid-refractory/dependent acute GVHD (HR 4.8, 95% CI 2.4-9.6), yet a significantly lower risk of relapse (HR 0.5, 95% CI, 0.3-0.9) and better progression-free survival (PFS; HR 0.7, 95% CI 0.5-0.9). There was no difference in the risk of grade III-IV acute GVHD, chronic GVHD, non-relapse mortality, or overall survival. MMF was associated with prolonged neutrophil engraftment by 2 days, and a higher risk of bacterial infections. In an exploratory stool microbiome analysis (n=16), we noted a higher relative abundance of β-glucuronidase-producing bacteria in the MMF group, which may have a role in the pathogenesis of MMF-related GVHD.
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Treatment of Allosensitized Patients Receiving Allogeneic Transplantation
Ciurea, S. O., Al Malki, M. M., Kongtim, P., Zou, J., Aung, F. M., Rondon, G., Chen, J., Taniguchi, M., Otoukesh, S., Nademanee, A., et al
Blood advances. 2021
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Editor's Choice
Abstract
Donor-specific anti-HLA antibodies (DSA) are a major cause of engraftment failure in patients receiving haploidentical stem cell transplantation (HaploSCT). Effective treatments are needed for these patients who often have no other donor options and/or are in need to proceed urgently to transplantation. We studied a multimodality treatment with alternate day plasma exchange, rituximab, intravenous gamma globulin (IvIg) and an irradiated donor buffy coat for patients with DSA at two institutions. Thirty-seven patients with a median age of 51 years were treated with this desensitization protocol. Treatment outcomes were compared with a control group of HaploSCT patients without DSA (N=345). Majority of patients in the DSA group were females (83.8% vs. 37.1% in controls, p<0.001) and received stem cells from a child as donor (67.6% vs. 44.1%, p=0.002). Mean DSA level before and after desensitization was 10,198 and 5,937 MFI, respectively with mean differences of 4,030 MFI. Fourteen of 30 tested patients (46.7%) had C1q positivity while 8 of 29 tested patients (27.6%) remained positive after desensitization. In multivariable analysis, patients with initial DSA >20,000 MFI and with persistent C1q+ after desensitization had a significantly lower engraftment rate, resulted in a significantly higher non-relapse mortality (NRM) and worse overall survival (OS) than controls whereas graft outcome and survivals of patients with initial DSA <20,000 MFI and those with negative C1q after treatment were comparable with controls. In conclusion, treatment with plasma exchange, rituximab, IvIg and donor buffy coat is effective in promoting engraftment in patients with DSA up to 20,000 MFI.
PICO Summary
Population
Patients with donor specific antibodies (DSAs) from two US centres, receiving allogeneic transplantation (DSA group, n=37)
Intervention
Desensitisation protocol: alternate day plasma exchange, rituximab, intravenous gamma globulin (IvIg) and an irradiated donor buffy coat (n=37)
Comparison
Patients without DSAs undergoing haploidentical transplantation (Control, n=345)
Outcome
The majority of patients in the DSA group were female (83.8% vs 37.1% in controls,) and received stem cells from a child as the donor (67.6% vs 44.1%). Mean DSA level before and after desensitization was 10 198 and 5937 mean fluorescence intensity (MFI), respectively, with mean differences of 4030 MFI. Fourteen of 30 tested patients (46.7%) had C1q positivity, while 8 of 29 tested patients (27.6%) remained positive after desensitization. In multivariable analysis, patients with initial DSA > 20 000 MFI and persistent positive C1q after desensitization had a significantly lower engraftment rate, which resulted in significantly higher non-relapse mortality and worse overall survival (OS) than controls, whereas graft outcome and survival of patients with initial DSA < 20 000 MFI and those with negative C1q after treatment were comparable with controls.
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9-year follow-up of patients with relapsed follicular lymphoma after nonmyeloablative allogeneic stem cell transplant and autologous transplant
Khouri, I. F., Milton, D. R., Gulbis, A. M., Jabbour, E. J., Nastoupil, L., Ledesma, C., Anderlini, P., Bashir, Q., Daher, M., Im, J. S., et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021
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Editor's Choice
Abstract
PURPOSE To compare outcomes between patients with relapsed follicular lymphoma (FL) who received a nonmyeloablative allogeneic stem cell transplant (alloSCT) and those who received an autologous transplant (autoSCT). EXPERIMENTAL DESIGN We evaluated 194 patients with FL who received an alloSCT (n = 98) or autoSCT (n = 96) at MD Anderson Cancer Center. The transplant type used was based on donor availability and by Medicare reimbursement guidelines. AlloSCT patients were enrolled in 4 consecutive trials in which they received fludarabine, cyclophosphamide (or bendamustine), and rituximab conditioning. AutoSCT patients received R-BEAM (rituximab, carmustine, etoposide, cytarabine, and melphalan). RESULTS The median follow-up of survivors was 108 months for the alloSCT group and 102 months for the autoSCT group. Overall survival was significantly better for alloSCT patients compared with autoSCT patients (62% vs. 46%; P = .048). Similarly, progression-free survival rates were 52% in alloSCT patients and 31% in autoSCT patients (P < .001), and the 8-year relapse rates were 11% and 43%, respectively (P < .0001). Only 3 patients in the alloSCT group relapsed beyond 3.5 years. In the alloSCT group, the rates for grade 2-4 acute graft-versus-host disease (GVHD), grade 3-4 acute GVHD, and extensive chronic GVHD were 22%, 9%, and 38%, respectively. In the autoSCT group, the 8-year incidence of secondary myelodysplasia was 11%. Non-relapse mortality was similar between the 2 groups (15% vs. 11% at 8 years; P = .27). CONCLUSIONS This study shows that alloSCT is curative and confers superior survival compared with autoSCT in patients with FL.
PICO Summary
Population
Patients with follicular lymphoma at a single US centre (n=194)
Intervention
Nonmyeloablative allogeneic stem cell transplant, receiving fludarabine, cyclophosphamide (or bendamustine), and rituximab conditioning (alloSCT, n=98)
Comparison
Autologous transplant with R-BEAM conditioning: rituximab, carmustine, etoposide, cytarabine, and melphalan (autoSCT, n=96)
Outcome
The median follow-up of survivors was 108 months for the alloSCT group and 102 months for the autoSCT group. Overall survival was significantly better for alloSCT patients compared with autoSCT patients (62% vs. 46%). Similarly, progression-free survival rates were 52% in alloSCT patients and 31% in autoSCT patients, and the 8-year relapse rates were 11% and 43%, respectively. Only 3 patients in the alloSCT group relapsed beyond 3.5 years. In the alloSCT group, the rates for grade 2-4 acute graft-versus-host disease (GVHD), grade 3-4 acute GVHD, and extensive chronic GVHD were 22%, 9%, and 38%, respectively. In the autoSCT group, the 8-year incidence of secondary myelodysplasia was 11%. Non-relapse mortality was similar between the 2 groups (15% vs. 11% at 8 years).
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Randomized phase II trial of extracorporeal phototherapy and steroids vs. steroids alone for newly diagnosed acute GVHD
Mehta, R. S., Bassett, R., Rondon, G., Overman, B. J., Popat, U. R., Hosing, C. M., Rezvani, K., Qazilbash, M. H., Anderlini, P., Jones, R. B., et al
Bone marrow transplantation. 2021
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Editor's Choice
Abstract
Steroids remain the initial therapy for acute graft-vs.-host disease (AGVHD). Strategies to improve response and minimize steroid exposure are needed. We report results of a randomized, adaptive, Bayesian-designed, phase II trial of prednisone with or without extracorporeal photopheresis (ECP) as an initial therapy for patients with newly diagnosed AGVHD. The primary endpoint was success at day 56 defined as: alive, in remission, achieving AGVHD response without additional therapy, and on <1?mg/kg at day 28 and <0.5?mg/kg on day 56 of steroids. Eighty-one patients were randomized to the ECP arm (n?=?51) or steroids alone (n?=?30). Median age was 54 years (range: 17-75); 90% had grade II AGVHD and 10% had grades III and IV AGVHD, with skin (85%), upper (22%)/lower (22%) gastrointestinal, and liver (10%) involvement. The ECP arm had a higher probability of success (0.815) and exceeded the predefined threshold for determining the investigational arm promising. ECP was potentially more beneficial than steroids-alone in skin-only AGVHD (response rate: 72% vs. 57%, respectively) than for visceral-organ AGVHD (47% vs. 43%, respectively). The addition of ECP to steroids may result in higher GVHD response as initial therapy for AGVHD, especially for patients with skin-only involvement.
PICO Summary
Population
Patients with newly-diagnosed acute graft-versus-host disease (AGVHD, n=81)
Intervention
Prednisone with extracorporeal photopheresis (ECP, n=51)
Comparison
Prednisone alone (n=30)
Outcome
The ECP arm had a higher probability of success (0.815) and exceeded the predefined threshold for determining the investigational arm promising. ECP was potentially more beneficial than steroids-alone in skin-only AGVHD (response rate: 72% vs. 57%, respectively) than for visceral-organ AGVHD (47% vs. 43%, respectively).
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8.
Bone Marrow versus Peripheral Blood Graft for Haploidentical HCT with Post Transplantation Cyclophosphamide
Mehta, R. S., Saliba, R. M., Alsfeld, L. C., Jorgensen, J. L., Wang, S. A., Anderlini, P., Al-Atrash, G., Bashir, Q., Ciurea, S. O., Hosing, C. M., et al
Transplantation and cellular therapy. 2021
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Editor's Choice
Abstract
BACKGROUND In the COVID-19 pandemic era, the numbers of haploidentical hematopoietic cell transplantation (HCT) with peripheral blood (PB) versus bone marrow (BM) grafts increased significantly, which may be associated with adverse outcomes. METHODS We compared outcomes of BM vs PB grafts in patients =18 years with hematological malignancy who underwent T-cell replete haploidentical HCT and graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide, tacrolimus and mycophenolate mofetil. FINDINGS Of 264 patients, 180 (68%) received BM and 84 (32%) received PB graft. Median age was 50 years in both groups. Majority (n=199, 75%) received reduced-intensity conditioning. More patients had acute leukemia or myelodysplastic syndrome in BM (n=152, 85%) than PB (n=46, 55%), p<0.01. The median time to neutrophil and platelet engraftment, and incidence of grade II-IV and III-IV acute GVHD (aGVHD) was comparable in both groups. Among grade II-IV aGVHD, steroid-refractory aGVHD (SR-aGVHD) was 9% (95% CI 5-18) in BM vs 32% (95% CI 19-54) in PB; hazard ratio (HR) 3.7, 95% CI 1.5-9.3, p=0.006. Chronic GVHD (cGVHD) was 8% (95% CI 4-13) vs 22% (95% CI 14-36); HR 3.0, 95% CI 1.4-6.6, p=0.005 and systemic therapy-requiring cGVHD was 2.5% (95% CI 1-7) vs 14% (95% CI 7-27), respectively; HR 5.6, 95% CI 1.7-18, p=0.004 at 1 year. PB group had a significantly higher risk of bacterial and viral infections with no appreciable advantage in the duration of hospitalization, immune reconstitution, relapse, non-relapse mortality, or survival. INTERPRETATION Our data suggest the use of BM over PB graft for haploidentical HCT.
PICO Summary
Population
Adult patients with haematological malignancies undergoing haploidentical transplantation (n=264)
Intervention
Bone marrow graft (n=180)
Comparison
Peripheral blood graft (n=84)
Outcome
Median age was 50 years in both groups. Majority (n=199, 75%) received reduced-intensity conditioning. More patients had acute leukemia or myelodysplastic syndrome in BM (n=152, 85%) than PB (n=46, 55%). The median time to neutrophil and platelet engraftment, and incidence of grade II-IV and III-IV acute GVHD (aGVHD) was comparable in both groups. Among grade II-IV aGVHD, steroid-refractory aGVHD (SR-aGVHD) was 9% (95% CI 5-18) in BM vs 32% (95% CI 19-54) in PB; hazard ratio (HR) 3.7, 95% CI 1.5-9.3. Chronic GVHD (cGVHD) was 8% (95% CI 4-13) vs 22% (95% CI 14-36); HR 3.0, 95% CI 1.4-6.6, and systemic therapy-requiring cGVHD was 2.5% (95% CI 1-7) vs 14% (95% CI 7-27), respectively; HR 5.6, 95% CI 1.7-18 at 1 year. PB group had a significantly higher risk of bacterial and viral infections with no appreciable advantage in the duration of hospitalization, immune reconstitution, relapse, non-relapse mortality, or survival
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9.
Third-Party BK Virus-Specific Cytotoxic T Lymphocyte Therapy for Hemorrhagic Cystitis Following Allotransplantation
Olson, A., Lin, R., Marin, D., Rafei, H., Bdaiwi, M. H., Thall, P. F., Basar, R., Abudayyeh, A., Banerjee, P., Aung, F. M., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2021;:Jco2002608
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Editor's Choice
Abstract
PURPOSE BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication of allogenic hematopoietic stem cell transplantation (AHSCT), particularly in recipients of alternative donor transplants, which are being performed in increasing numbers. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, without a definitive therapeutic option. METHODS We performed a clinical trial (ClinicalTrials.gov identifier: NCT02479698) to assess the feasibility, safety, and efficacy of administering most closely HLA-matched third-party BKV-specific cytotoxic T lymphocytes (CTLs), generated from 26 healthy donors and banked for off-the-shelf use. The cells were infused into 59 patients who developed BKV-HC following AHSCT. Comprehensive clinical assessments and correlative studies were performed. RESULTS Response to BKV-CTL infusion was rapid; the day 14 overall response rate was 67.7% (40 of 59 evaluable patients), which increased to 81.6% among evaluable patients at day 45 (40 of 49 evaluable patients). No patient lost a previously achieved response. There were no cases of de novo grade 3 or 4 graft-versus-host disease, graft failure, or infusion-related toxicities. BKV-CTLs were identified in patient blood samples up to 3 months postinfusion and their in vivo expansion predicted for clinical response. A matched-pair analysis revealed that, compared with standard of care, after accounting for prognostic covariate effects, treatment with BKV-CTLs resulted in higher probabilities of response at all follow-up timepoints as well as significantly lower transfusion requirement. CONCLUSION Off-the-shelf BKV-CTLs are a safe and effective therapy for the management of patients with BKV-HC after AHSCT.
PICO Summary
Population
Patients who developed BK-virus associated haemorrhagic cystitis (BKV-HC) following allogeneic transplantation (n=59)
Intervention
HLA-matched third-party BKV-specific cytotoxic T lymphocytes (CTLs)
Comparison
Matched-pair analysis of historical controls
Outcome
Response to BKV-CTL infusion was rapid; the day 14 overall response rate was 67.7% (40 of 59 evaluable patients), which increased to 81.6% among evaluable patients at day 45 (40 of 49 evaluable patients). No patient lost a previously achieved response. There were no cases of de novo grade 3 or 4 graft-versus-host disease, graft failure, or infusion-related toxicities. BKV-CTLs were identified in patient blood samples up to 3 months postinfusion and their in vivo expansion predicted for clinical response. A matched-pair analysis revealed that, compared with standard of care, after accounting for prognostic covariate effects, treatment with BKV-CTLs resulted in higher probabilities of response at all follow-up timepoints as well as significantly lower transfusion requirement.
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10.
Molecular disparity in human leukocyte antigens is associated with outcomes in haploidentical stem cell transplantation
Zou, J., Ciurea, S. O., Kongtim, P., Yi, M., Carmazzi, Y., Rondon, G., Srour, S., Partlow, D., Champlin, R. E., Cao, K.
Blood advances. 2020;4(15):3474-3485
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Editor's Choice
Abstract
Haploidentical donors are increasingly used for patients requiring hematopoietic stem cell transplantation (HSCT). Although several factors have been associated with transplant outcomes, the impact of HLA disparity in haploidentical HSCT (haplo-HSCT) remains unclear. We investigated the impact of HLA disparity quantified by mismatched eplets (ME) load of each HLA locus on the clinical outcome of 278 consecutive haploidentical transplants. Here, we demonstrated that the degree of HLA molecular mismatches, at individual HLA loci, may be relevant to clinical outcome in the haplo-HSCT. A significantly better overall survival was associated with higher ME load from HLA-A (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.95-0.99; P = .003) and class I loci (HR, 0.99; 95% CI, 0.97-0.99; P = .045) in the host-versus-graft direction. The apparent survival advantage of HLA-A ME was primarily attributed to reduced risk in relapse associated with an increase in HLA-A ME load (subdistribution HR, 0.95; 95% CI, 0.92-0.98; P = .004). Furthermore, we have identified an association between the risk of grade 3-4 acute graft-versus-host disease (GVHD) and a higher ME load at HLA-B and class I loci in graft-versus-host (GVH) direction. Additionally, GVH nonpermissive HLA-DPB1 mismatch defined by T-cell epitope grouping was significantly associated with relapse protection (subdistribution HR, 0.19; 95% CI, 0.06-0.59; P = .004) without a concurrent increase in GVHD. These findings indicate that alloreactivity generated by HLA disparity at certain HLA loci is associated with transplant outcomes, and ME analysis of individual HLA loci might assist donor selection and risk stratification in haplo-HSCT.
PICO Summary
Population
Patients receiving haploidentical transplantation (n=278)
Intervention
HLA disparity quantified by mismatched eplets (ME)
Comparison
None
Outcome
A significantly better overall survival was associated with higher ME load from HLA-A (hazard ratio [HR], 0.97) and class I loci (HR, 0.99) in the host-versus-graft direction. The apparent survival advantage of HLA-A ME was primarily attributed to reduced risk in relapse associated with an increase in HLA-A ME load (subdistribution HR, 0.95). Furthermore, we have identified an association between the risk of grade 3-4 acute graft-versus-host disease (GVHD) and a higher ME load at HLA-B and class I loci in graft-versus-host (GVH) direction. Additionally, GVH nonpermissive HLA-DPB1 mismatch defined by T-cell epitope grouping was significantly associated with relapse protection (subdistribution HR, 0.19) without a concurrent increase in GVHD.