Differences in Graft-versus-Host Disease Characteristics between Haploidentical Transplantation Using Post-Transplantation Cyclophosphamide and Matched Unrelated Donor Transplantation Using Calcineurin Inhibitors

We assessed differences in presentation and response to therapy in 394 consecutive patients who developed acute or chronic graft-versus-host disease (GVHD) after receiving their first allogeneic transplantation (HSCT) from a 10/10 HLA allele-matched unrelated donor (MUD; n = 179) using calcineurin inhibitors or a T cell-replete haploidentical donor (haplo; n = 215) and post-transplantation cyclophosphamide at our center between 2005 and 2017. The median duration of follow-up for survivors was 52.5 months. The cumulative incidences for grade II-IV and grade III-IV acute GVHD at day 180 post HCT were similar, at 39% and 14%, respectively, for haplo-HSCT compared with 50% and 16% for MUD HSCT (P not significant). Haplo-HSCT recipients had a lower cumulative incidence of moderate to severe chronic GVHD, at 22% (severe, 19%), compared with 31% (severe, 29%) for MUD HSCT recipients (P = .026). The time to onset of moderate to severe chronic GVHD was faster for haplo-HSCT recipients (213 days versus 280 days; P = .011). Among patients with grade II-IV acute GVHD, there was no significant between-group difference in organ involvement, with skin the most affected (75% for haplo-HSCT versus 70% for MUD HSCT), followed by the gastrointestinal tract (71% versus 69%) and liver (14% versus 17% MUD). For chronic GVHD, haplo-HSCT recipients had less involvement of the eyes (46% versus 75% for MUD; P < .001) and of the joints/fascia (12% versus 36%; P = .001). Also for cGVHD patients, haplo-HSCT recipients and MUD HSCT recipients had similar all-cause mortality (22% versus 18%; P = .89), but the former were more likely to be off immunosuppression at 2 years post-HCT (63% versus 43%; P = .03) compared with MUD.     

Comparable Outcomes of First-Line Hematopoietic Stem Cell Transplantation from Unrelated and Matched Sibling Donors in Adult Patients with Aplastic Anemia: A Retrospective Single-Center Study

To explore the feasibility of upfront unrelated donor (URD) hematopoietic stem cell transplantation (HSCT) in the treatment of adult aplastic anemia (AA), we conducted a retrospective, single-center study and compared the outcomes of adult patients who underwent first-line URD HSCT or matched sibling donor (MSD) HSCT between August 2012 and June 2018. In all, 23 URD HSCT recipients had an increased cumulative incidence of grade II acute graft-versus-host disease (aGVHD) (21.7% versus 3.4%; P =.007), but similar rates of secondary graft failure (8.7 ± 6.0% versus 6.9 ± 3.4%; P = .764), chronic GVHD (cGVHD) (18.2% versus 8.8%; P = .285), extensive cGVHD (9.1% versus 3.5%; P = .328), 5-year estimated overall survival (87.0% versus 94.2%; P = .501), and 5-year estimated failure-free survival (82.0% versus 89.3%; P = .404) compared with 58 MSD HSCT recipients treated during the same period. After using propensity score matching to reduce the influence of potential confounders, the 2 groups were well balanced in terms of pretransplantation clinical factors. The median survival time was similar, and no significant differences in the aforementioned outcomes were observed between the 2 groups. Our results suggest that URD HSCT may be an effective and feasible option for first-line therapy in adult AA patients who lack an MSD.     

Outcome of Donor Lymphocyte Infusion after T Cell–depleted Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndromes

Relapse occurs in 30%-50% of recipients of T cell–depleted (TCD) reduced-intensity conditioned (RIC) hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS). Despite limited published supportive data, donor lymphocyte infusion (DLI) is used preemptively (pDLI) to improve donor chimerism and prevent relapse, and therapeutically (tDLI) after disease recurrence. We evaluated the efficacy and toxicity of pDLI and tDLI in 113 patients after TCD (alemtuzumab, n = 99; antithymocyte globulin, n = 14) RIC HSCT for AML or MDS. Recipients of pDLI (n = 62) had an estimated 5-year overall survival (OS) of 80% and an event-free survival of 65%. More than one-half (52%; n = 32) of the patients received pDLI within 6 months post-HSCT; despite this, the 5-year incidence of graft-versus-host disease was only 31% (95% confidence interval [CI], 19%-43%). Recipients of tDLI (n = 51) had an estimated 5-year OS of 40% and a 5-year relapse/progression rate of 69% (95% CI, 54%-81%). Recipients of tDLI at >6 months post-HSCT had a significantly superior 5-year OS after tDLI compared with those treated earlier (P = .008). The cumulative incidence of graft-versus-host disease at 5 years after tDLI was 45% (95% CI, 23%-65%). We demonstrate that pDLI safely promotes durable remission after TCD RIC HSCT for AML or MDS, and that tDLI salvages patients after late relapse with greater efficacy.     

Long-Term Outcome and Evaluation of Organ Function in Pediatric Patients Undergoing Haploidentical and Matched Related Hematopoietic Cell Transplantation for Sickle Cell Disease

HLA-matched related donor (MRD) hematopoietic stem cell transplantation (HSCT) is a well-established therapy for patients with sickle cell disease (SCD); however, experience using alternative donors, including haploidentical donors, in HSCT for SCD is limited. We report the long-term outcomes of 22 pediatric patients who underwent related donor HSCT for SCD at St. Jude Children's Research Hospital, either a myeloablative sibling MRD HSCT (n = 14) or reduced-intensity parental haploidentical donor HSCT (n = 8). The median patient age was 11.0 ± 3.9 years in the MRD graft recipients and 9.0 ± 5.0 years in the haploidentical donor graft recipients. The median follow-up was 9.0 ± 2.3 years, with an overall survival (OS) of 93% and a recurrence/graft failure rate of 0%, for the MRD cohort and 7.4 ± 2.4 years, with an OS of 75%, disease-free survival of 38%, and disease recurrence of 38%, for the haploidentical donor cohort. We report the long-term hematologic response and organ function in patients undergoing MRD or haploidentical donor HSCT for severe SCD. Our data demonstrate long-term hematologic improvements after HSCT with sustained engraftment, and confirm that HSCT offers long-term protection from common complications of SCD, including stroke, pulmonary hypertension, acute chest, and nephropathy, regardless of donor source.     

Allogeneic Stem Cell Transplantation from HLA-Mismatched Donors for Pediatric Patients with Acute Lymphoblastic Leukemia Treated According to the 2003 BFM and 2007 International BFM Studies: Impact of Disease Risk on Outcomes

Allogeneic hematopoietic stem cell transplantation (HSCT) is beneficial for pediatric patients with relapsed or (very) high-risk acute lymphoblastic leukemia (ALL) in remission. A total of 1115 consecutive patients were included in the ALL SCT 2003 BFM study and the ALL SCT 2007 I-BFM study and were stratified according to relapse risk (standard versus high versus very high risk of relapse) and donor type (matched sibling versus matched donor versus mismatched donor). A total of 148 patients (60% boys; median age, 8.7 years; B cell precursor ALL, 75%) were transplanted from mismatched donors, which was defined as either less than 9/10 HLA-compatible donors or less than 5/6 unrelated cord blood after myeloablative conditioning regimen (total body irradiation based, 67%) for high relapse risk (HRR; n?=?42) or very HRR (VHRR) disease (n?=?106). The stem cell source was either bone marrow (n?=?31), unmanipulated peripheral stem cells (n?=?28), T cell ex vivo depleted peripheral stem cells (n?=?59), or cord blood (n?=?25). The median follow-up was 5.1 years. The 4-year rates of overall survival (OS) and event-free survival were 56%?±?4% and 52%?±?4%, respectively, for the entire cohort. Patients transplanted from mismatched donors for HRR disease obtained remarkable 4-year OS and event-free survival values of 82%?±?6% and 80%?±?6%, respectively, whereas VHRR patients obtained values of 45%?±?5% and 42%?±?5% (P?<?.001), respectively. The cumulative incidence of relapse was 29%?±?4% and that of nonrelapse mortality 19%?±?3%. The cumulative incidence of limited and extensive chronic graft-versus-host disease was 13%?±?3% and 15%?±?4%, respectively, among the 120 patients living beyond day 100. Multivariate analysis showed that OS was lower for transplanted VHRR patients (P?=?.002; hazard ratio [HR], 3.62; 95% confidence interval [CI], 1.60 to 8.20) and for patients beyond second complete remission (CR2) versus first complete remission (P?<?.001; HR, 3.68; 95% CI, 1.79 to 7.56); relapse occurred more frequently in patients with VHRR disease (P?=?.026; HR, 3.30; 95% CI, 1.16 to 9.60) and for those beyond CR2 (P?=?.005; HR, 4.16; 95% CI, 1.52 to 10.59). Nonrelapse mortality was not significantly higher for cytomegalovirus-positive recipients receiving cytomegalovirus-negative grafts (P?=?.12; HR, 1.96; 95% CI, .84 to 4.58). HSCT with a mismatched donor is feasible in pediatric ALL patients but leads to inferior results compared with HSCT with better matched donors, at least for patients transplanted for VHRR disease. The results are strongly affected by disease status. The main cause of treatment failure is still relapse, highlighting the urgent need for interventional strategies after HSCT for patients with residual leukemia before and/or after transplantation     

Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia from a Matched Donor versus an HLA-Identical Sibling: Is the Outcome Comparable? Results from the International BFM ALL SCT 2007 Study

Eligibility criteria for hematopoietic stem cell transplantation (HSCT) in acute lymphoblastic leukemia (ALL) vary according to disease characteristics, response to treatment, and type of available donor. As the risk profile of the patient worsens, a wider degree of HLA mismatching is considered acceptable. A total of 138 children and adolescents who underwent HSCT from HLA-identical sibling donors (MSDs) and 210 who underwent HSCT from matched donors (MDs) (median age, 9 years; 68% male) in 10 countries were enrolled in the International-BFM ALL SCT 2007 prospective study to assess the impact of donor type in HSCT for pediatric ALL.The 4-year event-free survival (65 ± 5% vs 61 ± 4%; P = .287), overall survival (72 ± 4% versus 68 ± 4%; P = .235), cumulative incidence of relapse (24 ± 4% versus 25 ± 3%; P = .658) and nonrelapse mortality (10 ± 3% versus 14 ± 3%; P = .212) were not significantly different between MSD and MD graft recipients. The risk of extensive chronic (cGVHD) was lower in MD graft recipients than in MSD graft recipients (hazard ratio [HR], .38; P = .002), and the risks of severe acute GVHD (aGVHD) and cGVHD were higher in peripheral blood stem cell graft recipients than in bone marrow graft recipients (HR, 2.06; P = .026). Compared with the absence of aGVHD, grade I-II aGVHD was associated with a lower risk of graft failure (HR, .63; P = .042) and grade III-IV aGVHD was associated with a higher risk of graft failure (HR, 1.85; P = .020) and nonleukemic death (HR, 8.76; P < .0001), despite a lower risk of relapse (HR, .32; P = .021). Compared with the absence of cGVHD, extensive cGVHD was associated with a higher risk of nonleukemic death (HR, 8.12; P < .0001).Because the outcomes of transplantation from a matched donor were not inferior to those of transplantation from an HLA-identical sibling, eligibility criteria for transplantation might be reviewed in pediatric ALL and possibly in other malignancies as well. Bone marrow should be the preferred stem cell source, and the addition of MTX should be considered in MSD graft recipients.     

Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation Achieved Outcomes Comparable With Matched Unrelated Donor Transplantation in Young Acquired Severe Aplastic Anemia

Salvage haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is considered in patients with severe aplastic anemia (SAA) if a matched unrelated donor (MUD) is unavailable. However, studies on haplo- and MUD transplantation in SAA are lacking. The present study retrospectively analyzed the outcomes of 89 young SAA patients who underwent unmanipulated alternative HSCT between September 2012 and September 2016 at our single center. Forty-one patients received haploidentical donors and forty-eight patients MUDs for HSCT. Most were heavily transfused and refractory to previous immunotherapy. The median durations for myeloid engraftment in the haplo- and MUD cohorts were 14 (range, 10 to 21) and 13 (range, 10 to 18) days, respectively. Compared with the MUD cohort, haplo-HSCT cohorts had an increased cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV (43.9%?±?7.8% versus 12.5%?±?4.8%, P?=?.001) and grades III to IV (21.1%?±?6.7% versus 6.6%?±?3.7%, P?=?.045) and similar limited chronic GVHD (47.7%?±?8.5% versus 38.5%?±?7.3%, P?=?.129) and extensive chronic GVHD (12.1%?±?6.8% versus 9.1%?±?4.3%, P?=?.198). The median follow-up time of the surviving patients was 26 months (range, 6 to 45). No significant differences were observed between haplo-HSCT and MUD HSCT cohorts in 3-year overall survival (80.3%?±?5.1% versus 89.6%?±?7.0%, P?=?.210), disease-free survival (76.4%?±?5.1% versus 89.4%?±?7.7%, P?=?.127), and GVHD-free failure-free survival (79.0%?±?8.6% versus 71.6%?±?9.3%, P?=?.976). Thus, haplo-HSCT, as salvage therapy, achieved similar outcomes as MUD HSCT in young SAA patients, thereby rendering it as an effective and safe option for SAA.     

Unrelated Donor Transplant Recipients Given Thymoglobuline Have Superior GRFS When Compared to Matched Related Donor Recipients Undergoing Transplantation without ATG

Recipients of allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated donors (URDs) and mismatched related donors (MMRDs) typically have a higher incidence of acute and chronic graft-versus-host disease (GVHD) compared with matched related donors (MRDs). Anti-T-cell globulins (ATGs) are often used to reduce GVHD in these recipients. We report the outcomes of 211 adult peripheral blood stem cell transplant recipients with myeloid malignancies who received a standardized transplant protocol, in which ATG (Thymoglobuline 4.5 mg/kg) was administered to recipients of URD and MMRD (n = 147) but not MRD (n = 64) transplant. For all patients, incidence of acute GVHD grades 2 to 4 was 21.4%, and chronic GVHD was 35.0%. Two-year overall survival was 63.2% (95% confidence interval, 55.8% to 71.5%), relapse-free survival was 55.3% (47.4% to 64.6%), and GVHD-free, relapse-free survival (GRFS) was 30.7% (23.2% to 40.8%). There were no differences between recipients of MRDs and other donors in relapse, nonrelapse mortality, and overall and relapse-free survival. However, compared with MRD, recipients from URDs and MMRDs had reduced moderate to severe chronic GVHD (10.4% versus 30.1%, P= .002), less chronic GVHD requiring systemic therapy (19.4% versus 38.9%, P = .006), and superior 2-year GRFS (35.5% versus 20.0%, P = .003). In this retrospective review of nonrandomized transplant groups, outcomes of HSCT performed using an URD with ATG during conditioning were superior to transplant from an MRD without ATG. The addition of Thymoglobuline to conditioning in HSCT from MRD should be further examined in prospective trials.     

Optimal Donor for African Americans with Hematologic Malignancy: HLA-Haploidentical Relative or Umbilical Cord Blood Transplant

Although hematopoietic cell transplantation from an HLA-matched unrelated donor is potentially curative for hematologic malignancies, survival is lower for African Americans compared with Caucasians. Because only approximately 20% of African Americans will have an HLA-matched unrelated donor, many of these patients undergo HLA-haploidentical relative or umbilical cord blood transplantation. In this study, we analyzed outcomes after HLA-haploidentical related donor (n = 249) and umbilical cord blood (n = 118) transplantations in African American patients with hematologic malignancy between 2008 and 2016. The predominant disease was acute myelogenous leukemia for recipients of both types of donor grafts. The incidences of grade II-IV and III-IV acute graft-versus-host disease were higher after umbilical cord blood transplantation compared with HLA-haploidentical relative transplantation (56% and 29%, respectively, versus 33% and 11%, respectively; P < .0001). The 2-year incidence of transplantation-related mortality adjusted for age and conditioning regimen intensity was higher after umbilical cord blood transplantation compared with HLA-haploidentical related donor transplantation (31% versus 18%; P = .008); however, there were no between-group differences in the 2-year adjusted incidence of relapse (30% versus 34%; P = .51), overall survival (54% versus 57%; P = .66), or disease-free survival (43% versus 47%; P = .46). Our findings show that the use of HLA-haploidentical and umbilical cord blood transplants expands the access to transplantation with comparable leukemia-free and overall survival for African Americans with hematologic malignancies.     

Transplantation-Related Mortality,Graft Failure,and Survival after Reduced-Toxicity Conditioning and Allogeneic Hematopoietic Stem Cell Transplantation in 100 Consecutive Pediatric Recipients

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning is associated with a 10%-40% risk of day +100 transplantation-related mortality (TRM). We evaluated the feasibility and safety of reduced-toxicity conditioning and allo-HSCT in 100 consecutive children and adolescent recipients (mean age, 9.2 ± 6.8 years). The mean duration of follow-up was 1278 ± 1042 days. Fifty patients had malignant disease. The median time to neutrophil recovery was 18 days, and the median time to platelet recovery was 43 days. Median donor chimerism in engrafted patients was 98% on day +100 and 98% on day +365. The cumulative incidence of acute graft-versus-host disease (GVHD) was 20% (95% confidence interval [CI], 12.1%-27.9%), and that of chronic GVHD was 13.5% (95% CI, 6.6%-20.4%). TRM was 3% (95% CI, 0%-6.4%) by day +100 and 13.6% (95% CI, 6.7%-20.5%) for the entire study period. The incidence of primary graft failure (PGF) was 16% overall, 31.4% after umbilical cord blood transplantation (UCBT), and 0% after allo-HSCT with matched unrelated or matched sibling donors (P < .0001). The incidence of PGF in UCBT recipients was 46.7% (14 of 30) in chemotherapy-naive recipients, versus 9.5% (2 of 21) in non–chemotherapy-naive recipients (P = .019). Five-year event-free survival was 59.5% ± 5%, and 5-year overall survival was 72.9% ± 5%. Only PGF and poor-risk disease status were significantly associated with decreased overall survival (P = .03). Reduced-toxicity conditioning allo-HSCT in pediatric recipients is associated with low TRM; however, chemotherapy-naive UCBT recipients have a significantly higher incidence of PGF.     

Vitamin D Levels Affect Outcome in Pediatric Hematopoietic Stem Cell Transplantation

The importance of vitamin D in immunologic processes has recently emerged, but whether it has any impact on the course of allogeneic hematopoietic stem cell transplantation (HSCT) has not been determined. Reports indicate that HSCT recipients, particularly children, often suffer from vitamin D deficiency. This study investigated the role of vitamin D in 123 children undergoing HSCT from 2004 to 2011. Vitamin D (ie, serum calcidiol) was analyzed in collected cryostored samples. Patients were grouped according to pre-HSCT calcidiol level: insufficient (<50 nm/L, n = 38) and sufficient (≥50 nm/L, n = 85). Older children who underwent transplants from January through June and children of Middle Eastern or African origin were more commonly found in the insufficient group. Acute grades II to IV graft-versus-host disease occurred more frequently in the vitamin D sufficient group (47% versus 30%, P = .05), whereas no difference was demonstrated for chronic graft-versus-host disease. The neutrophil granulocytes rose significantly faster in the vitamin D sufficient group. No difference in lymphocyte counts, immunoglobulin levels, or infectious disease burden during the first year post-HSCT were observed. Among children with malignancies, overall survival was significantly better in the sufficient group (87% versus 50%, P = .01). In addition, rejection (0% versus 11%, P = .06) and relapse (4% versus 33%, P = .03) rates were lower in patients with sufficient vitamin D levels. To conclude, vitamin D may have an important impact on the outcome of pediatric HSCT, particularly in patients with malignant disease. Further studies investigating whether vitamin D acts as an immunomodulator or is merely a surrogate marker of patient health or nutritional status are warranted.     

Bloodstream Infection after Stem Cell Transplantation in Children with Idiopathic Aplastic Anemia

Bloodstream infection (BSI) is the most common infectious complication of hematopoietic stem cell transplantation (HSCT) and can cause substantial morbidity and mortality. Identification of risk factors for BSI might be helpful in efforts to reduce transplantation-related death. This study analyzed the incidence of BSI and risk factors for BSI after HSCT in pediatric patients with aplastic anemia (AA). BSI occurred in 39 of the 351 patients with AA (11.1%). Onset of BSI occurred at a median of 8 days after HSCT (range, 0 to 92 days). The 5-year overall survival rate was lower in patients with BSI than in patients without BSI (63.32% ± 7.90% versus 93.35% ± 1.44%; P < .0001). Univariate analysis identified the following variables as associated with BSI: history of immunosuppressive therapy with antithymocyte globulin (ATG), transplantation from an unrelated donor, frequent blood transfusion before transplantation, major or major plus minor ABO type mismatch, graft-versus-host disease prophylaxis with tacrolimus and without cyclosporine, and long interval from diagnosis to transplantation. Among these factors, long interval from diagnosis to transplantation was the sole statistically significant risk factor for BSI on multivariate analysis. In patients who underwent HSCT from a related donor, age ≥14 years at transplantation was risk factor for BSI. In contrast, history of immunosuppressive therapy with ATG, frequent blood transfusion before HSCT, graft failure, and major or major plus minor ABO type mismatch were risk factors for BSI in patients who underwent HSCT from an unrelated donor. Because the overall 5-year survival rate without BSI was >90%, even in patients who were received a transplant from an unrelated donor, control of BSI is very important for successful HSCT in pediatric patients with AA.     

Long-Term Outcomes of Hematopoietic Stem Cell Transplantation for Severe Treatment-Resistant Autoimmune Cytopenia in Children

We analyzed the long-term outcomes of pediatric patients registered in the European Group for Blood and Marrow Transplantation database who underwent hematopoietic stem cell transplantation (HSCT) for severe treatment refractory autoimmune cytopenia. With a median follow-up of 100 months, event-free survival was 54% overall, with no significant difference between allogeneic HSCT (n = 15) and autologous HSCT (n = 7) recipients (58% versus 42%; P = .50). Despite a trend toward failure of response or relapse after autologous HSCT compared with allogeneic HSCT, the difference was not significant (43% versus 13%; P = .30). Treatment-related mortality was high in both HSCT groups (29% and 16%; P = .09). Based on the limited numbers of subjects in this retrospective analysis, both allogeneic and autologous HSCT may induce complete and persistent responses in approximately one-half of pediatric patients with severe refractory autoimmune cytopenia, although treatment-related toxicity is high.     

Comparison of Characteristics of Bacterial Bloodstream Infection between Adult Patients with Allogeneic and Autologous Hematopoietic Stem Cell Transplantation

Although autologous and allogeneic hematopoietic stem cell transplantation (HSCT) are fundamentally different procedures, a tailored approach to bacterial bloodstream infection (BSI) according to the type of HSCT has not yet been suggested. We evaluated the characteristics of BSI after HSCT, with a focus on comparison of BSIs between recipients of autologous HSCT (auto-HSCT) and allogeneic HSCT (allo-HSCT). Among 134 patients (59 received allo-HSCT and 75 received auto-HSCT) who underwent HSCT, BSIs were reported earlier in patients who underwent auto-HSCT, compared with those who underwent allo-HSCT (mean 12.1 ± 3.4 days versus 32.8 ± 27.1 days, P = .006). Among patients receiving allo-HSCT, postneutrophil-engraftment bacterial BSI showed an association with grade ≥2 acute graft-versus-host disease (GVHD). In patients who underwent auto-HSCT, results of multivariate analysis showed that not receiving prophylactic antibiotics (P = .004) and having elevated serum C-reactive protein (P = .034) were risk factors of BSI. Elevated CRP (P = .01) and acute GVHD ≥ grade 2 (P = .002) were independent risk factors in patients who underwent allo-HSCT. Those differences originated mainly from the impact of acute GVHD-related postengraftment BSIs of patients who underwent allo-HSCT. To establish the best defense strategy against BSI, the distinctive natures of bacterial BSI after HSCT between auto-HSCT and allo-HSCT should be considered.     

Umbilical Cord Blood as an Alternative Source of Reduced-Intensity Hematopoietic Stem Cell Transplantation for Chronic Epstein-Barr Virus–Associated T or Natural Killer Cell Lymphoproliferative Diseases

Chronic Epstein-Barr virus–associated T/natural killer cell lymphoproliferative diseases represented by chronic active Epstein-Barr virus infection are lethal but are curable with several courses of chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Recently, we reported that reduced-intensity conditioning (RIC) provided better outcomes than myeloablative conditioning because RIC was less toxic. However, it was unclear whether cord blood transplantation (CBT) works in the context of RIC. We retrospectively analyzed 17 patients who underwent RIC followed by bone marrow transplantation (RIC-BMT) and 15 patients who underwent RIC followed by CBT (RIC-CBT). The representative regimen was fludarabine and melphalan based. The overall survival rates with RIC-BMT and RIC-CBT were 92.9% ± 6.9% and 93.3% ± 6.4%, respectively (P = .87). One patient died of lung graft-versus-host disease after RIC-BMT, and 1 patient died of multiple viral infections after RIC-CBT. Although cytotoxic chemotherapy was also immunosuppressive and might contribute to better donor cell engraftment after RIC-HSCT, the rate of engraftment failure after RIC-CBT was still higher than that after RIC-BMT (not significant); however, patients who had experienced graft failure were successfully rescued with a second HSCT. Unrelated cord blood can be an alternative source for RIC-HSCT if a patient has no family donor.     

Long-Term Recipient Health-Related Quality of Life and Donor-Recipient Relationship following Sibling Pediatric Hematopoietic Stem Cell Transplantation

Despite the fact that the choice of donors and the number of sources of hematopoietic stem cells have increased, a sibling remains a preferred donor for allogeneic hematopoietic stem cell transplantation (HSCT). Transplant donation between siblings is a unique life experience that may have an impact on their future relationship. The aim of the study was to quantitatively measure the quality of life (QoL) in patients who underwent transplant and to describe the relationship between a recipient and a sibling donor after HSCT. We identified and invited 82 adults aged 18.0 to 38.7 years (median, 23.6) who underwent HSCT in our center and their sibling donors to participate in this survey. Forty-five patients (54.9%) and their siblings consented to take part in the study. The studied group consisted of 45 matched siblings donor (MSD)-HSCT recipients (19 women and 26 men) aged 18.0 to 36.2 (median, 28.5) years, who underwent MSD-HSCT at the age of 5.8 to 16.3 (median, 11.9) years, and their sibling donors aged 21.0 to 36.0 (median, 31.0) years, who were aged 11.2 to 20.2 (median, 15.5) years at bone marrow harvesting. For QoL and sibling relationship assessment, we used the Functional Assessment of Cancer Therapy–Bone Marrow Transplantation (FACT-BMT) and the Adult Sibling Relationship Questionnaire (ASQR). Higher scores indicate better quality of life in each scale of the FACT-BMT and the more significant is the factor in a sibling relationship measured by the ASQR. The questionnaires were given to both subgroups, HSCT recipients and donors, and the results were compared with each other. The overall result of the FACT-BMT questionnaire was 117 ± 35.0. The highest QoL was found in the functional (25.0 ± 3.5) and social well-being (25.0 ± 3.5) subscales, whereas the worst was in the emotional well-being (18.0 ± 9.5) subscale. Statistically, the QoL score was not influenced by current age (P = .378), age at the moment of HSCT (P = .256), and sex (P = .117). Being a recipient or a donor of HSCT was not a significant factor associated with warmth (2.6 ± 0.5 versus 3.1 ± 0.5; P = .830) and conflict (2.0 ± 0.7 versus 2.1 ± 1.2; P = .886) within the sibling relationship, whereas recipients scored significantly lower in rivalry within the sibling relationship compared with HSCT donors (0.8 ± 0.3 versus 1.2 ± 0.2; P = .012). The FACT Treatment Outcome Index remained the only significant predictor of warmth in the sibling relationship between HSCT recipient and donor. QoL in adult patients after HSCT in childhood was good. Sibling donor-recipient relationship is unbalanced, with a higher level of rivalry presented among donors. Further multicenter studies based on a larger cohort of patients are necessary to assess all aspects of the sibling relationship after transplantation experience.     

Infections after Allogenic Transplant with Post-Transplant Cyclophosphamide: Impact of Donor HLA Matching

Incidence and outcome of infections after allogeneic hematopoietic stem cell transplantation (HSCT) with post-transplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis are largely unknown. Study aims were to estimate the incidence of pre-engraftment bloodstream infections (PE-BSIs) and viral infections (VIs; cytomegalovirus [CMV], adenovirus [ADV], human herpes virus 6 [HHV6], and BK-polyomavirus hemorrhagic-cystitis [BKPyV-HC]), their predictive factors, and infection-related mortality (IRM) after HSCT with PT-Cy. We analyzed 235 patients: 62%, 21%, and 17% received haploidentical (haplo), matched-unrelated donor (MUD), and matched-related donor, respectively. Overall, 72 patients had 77 PE-BSI episodes at a median time of 13 days after HSCT: cumulative incidence function (CIF) at 28 days was 32%, without differences among donor types (P = .988). By multivariate analysis, CIF of PE-BSI was higher in patients with severe neutropenia before HSCT (adjusted hazard ratio [AHR] = 2.90) and in multidrug-resistant Gram-negative bacteria rectal carriers (AHR = 2.68). IRM at 30 days was 5%, without differences by donor type (P = .106). Overall, 208 patients experienced ≥1 VIs (first occurrence among CMV, HHV6, ADV, BKPyV-HC) at a median time of 20 days after HSCT: CIF at 90 days was 91%, significantly higher in MUD and haplo (P = .0089). By multivariate analysis, also acute GVHD grade ≥2 (AHR = 1.32) and host/donor CMV-serology mismatch (positive/positive versus negative/negative: AHR = 2.95, positive/negative versus negative/negative: AHR = 2.41, negative/positive versus negative/negative: AHR = 2.35) affected VIs occurrence. IRM at 180 days was 8%, without differences among donor types (P = .106). In conclusion, study results did not show a significant impact of donor type on PE-BSI incidence; conversely, MUD and haploidentical transplants retained a higher occurrence of VIs in the early phase after HSCT.     

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.     

Matched-Pair Analysis of Transplant from Haploidentical,Unmanipulated Bone Marrow Donor versus HLA Identical Sibling for Patients with Hematologic Malignancies

A matched-pair analysis of transplant-related outcomes was carried out in 116 of 255 consecutive patients who received transplants from an HLA identical sibling (n = 58) or haploidentical related donor (n = 58). The 2 patient series were matched with 9 variables: period of transplant, patient and donor age, sex, diagnosis, disease phase, conditioning regimen, donor-recipient sex, and cytomegalovirus (CMV) status combinations. As graft-versus-host disease (GVHD) prophylaxis, all patients received the standard cyclosporine and methotrexate association with the addition of anti-thymocyte globulins, mycophenolate mofetil, and basiliximab in haploidentical, unmanipulated bone marrow recipients. Anti-infectious management, transfusion policy, and supportive care were identical for all patients. By comparing the 2 patient series, no statistically significant difference was observed for the cumulative incidence of advanced acute and extensive chronic GVHD, transplant-related mortality, and relapse. With a median follow-up of 3.5 years, the 5-year disease-free survival was 37% ± 6% and 36% ± 6% for HLA identical sibling and haploidentical recipients, respectively. The results of transplant from HLA identical siblings and haploidentical donors are comparable. Regardless of the HLA matching, other factors known to affect the transplant outcomes, such as donor-recipient age, sex, and CMV status combinations, might drive the search for the best donor.     

Male Gonadal Function after Allogeneic Hematopoietic Stem Cell Transplantation in Childhood: A Cross-Sectional,Population-Based Study

Male gonadal dysfunction is a frequent late effect after pediatric hematopoietic stem cell transplantation (HSCT), but detailed insight into patterns of male gonadal function at long-term is limited by retrospective studies without semen sample data. In this study, we investigated the risk of azoospermia and testosterone deficiency, the diagnostic value of markers of spermatogenesis, and paternity at long-term follow-up after pediatric allogeneic HSCT. All male HSCT survivors age ≥18 years, transplanted in Denmark or Finland between 1980 and 2010, were invited to participate in this cross-sectional study. Examinations included a semen sample, measurements of reproductive hormones and testicular volume, and screening for chronic graft-versus-host disease (GVHD). Cumulative (pre-HSCT plus HSCT) treatment doses were calculated. Of 181 eligible patients, 98 participated, at a median 18 years (range, 8 to 35 years) after undergoing HSCT. Sperm was found in 30 patients, azoospermia in 42, and azoospermia during testosterone substitution in 24. A higher cumulative testicular irradiation dose was associated with increased risk of azoospermia and testosterone substitution (odds ratio [OR] per +1 Gy, 1.27; 95% confidence interval [CI], 1.14 to 1.46 [P < .001] and 1.21; 95% CI, 1.11 to 1.38 [P < .001], respectively). All patients treated with >12 Gy had azoospermia, and all but 1 patient treated with >16 Gy needed testosterone substitution. In patients treated with chemotherapy only (n = 23), a higher cumulative cyclophosphamide equivalent dose was associated with an increased risk of azoospermia (OR per +1 g/m², 1.34; 95% CI, 1.01 to 2.15; P = .037). Prepubertal stage at HSCT was a risk factor for testosterone substitution (OR, 15.31; 95% CI, 2.39 to 315; P = .017), whereas chronic GVHD was unrelated to gonadal dysfunction. Inhibin B was the best surrogate marker of azoospermia (area under the curve, .91; 95% CI, .85 to .98; 90% sensitivity and 83% specificity) compared with follicle-stimulating hormone and testicular volume. Of 24 males who had attempted to conceive, 6 had fathered children. In conclusion, the risk of male gonadal dysfunction after pediatric HSCT is high and depends primarily on the cumulative testicular irradiation dose and pubertal stage at transplantation. Our findings support the need for fertility preservation before HSCT, as well as for prolonged follow-up of pediatric HSCT recipients into adulthood.