Graft-versus-tumor effect according to type of graft-versus-host disease defined by National Institutes of Health consensus criteria and associated outcomes

The impact of National Institutes of Health consensus criteria (NCC) graft-versus-host disease (GVHD) on survival has rarely been investigated in a large cohort of patients with GVHD presenting before and after day 100 posttransplantation. We retrospectively investigated 775 patients who underwent allogeneic stem cell transplantation and assessed the GVHD effects on survival by the time-dependent covariates in Cox proportional hazards regression models. Using the NCC, the patients were classified into 4 groups: (1) no GVHD (n?= 251); (2) acute GVHD (aGVHD) only (n = 199), including 26 patients with late aGVHD; (3) classic chronic GVHD (cGVHD; n = 232); and (4) overlap syndrome (OS; n = 93). Multivariate analyses showed that classic cGVHD (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.27-0.77) and OS (HR, 0.52; 95% CI, 0.28-0.96) were associated with significantly decreased risk of relapse, whereas aGVHD only was not associated with relapse rate (HR, 1.11; 95% CI, 0.76-1.63). All aGVHD events, including the period of aGVHD in patients who developed cGVHD after aGVHD, also did not affect the risk of relapse (HR, 0.74; 95% CI, 0.49-1.12). All types of GVHD were significantly associated with higher nonrelapse mortality in common. Finally, patients with aGVHD only had significantly lower overall survival and disease-free survival compared with those without GVHD, in contrast to favorable survival outcomes in patients with cGVHD without previous aGVHD. This study demonstrates that NCC GVHD type is associated with different graft-versus-tumor effects. Further studies are needed to investigate risk factors, pathogenesis, and biomarkers for each type of NCC GVHD.     

Transplantation from Matched Siblings Using Once-Daily Intravenous Busulfan/Fludarabine with Thymoglobulin: A Myeloablative Regimen with Low Nonrelapse Mortality in All But Older Patients with High-Risk Disease

Two hundred patients received hematopoietic stem cell transplantation (HSCT) from matched sibling donors (MSD) after myeloablative conditioning including fludarabine (Flu) and once-daily intravenous busulfan (Bu). Thymoglobulin (TG) was added to methotexate (MTX) and cyclosporine (CsA) as graft-versus-host disease (GVHD) prophylaxis. For low-risk (acute leukemia CR1/CR2, CML CP1) patients projected 5-year nonrelapse mortality (NRM) and overall survival (OS) were 4% and 76% for those ≤45 years old (n = 54) and 6% and 83% for those >45 (n = 31). For high-risk (HR) patients NRM was 6% versus 27% (18% at 1 year) (P = .04) and OS 64% versus 37% (P = .47) in younger (n = 40) and older (n = 75) patients, respectively. To correct for imbalance in HR diagnoses each of 17 younger HR patients were matched with 2 older HR (OHR) patients by diagnosis and details of stage, and thereafter for other risk factors. For the younger HR and OHR patients, respectively, OS was 70% versus 37% (P = .02) and NRM 0 versus 34% (P = .02). When outcomes of OHR patients were compared with the other 3 groups combined NRM was 27% versus 5%, respectively (P = .002). Incidence of acute graft-versus-host disease (aGVHD) grade II-IV, aGVHD grade III-IV, and chronic GVHD (cGVHD) was 23% versus 10% (P = .02), 4% versus 2% (P = ns), and 66% versus 41% (P = .001), respectively. Nine of 14 nonrelapse deaths in the OHR group were related to GVHD or its treatment compared with 3 of 6 in all others (P value for GVHD related death = .01). Multivariate analysis of OS and DFS correcting for potentially confounding pretransplant factors identified only the OHR patients as having significantly increased risk (relative risk [RR] 3.32, confidence interval [CI] 1.71-6.47, P < .0001, and RR 3.32, CI 1.71-6.43, P < .0001, respectively). The effect of age on NRM is only apparent in HR patients, and is not explained by heterogeneity in diagnoses. Older HR patients experience more GVHD and more GVHD-related death than others, but NRM is no higher than reported with many nonmyeloablative regimens.     

Prognostic Factors of Chronic Graft-versus-Host Disease Following Allogeneic Peripheral Blood Stem Cell Transplantation: The National Institutes Health Scale Plus the Type of Onset Can Predict Survival Rates and the Duration of Immunosuppressive Therapy

Several grading systems have been developed in the bone marrow transplantation setting in attempts to predict survival in patients with chronic graft-versus-host disease (cGVHD). In this study, we evaluated the prognostic value of the National Institutes of Health (NIH) scoring system and investigated for any additional prognostic factors in a series of 171 patients undergoing peripheral blood stem cell transplantation (PBSCT) from matched related donors. The cumulative incidence of cGVHD was 70%; cumulative incidences of mild, moderate, and severe cGVHD were 29%, 42% and 28%, respectively. Overall, 68% of patients were free from immunosuppression 5 years after transplantation. Absence of previous acute GVHD (aGVHD; hazard ratio [HR] = 2; P = .004) and mild cGVHD (HR = 4.2; P = .007) increased the probability of being off immunosuppressive treatment by the last follow-up. Overall survival (OS) at 5 years was 52%. Severe cGVHD, according to the NIH scoring system (HR = 13.27; P = .001) adversely influenced outcome, whereas de novo onset (HR = 0.094; P = .003) had a more favorable impact on survival. The combination of both variables allowed us to identify 4 different subgroups of patients with OS of 82%, 70%, 50%, and 25%. Our findings indicate that the NIH scoring system has some prognostic value in patients undergoing PBSCT and, together with the type of onset, must be considered to predict the possible outcome of patients who develop cGVHD.     

Peripheral Blood Eosinophilia Has a Favorable Prognostic Impact on Transplant Outcomes after Allogeneic Peripheral Blood Stem Cell Transplantation

Peripheral eosinophilia after allogeneic stem cell transplant (ASCT) may reflect the activation of the Th2 cytokine pathway. A retrospective analysis was performed to evaluate the impact of early- (before day 100: EEo) or late-onset (beyond day 100: LEo) eosinophilia (≥0.5 × 10⁹/L in peripheral blood) on transplant outcomes after peripheral blood SCT (PBSCT) in 237 patients. The incidence of EEo and LEo was 43% at day 100 and 62% at 2 years, respectively. Compared with patients without LEo, improved transplant outcomes were observed in patients with LEo: better overall survival (OS; 86% versus 41%, P = 5 × 10⁻¹¹), lower nonrelapse mortality (NRM; 10% versus 37%, P = 3 × 10⁻⁶), lower relapse incidence (11% versus 31%, P = 3 × 10⁻⁵), and higher GVHD-specific survival (GSS; 90% versus 64%, P = 1 × 10⁻⁶) were observed. In addition, similar finding was observed when transplant outcomes were analyzed according to the occurrence of eosinophilia at the onset of cGVHD. The multivariate analyses confirmed a favorable implication of LEo on OS, NRM, and GSS. LEo was associated with: (1) less severe chronic GVHD (cGVHD), (2) higher prevalence of autoantibodies, and (3) rapid lymphocyte count recovery after ASCT. In summary, the development of eosinophila after allogeneic PBSCT seemed to be a prognostic marker for improving transplant outcome.     

Clinical significance of platelet count at day +60 after allogeneic peripheral blood stem cell transplantation

Thrombocytopenia (TP) is a frequent complication after allogeneic stem cell transplantation (SCT) and regarded as a poor prognostic factor, especially in patients with chronic graft-versus-host disease (GVHD), although various factors were related to the development of TP after allogeneic SCT. Sixty-three patients receiving allogeneic peripheral blood stem cell transplantation (PBSCT) were stratified according to platelet count (PC) at day +60 and analyzed in terms of overall survival (OS) and the incidence of non-relapse mortality (NRM). Ten patients (15.9%) were stratified in group 1 (PC /= 80 x 10(9)/L). Group 3 was associated with lower incidence of extensive chronic GVHD (p=0.013), better 3-yr OS (p=0.0030), and lower NRM rate (p<0.0001). In multivariate analyses, the PC at day +60 was identified as an independent prognostic factor (p=0.003) together with CD34+ cell dose (p<0.001), disease risk (p=0.004), and acute GVHD (p=0.033) in terms of NRM, and the PC (p=0.047) and CD34+ cell dose (p=0.026) in terms of incidence of infectious events. Measuring the platelet count at day +60 is a simple method for predicting the risk of chronic GVHD development and prognosis after allogeneic PBSCT.     

Validation of National Institutes of Health Global Scoring System for Chronic Graft-Versus-Host Disease (GVHD) According to Overall and GVHD-Specific Survival

A new severity grading system for graft-versus-host disease (GVHD) was established by the National Institutes of Health (NIH) consensus criteria (NCC). However, its prognostic value still needs to be validated. Four hundred twenty-five consecutive patients who survived beyond 100 days after allogeneic stem cell transplantation were reviewed and reclassified using NCC. GVHD-specific survival (GSS) and cumulative incidence of relapse were compared according to the NIH global score at the onset and peak of chronic GVHD (cGVHD). Of 346 patients with cGVHD diagnosed by the Revised Seattle Criteria, 317 patients were reclassified according to the NCC as classic cGVHD (n = 144) and overlap syndrome (n = 173). The NIH global scores at onset were mild (43.2%), moderate (42.3%), and severe (14.5%), whereas more moderate (55.5%) and severe (31.6%) cGVHD was observed at the peak of cGVHD. With a median follow-up duration of 34 months, the 5-year GSS was significantly worse for the severe group than the moderate/mild groups at onset and at peak: 50.9% ± 7.8% versus 89.7% ± 3.2% versus 93.5% ± 2.4% at onset (P < .001) and 69.1% ± 5.2% versus 93.2% ± 2.1% versus 97.3% ± 2.7% at peak (P < .001). Severe NIH global score at onset and peak were confirmed as a poor prognostic factor for GSS in multivariate analysis. The cumulative incidence of relapse did not differ among the severity groups at onset or peak. In conclusion, the new NIH global scoring system was shown to differentiate a high-risk group of patients (with severe grade cGVHD) in terms of long-term transplant outcomes.     

Extended mycophenolate mofetil and shortened cyclosporine failed to reduce graft-versus-host disease after unrelated hematopoietic cell transplantation with nonmyeloablative conditioning.

We previously reported data from 103 patients with hematologic malignancies (median age 54 years) who received peripheral blood stem cell (PBSC) grafts from HLA-matched unrelated donors after nonmyeloablative conditioning and were given postgrafting immunosuppression consisting of mycophenolate mofetil (MMF; administered from day 0 until day +40 with taper through day +96) and cyclosporine (CSP; given from day -3 to day +100, with taper through day 180) (historical patients). The incidences of grade II-IV acute and extensive chronic graft-versus-host disease (aGVHD, cGVHD) were 52% and 49%, respectively, and the 1-year probabilities of relapse, nonrelapse mortality (NRM), and progression-free survival (PFS) were 26%, 18%, and 56%, respectively. Here, we treated 71 patients with hematologic malignancies (median age 56 years) with unrelated PBSC grafts and investigated whether postgrafting immunosuppression with an extended course of MMF, given at full dosing until day +150 and then tapered through day +180, and a shortened course of CSP, through day +80, would promote tolerance induction and reduce the incidence of GVHD (current patients). We observed 77% grade II-IV aGVHD and 45% extensive cGVHD (P=.03, and P=.43, respectively, in current compared to historical patients). The 1-year probabilities of relapse, NRM, and PFS were 23%, 29%, and 47%, respectively (P=.89, P=.02, and P=.08 compared to the historical patients). We conclude that postgrafting immunosuppression with extended MMF and shortened CSP failed to decrease the incidence of GVHD among unrelated PBSC recipients given nonmyeloablative conditioning.     

T Cell-Replete Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for Hodgkin Lymphoma Relapsed after Autologous Transplantation: Reduced Incidence of Relapse and of Chronic Graft-versus-Host Disease Compared with HLA-Identical Related Donors

Allogeneic hematopoietic stem cell transplantation (SCT) represents a potential curative strategy for patients with Hodgkin lymphoma (HL) relapsing after autologous SCT (ASCT), but the incidence of disease relapse is still high. We performed a retrospective study on 64 patients with HL relapsing after ASCT to compare outcomes after HLA-identical SCT (HLAid-SCT; n?=?34) and haploidentical SCT with post-transplantation cyclophosphamide (PT-Cy) (Haplo-SCT; n?=?30). All patients engrafted, with a significantly shorter median time for neutrophil and platelet engraftment after HLAid compared with Haplo-SCT (14 days versus 19 days and 11 days versus 23 days, respectively; P?<?.005). With a median follow-up of 47 months, 3-year overall survival (OS), 3 -year progression-free survival (PFS), and 1-year nonrelapse mortality (NRM) were 53%, 44% and 17%, respectively. Recipients of Haplo-SCT were less likely to experience disease relapse (3-year cumulative incidence of relapse, 13% versus 62%; P?=?.0001) and chronic graft- versus-host disease (GVHD; 3% versus 32%; P?=?.003), resulting in improved PFS (60% versus 29%; P?=?.04) and GVHD-free/relapse-free survival (47% versus 17%; P?=?.06). The 3-year OS did not differ between the 2 groups (56% versus 54%; P?not significant), and NRM was higher after Haplo-SCT, but the difference did not reach statistical significance (26% versus 9%; P?=?.09). On multivariate Cox regression analysis, receipt of Haplo-SCT (hazard ratio [HR], .17; P?=?.02) and achieving optimal disease control (complete remission before SCT: HR, .6; P?<?.0001) were the only independent variables associated with a reduced risk of disease relapse. Haplo-SCT is a valid option for patients with HL relapsing after ASCT, with a reduced incidence of relapse compared with HLAid SCT.     

Pulmonary Symptoms Measured by the National Institutes of Health Lung Score Predict Overall Survival,Nonrelapse Mortality,and Patient-Reported Outcomes In Chronic Graft-Versus-Host Disease

The 2005 National Institutes of Health (NIH) Consensus Conference recommended assessment of lung function in patients with chronic graft-versus-host disease (GVHD) by both pulmonary function tests (PFTs) and assessment of pulmonary symptoms. We tested whether pulmonary measures were associated with nonrelapse mortality (NRM), overall survival (OS), and patient-reported outcomes (PRO). Clinician and patient-reported data were collected serially in a prospective, multicenter, observational study. Available PFT data were abstracted. Cox regression models were fit for outcomes using a time-varying covariate model for lung function measures and adjusting for patient and transplantation characteristics and nonlung chronic GVHD severity. A total of 1591 visits (496 patients) were used in this analysis. The NIH symptom-based lung score was associated with NRM (P = .02), OS (P = .02), patient-reported symptoms (P < .001) and functional status (P < .001). Worsening of NIH symptom-based lung score over time was associated with higher NRM and lower survival. All other measures were not associated with OS or NRM; although, some were associated with patient-reported lung symptoms. In conclusion, the NIH symptom-based lung symptom score of 0 to 3 is associated with NRM, OS, and PRO measures in patients with chronic GVHD. Worsening of the NIH symptom-based lung score was associated with increased mortality.     

A Prospective,Longitudinal Observation of the Incidence,Treatment, and Survival of Late Acute and Chronic Graft-versus-Host Disease by National Institutes of Health Criteria in a Japanese Cohort

To prospectively validate the incidence, manifestations, and outcomes of graft-versus-host disease (GVHD) by National Institutes of Health criteria, we recruited 406 hematopoietic stem cell transplantation recipients at 16 transplant centers in Japan from May 2012 to June 2014. The 2-year cumulative incidence of late acute and chronic GVHD was 3.2% (n = 13) and 35.4% (n = 145), with a median onset of 3.6 and 4.7 months after transplant, respectively. The global severity at onset was mild in 30.3%, moderate in 43.5%, and severe in 26.2%. Eighty-two patients were followed up for 2 years, with 79.3% still manifesting GVHD symptoms, and 80.6% (n = 117) of the patients received systemic immunosuppressive treatment (IST), with a 2-year cumulative incidence of IST termination of 33.1%. Severe patients showed a significantly lower rate of IST termination than those with mild and moderate severities (mild, 38.5%; moderate, 40.9%; and severe, 17.2%). The 2-year incidence of nonrelapse mortality (NRM) and relapse was not significantly different according to the severity at onset (NRM: mild [16.6%] versus moderate [8.7%] versus severe [16.1%]; relapse: mild [14.9%] versus moderate [14.7%] versus severe [5.3%]). As a result, 2-year overall survival (OS) and GVHD-specific survival (GSS) were equivalent according to the severity at onset (mild: OS = 81.0%, GSS = 85.7%; moderate: OS = 84.2%, GSS = 92.5%; severe: OS = 83.9%, GSS = 89.2%). Our study helped identify the characteristics of late acute and chronic GVHD in Japanese patients. Further investigation is needed to identify an optimal endpoint for survival prediction.     

Clofarabine and Treosulfan as Conditioning for Matched Related and Unrelated Hematopoietic Stem Cell Transplantation: Results from the Clo3o Phase II Trial

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be curative for patients with hematologic malignancies. The ideal conditioning regimen before allo-HSCT has not been established. We conducted a Phase II study to evaluate the tolerability and efficacy of clofarabine and treosulfan as conditioning regimen before allo-HSCT. The primary objective was to evaluate the cumulative incidence of nonrelapse mortality (NRM) on day +100. Forty-four patients (36 with acute myelogenous leukemia, 5 with acute lymphoblastic leukemia, 3 with myelodysplastic syndromes) were enrolled. The median patient age was 47 years, and the median duration of follow-up was 27 months. The conditioning regimen was based on clofarabine 40 mg/m² (days -6 to -2) and treosulfan 14 g/m² (days -6 to -4). Allogeneic hematopoietic stem cells were derived from a sibling (n = 22) or a well-matched unrelated donor (n = 22). Graft-versus-host disease (GVHD) prophylaxis consisted of antithymocyte globulin, rituximab, cyclosporine, and a short-course of methotrexate. The regimen allowed for rapid engraftment and a 100-day NRM of 18%, due mainly to bacterial infections. The incidences of grade II-IV acute GVHD and chronic GVHD were 16% and 19%, respectively. The rates of overall survival (OS), progression-free survival, and relapse at 2 years were 51%, 31%, and 50%, respectively. Significantly different outcomes were observed between patients with low-intermediate and patients with high-very high Disease Risk Index (DRI) scores (1-year OS, 78% and 24%, respectively). Our findings show that the use of treosulfan and clofarabine as a conditioning regimen for allo-HSCT is feasible, with a 78% 1-year OS in patients with a low-intermediate DRI score. However, 1-year NRM was 18%, and despite the intensified conditioning regimen, relapse incidence remains a major issue in patients with poor prognostic risk factors.     

Stem cell transplantation using non-myeloablative conditioning regimen with fludarabine for hematological malignancies

Stem cell transplantation (SCT) is a useful treatment for hematological malignancies, but it is limited to younger patients because of its high treatment-related mortality. Fludarabine (Flu), a novel anticancer agent with potent immunosuppressive activity, used as a conditioning regimen (reduced intensity transplantation; RIST), can decrease treatment-related mortality, as recently reported. However, the best drug combination and the best timing for RIST remain unknown. We herein report the SCT outcomes of 36 patients undergoing Flu treatment at our institution since December 2002 and retrospectively analyze the results. RIST conditioning with Flu was well-tolerated. No severe toxicity related conditioning regimens was observed in our patients, even though there were 10 patients with a history of autologous (n = 5) or allogeneic stem cell transplantation (n = 5). Hematological engraftment was found in 33 patients. The median times for reconstitution of WBCs, RBCs, and platelets were 16 days, 27.5 days and 34 days, respectively. Stable complete donor chimerism after SCT was present in all patients with WBC engraftment, and no patients experienced late rejection. Thirty-two patients were evaluated for acute graft versus host disease (aGVHD). Nine patients had no aGVHD. The incidence of grade I/II and III/IV aGVHD was 78% and 22%, respectively. Skin lesions were the major sites of involvement. Gut involvement was present in 9 patients. All 4 patients with grade IV GVHD had stage four hepatic GVHD. Twenty-two patients were analyzed for chronic GVHD (cGVHD). Twelve patients had no cGVHD, 6 had limited type and 4 had extended type. The overall survival (OS), relapse rate (RR), and non-relapse mortality (NRM) in all patients over 7 years were found to be 41.7%, 20.1%, and 34.6%, respectively. Induction failures were present in 5 cases of AML and 1 case of NHL. Disease progression was the primary cause of death, which occurred in 12 of 21 patients. Six patients died of grade IV GVHD (n = 2) or complicated fungal infection contracted during the GVHD treatment (n = 4). One patient died of secondary MSD, which originated from donor hematopoietic cells. Two patients died of cerebral bleeding and cardiac rapture, respectively. We found that the patients' state on SCT was the most important factor in long-term survival. The OS of standard risk and high risk patients with hematological malignancies were 75% and 30.3%. We concluded that stem cell transplantation using a non-myeloablative conditioning regimen with Flu was a useful therapeutic approach for patients with hematological malignancies.     

Lower Graft-versus-Host Disease and Relapse Risk in Post-Transplant Cyclophosphamide–Based Haploidentical versus Matched Sibling Donor Reduced-Intensity Conditioning Transplant for Hodgkin Lymphoma

Classic Hodgkin lymphoma (cHL) patients with relapsed or refractory disease may benefit from allogeneic hematopoietic cell transplantation (allo-HCT), but many lack a matched sibling donor (MSD). Herein, we compare outcomes of 2 reduced-intensity conditioning (RIC) HCT platforms in cHL: T cell–replete related donor haploidentical (haplo) HCT with a post-transplant cyclophosphamide (PTCy)-based approach versus an MSD/calcineurin inhibitor (CNI)-based approach. The study included 596 adult patients who underwent a first RIC allo-HCT for cHL between 2008 and 2016 using either a haplo-PTCy (n = 139) or MSD/CNI-based (n = 457) approach. Overall survival (OS) was the primary endpoint. Secondary endpoints included acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD), nonrelapse mortality (NRM), relapse/progression, and progression-free survival (PFS). On multivariate analysis, there was no significant difference between haplo/PTCy and MDS/CNI-based approaches in terms of OS (hazard ratio [HR], 1.07; 95% confidence interval [CI], .79 to 1.45; P = .66) or PFS (HR, .86; 95% CI, .68 to 1.10; P = .22). Haplo/PTCy was associated with a significantly higher risk of grades II to IV aGVHD (odds ratio [OR], 1.73, 95% CI, 1.16 to 2.59; P = .007), but the risk of grades III to IV aGVHD was not significantly different between the 2 cohorts (OR, .61; 95% CI, .29 to 1.27; P = .19). The haplo/PTCy platform provided a significant reduction in cGVHD risk (HR, .45; 95% CI, .32 to .64; P < .001), and a significant reduction in relapse risk (HR, .74; 95% CI, .56 to .97; P = .03). There was a statistically nonsignificant trend toward higher NRM with a haplo/PTCy approach (HR, 1.65; 95% CI, .99 to 2.77; P = .06). Haplo/PTCy-based approaches are associated with lower incidences of cGVHD and relapse, with PFS and OS outcomes comparable with MSD/CNI-based approaches. There was a leaning toward higher NRM with a haplo/PTCy-based platform. These data show that haplo/PTCy allo-HCT in cHL results in survival comparable with MSD/CNI-based allo-HCT.     

Myeloablative Unrelated Cord Blood Transplantation in Adolescents and Young Adults with Acute Leukemia

Outcomes for adolescents and young adults (AYAs) with leukemia differ from other age groups and are still under-represented in clinical research. The aim of this study was to analyze outcomes of umbilical cord blood transplant (UCBT) in AYAs with acute leukemia reported to Eurocord/European Society for Blood and Marrow Transplantation. Patients (N = 504) had acute lymphoblastic (59%) or myeloid leukemia (41%), were aged 15 to 25 years, and received UCBT after myeloablative conditioning regimens between 2004 and 2016. The primary endpoint was 3-year overall survival (OS). Median follow-up was 3.9 years. Transplant was single in 58% and double UCBT in 42%. Three-year OS was 45% and leukemia free survival (LFS) was 41%. Cumulative incidence functions (CIFs) of nonrelapse mortality (NRM) and relapse were 31% and 28%, respectively. CIF of acute graft-versus-host disease (GVHD) grades II to IV at day 100 was 28%. Three-year CIF of chronic GVHD was 25%. In adjusted analysis, better disease status at UCBT (hazard ratio [HR], 2.74; P < .001) and more recent UCBT (HR, 1.43; P = .01) were associated with increased OS, and a similar effect of these factors was observed on LFS. Contrastingly, the use of antithymocyte globulin had a negative effect in LFS. The risk of acute GVHD grades II to IV increased with the use of double UCBT (HR, 1.65; P = .02) and decreased with more recent transplant period (HR, .65; P = .02) and antithymocyte globulin use (HR, .55; P = .01). Outcomes of AYA UCBT improved in more recent years, becoming comparable with pediatric results. Demonstrating the feasibility of UCBT in AYAs facilitates stem cell source selection and provides the basis for future prospective studies.     

Haploidentical Transplants with Post-Transplant Cyclophosphamide for Relapsed or Refractory Hodgkin Lymphoma: The Role of Comorbidity Index and Pretransplant Positron Emission Tomography

Disease relapse remains an unmet medical need for patients with Hodgkin lymphoma (HL) receiving an allogeneic hematopoietic cell transplantation (HCT). With the aim of identifying patients at high risk for post-transplant relapse, we retrospectively reviewed 41 HL patients who had received haploidentical (haplo) nonmyeloablative (NMA) HCT with high dose post-transplant cyclophosphamide (PT-Cy) for graft-versus-host (GVHD) prophylaxis. Primary refractory disease, relapse within 6 months from autologous stem cell transplantation, age, pretransplant chemotherapy, HCT comorbidity index (HCT-CI), sex mismatch, tumor burden and pretransplant fluorodeoxyglucose positron emission tomography (FDG-PET) status, assessed by Deauville score, were analyzed as variables influencing outcomes. All but 1 patient engrafted: median time to neutrophil and platelet recovery was 15 (interquartile range, 13 to 23) days and 19 (interquartile range, 12 to 28) days, respectively. Cumulative incidence of severe (grade III to IV) acute graft-versus-host disease (GVHD) and 3-year moderate-severe chronic GVHD was 2.4% and 11.8%, respectively. The 3-year overall (OS), progression free (PFS), and graft relapse-free survival (GRFS) were 75.6%, 43.9%, and 39%, respectively. On multivariate analysis, 3-year OS was significantly worse in patients with HCT-CI ≥3 (hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.1 to 21.8; P?=?.03). Three-year relapse rate, 3-year PFS, and 3-year GRFS were significantly worse in patients with HCT-CI ≥3 (HR, 3.5; 95% CI, 1.3 to 9.3; P = .01; HR, 3.3; 95% CI, 1.2 to 9.0; P?=?.02; and HR, 4.2; 95% CI, 1.7 to 9.9; P?=?.001, respectively) and in patients with a Deauville score ≥4 on pretransplant FDG-PET (HR, 4.4; 95% CI, 1.6-12.4; P?=?.005, HR, 3.8; 95% CI, 1.5 to 9.7; P?=?.005; and 3.2; 95% CI, 1.3 to 7.9; P?=?.01, respectively). On univariate analysis, 3-year NRM was significantly worse only in patients with a HCT-CI ≥3 (HR, 17.6; 95% CI, 1.4 to 221.0). Among relapsed or refractory HL patients undergoing haplo NMA HCT with PT-Cy, pretransplant FDG-PET with a Deauville score ≥4 and HCT-CI ≥3 identified patients at high risk of relapse. Moreover, an HCT-CI ≥3 was associated with higher NRM and lower OS.     

Grade II Acute Graft-versus-Host Disease and Higher Nucleated Cell Graft Dose Improve Progression-Free Survival after HLA-Haploidentical Transplant with Post-Transplant Cyclophosphamide

Compared with standard graft-versus-host disease (GVHD) prophylaxis platforms, post-transplantation cyclophosphamide (PTCy) after T cell–replete HLA-haploidentical (haplo) bone marrow transplantation (BMT) reduces the risk of grades III to IV acute (a) and chronic (c) GVHD, but maintains similar rates of grade II aGVHD. Given that mild GVHD has been associated with reduced treatment failure in HLA-matched BMT, we evaluated the risk factors for and effects of GVHD on survival in 340 adults with hematologic malignancies who engrafted after nonmyeloablative haplo-BMT with PTCy, mycophenolate mofetil, and tacrolimus. The cumulative incidence at 100 days of grade II and grades III to IV aGVHD were 30% (95% confidence interval [CI], 25% to 35%) and 2% (95% CI, 1% to 4%), respectively. The 1-year cumulative incidence of cGVHD was 10% (95% CI, 7% to 13%). In landmark analyses at 100 days, the 4-year probabilities of overall survival (OS) and progression-free survival (PFS) were, 48% (95% CI, 41% to 56%) and 39% (95% CI, 32% to 47%) for patients without grades II to IV aGVHD, compared with 63% (95% CI, 53% to 73%) and 59% (95% CI, 50% to 71%) for patients with grade II aGVHD (P?=?.05 and P?=?.009). In multivariable modeling, when compared with patients who never experienced GVHD, the hazard ratio (HR) for OS and PFS in patients with grade II aGVHD was .78 (95% CI, .54 to 1.13; P?=?.19) and .69 (95% CI, .48 to .98; P?=?.04). Higher nucleated cell graft dose was also associated with improved OS (HR, .88; 95% CI, .78 to 1.00; P = .05) and PFS (HR, .89; 95% CI, .79 to 1.0; P?=?.05) and decreased risk of grades III to IV aGVHD (subdistribution HR, .66; 95% CI, .46 to .96; P?=?.03). PTCy reduces grades III to IV aGVHD and cGVHD, but retains similar incidence of grade II aGVHD, the development of which improves PFS. Higher nucleated cell graft dose goals may also improve survival after nonmyeloablative haplo-BMT with PTCy.     

Impact of T Cell Dose on Outcome of T Cell-Replete HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation

Data on whether the T cell dose of allogeneic peripheral blood stem cell (PBSC) products influences transplantation outcomes are conflicting. Using the Center for International Blood and Marrow Transplant Research database, we identified 2736 adult patients who underwent first allogeneic PBSC transplantation for acute leukemia or myelodysplastic syndrome between 2008 and 2014 using an HLA-matched sibling donor (MSD) or an 8/8-matched unrelated donor (MUD). We excluded ex vivo and in vivo T cell-depleted transplantations. Correlative analysis was performed between CD3⁺ T cell dose and the risk of graft-versus-host-disease (GVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS). Using maximum likelihood estimation, we identified CD3⁺ T cell dose cutoff that separated the risk of acute GVHD (aGVHD) grade II-IV in both the MSD and MUD groups. A CD3⁺ T cell dose cutoff of 14 × 10⁷ cells/kg identified MSD/low CD3⁺ (n = 223) and MSD/high CD3⁺ (n = 1214), and a dose of 15 × 10⁷ cells/kg identified MUD/low CD3⁺ (n = 197) and MUD/high CD3⁺ (n = 1102). On univariate analysis, the MSD/high CD3⁺ group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MSD/low CD3⁺ group (33% versus 25%; P = .009). There were no differences between the 2 groups in engraftment rate, risk of aGVHD grade III-IV or chronic GVHD (cGVHD), NRM, relapse, DFS, or OS. The MUD/high CD3⁺ group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MUD/low CD3⁺ group (49% versus 41%; P = .04). There were no differences between the 2 groups in engraftment rate, risk of severe aGVHD or cGVHD, NRM, relapse, DFS, or OS. Multivariate analysis of the MSD and MUD groups failed to show an association between CD3⁺ T cell dose and the risk of either aGVHD grade II-IV (P = .10 and .07, respectively) or cGVHD (P = .80 and .30, respectively). Subanalysis of CD4⁺ T cells, CD8⁺ T cells, and CD4+/CD8+ ratio failed to identify cutoff values predictive of transplantation outcomes; however, using the log-rank test, the sample size was suboptimal for identifying a difference at this cutoff cell dose. In this registry study, the CD3⁺ T cell dose of PBSC products did not influence the risk of aGVHD or cGVHD or other transplantation outcomes when using an MSD or an 8/8-matched MUD. Subset analyses of CD4⁺ and CD8⁺ T cell doses were not possible given our small sample size.     

Standard Antithymocyte Globulin Dosing Results in Poorer Outcomes in Overexposed Patients after Ex Vivo CD34+ Selected Allogeneic Hematopoietic Cell Transplantation

Antithymocyte globulin (ATG) use mitigates the risk of graft rejection and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), but ATG overexposure in the setting of lymphopenia negatively affects immune recovery. We hypothesized that standard empiric weight-based dosing of ATG, used to prevent graft rejection in ex vivo CD34-selected allo-HCT, may lead to serious adverse consequences on outcomes in certain patients. We evaluated 304 patients undergoing myeloablative-conditioned ex vivo CD34-selected allo-HCT with HLA-matched donors for the treatment of hematologic malignancies. Patients received rabbit ATG at a dose of 2.5 mg/kg/day i.v. on days -3 and/or -2. An ATG dosing cutoff of 450 mg was used for statistical analyses to assess the relationship between ATG and overall survival (OS). Among all patients, median total ATG dose was 360 mg (range, 130 to 510 mg); 279 (92%) received a total dose of ATG ≤450 mg, and 25 (8%) received a total dose >450 mg. On the first day of ATG administration (day -3), the median absolute lymphocyte count was .0 K/µL. For patients who received a total dose of ATG >450 mg or ≤450 mg, the incidences of acute and late-acute GVHD grade II-IV were statistically similar. At 3 years post-HCT, for patients who received a total dose of ATG >450 mg or ≤450 mg, nonrelapse mortality (NRM) rates were 35% and 18%, respectively (P = .029), disease-free survival (DFS) rates were 37% and 61%, respectively (P = .003), and OS rates were 40% and 67%, respectively (P = .001). Among all patient and HCT characteristics in multivariable analyses, receipt of a total dose of ATG >450 mg was associated with an increased risk of NRM (hazard ratio [HR], 2.9; P = .01), shorter DFS (HR, 2.0; P = .03), and inferior OS (HR, 2.1; P = .01). In summary, the use of weight-based ATG at a time of relative lymphopenia before ex vivo CD34-selected allo-HCT results in overdosing in heavier patients, leading to higher NRM and lower DFS and OS. Further pharmacokinetic investigation in this setting is critical to determining the optimal dosing strategy for ATG.     

A randomized double-blind trial of hydroxychloroquine for the prevention of chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation.

Hydroxychloroquine (HCQ) is an immunosuppressive lysosomotropic amine that has activity against graft-versus-host disease (GVHD). In a single-institution phase III trial, 95 recipients of allogeneic peripheral blood stem cell (PBSC) transplantation were randomized to receive, in a double-blind fashion, and in addition to prophylactic cyclosporine A (CSA), HCQ, or placebo starting 21 days pretransplant and continued until day +365. HCQ was very well tolerated and not associated with side effects. Overall, the incidence of acute GVHD (aGVHD) was 59% in both arms, and severe aGVHD occurred in 11% (HCQ) and 14% (placebo) (P = .76). Sixty percent and 78% of patients developed chronic GVHD (cGVHD) in the HCQ and the placebo arms, respectively (P = .15). With a median follow-up of 18 months, relapse-free and overall survivals (OS) were comparable in both groups. In summary, in this randomized trial, the addition of HCQ to single-agent CSA had no effects on aGVHD or cGVHD or survival.