稲本 賢弘

Patients with aggressive adult T-cell leukemia-lymphoma (ATL) have dismal outcomes with intensive chemotherapy. Early up-front allogeneic hematopoietic stem cell transplantation (allo-HSCT) is generally recommended. However, the choice of stem cell source, i.e., unrelated bone marrow transplant (UBMT) or cord blood transplantation (CBT), when an HLA-matched related donor is unavailable remains controversial. Thus, we undertook a decision analysis to compare the outcomes of two therapeutic strategies: chemotherapy followed by up-front UBMT at 6 months, and chemotherapy followed by up-front CBT at 3 months. Patients were stratified into low-, intermediate-, and high-risk groups according to the modified ATL-prognostic index. The model simulated life expectancy (LE) and quality-adjusted LE (QALE). LE following up-front UBMT was higher than that following up-front CBT in the low-risk group (2.63 vs. 2.28 years), but was comparable in the intermediate- (2.06 vs. 2.01 years) and high-risk groups (1.25 vs. 1.30 years). The Monte Carlo simulation for LE and QALE in each risk group showed that there was significant uncertainty in all categories. In conclusion, up-front UBMT was superior to up-front CBT in the low-risk group, but the strategies were comparable in the intermediate- and high-risk groups.

By evaluating risks of late mortality and causes of death among long-term survivors after autologous hematopoietic stem cell transplantation (HSCT) in Japan, we clarified what we should focus on during follow-up to reduce them. The study cohort included 6,780 patients who had survived for ≥2 years after the first autologous HSCT performed from 1974 to 2012 for hematological diseases. With a median follow-up of 6.0 years among survivors, overall survival probabilities at 5 and 10 years after HSCT were 92% and 83%, respectively. Eight hundred thirty deaths occurred: 451, recurrent primary diseases; 87, subsequent solid cancers; 57, subsequent hematological malignancies; 55, infections; 41, respiratory diseases; 19, cardiovascular diseases; 15, liver diseases; 10, neurological diseases; and 7, kidney/genitourinary diseases (Except small numbers of other causes and missing). According to the log-rank test, the risk of overall mortality was remarkably increased among HSCT recipients compared with the that in the general Japanese population (observed/expected ratio [O/E]=5.4; 95% confidence interval [CI], 5.0-5.8). The risks of cause-specific mortality increased with infection (O/E=6.8; 95% CI, 5.1-8.8), subsequent solid cancers (O/E=1.4; 95% CI, 1.1-1.7), subsequent hematological malignancies (O/E=14.3; 95% CI, 10.8-18.5), kidney/genitourinary diseases (O/E=3.4; 95% CI, 1.4-7.1), respiratory disease (O/E=9.0; 95% CI, 6.5-1.2), and liver diseases (O/E=2.6; 95% CI, 1.4-4.2). Long-term survivors after autologous HSCT are at an increased risk of death due to secondary cancers, infections, and any organ diseases as well as recurrence compared to the general population. When monitoring these patients in the outpatient clinic, it is important for physicians to predict a change in the patient's condition and to start treatment earlier.

Little is known about the prognostic significance of muscle loss for allogeneic hematopoietic stem cell transplantation (allo-HCT). We retrospectively analyzed consecutive patients who received allo-HCT from 2013 to 2015. All patients underwent computed tomography (CT) imaging and bioelectrical impedance analysis (BIA) within 30 days before allo-HCT. Skeletal muscle area (cm2) at the third lumbar vertebra level on CT imaging and skeletal muscle mass (kg) measured by BIA were normalized by height in meters squared (m2) to calculate the skeletal muscle area index (SMI) and skeletal muscle mass index (SMMI). SMI and SMMI were significantly correlated (r = 0.744; P < 0.001). The cumulative incidence of 1-year non-relapse mortality (NRM) was significantly higher in patients with low SMI than high SMI (17% versus 0%, respectively; P = 0.023). Overall survival was shorter in patients with low SMI than high SMI (56% versus 93%, respectively; P < 0.001). In univariate analysis, low SMI was associated with increased risk of NRM (HR 7.46; 95% CI 1.05-52.98; P = 0.044), and in multivariate analysis it was associated with higher overall mortality (HR 5.35; 95% CI 1.71-16.72; P = 0.004). These results suggest that low muscle mass is an independent predictor of mortality after allo-HCT.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication after hematopoietic stem cell transplantation (HSCT). Several studies of risk factors for PTLD have been reported; however, the probability of, and risk factors for, PTLD in patients with lymphoma is unknown. Japanese nationwide transplant registry data from 5270 patients with lymphoma after allogeneic HSCT were analyzed. Mature B-cell, T/NK-cell, and T-cell lymphoblastic subtypes accounted for 49%, 26%, and 9.6% of lymphoma cases, respectively. Rituximab was used in 1678 lymphoma patients, most of whom (89%) received HSCT for mature B-cell lymphoma. Thirty-one patients with lymphoma developed PTLD, representing a probability of 0.77% at 2 years post-HSCT, which did not differ significantly from that in patients with other diseases (P = .98). Year of HSCT after 2010 (hazard ratio [HR] = 5.6, 95% confidence interval [CI], 1.48-21.3), antithymocyte globulin (ATG) use in the conditioning regimen (HR = 4.5, 95% CI, 1.61-12.5), and no rituximab use before HSCT (HR = 3.2, 95% CI, 1.26-7.90) were identified as risk factors for PTLD. Probabilities of PTLD at 1 year post-HSCT according to rituximab and ATG use were 0.23% (rituximab+, ATG-), 0.75% (rituximab-, ATG-), 1.25% (rituximab+, ATG+), and 3.53% (rituximab-, ATG+). Regarding lymphoma subtypes, patients with mature B-cell lymphoma had the lowest incidence of PTLD (0.35% at 2 years). Among high-risk patients receiving ATG, the mortality rate due to infection was elevated in those previously treated with rituximab (22%) relative to those without (14%); however, the difference was not significant (P = .10). Rituximab use before HSCT significantly reduces the risk of PTLD. Adding rituximab to the conditioning regimen is potentially a good strategy to prevent the development of PTLD in high-risk patients.

Implementation of the 2014 National Institutes of Health (NIH) response algorithm for joint/fascia graft-versus-host disease (GVHD) has identified real-world limits to its application. To refine the 2014 NIH response algorithm, we analyzed multicenter prospective observational data from the Chronic GVHD Consortium. The training cohort included 209 patients and the replication cohort included 191 patients with joint/fascia involvement during their course of chronic GVHD. Linear mixed models with random patient effect were used to evaluate correlations between response categories and clinician- or patient-perceived changes in joint status as an anchor of response. Analysis of the training cohort showed that a 2-point change in total photographic range of motion (P-ROM) score was clinically meaningful. The results also suggested that a change from 0 to 1 on the NIH joint/fascia score should not be considered as worsening and suggested that both the NIH joint/fascia score and total P-ROM score, but not individual P-ROM scores, should be used for response assessment. On the basis of these results, we developed an evidence-based refined algorithm, the utility of which was examined in an independent replication cohort. Using the refined algorithm, ∼40% of responses were reclassified, largely mitigating most divergent responses among individual joints and changes from 0 to 1 on the NIH joint/fascia score. The refined algorithm showed robust point estimates and tighter 95% confidence intervals associated with clinician- or patient-perceived changes, compared with the 2014 NIH algorithm. The refined algorithm provides a superior, evidence-based method for measuring therapeutic response in joint/fascia chronic GVHD.

BACKGROUND AND OBJECTIVES: Allogenic hematopoietic stem cell transplantation (allo-SCT) is a curative therapy for hematological malignancies, but transplant-related mortality (TRM) remains a concern. This study aimed to determine the efficacy of capsule endoscopy (CE) by evaluating the correlation between inflammatory findings on CE and TRM. METHODS: The data of patients after allo-SCT were retrospectively collected. The association between findings on CE and TRM at 100 days from the CE was evaluated. RESULTS: Of the 94 patients included in the study, 47 showed inflammatory findings on CE. The findings were diagnosed as graft-versus-host disease (GVHD; n = 17), cytomegalovirus (CMV) infection (n = 14), and GVHD with CMV infection (n = 16). Of the 47 patients, 13 (28%) had TRM. Endoscopic diagnoses of these TRM cases were GVHD (n = 4), CMV infection (n = 0), and GVHD with CMV infection (n = 9). In contrast, in the remaining 47 patients who showed no inflammatory findings on CE, 2 patients (4%) had TRM. The proportion of TRM was higher in patients with inflammatory findings than in those without it (28 vs. 4%, p < 0.01). CONCLUSIONS: CE may predict TRM in patients who developed gastrointestinal symptoms after allo-SCT.

BACKGROUND: The number of long-term survivors after allogeneic hematopoietic stem cell transplantation (HSCT) has increased recently. Esophageal squamous cell carcinoma occurs at a particularly high incidence as a secondary cancer after HSCT. However, standard treatment for these patients has not been established yet. The objectives of this study were to investigate outcomes of esophagectomy for esophageal carcinoma developed in HSCT patients, and to provide the appropriate perioperative management. METHODS: Ten HSCT patients underwent esophagectomy for esophageal squamous cell carcinoma between December 2007 and September 2017 at the National Cancer Center Hospital. The surgical outcomes and long-term prognosis of these patients were reviewed retrospectively. RESULTS: In the former group, 5 of the 7 patients (71.4%) developed pneumonia after esophagectomy, with two of them requiring intubation because of respiratory failure. None of the three patients of the latter group, who received broad-spectrum antibiotics for more than 7 days after the surgery, developed any postoperative complications. The estimated survival probability of these patients at 5 years after the surgery was 53.3%. CONCLUSIONS: HSCT patients have an extremely high risk of developing pneumonia after esophagectomy, and the condition can easily become serious. Therefore, broad-spectrum antibiotics should be administered prophylactically to prevent severe pneumonia during the perioperative period in these patients.

How low-dose anti-thymocyte globulin (ATG) for prophylaxis of graft-versus-host disease (GVHD) influences immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HCT) remains incompletely understood. We prospectively enrolled 41 consecutive adult patients and conducted cytometry-based immunophenotyping for 12 months after allo-HCT. Rabbit ATG (Thymoglobulin) was administered at a median total dose of 1.75 mg/kg in 16 of the 41 patients. Compared with patients who did not receive ATG, those who did had a significantly smaller number of naïve T cells (especially CD4+ ) within three months after allo-HCT. No significant difference was observed between the two groups in the reconstitution of other T cells (effector, memory, Th1, Th2, Th17, Treg, and Tfh), B cells (transitional, naïve, memory, and plasmablast), NK cells (regulatory and cytolytic), or dendritic cells (myeloid and plasmacytoid). Patients with fewer CD4+ naïve T cells than the median count (7.60 cells/µL) at two months after allo-HCT developed chronic GVHD less frequently than those with CD4+ naïve T cells above the median count (2-year cumulative incidences were 0.31 and 0.53, respectively; p = 0.133). This pilot study suggests low-dose Thymoglobulin suppresses the recovery of naïve T cells after allo-HCT, which may contribute to a lower incidence of chronic GVHD.

We report a case of a 16-year-old woman who achieved her third complete remission of acute lymphoblastic leukemia after undergoing allogeneic stem cell transplantation for the second time from an unrelated donor. On post-transplantation day 30, she showed weight gain, hepatomegaly, right hypochondriac pain, and ascites. On day 35, ultrasonography (US) revealed portal vein regurgitation. She was subsequently diagnosed with late-onset sinusoidal obstruction syndrome (SOS) and was transferred to the intensive care unit (ICU) on day 36 for multiple organ dysfunction syndrome (MODS) and disseminated intravascular coagulation, requiring mechanical ventilation. Her SOS was graded as very severe upon ICU admission. Recombinant human soluble thrombomodulin (380 U/kg/day) and methylprednisolone (2 mg/kg/day) therapies were initiated. Additionally, her intra-abdominal pressure had increased to 19 mmHg, which was thought to be the cause of MODS. Ascites drainage (1,000 ml/day), according to the treatment for abdominal compartment syndrome, improved her SOS and MODS. She was weaned from mechanical ventilation on the 10th day after ICU transfer, and US showed resolution of the portal vein regurgitation. She was transferred to the general ward on the 14th day. She had not experienced disease recurrence at her last visit (527 days after the second transplantation).

OBJECTIVE: CD204+ tumor-associated macrophages are associated with adverse outcomes of various malignancies. We performed a study to elucidate the role of CD204+ macrophages in allogeneic hematopoietic cell transplantation (allogeneic HCT). METHODS: In a total of 81 patients who received allogeneic HCT for non-remission malignant lymphoma, immunohistochemical staining of CD204 using specimens preserved before allogeneic HCT was performed. According to the average number of CD204+ macrophages in a high-power field, patients were categorized into three groups: low (<25th percentile), intermediate (≥25th percentile and <50th percentile), and high (≥50th percentile). RESULTS: The B-cell lymphoma proportion was higher in the low group, while T-cell lymphoma and adult T-cell leukemia proportions were higher in the high group. The 3-year overall survival (OS) was poorest in the high group; low vs intermediate vs high = 83.3% vs 43.7% vs 20.2% (P < .01). The 3-year cumulative incidences of relapse were significantly higher in the high group than the intermediate and low groups: 67.0% vs 38.1% vs 18.2% (P < .01). In multivariate analyses, the numbers of CD204+ macrophages were independent risk factors of poorer OS and cumulative incidences of relapse. CONCLUSIONS: CD204+ macrophages might be associated with poorer prognosis in allogeneic HCT for malignant lymphomas.

The role of hematopoietic cell transplantation (HCT) in adults with acute lymphoblastic leukemia (ALL) is reviewed and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the recommendations. A panel of ALL experts developed consensus on the treatment recommendations based on the evidence. Allogeneic HCT offers a survival benefit in selected patients with ALL, and this review summarizes the standard indications as well as the areas of controversy. There is now greater experience with pediatric-inspired chemotherapy regimens that has transformed upfront therapy for adult ALL, resulting in higher remission rates and overall survival. This in turn has increased the equipoise around decision making for ALL in first complete remission (CR1) when there is no measurable residual disease (MRD) at the end of induction and/or consolidation. Randomized studies are needed for adults with ALL to compare allogeneic HCT in CR1 with pediatric-inspired chemotherapy alone. Indications for transplantation in the evolving landscape of MRD assessments and novel targeted and immune therapeutics remain important areas of investigation.

Although differences in the incidence of chronic graft-versus-host disease (GVHD) across the races have been suggested, these have not been systematically investigated. This study compared the incidence, sites, severity, and outcomes of late acute GVHD and chronic GVHD according to National Institutes of Health (NIH) consensus criteria between Japanese (n = 413) and white (n = 708) patients after first allogeneic hematopoietic cell transplantation. Analysis was stratified according to bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT). Japanese patients, compared with white patients, had a similar incidence of late acute GVHD (BMT, 19% vs 16%; PBSCT, 19% vs 16%) but experienced more frequent liver late acute GVHD as defined by transaminase elevation (BMT, 79% vs 8%; PBSCT, 92% vs 33%) and less frequent gastrointestinal late acute GVHD (BMT, 11% vs 58%; PBSCT, 20% vs 68%). Japanese patients were more likely to discontinue systemic immunosuppression after late acute GVHD than white patients (hazard ratio, 3.68; 95% confidence interval, 1.96-6.94; P < .001). Japanese patients, compared with white patients, had a lower incidence of chronic GVHD (BMT, 15% vs 30% [P = .002]; PBSCT, 37% vs 45% [P < .001]) and experienced more frequent chronic GVHD of the mouth, eyes, and liver and less frequent gastrointestinal chronic GVHD. The duration of immunosuppressive treatment of NIH chronic GVHD was similar between the races. These differences could not be entirely attributed to practice variation between the centers. This study shows that the incidence, affected sites, severity, and clinical outcomes of late acute GVHD and NIH chronic GVHD differ between Japanese and white patients.

The aim of this study was to determine whether impaired quality of life (QOL) persisted among patients who experienced resolved chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Eligible participants were patients who were relapse-free for 3 years after allo-HCT who were age ≥16 years at the time of transplantation and age ≥20 years without relapse at the time of the survey. The Medical Outcomes Study's 36-Item Short-Form Survey (SF-36), the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), and a visual analog scale (VAS) were administered to assess QOL. Physicians evaluated the current status of chronic GVHD at survey using National Institutes of Health (NIH) criteria, and pretransplantation characteristics and history of GVHD were extracted from the national transplant registry database. Patients without currently active GVHD but with a history of chronic GVHD were categorized as having "resolved GVHD." Of 1250 patients informed of the study, 1216 provided consent and 1130 were included in the final analysis. A total of 745 patients (66%) had currently active chronic GVHD, 149 (13%) had resolved chronic GVHD, and 236 (21%) never had chronic GVHD after allo-HCT. Multivariable analyses showed that compared with patients with resolved or no chronic GVHD, those with active chronic GVHD reported significantly poorer QOL. The QOL scores were similar in patients with resolved chronic GVHD and those without chronic GVHD. Greater between-group differences were observed in SF-36 Physical component and VAS scores in patients age ≥50 years, but the differences were not statistically significant. Our data indicate that only currently active chronic GVHD has a significant impact on physical, mental, and social QOL in allo-HCT survivors, whereas previous chronic GVHD does not impair QOL if it has been resolved.

Combination therapy with a calcineurin inhibitor (CNI), such as cyclosporine (CSA) or tacrolimus (Tac), and methotrexate (MTX) or mycophenolate mofetil (MMF) is a widely used approach to graft-versus-host disease (GVHD) prevention. Data on the comparative effectiveness of MMF compared with MTX are limited and conflicting, however. We analyzed data from the Center for International Blood and Marrow Transplant Research for adult patients undergoing first myeloablative hematopoietic cell transplantation (HCT) from an HLA-identical matched related donor (MRD; n = 3979) or matched unrelated donor (URD; n = 4163) using CSA+MMF, CSA+MTX, Tac+MMF, or Tac+MTX for GVHD prevention between 2000 and 2013. Within the MRD cohort, 2252 patients received CSA+MTX, 1391 received Tac+MTX, 114 received CSA+MMF, and 222 received Tac+MMF. Recipients of CSA+MMF had a higher incidence of acute GVHD grade II-IV (hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.24 to 2.20; P < .001) and grade III-IV (HR, 1.92; 95% CI, 1.31 to 2.83; P < .001) compared with Tac+MTX. The use of CSA+MMF was also associated with inferior overall survival (OS) (HR, 2.31; 95% CI, 1.73 to 3.09; P < .001) due to higher transplantation-related mortality (TRM) (HR, 4.03; 95% CI, 2.61 to 6.23; P < .001) compared with Tac+MTX. Within the URD cohort, 974 patients received CSA+MTX, 2697 received Tac+MTX, 68 received CSA+MMF, and 424 received Tac+MMF. CSA+MMF was again significantly associated with a higher incidence of grade III-IV acute GVHD (HR, 2.31; 95% CI, 1.57 to 3.42; P <0001), worse OS (HR, 2.36; 95% CI, 1.67 to 3.35; P < .001), and higher TRM (HR, 3.09; 95% CI, 2.00 to 4.77; P < .001), compared with Tac+MTX and other regimens. Thus, this large retrospective comparison of MMF versus MTX in combination with CSA or Tac demonstrates significantly worse GVHD and survival outcomes with CSA+MMF compared with Tac+MTX.

PURPOSE: To develop a prognostic model and cytogenetic risk classification for previously treated patients with chronic lymphocytic leukemia (CLL) undergoing reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT). EXPERIMENTAL DESIGN: We performed a retrospective analysis of outcomes of 606 patients with CLL who underwent RIC allogeneic HCT between 2008 and 2014 reported to the Center for International Blood and Marrow Transplant Research. RESULTS: On the basis of multivariable models, disease status, comorbidity index, lymphocyte count, and white blood cell count at HCT were selected for the development of prognostic model. Using the prognostic score, we stratified patients into low-, intermediate-, high-, and very-high-risk [4-year progression-free survival (PFS) 58%, 42%, 33%, and 25%, respectively, P < 0.0001; 4-year overall survival (OS) 70%, 57%, 54%, and 38%, respectively, P < 0.0001]. We also evaluated karyotypic abnormalities together with del(17p) and found that del(17p) or ≥5 abnormalities showed inferior PFS. Using a multivariable model, we classified cytogenetic risk into low, intermediate, and high (P < 0.0001). When the prognostic score and cytogenetic risk were combined, patients with low prognostic score and low cytogenetic risk had prolonged PFS (61% at 4 years) and OS (75% at 4 years). CONCLUSIONS: In this large cohort of patients with previously treated CLL who underwent RIC HCT, we developed a robust prognostic scoring system of HCT outcomes and a novel cytogenetic-based risk stratification system. These prognostic models can be used for counseling patients, comparing data across studies, and providing a benchmark for future interventions. For future study, we will further validate these models for patients receiving targeted therapies prior to HCT.

The use of granulocyte colony-stimulating factor-mobilized peripheral blood stem cells (PBSCs) and sex-mismatched hematopoietic cell transplantation (HCT), especially with female donors and male recipients (FtoM), is known to be associated with an increased risk of chronic graft-versus-host disease (GVHD) compared with transplantation with bone marrow (BM). This raises the question of whether the use of PBSCs in FtoM HCT might affect allogeneic responses, resulting in fatal complications. Using a Japanese transplantation registry database, we analyzed 1132 patients (FtoM, n = 315; MtoF, n = 260; sex-matched, n = 557) with standard-risk diseases who underwent HCT with an HLA-matched related donor without in vivo T-cell depletion between 2013 and 2016. The impact of PBSC vs BM on transplantation outcomes was separately assessed in FtoM, MtoF, and sex-matched HCT. Overall survival (OS) and nonrelapse mortality (NRM) at 2 years post-HCT were significantly worse in patients with PBSCs vs those with BM in FtoM HCT (2-year OS, 76% vs 62%; P = .0084; 2-year NRM, 10% vs 21%; P = .0078); no differences were observed for MtoF or sex-matched HCT. Multivariate analyses confirmed the adverse impact of PBSCs in FtoM HCT (hazard ratio [HR] for OS, 1.91; P = .025; HR for NRM, 3.70; P = .0065). In FtoM HCT, patients with PBSCs frequently experienced fatal GVHD and organ failure. In conclusion, the use of PBSCs in FtoM HCT was associated with an increased risk of NRM in the early phase, resulting in inferior survival. This suggests that, when we use female-related donors for male patients in HCT, BM may result in better outcomes than PBSCs.

The clinical significance of extramedullary relapse (EMR) of acute myelogenous leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains poorly defined. Here we report the clinical outcomes of patients who underwent allo-HSCT for AML at our institution between 2000 and 2012. A total of 293 patients with AML who underwent allo-HSCT were included. The median duration of follow-up in survivors was 1840 days. Disease status at the time of allo-HSCT was complete remission in 192 patients and nonremission in 101 patients. A total of 110 patients experienced AML relapse after allo-HSCT, including 18 with EMR only, 83 with bone marrow relapse (BMR) only, and 9 with both EMR and BMR. The 5-year cumulative incidence of EMR after allo-HSCT was 9.5%, whereas that of BMR only was 28.9%. In multivariate analysis, peripheral blood stem cell transplantation was associated with an increased risk of EMR. The 2-year overall survival after post-transplantation relapse was 7.5% in patients with BMR only, 11.1% in those with both EMR and BMR, and 27.5% in those with EMR only (P < .05). Although the short-term survival was better in patients with EMR only, they rarely achieved long-term survival. Appropriate strategies for both post-transplantation EMR and BMR are needed.

Anticonvulsant administration is the standard of care for prevention of busulfan-induced seizures (BIS) in hematopoietic stem cell transplantation (HSCT). While valproate interacts with other drugs, including carbapenem antibiotics, levetiracetam has no known clinically significant interactions. Only a few reports have discussed the use of levetiracetam for the prevention of BIS in HSCT recipients. This retrospective study aimed to evaluate the efficacy and safety of valproate and levetiracetam for BIS prophylaxis in adult HSCT recipients. We identified patients who received valproate or levetiracetam to prevent BIS at the National Cancer Center Hospital from December 2015 to November 2017. Ninety-one patients were analyzed (valproate group 45; levetiracetam group 46). No BIS occurred in either group. The pattern of anticonvulsant-related adverse events was similar in both groups, except for a higher incidence of rash in the valproate group. Carbapenem antibiotics were more frequently used in the levetiracetam group than in the valproate group. In conclusion, valproate and levetiracetam are effective and safe for the prophylaxis of BIS. Levetiracetam may be more useful in patients colonized with extended-spectrum beta-lactamase-producing bacteria due to its lack of any clinically significant drug-drug interactions.

<title>Abstract</title> We report graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) (a composite end point of survival without grade III-IV acute GVHD [aGVHD], systemic therapy–requiring chronic GVHD [cGVHD], or relapse) and cGVHD-free relapse-free survival (CRFS) among pediatric patients with acute leukemia (n = 1613) who underwent transplantation with 1 antigen–mismatched (7/8) bone marrow (BM; n = 172) or umbilical cord blood (UCB; n = 1441). Multivariate analysis was performed using Cox proportional hazards models. To account for multiple testing, P &amp;lt; .01 for the donor/graft variable was considered statistically significant. Clinical characteristics were similar between UCB and 7/8 BM recipients, because most had acute lymphoblastic leukemia (62%), 64% received total body irradiation–based conditioning, and 60% received anti-thymocyte globulin or alemtuzumab. Methotrexate-based GVHD prophylaxis was more common with 7/8 BM (79%) than with UCB (15%), in which mycophenolate mofetil was commonly used. The univariate estimates of GRFS and CRFS were 22% (95% confidence interval [CI], 16-29) and 27% (95% CI, 20-34), respectively, with 7/8 BM and 33% (95% CI, 31-36) and 38% (95% CI, 35-40), respectively, with UCB (P &amp;lt; .001). In multivariate analysis, 7/8 BM vs UCB had similar GRFS (hazard ratio [HR], 1.12; 95% CI, 0.87-1.45; P = .39), CRFS (HR, 1.06; 95% CI, 0.82-1.38; P = .66), overall survival (HR, 1.07; 95% CI, 0.80-1.44; P = .66), and relapse (HR, 1.44; 95% CI, 1.03-2.02; P = .03). However, the 7/8 BM group had a significantly higher risk for grade III-IV aGVHD (HR, 1.70; 95% CI, 1.16-2.48; P = .006) compared with the UCB group. UCB and 7/8 BM groups had similar outcomes, as measured by GRFS and CRFS. However, given the higher risk for grade III-IV aGVHD, UCB might be preferred for patients lacking matched donors.

Primary graft failure is a lethal complication that occurs after allogeneic stem cell transplantation (allo-SCT) and requires retransplantation. We retrospectively assessed 1,355 patients who underwent allo-SCT at our institute. Following allo-SCT, the cumulative incidence of subsequent neutrophil engraftment was calculated each day after day 5 among patients with white blood cell (WBC) count<100 cells/μL on the respective day. The number of patients with WBC count<100 cells/μL at days 14, 21, and 28 were 372, 55, and 21, respectively. In patients with WBC count<100 cells/μL on day 14, the cumulative incidence of engraftment was lower in recipients of peripheral blood stem cells (PBSCs) and cord blood (CB) compared with recipients of bone marrow (BM) (BM vs. PBSCs vs. CB, 93% vs. 79% vs. 77%, P<0.01). In patients with WBC count<100 cells/μL after day 14, the cumulative incidence of engraftment in recipients of PBSCs became progressively lower (25% at day 21 and 0% at day 28). In patients with WBC count<100 cells/μL on day 28, the cumulative incidence of engraftment was 100% in patients with donor chimerism≥95%, while it was only 13% in those with chimerism<95% (P<0.01). These data provide important information that could be useful in deciding the appropriate time for performing tests in patients with donor chimerism and in those that require retransplantation.

Non-graft-versus-host disease (GVHD) ocular complications are generally uncommon after hematopoietic cell transplantation (HCT) but can cause prolonged morbidity affecting activities of daily living and quality of life. Here we provide an expert review of non-GVHD ocular complications in a collaboration between transplantation physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Complications discussed in this review include cataracts, glaucoma, ocular infections, ocular involvement with malignancy, ischemic microvascular retinopathy, central retinal vein occlusion, retinal hemorrhage, retinal detachment and ocular toxicities associated with medications. We summarize the incidence, risk factors, screening, prevention, and treatment of individual complications and generate evidence-based recommendations. Baseline ocular evaluation before HCT should be considered in all patients who undergo HCT. Follow-up evaluations should be considered according to clinical signs and symptoms and risk factors. Better preventive strategies and treatments remain to be investigated for individual ocular complications after HCT. Both transplantation physicians and ophthalmologists should be knowledgeable about non-GVHD ocular complications and provide comprehensive collaborative team care.

Ocular graft-versus-host disease (GVHD) occurs in more than half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity, which affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD, regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed in this review. Ocular GVHD has at least three biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have found several novel pathogenic mechanisms, including renin angiotensin system and endoplasmic reticulum stress signaling that can be targeted by therapeutic agents. Many studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. Efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important for all health professionals taking care of HCT recipients to have adequate knowledge of ocular GVHD for optimal care.

Non-graft-vs.-host disease (non-GVHD) ocular complications are generally uncommon after hematopoietic cell transplantation (HCT), but can cause prolonged morbidity affecting activities of daily living and quality of life. Here we provide an expert review of non-GVHD ocular complications in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Complications discussed in this review include cataracts, glaucoma, ocular infections, ocular involvement with malignancy, ischemic microvascular retinopathy, central retinal vein occlusion, retinal hemorrhage, retinal detachment, and ocular toxicities associated with medications. We have summarized incidence, risk factors, screening, prevention and treatment of individual complicastions and generated evidence-based recommendations. Baseline ocular evaluation before HCT should be considered in all patients who undergo HCT. Follow-up evaluations should be considered according to clinical symptoms, signs and risk factors. Better preventive strategies and treatments remain to be investigated for individual ocular complications after HCT. Both transplant physicians and ophthalmologists should be knowledgeable of non-GVHD ocular complications and provide comprehensive collaborative team care.

In the original version of this article, author 'Aisha Al-Khinji' was incorrectly listed as 'Aisha Ahmed'. This has now been corrected in both the PDF and HTML versions of the article to 'Aisha Al-Khinji'.

Hematologic malignancies treated with allogeneic hematopoietic cell transplantation (allo-HCT) have a variable incidence of post-transplantation central nervous system (CNS) relapse, with acute lymphoblastic leukemia (ALL) representing the most common disease histology. Although data supporting post-transplantation CNS prophylaxis for ALL in the pre-CNS penetrant systemic therapy era established this as standard practice, controversy exists regarding the role of post-transplantation CNS prophylaxis in the contemporary era. Here we review the most relevant (albeit exclusively retrospective) literature to date on the role of post-transplantation CNS prophylaxis in ALL. Given the paucity of data supporting the routine practice of post-transplantation CNS prophylaxis for ALL in the contemporary era, this position statement is anticipated to further stoke controversy and discussion within the transplantation community. Ultimately, only well-designed prospective clinical studies will elucidate the role of routine post-transplantation CNS prophylaxis.

The need for long-term follow-up (LTFU) after allogeneic hematopoietic cell transplantation (HCT) has been increasingly recognized for managing late effects such as subsequent cancers and cardiovascular events. A substantial population, however, has already terminated LTFU at HCT centers. To better characterize follow-up termination, we analyzed the Japanese transplant registry database. The study cohort included 17 980 survivors beyond 2 years who underwent their first allogeneic HCT between 1974 and 2013. The median patient age at HCT was 34 years (range, 0-76 years). Follow-up at their HCT center was terminated in 4987 patients. The cumulative incidence of follow-up termination was 28% (95% confidence interval [CI], 27%-29%) at 10 years, increasing to 67% (95% CI, 65%-69%) at 25 years after HCT. Pediatric patients showed the lowest probability of follow-up termination for up to 16 years after HCT, whereas adolescent and young adult (AYA) patients showed the highest probability of follow-up termination throughout the period. Follow-up termination was most often made by physicians based on the patient's good physical condition. Multivariate analysis identified 6 factors associated with follow-up termination: AYA patients, female patients, standard-risk malignancy or nonmalignant disease, unrelated bone marrow transplantation, HCT between 2000 and 2005, and absence of chronic graft-versus-host disease. These results suggest the need for education of both physicians and patients about the importance of LTFU, even in survivors with good physical condition. The decreased risk for follow-up termination after 2005 may suggest the increasing focus on LTFU in recent years.

To characterize the incidences and outcomes of late acute (LA) and chronic graft-versus-host disease (GVHD) in East Asians according to the 2014 National Institutes of Health criteria, we retrospectively analyzed 506 consecutive Japanese patients who had a first allogeneic hematopoietic cell transplantation (HCT) at our center between 2006 and 2013. According to manifestations at onset 91 patients (60%) had LA GVHD and 60 (40%) had chronic GVHD. The cumulative incidences of LA and chronic GVHD were 20% and 17%, respectively, at 48 months after HCT. The involved sites at the onset of LA GVHD included the skin (71%), gut (13%), and liver (8%). The cumulative incidences of relapse, nonrelapse mortality (NRM), transition to chronic GVHD, and discontinued systemic treatment were 11%, 6%, 22%, and 46%, respectively, at 48 months after onset of LA GVHD. Cox models showed that prior acute GVHD was associated with NRM, and HCT from a female donor to a male patient, myeloablative conditioning, and low Karnofsky performance status were associated with a longer duration of systemic treatment after LA GVHD. The most frequently involved sites at the onset of chronic GVHD included the mouth (83%), liver (75%), skin (69%), and eyes (62%). Cox models showed that use of antithymocyte globulin in conditioning regimens was associated with a higher risk of discontinued systemic treatment after the onset of chronic GVHD. The cumulative incidences of relapse, NRM, and discontinued systemic treatment were 16%, 11%, and 41%, respectively, at 48 months after the onset of chronic GVHD. Our results suggested several potential differences between Japanese patients and those of other ethnicities. A direct comparison is needed to formally investigate ethnic differences.

We analyzed late fatal infections (LFIs) in allogeneic stem cell transplantation (HCT) recipients reported to the Center for International Blood and Marrow Transplant Research. We analyzed the incidence, infection types, and risk factors contributing to LFI in 10,336 adult and 5088 pediatric subjects surviving for ≥2 years after first HCT without relapse. Among 2245 adult and 377 pediatric patients who died, infections were a primary or contributory cause of death in 687 (31%) and 110 (29%), respectively. At 12 years post-HCT, the cumulative incidence of LFIs was 6.4% (95% confidence interval [CI], 5.8% to 7.0%) in adults, compared with 1.8% (95% CI, 1.4% to 2.3%) in pediatric subjects; P < .001). In adults, the 2 most significant risks for developing LFI were increasing age (20 to 39, 40 to 54, and ≥55 years versus 18 to 19 years) with hazard ratios (HRs) of 3.12 (95% CI, 1.33 to 7.32), 3.86 (95% CI, 1.66 to 8.95), and 5.49 (95% CI, 2.32 to 12.99) and a history of chronic graft-versus-host disease GVHD (cGVHD) with ongoing immunosuppression at 2 years post-HCT compared with no history of GVHD with (HR, 3.87; 95% CI, 2.59 to 5.78). In pediatric subjects, the 3 most significant risks for developing LFI were a history of cGVHD with ongoing immunosuppression (HR, 9.49; 95% CI, 4.39 to 20.51) or without ongoing immunosuppression (HR, 2.7; 95% CI, 1.05 to 7.43) at 2 years post-HCT compared with no history of GVHD, diagnosis of inherited abnormalities of erythrocyte function compared with diagnosis of acute myelogenous leukemia (HR, 2.30; 95% CI, 1.19 to 4.42), and age >10 years (HR, 1.92; 95% CI, 1.15 to 3.2). This study emphasizes the importance of continued vigilance for late infections after HCT and institution of support strategies aimed at decreasing the risk of cGVHD.

Ocular graft-versus-host disease (GVHD) occurs in more than one-half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity that affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplantation physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed. Ocular GVHD involves at least 3 biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have identified several novel pathogenic mechanisms, including the renin angiotensin system and endoplasmic reticulum stress signaling, which can be targeted by therapeutic agents. Numerous studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. The efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important that all health professionals caring for HCT recipients have adequate knowledge of ocular GVHD to provide optimal care.

The combination of a calcineurin inhibitor (CNI) such as tacrolimus (TAC) or cyclosporine (CYSP) with methotrexate (MTX) or with mycophenolate mofetil (MMF) has been commonly used for graft-versus-host disease (GVHD) prophylaxis after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT), but there are limited data comparing efficacy of the 2 regimens. We evaluated 1564 adult patients who underwent RIC alloHCT for acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) from 2000 to 2013 using HLA-identical sibling (matched related donor [MRD]) or unrelated donor (URD) peripheral blood graft and received CYSP or TAC with MTX or MMF for GVHD prophylaxis. Primary outcomes of the study were acute and chronic GVHD and overall survival (OS). The study divided the patient population into 4 cohorts based on regimen: MMF-TAC, MMF-CYSP, MTX-TAC, and MTX-CYSP. In the URD group, MMF-CYSP was associated with increased risk of grade II to IV acute GVHD (relative risk [RR], 1.78; P < .001) and grade III to IV acute GVHD (RR, 1.93; P = .006) compared with MTX-TAC. In the URD group, use of MMF-TAC (versus MTX-TAC) lead to higher nonrelapse mortality. (hazard ratio, 1.48; P = .008). In either group, no there was no difference in chronic GVHD, disease-free survival, and OS among the GVHD prophylaxis regimens. For RIC alloHCT using MRD, there are no differences in outcomes based on GVHD prophylaxis. However, with URD RIC alloHCT, MMF-CYSP was inferior to MTX-based regimens for acute GVHD prevention, but all the regimens were equivalent in terms of chronic GVHD and OS. Prospective studies, targeting URD recipients are needed to confirm these results.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment of chronic myeloid leukemia (CML). Optimal conditioning intensity for allo-HCT for CML in the era of tyrosine kinase inhibitors (TKIs) is unknown. Using the Center for International Blood and Marrow Transplant Research database, we sought to determine whether reduced-intensity/nonmyeloablative conditioning (RIC) allo-HCT and myeloablative conditioning (MAC) result in similar outcomes in CML patients. We evaluated 1395 CML allo-HCT recipients between the ages of 18 and 60 years. The disease status at transplant was divided into the following categories: chronic phase 1, chronic phase 2 or greater, and accelerated phase. Patients in blast phase at transplant and alternative donor transplants were excluded. The primary outcome was overall survival (OS) after allo-HCT. MAC (n = 1204) and RIC allo-HCT recipients (n = 191) from 2007 to 2014 were included. Patient, disease, and transplantation characteristics were similar, with a few exceptions. Multivariable analysis showed no significant difference in OS between MAC and RIC groups. In addition, leukemia-free survival and nonrelapse mortality did not differ significantly between the 2 groups. Compared with MAC, the RIC group had a higher risk of early relapse after allo-HCT (hazard ratio [HR], 1.85; P = .001). The cumulative incidence of chronic graft-versus-host disease (cGVHD) was lower with RIC than with MAC (HR, 0.77; P = .02). RIC provides similar survival and lower cGVHD compared with MAC and therefore may be a reasonable alternative to MAC for CML patients in the TKI era.

BACKGROUND: Exposures to DNA-damaging drugs and ionizing radiations increase risks of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). METHODS: 9028 recipients of hematopoietic cell autotransplants (1995-2010) for Hodgkin lymphoma (HL; n = 916), non-Hodgkin lymphoma (NHL; n = 3546) and plasma cell myeloma (PCM; n = 4566), reported to the CIBMTR, were analyzed for risk of subsequent AML or MDS. RESULTS: 335 MDS/AML cases were diagnosed posttransplant (3.7%). Variables associated with an increased risk for AML or MDS in multivariate analyses were: (1) conditioning with total body radiation versus chemotherapy alone for HL (HR = 4.0; 95% confidence interval [1.4, 11.6]) and NHL (HR = 2.5 [1.1, 2.5]); (2) ≥3 versus 1 line of chemotherapy for NHL (HR = 1.9 [1.3, 2.8]); and (3) subjects with NHL transplanted in 2005-2010 versus 1995-1999 (HR = 2.1 [1.5, 3.1]). Using Surveillance, Epidemiology and End Results (SEER) data, we found risks for AML/MDS in HL, NHL and PCM to be 5-10 times the background rate. In contrast, relative risks were 10-50 for AML and approximately 100 for MDS in the autotransplant cohort. CONCLUSIONS: There are substantial risks of AML and MDS after autotransplants for HL, NHL and PCM.

Upper gastrointestinal acute graft-versus-host disease is reported in approximately 30% of hematopoietic stem cell transplant recipients developing acute graft-versus-host disease. Currently classified as Grade II in consensus criteria, upper gastrointestinal acute graft-versus-host disease is often treated with systemic immunosuppression. We reviewed the Center for International Blood and Marrow Transplant Research database to assess the prognostic implications of upper gastrointestinal acute graft-versus-host disease in isolation or with other acute graft-versus-host disease manifestations. 8567 adult recipients of myeloablative allogeneic hematopoietic stem cell transplant receiving T-cell replete grafts for acute leukemia, chronic myeloid leukemia or myelodysplastic syndrome between 2000 and 2012 were analyzed. 51% of transplants were from unrelated donors. Reported upper gastrointestinal acute graft-versus-host disease incidence was 12.1%; 2.7% of recipients had isolated upper gastrointestinal acute graft-versus-host disease, of whom 95% received systemic steroids. Patients with isolated upper gastrointestinal involvement had similar survival, disease-free survival, transplant-related mortality, and relapse as patients with Grades 0, I, or II acute graft-versus-host disease. Unrelated donor recipients with isolated upper gastrointestinal acute graft-versus-host disease had less subsequent chronic graft-versus-host disease than those with Grades I or II disease (P=0.016 and P=0.0004, respectively). Upper gastrointestinal involvement added no significant prognostic information when present in addition to other manifestations of Grades I or II acute graft-versus-host disease. If upper gastrointestinal symptoms were reclassified as Grade 0 or I, 425 of 2083 patients (20.4%) with Grade II disease would be downgraded, potentially impacting the interpretation of clinical trial outcomes. Defining upper gastrointestinal acute graft-versus-host disease as a Grade II entity, as it is currently diagnosed and treated, is not strongly supported by this analysis. The general approach to diagnosis, treatment and grading of upper gastrointestinal symptoms and their impact on subsequent acute graft-versus-host disease therapy warrants reevaluation.

Adult T cell leukemia/lymphoma (ATL) is an aggressive T cell lymphoma with a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be a curative treatment for ATL, a significant proportion of allo-HSCT recipients suffer from relapse/progression of ATL. Here we aimed to clarify the risk factors for and outcomes after posttransplant relapse/progression. We retrospectively reviewed 76 patients with ATL who received allo-HSCT at our institute. At the time of allo-HSCT, disease status was complete response in 17 patients, partial response in 29, stable disease (SD) in 18, and progressive disease (PD) in 12. In multivariate analysis, SD/PD at allo-HSCT, lymphoma subtype, reduced-intensity conditioning regimen, and time from diagnosis to allo-HSCT were associated with risk of relapse/progression. After allo-HSCT, 26 patients had relapse/progression at a median of 66 days (range, 13-2064 days). The 2-year overall survival rate after relapse/progression was only 19%. Compared with acute-type, lymphoma-type experienced local recurrence more frequently (1/15 acute vs. 7/11 lymphoma, P < 0.01) and had a significantly longer OS after relapse/progression (median; 112 days in acute vs. 554 days in lymphoma, P < 0.01). Since the prognosis of patients with ATL who experienced relapse/progression after allo-HSCT was poor, strategies to reduce the risk of these outcomes are warranted.

For patients with acute lymphoblastic leukemia (ALL), allogeneic hematopoietic cell transplantation (alloHCT) offers a potential cure. Life-threatening complications can arise from alloHCT that require the application of sophisticated health care delivery. The impact of country-level economic conditions on post-transplantation outcomes is not known. Our objective was to assess whether these variables were associated with outcomes for patients transplanted for ALL. Using data from the Center for Blood and Marrow Transplant Research, we included 11,261 patients who received a first alloHCT for ALL from 303 centers across 38 countries between the years of 2005 and 2013. Cox regression models were constructed using the following macroeconomic indicators as main effects: Gross national income per capita, health expenditure per capita, and Human Development Index (HDI). The outcome was overall survival at 100 days following transplantation. In each model, transplants performed within lower resourced environments were associated with inferior overall survival. In the model with the HDI as the main effect, transplants performed in the lowest HDI quartile (n = 697) were associated with increased hazard for mortality (hazard ratio, 2.42; 95% confidence interval, 1.64 to 3.57; P < .001) in comparison with transplants performed in the countries with the highest HDI quartile. This translated into an 11% survival difference at 100 days (77% for lowest HDI quartile versus 88% for all other quartiles). Country-level macroeconomic indices were associated with lower survival at 100 days after alloHCT for ALL. The reasons for this disparity require further investigation.

Amphiregulin (AREG) is an epidermal growth factor receptor ligand that can restore integrity to damaged intestinal mucosa in murine models of acute graft-versus-host disease (aGVHD). We previously reported that circulating AREG is elevated in late-onset aGVHD (occurring after 100 days posttransplant), but its clinical relevance in the context of aGVHD risk is unknown. We measured AREG in 251 aGVHD onset blood samples from Blood and Marrow Clinical Trials Network (BMT CTN) primary treatment trials and determined their association with GVHD severity, day 28 complete or partial response (CR/PR) to first-line therapy, overall survival (OS), and nonrelapse mortality (NRM). Every doubling of plasma AREG was associated with a 33% decrease in the odds of day 28 CR/PR (odds ratio [OR], 0.67; P < .01). An AREG threshold of 33 pg/mL or greater divided patients with Minnesota standard-risk (SR) aGVHD into a distinct group with a significantly lower likelihood of: day 28 CR/PR (72% vs 85%; P = .02); greater 2-year NRM (42% vs 15%; P < .01); and inferior OS (40% vs 66%; P < .01). High AREG ≥ 33 pg/mL also stratified patients with Minnesota high-risk (HR) aGVHD: day 28 CR/PR (54% vs 83%; P = .03) and 2-year NRM (53% vs 11%; P < .01), with a trend toward inferior 2-year OS (37% vs 60%; P = .09). High-circulating AREG (≥33 pg/mL) reclassifies patients into HR subgroups and thereby further refines the Minnesota aGVHD clinical risk score.

To characterize the outcomes of patients who developed a particular subsequent solid cancer after hematopoietic cell transplantation (HCT), age at cancer diagnosis, survival, and causes of death were compared with the respective primary cancer in the general population, using data from the national HCT registry and population-based cancer registries in Japan. Among 31 867 patients who underwent a first HCT between 1990 and 2013 and had progression-free survival at 1 year, 713 patients developed subsequent solid cancer. The median age at subsequent solid cancer diagnosis was 55 years, which was significantly younger than the 67 years for primary cancer patients in the general population (P < .001). The overall survival probability was 60% at 3 years after diagnosis of subsequent solid cancer and differed according to cancer type. Development of most solid cancers was associated with an increased risk of subsequent mortality after HCT. Subsequent solid cancers accounted for 76% of causes of death. Overall survival probabilities adjusted for age, sex, and year of diagnosis were lower in the HCT population than in the general population for colon, bone/soft tissue, and central nervous system cancers and did not differ statistically for other cancers. In conclusion, most subsequent solid cancers occurred at younger ages than primary cancers, emphasizing the need for cancer screening at younger ages. Subsequent solid cancers showed similar or worse survival compared with primary cancers. Biological and genetic differences between primary and subsequent solid cancers remain to be determined.

Significant advances in hematopoietic cell transplantation (HCT) have increased the long-term survivorship of its recipients, but because of unique complications arising from radiation and chemotherapy, recipients require lifelong follow-up. To evaluate current survivorship or long-term follow-up (LTFU) clinics specifically for HCT survivors and to evaluate the potential barriers in their establishment, the American Society for Blood and Marrow Transplantation (ASBMT) Practice Guidelines Committee electronically surveyed 200 HCT programs to gather quantitative and qualitative data about models of care. Among 77 programs (38.5%) that responded, 45% indicated presence of an LTFU clinic; however, LTFU care models varied with respect to services provided, specialist availability, type of patients served, and staffing. Among 55% of programs without an LTFU clinic, 100% agreed that allogeneic HCT survivors have unique needs separate from graft-versus-host disease and that complications could arise during the transition of care either from pediatric to adult settings or away from the HCT center. Lack of expertise, logistics, financial issues, and the observation that 84% of individual practitioners prefer to provide survivorship care were the identified obstacles to establishing new LTFU clinics. The ASBMT hopes that policymakers, HCT providers, and institutions will benefit from the results of this survey and recommends that delivering guidelines-driven screening and expert management of late effects is the goal of first-rate HCT survivorship care.

Optimal donor selection is critical for successful allogeneic hematopoietic cell transplantation (HCT). Donor sex and parity are well-established risk factors for graft-versus-host disease (GVHD), with male donors typically associated with lower rates of GVHD. Well-matched unrelated donors (URDs) have also been associated with increased risks of GVHD as compared with matched sibling donors. These observations raise the question of whether male URDs would lead to more (or less) favorable transplant outcomes as compared with parous female sibling donors. We used the Center for International Blood and Marrow Transplant Research registry to complete a retrospective cohort study in adults with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, who underwent T-cell replete HCT from these 2 donor types (parous female sibling or male URD) between 2000 and 2012. Primary outcomes included grade 2 to 4 acute GVHD (aGVHD), chronic GVHD (cGVHD), and overall survival. Secondary outcomes included disease-free survival, transplant-related mortality, and relapse. In 2813 recipients, patients receiving male URD transplants (n = 1921) had 1.6 times higher risk of grade 2 to 4 aGVHD (P < .0001). For cGVHD, recipient sex was a significant factor, so donor/recipient pairs were evaluated. Female recipients of male URD grafts had a higher risk of cGVHD than those receiving parous female sibling grafts (relative risk [RR] = 1.43, P < .0001), whereas male recipients had similar rates of cGVHD regardless of donor type (RR = 1.09, P = .23). Donor type did not significantly affect any other end point. We conclude that when available, parous female siblings are preferred over male URDs.

Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy with many highly effective therapies. Chemorefractory disease, often characterized by deletion of chromosome 17p, has historically been associated with very poor outcomes, leading to the application of allogeneic hematopoietic stem cell transplantation (allo-HCT) for medically fit patients. Although the use of allo-HCT has declined since the introduction of novel targeted therapy for the treatment of CLL, there remains significant interest in understanding factors that may influence the efficacy of allo-HCT, the only known curative treatment for CLL. The potential benefit of transplantation is most likely due to the presence of alloreactive donor T cells that mediate the graft-versus-leukemia (GVL) effect. The recognition of potentially tumor-specific antigens in the context of class I and II major histocompatibility complex on malignant B lymphocytes by donor T cells may be influenced by subtle differences in the highly polymorphic HLA locus. Given previous reports of specific HLA alleles impacting the incidence of CLL and the clinical outcomes of allo-HCT for CLL, we sought to study the overall survival and progression-free survival of a large cohort of patients with CLL who underwent allo-HCT from fully HLA-matched related and unrelated donors at Center for International Blood and Marrow Transplant Research transplantation centers. We found no statistically significant association of allo-HCT outcomes in CLL based on previously reported HLA combinations. Additional study is needed to further define the immunologic features that portend a more favorable GVL effect after allo-HCT for CLL.

BACKGROUND: Autologous hematopoietic cell transplantation (auto-HCT) is a standard therapy for relapsed classic Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL); however, long-term outcomes are not well described. METHODS: This study analyzed survival, nonrelapse mortality, late effects, and subsequent malignant neoplasms (SMNs) in 1617 patients who survived progression-free for ≥2 years after auto-HCT for cHL or DLBCL between 1990 and 2008. The median age at auto-HCT was 40 years; the median follow-up was 10.6 years. RESULTS: The 5-year overall survival rate was 90% (95% confidence interval [CI], 87%-92%) for patients with cHL and 89% (95% CI, 87%-91%) for patients with DLBCL. The risk of late mortality in comparison with the general population was 9.6-fold higher for patients with cHL (standardized mortality ratio [SMR], 9.6) and 3.4-fold higher for patients with DLBCL (SMR, 3.4). Relapse accounted for 44% of late deaths. At least 1 late effect was reported for 9% of the patients. A total of 105 SMNs were confirmed: 44 in the cHL group and 61 in the DLBCL group. According to a multivariate analysis, older age, male sex, a Karnofsky score < 90, total body irradiation (TBI) exposure, and a higher number of lines of chemotherapy before auto-HCT were risk factors for overall mortality in cHL. Risk factors in DLBCL were older age and TBI exposure. A subanalysis of 798 adolescent and young adult patients mirrored the outcomes of the overall study population. CONCLUSIONS: Despite generally favorable outcomes, 2-year survivors of auto-HCT for cHL or DLBCL have an excess late-mortality risk in comparison with the general population and experience an assortment of late complications. Cancer 2018;124:816-25. © 2017 American Cancer Society.