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Comparing transplant outcomes in ALL patients after haploidentical with PTCy or matched unrelated donor transplantation
Al Malki, M. M., Yang, D., Labopin, M., Afanasyev, B., Angelucci, E., Bashey, A., Socie, G., Karduss-Urueta, A., Helbig, G., Bornhauser, M., et al
Blood advances. 2020;4(9):2073-2083
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Editor's Choice
Abstract
We compared outcomes of 1461 adult patients with acute lymphoblastic leukemia (ALL) receiving hematopoietic cell transplantation (HCT) from a haploidentical (n = 487) or matched unrelated donor (MUD; n = 974) between January 2005 and June 2018. Graft-versus-host disease (GVHD) prophylaxis was posttransplant cyclophosphamide (PTCy), calcineurin inhibitor (CNI), and mycophenolate mofetil (MMF) for haploidentical, and CNI with MMF or methotrexate with/without antithymoglobulin for MUDs. Haploidentical recipients were matched (1:2 ratio) with MUD controls for sex, conditioning intensity, disease stage, Philadelphia-chromosome status, and cytogenetic risk. In the myeloablative setting, day +28 neutrophil recovery was similar between haploidentical (87%) and MUD (88%) (P = .11). Corresponding rates after reduced-intensity conditioning (RIC) were 84% and 88% (P = .47). The 3-month incidence of grade II-IV acute GVHD (aGVHD) and 3-year chronic GVHD (cGVHD) was similar after haploidentical compared with MUD: myeloablative conditioning, 33% vs 34% (P = .46) for aGVHD and 29% vs 31% for cGVHD (P = .58); RIC, 31% vs 30% (P = .06) for aGVHD and 24% vs 29% for cGVHD (P = .86). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 44% and 51% with haploidentical and MUD (P = .56). Corresponding rates after RIC were 43% and 42% (P = .6). In this large multicenter case-matched retrospective analysis, despite the limitations of a registry-based study (ie, unavailability of key elements such as minimal residual disease testing), our analysis indicated that outcomes of patients with ALL undergoing HCT from a haploidentical donor were comparable with 8 of 8 MUD transplantations.
Clinical Commentary
Dr. Julia Wolf, University Hospitals Bristol and Weston NHS Foundation Trust
What is known?
Allogeneic stem cell transplant is a potentially curative treatment option for adults with acute lymphoblastic leukaemia (ALL). Transplant outcomes are, amongst other factors, dependent on optimal donor selection; despite a plethora of recent advances, donor availability is an area of unmet need for many patients. A fully HLA matched sibling donor is the preferred donor choice but is available in <30% of patients. Several studies have shown that comparable results can be achieved with a fully matched unrelated donor (MUD), but availability can be as low as 20% in non-Caucasian individuals. Haploidentical donor options are available for the vast majority of patients but historically their utility was limited by high rates of GvHD, treatment related morbidity and mortality and graft rejection. The addition of post-transplant cyclophosphamide (PtCy), calcineurin inhibitors (CNI) and mycofenolate mofetil (MMF) as GvHD prophylaxis has reduced these risks and is now a frequently employed approach for haploidentical haematopoietic stem cell transplant (HaploSCT) making it an attractive alternative to conventional donor transplant.
Several recent studies have compared MUD alloSCT and HaploSCT approaches in ALL in recent years. Most notably this has included an analysis of the European Bone Marrow Transplant (EBMT) group registry which included 1234 patients with ALL and shows comparable outcomes between HaploSCT and MUD alloSCT.
What did this paper set out to examine?
This retrospective multicentre cohort study aims to compare outcomes of HaploSCT & PtCy with MUD alloSCT in ALL in terms of engraftment, acute and chronic graft versus host disease (GvHD) incidence and severity, relapse free survival (RFS), non-relapse mortality (NRM) and overall survival (OS).
It is the first study to explicitly compare haploidentical allogeneic stem cell transplant (HaploSCT) with matched unrelated donor allogeneic stem cell transplant (MUD alloSCT) in terms of conditioning intensity, Philadelphia chromosome status and graft source. It also provides additional extensive, multinational data with matched pair analysis on outcomes of patients in both groups.
What did they show?
The authors compared data from 1461 adult patients (HaploSCT = 487 vs MUD = 974). Data from two separate registries was used: the EBMT registry alone was used for MUD alloSCT while the Haploidentical Transplant and Cellular Therapy Research Consortium (TCT-RC) was used in combination with Acute Leukaemia Working Party subgroup of the EBMT registry data for assessment of HaploSCT. The reason for using two databases is not explicitly stated although it is believed that this was done to increase sample size in the HaploSCT cohort.
Patients >18 years old with ALL over a 13.5-year period from January 2005 to June 2018 receiving their first alloSCT were included in the analysis. Exclusion criteria were fairly selected. GvHD prophylaxis was with PtCy, CNI and MMF in the HaploSCT group and with CNI and methotrexate or MMF in the MUD group. 64% of MUD patients also received ATG. Cohorts were matched at 1:2 (HaploSCT : MUD) for sex, cytogenetic risk, Philadelphia chromosome status, disease stage and intensity of conditioning (reduced intensity vs myeloablative). Statistical analysis was appropriate for the question to be answered.
RESULTS: HaploSCT and MUD alloSCT were comparable in terms of neutrophil engraftment, RFS and OS regardless of conditioning intensity, Philadelphia chromosome status and graft source. 3-year OS was 44% in the HaploSCT group vs 51% in the MUD group using myeloablative conditioning (p=5.56) with rates of 43% (HaploSCT) and 42% (MUD) for reduced intensity conditioning (p=5.6).
The overall incidence of acute and chronic GvHD was similar between the groups but there was an increased incidence in grade III-IV GvHD in HaploSCT when peripheral blood stem cells were used. Additionally, mortality form GvHD was higher in the MUD group. This is in keeping with results reported in the literature.
What are the implications for practice and for future work?
HaploSCT is becoming an increasingly attractive option for patients without matched sibling transplant. The comparable overall survival and now much more manageable GvHD risk will afford a previously difficult to manage cohort of patients a further option of curative treatment.
This study adds to the growing evidence base but did have some limitations. Firstly, the study is retrospective and uses registry-based data. While the registries used are of high quality, there are inherent concerns about missing data points and differences between the two databases used. The authors agreed that the variability of the condition regimes used added a further layer of complexity.
Prospective data with intention to treat analysis is required to further assess the comparability of HaploSCT and MUD for ALL patients.
PICO Summary
Population
Adult patients with acute lymphoblastic leukaemia (n=1461)
Intervention
HSCT from a haploidentical donor (n = 487)
Comparison
HSCT from a matched unrelated donor (n = 974)
Outcome
In the myeloablative setting, day +28 neutrophil recovery was similar between haploidentical (87%) and MUD (88%). Corresponding rates after reduced-intensity conditioning (RIC) were 84% and 88%. The 3-month incidence of grade II-IV acute GVHD (aGVHD) and 3-year chronic GVHD (cGVHD) was similar after haploidentical compared with MUD: myeloablative conditioning, 33% vs 34% for aGVHD and 29% vs 31% for cGVHD; RIC, 31% vs 30% for aGVHD and 24% vs 29% for cGVHD. Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 44% and 51% with haploidentical and MUD. Corresponding rates after RIC were 43% and 42%.
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2.
External Validation of Models for KIR2DS1/KIR3DL1-informed Selection of Hematopoietic Cell Donors fails
Schetelig, J., Baldauf, H., Heidenreich, F., Massalski, C., Frank, S., Sauter, J., Stelljes, M., Ayuk, F., Bethge, W. A., Bug, G., et al
Blood. 2020
Abstract
Several studies suggest that harnessing Natural Killer (NK) cell reactivity mediated through Killer cell Immunoglobulin-like Receptors (KIR) could reduce the risk of relapse after allogeneic Hematopoietic Cell Transplantation (HCT). Based on one promising model, information on KIR2DS1 and KIR3DL1 and their cognate ligands can be used to classify donors as KIR-advantageous or disadvantageous. This study was aimed at externally validating this model in unrelated donor HCT. The impact of the predictor on Overall Survival (OS) and relapse incidence was tested in a Cox regression model adjusted for patient age, a modified disease risk index, performance status, donor age, HLA-match, sex-match, CMV-match, conditioning intensity, type of T-cell depletion and graft type. Data from 2222 patients with AML or MDS were analyzed. KIR genes were typed using high-resolution amplicon-based next generation sequencing. In univariable analyses and subgroup analyses, OS and the cumulative incidence of relapse of patients with a KIR-advantageous donor were comparable to patients with a KIR-disadvantageous donor. The adjusted hazard ratio from the multivariable Cox regression model was 0.99 (Wald-test: p=0.93) for OS and 1.04 (Wald-test: p=0.78) for relapse incidence. We also tested the impact of activating donor KIR2DS1 and inhibition by KIR3DL1 separately, but did not find a significant impact on OS and the risk of relapse. Thus, our study shows that the proposed model does not universally predict NK-mediated disease control. Deeper knowledge of NK-mediated alloreactivity is necessary to predict its contribution to graft-versus leukemia reactions and to eventually utilize KIR-genotype information for donor selection.
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3.
Relative impact of HLA- matching and non-HLA donor characteristics on outcome of allogeneic stem cell transplantation for AML and MDS
Ayuk, F., Beelen, D. W., Bornhauser, M., Stelljes, M., Zabelina, T., Finke, J., Kobbe, G., Wolff, D., Wagner, E. M., Christopeit, M., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
Increasing donor-recipient HLA-disparity is associated with negative outcome of allogeneic hematopoietic stem cell transplantation (HSCT), but its relative relevance amidst non-HLA donor characteristic is not well established. We addressed this question in 3215 HSCT performed between 2005 and 2013 in Germany for AML or MDS. Donors were HLA-matched related (MRD; n=872) or unrelated (10/10MUD, n=1553), or HLA-mismatched unrelated (<10/10MMUD, n= 790). Overall survival (OS) was similar after MRD compared to 10/10MUD HSCT, reflecting opposing hazards of relapse (hazards ratio [HR] 1.32, p<0.002) and non-relapse mortality (NRM; HR 0.63, p<0.001). After UD HSCT, increasing HLA disparity was associated with inferior OS (HR 1.21, p<0.02 and HR 1.57, p<.001 for 9/10- and ≤8/10MMUD respectively compared to 10/10MUD). Amongst non-HLA donor characteristics, age, sex-mismatching (male recipient / female donor) and CMV-mismatching (positive recipient / negative donor) impacted OS. Multivariate subgroup analysis showed that OS was similar after HSCT from the youngest 9/10MMUD (<30 years) compared to the oldest 10/10MUD (>40 years), (HR 1.18, p=0.25), and also in male patients transplanted from female 10/10MUD compared to male 9/10MMUD (HR 0.89, p=0.46). In contrast, OS of CMV-positive patients tended to be better with CMV-negative 10/10MUD compared to CMV-positive 9/10MMUD (HR 1.31, p =0.04). Due to low patient numbers in subgroups definite conclusions and establishment of a hierarchy amongst HLA-matching and non-HLA donor characteristics could not be made. Our data suggest that the impact of donor age and sex-mismatch but not CMV-mismatch on outcome of allogeneic HSCT may be comparable to that of single HLA-disparity.
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4.
Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation
Frick, M., Chan, W., Arends, C. M., Hablesreiter, R., Halik, A., Heuser, M., Michonneau, D., Blau, O., Hoyer, K., Christen, F., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2018;:Jco2018792184
Abstract
PURPOSE Clonal hematopoiesis of indeterminate potential (CHIP) occurs in the blood of approximately 20% of older persons. CHIP is linked to an increased risk of hematologic malignancies and of all-cause mortality; thus, the eligibility of stem-cell donors with CHIP is questionable. We comprehensively investigated how donor CHIP affects outcome of allogeneic hematopoietic stem-cell transplantation (HSCT). METHODS We collected blood samples from 500 healthy, related HSCT donors (age ≥ 55 years) at the time of stem-cell donation for targeted sequencing with a 66-gene panel. The effect of donor CHIP was assessed on recipient outcomes, including graft-versus-host disease (GVHD), cumulative incidence of relapse/progression (CIR/P), and overall survival (OS). RESULTS A total of 92 clonal mutations with a median variant allele frequency of 5.9% were identified in 80 (16.0%) of 500 donors. CHIP prevalence was higher in donors related to patients with myeloid compared with lymphoid malignancies (19.2% v 6.3%; P ≤ .001). In recipients allografted with donor CHIP, we found a high cumulative incidence of chronic GVHD (cGVHD; hazard ratio [HR], 1.73; 95% CI, 1.21 to 2.49; P = .003) and lower CIR/P (univariate: HR, 0.62; 95% CI, 0.40 to 0.97; P = .027; multivariate: HR, 0.63; 95% CI, 0.41 to 0.98; P = .042) but no effect on nonrelapse mortality. Serial quantification of 25 mutations showed engraftment of 24 of 25 clones and disproportionate expansion in half of them. Donor-cell leukemia was observed in two recipients. OS was not affected by donor CHIP status (HR, 0.88; 95% CI, 0.65 to 1.321; P = .434). CONCLUSION Allogeneic HSCT from donors with CHIP seems safe and results in similar survival in the setting of older, related donors. Future studies in younger and unrelated donors are warranted to extend these results. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that donor CHIP might foster cGVHD development and reduce relapse/progression risk.
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5.
Allogeneic hematopoietic cell transplantation in intermediate risk acute myeloid leukemia negative for FLT3-ITD, NPM1- or biallelic CEBPA mutations
Heidrich, K., Thiede, C., Schafer-Eckart, K., Schmitz, N., Aulitzky, W. E., Kramer, A., Rosler, W., Hanel, M., Einsele, H., Baldus, C. D., et al
Annals of Oncology. 2017;28(11):2793-2798
Abstract
Background: The value of allogeneic hematopoietic cell transplantation (alloHCT) as postremission treatment is not well defined for patients with intermediate-risk acute myeloid leukemia (AML) without FLT3-ITD, biallelic CEBPA-, or NPM1 mutations (here referred to as NPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML) in first complete remission (CR1). Patients and methods: We addressed this question using data from two prospective randomized controlled trials on intensive induction- and risk-stratified postremission therapy. The NPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML subgroup comprised 497 patients, aged 18-60years. Results: In donor versus no-donor analyses, patients with a matched related donor had a longer relapse-free survival (HR 0.5; 95% CI 0.3-0.9, P=0.02) and a trend toward better overall survival (HR 0.6, 95% CI 0.3-1.1, P=0.08) compared with patients who received postremission chemotherapy. Notably, only 58% of patients in the donor group were transplanted in CR1. We therefore complemented the donor versus no-donor analysis with multivariable Cox regression analyses, where alloHCT was tested as a time-dependent covariate: overall survival (HR 0.58, 95% CI 0.37-0.9, P=0.02) and relapse-free survival (HR 0.51, 95% CI 0.34-0.76; P=0.001) for patients who received alloHCT compared with chemotherapy in CR1 were significantly longer. Conclusion: Outside clinical trials, alloHCT should be the preferred postremission treatment of patients with intermediate risk NPM1mut-neg/CEBPAdm-neg/FLT3-ITDneg AML in CR1. Cinicaltrials.gov identifier: NCT00180115, NCT00180102.
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6.
The impact of HLA matching on outcomes of unmanipulated haploidentical HSCT is modulated by GVHD prophylaxis
Lorentino, F., Labopin, M., Fleischhauer, K., Ciceri, F., Mueller, C. R., Ruggeri, A., Shimoni, A., Bornhauser, M., Bacigalupo, A., Gulbas, Z., et al
Blood Advances. 2017;1(11):669-680
Abstract
Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with unmanipulated grafts is increasingly adopted for high-risk acute leukemia, with acute graft-versus-host disease (aGVHD) prophylaxis based on antithymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCy) as main platforms. No consensus exists on selection criteria over several haploidentical donors. We evaluated the impact of donor-recipient antigenic and allelic HLA-A, -B, -C, and -DRB1 mismatches on mismatched haplotype on outcomes of 509 unmanipulated haplo-HSCTs performed for acute leukemia under a PTCy (N = 313) or ATG (N = 196) regimen. An antigenic but not allelic mismatch at the HLA-DRB1 locus was an independent risk factor for grade >=2 aGVHD in PTCy (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.2-4.0; P = .02) but not in ATG regimens (HR, 1.3; 95% CI, 0.4-3.4; P = .6). Moreover, the hazards of aGVHD were significantly associated with other factors influencing alloreactivity, including peripheral blood as stem cell source (HR, 2.2; 95% CI, 1.4-3; P < .01), reduced-intensity conditioning (HR, 0.6; 95% CI, 0.4-0.9; P = .04), and female donors (HR, 1.8; 95% CI, 1-3.2; P = .05), in PTCy but not ATG regimens. No significant associations were found between cumulative number of HLA mismatches and GVHD, or between HLA-matching status and other study end points including transplant-related mortality, disease-free survival, and relapse. Based on these data, the role of HLA mismatching on unshared haplotype appears not to be sufficiently prominent to justify its consideration in haploidentical donor selection. However, the role of HLA matching in haploidentical HSCT might be modulated by GVHD prophylaxis, calling for further investigations in this increasingly relevant field. Conflict-of-interest disclosure: The authors declare no competing financial interests.