Subsequent neoplasms and late mortality in children undergoing allogeneic transplantation for nonmalignant diseases.

We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range, <1 to 20) from the Center for International Blood and Marrow Transplant Research (1995-2012) registry. Standardized mortality ratios (SMRs) in 2-year survivors and standardized incidence ratios (SIRs) were calculated to compare mortality and SN rates with expected rates in the general population. Median follow-up of survivors was 7.8 years. Diagnoses included severe aplastic anemia (SAA; 24%), Fanconi anemia (FA; 10%), other marrow failure (6%), hemoglobinopathy (15%), immunodeficiency (23%), and metabolic/leukodystrophy syndrome (22%). Ten-year survival was 93% (95% confidence interval [95% CI], 92% to 94%; SMR, 4.2; 95% CI, 3.7-4.8). Seventy-one patients developed SNs (1.2%). Incidence was highest in FA (5.5%), SAA (1.1%), and other marrow failure syndromes (1.7%); for other NMDs, incidence was <1%. Hematologic (27%), oropharyngeal (25%), and skin cancers (13%) were most common. Leukemia risk was highest in the first 5 years posttransplantation; oropharyngeal, skin, liver, and thyroid tumors primarily occurred after 5 years. Despite a low number of SNs, patients had an 11-fold increased SN risk (SIR, 11; 95% CI, 8.9-13.9) compared with the general population. We report excellent long-term survival and low SN incidence in an international cohort of children undergoing HCT for NMDs. The risk of SN development was highest in patients with FA and marrow failure syndromes, highlighting the need for long-term posttransplantation surveillance in this population.

Prevalence of decisional regret among patients who underwent allogeneic hematopoietic stem cell transplantation and associations with quality of life and clinical outcomes.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (alloHCT) is potentially curative but with known negative effects on quality of life. In the current study, the authors investigated whether patients expressed regret after undergoing HCT and the relationships between clinical outcomes and quality of life. METHODS: Center for International Blood and Marrow Transplant Research data from 184 adults who completed the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) before undergoing alloHCT and at day 100 were used. Additional time points were 6 months and 12 months. Regret was measured using a FACT-BMT item not included in scoring: "I regret having the bone marrow transplant." The authors evaluated FACT-BMT scores and regret using Student t-tests. Covariance pattern models were used to determine predictors of regret over time, including baseline characteristics and post-alloHCT outcomes (acute or chronic graft-versus-host-disease, disease recurrence). RESULTS: At 100 days, 6 months, and 12 months, approximately 6% to 8% of patients expressed regret; a total of 15% expressed regret at any time point. Regret was found to be associated with lower FACT-BMT scores at 6 months and 12 months (P < .001). Higher baseline FACT-BMT and social well-being scores were associated with a reduced risk of expressing regret. The risk of regretting transplantation was 17.5 percentage points (95% confidence interval, 5.5-29.7 percentage points) greater in patients who developed disease recurrence after HCT compared with patients who did not. CONCLUSIONS: Among patients who underwent alloHCT and lived to 100 days, the majority did not report regretting their transplantation. Regret was found to be related to disease recurrence. Social connectedness may serve as a protective factor against later regret. Future work should explore regret in other patient groups and use qualitative methods to inform best practices for reducing regret.

Late effects after ablative allogeneic stem cell transplantation for adolescent and young adult acute myeloid leukemia.

There is marked paucity of data regarding late effects in adolescents and young adults (AYAs) who undergo myeloablative conditioning (MAC) allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). We evaluated late effects and survival in 826 1-year disease-free survivors of MAC HCT for AYA AML, with an additional focus on comparing late effects based upon MAC type (total body irradiation [TBI] vs high-dose chemotherapy only). The estimated 10-year cumulative incidence of subsequent neoplasms was 4% (95% confidence interval [CI], 2%-6%); 10-year cumulative incidence of nonmalignant late effects included gonadal dysfunction (10%; 95% CI, 8%-13%), cataracts (10%; 95% CI, 7%-13%), avascular necrosis (8%; 95% CI, 5%-10%), diabetes mellitus (5%; 95% CI, 3%-7%), and hypothyroidism (3%; 95% CI, 2%-5%). Receipt of TBI was independently associated with a higher risk of cataracts only (hazard ratio [HR], 4.98; P < .0001) whereas chronic graft-versus-host disease (cGVHD) was associated with an increased risk of cataracts (HR, 3.22; P = .0006), avascular necrosis (HR, 2.49; P = .006), and diabetes mellitus (HR, 3.36; P = .03). Estimated 10-year overall survival and leukemia-free survival were 73% and 70%, respectively, and did not differ on the basis of conditioning type. In conclusion, late effects among survivors of MAC HCT for AYA AML are frequent and are more closely linked to cGVHD than type of conditioning.

Risk factors for the development of cutaneous melanoma after allogeneic hematopoietic cell transplantation.

BACKGROUND: Melanoma risk is increased after allogeneic hematopoietic cell transplantation (HCT), but specific risk factors are unknown. OBJECTIVE: Investigate risk factors for melanoma after allogeneic hematopoietic cell transplantation. METHODS: We conducted a nested case-control study of 140 melanoma cases and 557 controls (matched by age at HCT, sex, primary disease, survival time) through the Center for International Blood and Marrow Transplant Research. RESULTS: Melanoma risk was significantly increased among HCT survivors who received total body irradiation-based myeloablative conditioning (multivariable adjusted odds ratio [OR] = 1.77; 95% confidence interval [CI] = 1.00-3.15) or reduced-intensity conditioning containing melphalan (OR = 2.60; 95% CI = 1.13-6.02) or fludarabine (OR = 2.72; 95% CI = 1.02-7.30) versus busulfan-based myeloablative regimens; were diagnosed with acute graft-versus-host disease (GVHD) with stage 2+ skin involvement (OR = 1.92; 95% CI = 1.19-3.10), chronic GvHD without skin involvement (OR = 1.91; 95% CI = 1.03-3.57), or keratinocytic carcinoma (OR = 2.37; 95% CI = 1.16-4.83); and resided in areas with higher ambient ultraviolet radiation (ORtertile3 = 1.64; 95% CI = 1.01-2.67). LIMITATIONS: Data on individual-level ultraviolet radiation exposure and clinical data on melanoma characteristics were lacking. Additionally, misclassification of melanoma is possible as not all pathology reports were available for review. CONCLUSION: These results emphasize the importance of adherence to current surveillance guidelines (routine skin examination, photoprotection recommendations), particularly for HCT survivors at highest risk.

Female Sex is Associated With Poor Health-related Quality of Life in Children at 12 Months Post-Hematopoietic Cell Transplantation.

To study the factors associated with poorer health-related quality of life at 1-year post-allogeneic hematopoietic cell transplantation (alloHCT), a secondary analysis of a prospective feasibility study was performed. Pediatric Quality of Life Inventory questionnaires were collected in 76 children undergoing alloHCT at baseline (within 30 d before transplantation), day 100, 6 months, and 12 months posttransplantation. The global score improved post-HCT (baseline: 67.1, 12 mo: 76.6). Females (odds ratio, 6.5; 95% confidence interval, 1.002-42.17; P=0.04) and patients with low baseline scores (odds ratio, 7.2; 95% confidence interval, 1.07-48.63; P=0.04) had lower scores at 12 months post-HCT and suggest a target group for early interventions such as physical exercise, stress management, and cognitive behavior therapy.

Characteristics of Late Fatal Infections after Allogeneic Hematopoietic Cell Transplantation.

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.

Outcomes after Second Hematopoietic Cell Transplantation in Children and Young Adults with Relapsed Acute Leukemia.

Children with acute leukemia who relapse after hematopoietic cell transplantation (HCT) have few therapeutic options. We studied 251 children and young adults with acute myelogenous or lymphoblastic leukemia who underwent a second HCT for relapse after their first HCT. The median age at second HCT was 11 years, and the median interval between first and second HCT was 17 months. Most of the patients (n = 187; 75%) were in remission, received a myeloablative conditioning regimen (n = 157; 63%), and underwent unrelated donor HCT (n = 230; 92%). The 2-year probability of leukemia-free survival (LFS) was 33% after transplantation in patients in remission, compared with 19% after transplantation in patients not in remission (P = .02). The corresponding 8-year probabilities were 24% and 10% (P = .003). A higher rate of relapse contributed to the difference in LFS. The 2-year probability of relapse after transplantation was 42% in patients in remission and 56% in those in relapse (P = .05). The corresponding 8-year probabilities were 49% and 64% (P = .04). These data extend the findings of others showing that patients with a low disease burden are more likely to benefit from a second transplantation. Late relapse led to a 10% decrement in LFS beyond the second year after second HCT. This differs from first HCT, in which most relapses occur within 2 years after HCT.

Post-transplantation employment status of adult survivors of childhood allogeneic hematopoietic cell transplant: A report from the Center for International Blood and Marrow Transplant Research (CIBMTR).

BACKGROUND: Data are scarce regarding employment outcomes of survivors of childhood allogeneic hematopoietic cell transplantation (alloHCT) and the factors that affect their employment status. METHODS: By using the Center for International Blood and Marrow Transplant Research database, the authors studied employment outcomes of ≥1-year survivors of childhood alloHCT who were age ≥18 years at their most recent assessment (year of transplantation, 1985-2010). Employment status was assessed at their attained ages (ages 18-22, 23-27, and 28-32 years) and according to transplantation center (TC) location (United States or International). A multivariable analysis assessing the factors that affected employed status (full-time/part-time work or student) was performed. RESULTS: Unemployment rates among 2844 survivors were persistently high at all attained ages (United States TCs: ages 18-22 [14%], 23-27 [15%], and 28-32 [13%] years; International TCs: ages 18-22 [56%], 23-27 [53%], and 28-32 [68%] years). The factors associated a with higher likelihood of employment included: older age at alloHCT (ages 5-9-years: hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.65-2.6; ages 10-14 years: HR, 4.43; 95% CI, 3.58-5.47; ages 15-18-years: HR, 7.13; 95% CI, 5.72-8.88), myeloablative conditioning without total body irradiation (TBI) (HR, 1.56; 95% CI, 1.38-1.77), reduced-intensity conditioning with TBI (HR, 1.47; 95% CI, 1.19-1.8) or without TBI (HR, 2.51; 95% CI, 2.15-2.92), and US-based TC (HR, 1.84; 95% CI, 1.62-2.08). CONCLUSIONS: Young adult survivors of childhood alloHCT have high unemployment rates at all studied attained ages after HCT. Future efforts should be directed toward understanding the causes of unemployment their and relation to quality of life using patient-reported outcome measures.

Risk of acute myeloid leukemia and myelodysplastic syndrome after autotransplants for lymphomas and plasma cell myeloma.

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.