Racial/ ethnic disparities in availability of volunteer unrelated donors for allogeneic transplantation.

Despite the global unrelated donor (URD) registry size, the degree to which URD availability is a transplant barrier is not established. We evaluated the availability of 3,843 URDs requested for 455 diverse adult patients (predominantly with acute leukemia). URDs for non-Europeans were more likely to be domestic and had markedly lower Donor Readiness Scores. Of URDs requested for confirmatory HLA-typing (CT) alone (i.e. without simultaneous workup), 1,894/3,529 (54%) were available. Availability of domestic URDs was 45%. Donor Readiness Score was highly predictive of CT availability. Compared with Europeans (n=335), more non-European patients (n=120) had >10 URDs requested and <5 available. Of workup requests (after CT or CT-workup), <70% (604/889, 68%) were available. More non-Europeans had <2 URDs available. URD availability for CT was markedly worse for non-Europeans, with availabilities for African, non-Black Hispanic, and Asian patients of 150/458 (33%), 120/258 (47%) and 119/270 (44%), respectively, with further decrements in URD workup availability. Our data suggest the functional size of the URD pool is much smaller than appreciated, mandating major operational changes for transplant Centers and donor registries. Likelihood of donor availability should have a high priority in donor selection. Considering patient ancestry and URD Donor Readiness Scores, Centers should pursue, and registries permit, simultaneous pursuit of many URDs, and abandon futile searches. Patients should be informed about their likelihood of donor availability and alternative options. Finally, while registries should address high URD attrition and speed procurement, use of all HLA-disparate graft types is needed to facilitate timely transplantation for all.

Outcomes and Management of the SARS-CoV2 Omicron Variant in Recipients of Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy.

Hematopoietic cell transplantation (HCT) and chimeric antigen receptor T cell therapy (CAR-T) recipients who develop Coronavirus disease 2019 (COVID-19) can have decreased overall survival (OS), likely due to disease-inherent and therapy-related immunodeficiency. The availability of COVID-19-directed therapies and vaccines have improved COVID-19-related outcomes, but immunocompromised individuals remain vulnerable. Specifically, the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant infections, including Omicron and its sublineages, particularly in HCT recipients, remain to be defined. The aim of this study was to compare the impact of SARS-CoV-2 Omicron infections in HCT/CAR-T recipients with outcomes previously reported for ancestral SARS-CoV-2 infections early in the pandemic (March to June 2020). This was a retrospective analysis of adult HCT/CAR-T recipients diagnosed with COVID-19 at Memorial Sloan Kettering Cancer Center between July 2021 and July 2022. We identified 353 patients (172 autologous HCT recipients [49%], 152 allogeneic HCT recipients [43%], and 29 CAR-T recipients [8%]), with a median time from HCT/CAR-T to SARS-CoV-2 infection of 1010 days (interquartile range, 300 to 2046 days). Forty-one patients (12%) were diagnosed with COVID-19 during the delta wave, and 312 patients (88%) were diagnosed during the Omicron wave. Risk factors associated with increased odds of COVID-19-related hospitalization were the presence of 2 or more comorbidities (odds ratio [OR], 4.9; 95% confidence interval [CI], 2.4 to 10.7; P < .001), CAR-T therapy compared to allogeneic HCT (OR, 7.7; 95% CI, 3.0 to 20.0; P < .001), hypogammaglobulinemia (OR, 2.71; 95% CI, 1.06 to 6.40; P = .027), and age at COVID-19 diagnosis (OR, 1.03; 95% CI, 1.0 to 1.05; P = .04). In contrast, infection during the Omicron variant BA5/BA4-dominant period compared to variant BA1 (OR, .21; 95% CI, .03 to .73; P = .037) and more than 3 years from HCT/CAR-T therapy to COVID-19 diagnosis compared to early infection at <100 days (OR, .31; 95% CI, .12 to .79; P = .011) were associated with a decreased odds for hospitalization. The OS at 12 months from COVID-19 diagnosis was 89% (95% CI, 84% to 94%), with 6 of 26 deaths attributable to COVID-19. Patients with the ancestral strain of SAR-CoV-2 had a lower OS at 12 months, with 73% (95% CI, 62% to 84%) versus 89% (95% CI, 84% to 94%; P < .001) in the Omicron cohort. Specific COVID-19 treatment was administered in 62% of patients, and 84% were vaccinated with mRNA COVID-19 vaccines. Vaccinated patients had significantly better OS than unvaccinated patients (90% [95% CI, 86% to 95%] versus 82% [95% CI, 72% to 94%] at 12 months; P = .003). No significant difference in OS was observed in patients infected with the Omicron and those infected with the Delta variant (P = .4) or treated with specific COVID-19 treatments compared with those not treated (P = .2). We observed higher OS in HCT and CAR-T recipients infected with the Omicron variants compared to those infected with the ancestral strain of SARS-CoV2. The use of COVID-19 antivirals, mAbs, and vaccines might have contributed to the improved outcomes.

Prospective analysis to determine barriers to allogeneic hematopoietic cell transplantation in patients with acute leukemia.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for patients with acute leukemia. Despite this, studies have shown that only a minority of patients ultimately proceed to allo-HCT. The primary objective of this prospective, observational study was to identify the rate of allo-HCT in patients for whom it was recommended, and reasons why patients deemed appropriate and eligible for HCT did not subsequently undergo transplant. Between April 2016 and April 2021, adult patients with newly diagnosed or relapsed/refractory acute leukemia were enrolled at the time of induction/reinduction therapy. Initial transplantation workup and allo-HCT recommendations were made during the early phase of induction/reinduction. Of the 307 enrolled patients, allo-HCT was recommended to 85% (n = 259), of whom 66% (n = 170) underwent transplant. Donor sources comprised 54% human leukocyte antigen (HLA)-matched unrelated donors, 20% HLA-matched sibling donors and HLA-mismatched graft sources with 15% umbilical cord blood units, 8% HLA-mismatched unrelated donors, and 4% HLA-haploidentical donors. The most common reason for transplant disqualification in the 89 patients in whom it was initially recommended was persistent/relapsed disease (70%), followed by early patient death (10%). In this prospective study, we report a high allo-HCT rate, which may be due to early transplant referral and workup. The main allo-HCT barrier was disease control, followed by early patient death. With the increasing availability of HLA-mismatched graft sources, the lack of donor availability was not a transplant barrier. Further development of novel transplant strategies for patients not achieving remission and improvements in induction regimens could result in increased allo-HCT utilization.

The Simplified Comorbidity Index predicts non-relapse mortality in reduced-intensity conditioning allogeneic haematopoietic cell transplantation.

Comorbidity assessment before allogeneic haematopoietic cell transplantation (allo-HCT) is essential for estimating non-relapse mortality (NRM) risk. We previously developed the Simplified Comorbidity Index (SCI), which captures a small number of 'high-yield' comorbidities and older age. The SCI was predictive of NRM in myeloablative CD34-selected allo-HCT. Here, we evaluated the SCI in a single-centre cohort of 327 patients receiving reduced-intensity conditioning followed by unmanipulated allografts from HLA-matched donors. Among the SCI factors, age above 60, mild renal impairment, moderate pulmonary disease and cardiac disease were most frequent. SCI scores ranged from 0 to 8, with 39%, 20%, 20% and 21% having scores of 0-1, 2, 3 and ≥4 respectively. Corresponding cumulative incidences of 3-year NRM were 11%, 16%, 22% and 27%; p = 0.03. In multivariable models, higher SCI scores were associated with incremental risks of all-cause mortality and NRM. The SCI had an area under the receiver operating characteristic curve of 65.9%, 64.1% and 62.9% for predicting 1-, 2- and 3-year NRM versus 58.4%, 60.4% and 59.3% with the haematopoietic cell transplantation comorbidity index. These results demonstrate for the first time that the SCI is predictive of NRM in patients receiving allo-HCT from HLA-matched donors after reduced-intensity conditioning.

Tissue-specific features of the T cell repertoire after allogeneic hematopoietic cell transplantation in human and mouse.

T cells are the central drivers of many inflammatory diseases, but the repertoire of tissue-resident T cells at sites of pathology in human organs remains poorly understood. We examined the site-specificity of T cell receptor (TCR) repertoires across tissues (5 to 18 tissues per patient) in prospectively collected autopsies of patients with and without graft-versus-host disease (GVHD), a potentially lethal tissue-targeting complication of allogeneic hematopoietic cell transplantation, and in mouse models of GVHD. Anatomic similarity between tissues was a key determinant of TCR repertoire composition within patients, independent of disease or transplant status. The T cells recovered from peripheral blood and spleens in patients and mice captured a limited portion of the TCR repertoire detected in tissues. Whereas few T cell clones were shared across patients, motif-based clustering revealed shared repertoire signatures across patients in a tissue-specific fashion. T cells at disease sites had a tissue-resident phenotype and were of donor origin based on single-cell chimerism analysis. These data demonstrate the complex composition of T cell populations that persist in human tissues at the end stage of an inflammatory disorder after lymphocyte-directed therapy. These findings also underscore the importance of studying T cell in tissues rather than blood for tissue-based pathologies and suggest the tissue-specific nature of both the endogenous and posttransplant T cell landscape.

Third-party cytomegalovirus-specific T cells improved survival in refractory cytomegalovirus viremia after hematopoietic transplant.

BackgroundRefractory CMV viremia and disease are associated with significant morbidity and mortality in recipients of hematopoietic stem cell transplant (HCT).MethodsIn phase I/II trials, we treated 67 subjects for CMV viremia or disease arising after HCT with adoptive transfer of banked, third-party, CMVpp65-sensitized T cells (CMVpp65-VSTs). All were evaluable for toxicity and 59 for response. Evaluable subjects had CMV disease or persisting viremia that had failed at least 2 weeks of induction therapy with a median of 3 antiviral drugs; 84.7% had more than 3 of 11 high-risk features. CMVpp65-VSTs were specific for 1 to 3 CMVpp65 epitopes, presented by a limited set of HLA class I or II alleles, and were selected based on high-resolution HLA matching at 2 of 10 HLA alleles and matching for subject and subject's HCT donor for 1 or more alleles through which the CMVpp65-VSTs were restricted.ResultsT cell infusions were well tolerated. Of 59 subjects evaluable for response, 38 (64%) achieved complete or durable partial responses.ConclusionsRecipients responding to CMVpp65VSTs experienced an improved overall survival. Of the risk factors evaluated, transplant type, recipient CD4+ and CD8+ T cell levels prior to adoptive therapy, and the HLA restriction of CMVpp65-VSTs infused each significantly affected responses. In addition, CMVpp65-specific T cells of HCT donor or recipient origin contributed to the durability of both complete and partial responses.Trial RegistrationNCT00674648; NCT01646645; NCT02136797 (NIH).FundingNIH (P01 CA23766, R21 CA162002 and P30 CA008748); Aubrey Fund; Claire Tow Foundation; Major Family Foundation; "Rick" Eisemann Pediatric Research Fund; Banbury Foundation; Edith Robertson Foundation; Larry Smead Foundation.

An Optimized Search Prognosis Tool to Predict 8/8 HLA Allele-Matched Unrelated Donor Procurement.

For patients in need of allogeneic transplantation who lack an HLA-identical sibling, an 8/8 HLA allele-matched unrelated donor (URD) is a standard alternative. However, delays in URD procurement can adversely impact patient care. Recipient genotype and search assessment (MSKv1.0)-based tools can predict search prognosis for many, but both tools have lower performance in non-European ancestry patients. Using the MSKv1.0 tool, we analyzed searches from 1530 potential allograft recipients (including 863 who underwent transplantation) with the aim of creating an optimized MSKv2.0 search prognosis tool that can classify a URD search as either Good or Poor with a high level of accuracy while also limiting an ambiguous Fair search prognosis regardless of patient ancestry. By MSKv2.0, the 8/8 URD search prognosis distribution was 57% Good, 21% Fair, and 22% Poor in Europeans and 15% Good, 21% Fair, and 63% Poor in non-Europeans. Importantly, compared to MSKv1.0, the likelihood of Fair categorization was reduced to <25% with comparable Fair rates (P = .847) in both European and non-European groups. Moreover, all patients with an MSKv2.0 Good prognosis had an 8/8 URD identified, and almost all of those who underwent transplantation had an 8/8 URD (Europeans, 99%; non-Europeans, 98%; P = .504). The MSKv2.0 tool also was highly accurate at classifying Poor searches, with <10% identifying an 8/8 URD, and almost all patients who underwent transplantation (Europeans, 95%; non-Europeans, 96%) receiving an alternative donor. Using preliminary search results, MSKv2.0 accurately classifies patients by likelihood of 8/8 URD procurement, greatly facilitating triage to 8/8 URD (Good prognosis) or alternative donor (Poor prognosis) transplantations.

Analysis of disparities in time to allogeneic transplantation in adults with acute myelogenous leukemia.

Although alternative donors extend transplant access, whether recipient ancestry affects the time to allogeneic transplant is not established. We analyzed the likelihood of clinically significant delays to allograft by patient ancestry in 313 adult patients with acute myelogenous leukemia (AML) who underwent transplantation. Non-European ancestry patients (n = 99) were more likely than Europeans (n = 214) to receive HLA-mismatched donor allografts (45% vs 24%). Overall, the median time from transplant indication to allograft was 127 days (range, 57-1683). In multivariable analysis, non-Europeans had an increased risk of prolonged indication to transplant time >180 days owing to significant delays in indication to consult >90 days and consult to transplant >120 days. Compared with recipients of HLA-matched unrelated donors (URDs), HLA-mismatched adult donor recipients were at an increased risk of delayed indication to transplant, whereas HLA-identical sibling and cord blood recipients were at a lower risk. Subanalysis showed more indication to transplant delays >180 days in non-European (44%) vs European (19%) 8/8 URD recipients. Finally, the pandemic further exacerbated delays for non-Europeans. In summary, although non-European patients with AML are less likely to receive 8/8 URDs as expected, if they do, their transplants are delayed. HLA-identical siblings and cord blood facilitate the fastest transplants regardless of patient ancestry, whereas other adult donor transplants are delayed. Strategies to mitigate referral barriers, hasten donor evaluation, and use all alternative donor sources are critical to ensure timely transplantation for patients with AML.

Extended-duration letermovir prophylaxis for cytomegalovirus infection after cord blood transplantation in adults.

Cord blood transplantation (CBT) can be complicated by a high incidence of clinically significant cytomegalovirus infection (csCMVi). We have investigated the efficacy of extended letermovir prophylaxis in seropositive adult CBT recipients. The aim was to continue prophylaxis for ≥6 months (insurance permitting). By day 100, the incidence of csCMVi was 0% in 28 patients who received letermovir prophylaxis. Moreover, of 24 patients alive at day 100, none had csCMVi by day 180, having continued prophylaxis for all (n = 20) or part (n = 4) of that period. Overall, 20 patients stopped letermovir at a median of 354 days (range, 119-455 days) posttransplant, with only 5 requiring 1 (n = 4) or 2 (n = 1) courses of valganciclovir (median total duration, 58 days; range, 12-67 days) for postprophylaxis viremia, with no subsequent csCMVi. There were no toxicities attributable to letermovir. Of the 62 historic control subjects who received acyclovir only, 51 developed csCMVi (median onset, 34 days; range, 5-74 days), for a day 100 incidence of 82% (95% confidence interval, 73-92). Seven patients developed proven/probable CMV disease, and 6 died before day 100 (3 with proven/probable CMV pneumonia). Forty-five patients required extended therapy during the first 6 months for 1 (n = 10), 2 (n = 14), or 3/persistent (n = 21) csCMVi, with 43 (84%) of 51 developing significant treatment toxicities. Letermovir is a highly effective, well-tolerated prophylaxis that mitigates CMV infection, CMV-related mortality, and antiviral therapy toxicities in CBT recipients. Our data support prophylaxis duration of at least 6 months after CBT.

Atypical pathogens presenting with pulmonary consolidations detected by cell-free DNA next-generation sequencing in patients with hematologic malignancies.

Identification of pathogens with pulmonary presentation in patients with hematologic malignancies may be challenging due to diagnostic difficulty related to the underlying malignancy and limitations of conventional microbiologic methods. Herein, we present a case series of three patients with pulmonary consolidations due to Legionella bozemanae necrotizing pneumonia, Pneumocystis jirovecii pneumonia, and disseminated Scedosporium infection, who were diagnosed by microbial cell-free DNA next-generation sequencing. We observed that this new sequencing modality was in agreement with gold-standard diagnostics, posing a potential solution to the problem of limited capability in diagnosing infections in hematological malignancy patients.

The Simplified Comorbidity Index: a new tool for prediction of nonrelapse mortality in allo-HCT.

Individual comorbidities have distinct contributions to nonrelapse mortality (NRM) following allogeneic hematopoietic cell transplantation (allo-HCT). We studied the impact of comorbidities individually and in combination in a single-center cohort of 573 adult patients who underwent CD34-selected allo-HCT following myeloablative conditioning. Pulmonary disease, moderate to severe hepatic comorbidity, cardiac disease of any type, and renal dysfunction were associated with increased NRM in multivariable Cox regression models. A Simplified Comorbidity Index (SCI) composed of the 4 comorbidities predictive of NRM, as well as age >60 years, stratified patients into 5 groups with a stepwise increase in NRM. NRM rates ranged from 11.4% to 49.9% by stratum, with adjusted hazard ratios of 1.84, 2.59, 3.57, and 5.38. The SCI was also applicable in an external cohort of 230 patients who underwent allo-HCT with unmanipulated grafts following intermediate-intensity conditioning. The area under the receiver operating characteristic curve (AUC) of the SCI for 1-year NRM was 70.3 and 72.0 over the development and external-validation cohorts, respectively; corresponding AUCs of the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) were 61.7 and 65.7. In summary, a small set of comorbidities, aggregated into the SCI, is highly predictive of NRM. The new index stratifies patients into distinct risk groups, was validated in an external cohort, and provides higher discrimination than does the HCT-CI.

Hematopoietic Cell Transplantation is Feasible in Patients with Prior COVID-19 Infection.

There are limited data on outcomes of patients with prior Coronavirus disease 2019 (COVID-19) who proceeded to autologous or allogeneic hematopoietic cell transplantation (HCT). Whether these patients are more susceptible to poor outcomes and recurrence of COVID-19 is unknown. We report a retrospective analysis of outcomes of 15 consecutive patients with hematologic malignancies who experienced COVID-19 and subsequently underwent autologous (n = 8) or allogeneic (n = 7) HCT between June 17, 2020, and February 17, 2021. The cohort included patients with asymptomatic past infections or symptomatic COVID-19 disease. Data were obtained from chart review. Descriptive statistics were used to summarize patient characteristics. Among eight patients who underwent autologous HCT, four had a diagnosis of multiple myeloma and four had a diagnosis of non-Hodgkin's lymphoma. Four of these eight patients did not test positive for anti-SARS-CoV-2 IgG antibody at any point during the course of treatment. The other four patients had detectable anti-SARS-CoV-2 IgG antibodies before undergoing autologous HCT, but only two of these patients remained anti-SARS-CoV-2 IgG antibody-positive at their last follow-up. One patient died from progression of disease. Seven patients with prior COVID-19 underwent allogeneic HCT for acute lymphoblastic leukemia (n = 3), acute myelogenous leukemia (n = 1), chronic myelogenous leukemia in lymphoid blast crisis (n = 1), myelodysplastic syndrome (n = 1), or myelofibrosis (n = 1). Three of the seven patients tested positive for anti-SARS-CoV-2 IgG antibodies following the initial COVID-19 diagnosis; however, only one of these patients retained anti-SARS-CoV-2 IgG antibody following allogeneic HCT. One patient died of infection (fungal and Pneumocystis jirovecii pneumonia) occurring in the context of ongoing treatment for graft-versus-host disease. None of the 15 patients had recurrent COVID-19 infection. Based on our experience, autologous and allogeneic HCT can be safely performed in selected patients with previous COVID-19 infection.

Post-Transplantation Cyclophosphamide Is Associated with an Increase in Non-Cytomegalovirus Herpesvirus Infections in Patients with Acute Leukemia and Myelodysplastic Syndrome.

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis in recipients of haploidentical and fully matched transplantations is on the increase. Published studies have reported an increased incidence of cytomegalovirus (CMV) infection with the use of PTCy. Limited data exist on the incidence and outcomes of infection with non-CMV herpesviruses (NCHV) in this setting. The aim of this study was to evaluate the cumulative incidence of NCHV infections and the association of NCHV infections with transplantation-specific outcomes in recipients of haploidentical transplantation with PTCy (HaploCy), matched sibling donor transplantation with PTCy (SibCy), and matched sibling donor transplantation with calcineurin inhibitor-based prophylaxis (SibCNI). We hypothesized that, like CMV infection, HaploCy recipients of also will have a higher risk of NCHV infections. Using the Center for International Blood and Marrow Transplantation Research database, we analyzed 2765 patients (HaploCy, n = 757; SibCNI, n = 1605; SibCy, n = 403) who had undergone their first hematopoietic stem cell transplantation (HCT) between 2012 and 2017 for acute myelogenous leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. The cumulative incidence of NCHV at 6 months post-NCT was 13.9% (99% confidence interval], 10.8% to 17.3%) in the HaploCy group, 10.7% (99% CI, 7.1% to 15%) in the SibCy group, and 5.7% (99% CI, 4.3% to 7.3%) in the Sib CNI group (P < .001). This was due primarily to a higher frequency of human herpesvirus 6 viremia reported in patients receiving PTCy. The incidence of Epstein-Barr viremia was low in all groups, and no cases of post-transplantation lymphoproliferative disorder were seen in either PTCy group. The incidence of NCHV organ disease was low in all 3 cohorts. The development of NCHV infection was associated with increased treatment-related mortality, particularly in the HaploCy group. There was no association with the development of GVHD, relapse, or disease-free survival. Patients in PTCy cohorts who did not develop NCHV infection had lower rates of cGVHD. This study demonstrates that the use of PTCy is associated with an increased risk of NCHV infection. The development of NCHV infection was associated with increased nonrelapse mortality, especially in the HaploCy group. Prospective trials should consider viral surveillance strategies in conjunction with assessment of immune reconstitution for a better understanding of the clinical relevance of viral reactivation in different HCT settings.

Predictors of Humoral Response to SARS-CoV-2 Vaccination after Hematopoietic Cell Transplantation and CAR T-cell Therapy.

Cellular therapies including allogeneic hematopoietic cell transplant (allo-HCT) and autologous hematopoietic cell transplant (auto-HCT) and chimeric antigen receptor (CAR) T-cell therapy render patients severely immunocompromised for extended periods after therapy, and data on responses to COVID-19 vaccines are limited. We analyzed anti-SARS-CoV-2 spike IgG Ab (spike Ab) titers and neutralizing Ab among 217 recipients of cellular treatments (allo-HCT, n = 149; auto-HCT, n = 61; CAR T-cell therapy, n = 7). At 3 months after vaccination, 188 patients (87%) had positive spike Ab levels and 139 (77%) had positive neutralization activity compared with 100% for both in 54 concurrent healthy controls. Time from cellular therapy to vaccination and immune recovery post-cellular therapy were associated with response. Vaccination against COVID-19 is an important component of post-cellular therapy care, and predictors of quantitative and qualitative response are critical in informing clinical decisions about optimal timing of vaccines and the requirement for booster doses. Significance: Identifying predictors of response to vaccination against SARS-CoV-2 in patients following cellular therapy is critical to managing this highly vulnerable patient population. To date, this is the most comprehensive study evaluating quantitative and qualitative responses to vaccination, providing parameters most predictive of response and potentially informing booster vaccination strategies.See related article by Chung et al., p. 568. This article is highlighted in the In This Issue feature, p. 549.

Guidelines for the Prevention and Management of Graft-versus-Host Disease after Cord Blood Transplantation.

The incidence of graft-versus-host disease (GVHD) after cord blood (CB) transplantation (CBT) is lower than expected given the marked degree of human leukocyte antigen (HLA)-mismatch of CB grafts. While the exact mechanism that underlies this biology remains unclear, it is hypothesized to be due to the low number of mostly immature T-cells infused as part of the graft1,2, and increased tolerance of CB-derived lymphocytes induced by the state of pregnancy. Nevertheless, acute GVHD (aGVHD) is a significant complication of CBT. In contrast, the incidence of chronic GVHD (cGVHD) following CBT is lower than what is observed following matched related or unrelated donor HSC transplantation (HSCT)3-6. This review outlines the guidelines for the prevention and management of acute and chronic GVHD following CBT.

Relapse after Allogeneic Stem Cell Transplantation of Acute Myelogenous Leukemia and Myelodysplastic Syndrome and the Importance of Second Cellular Therapy.

Patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) generally have poor overall survival (OS). Interventions that result in improved OS after relapse are not well established. The efficacy of second cellular therapy and specific indications are matters of debate. This study was conducted to evaluate factors associated with postrelapse survival and the efficacy of a second course of cellular therapy. We retrospectively analyzed consecutive patients with AML and MDS who underwent a first allo-HCT between 2010 and 2017 at our center but subsequently relapsed. One hundred and four patients with AML and 44 patients with MDS were included (total n = 148). Bone marrow (BM) and peripheral blood stem cell grafts were either unmodified or T cell-depleted (TCD) by CD34+ selection ex vivo. Forty-five patients (30.4%) received a second cellular therapy after relapse, either a second allo-HCT (n = 28; 18.9%) or donor leukocyte infusion (DLI) (n = 17; 11.5%). The median age at transplantation was 60 years (range, 24 to 78 years). The median time to relapse (TTR) after transplantation was 6.5 months (range, 1 to 60.9 months), and the ensuing median OS was 6 months (95% confidence interval [CI], 4.8 to 8.9 months). In univariable analysis, longer TTR, relapse type (measurable residual disease versus morphologic), relapse occurring in the most recent years, and receipt of cellular therapy after relapse were associated with better outcomes, whereas adverse cytogenetics and/or abnormality of TP53, as well as NPM1 mutation in patients with AML, were associated with adverse outcomes. Relapse type, year of relapse, and a variable resulting from the combination of TTR and receipt of second cellular therapy remained significantly associated with postrelapse survival in multivariable analysis. In a separate multivariable model, adjusted only for TTR, relapse type, and receipt of second cellular therapy, an adverse effect of NPM1 mutation on survival was confirmed. We could not show an effect of post-transplantation maintenance on survival after relapse. In both univariable and multivariable analysis, we found a positive association for second cellular therapy with survival after relapse in patients who relapsed early (<6 months) after allo-HCT and a similar trend in patients who relapsed late (>12 months) after transplantation. Two-year OS after a second cellular therapy was 44.9% (95% CI, 28.5% to 61.4%), and it was significantly better in patients with <5% BM blasts before cell infusion. We could not show different effects on survival after second cellular therapy for DLI versus second allo-HCT in univariable analysis. Survival after relapse is improving over time, but this remains a challenging event, especially for patients who relapse early after transplantation. We found that a second cellular therapy could offer a benefit even in these cases. Nonetheless, more research is needed to clarify the most appropriate treatment choices after relapse. These are probably driven by underlying genetic and immunologic conditions, which should be the focus of future studies.