Unrelated Donor Hematopoietic Cell Transplantation Recipients Research Articles

The Adverse Event Landscape of Stem Cell Transplant: Evidence for aGVHD Driving Early Transplant Associated Toxicities

Although unrelated-donor (URD) hematopoietic cell transplantation (HCT) is associated with many toxicities, a detailed analysis of adverse events, as defined by the Common Terminology Criteria for Adverse Events (CTCAE), has not previously been curated. This represents a major unmet need, especially as it relates to assessing the safety of novel agents. We analyzed a detailed AE database from the "ABA2" randomized, double-blind, placebo-controlled clinical trial of abatacept for acute graft-versus-host disease (aGVHD) prevention, for which the FDA mandated a detailed AE assessment through Day +180, and weekly neutrophil and platelet counts through Day +100. These were analyzed for their relationship to key transplant outcomes, with a major focus on the impact of aGVHD on the development/severity of AEs. A total of 2102 AEs and 1816 neutrophil/platelet counts were analyzed from 142 8/8-HLA-matched URD HCT recipients on ABA2 (placebo cohort, n = 69, abatacept cohort, n = 73). This analysis resulted in 2 major observations. (1) Among graft source, conditioning intensity, age, and Grade 2 to 4 aGVHD, only aGVHD impacted Grade 3 to 5 AE acquisition after the first month post-transplant. (2) The development of Grade 3 to 4 aGVHD was associated with thrombocytopenia. We have created a detailed resource for the transplant community by which to contextualize clinical toxicities after transplant. It has identified aGVHD as a major driver of post-HCT Grade 3 to 5 AEs, and underscored a link between aGVHD and thrombocytopenia. This establishes a critical safety framework upon which the impact of novel post-transplant aGVHD therapeutics should be evaluated. This trial was registered at www.clinicaltrials.gov (#NCT01743131).

The Effect of Donor Graft Cryopreservation on Allogeneic Hematopoietic Cell Transplantation Outcomes: A Center for International Blood and Marrow Transplant Research Analysis. Implications during the COVID-19 Pandemic

The COVID-19 pandemic has resulted in the increased use of cryopreserved grafts for allogeneic hematopoietic cell transplantation (HCT). However, information about the effect of cryopreservation on outcomes for patients receiving allogeneic donor grafts is limited. We evaluated outcomes of HCT recipients who received either fresh or cryopreserved allogeneic bone marrow (BM) or peripheral blood stem cell (PBSC) grafts reported to the Center for International Blood and Marrow Transplant Research. A total of 7397 patients were included in the analysis. Recipients of cryopreserved graft were divided into 3 cohorts based on graft source: HLA-matched related PBSC donors (n=1051), matched unrelated PBSC donors (n=678), and matched related or unrelated BM donors (n=154). These patients were propensity score matched with 5514 patients who received fresh allografts. The primary endpoint was engraftment. Multivariate analyses showed no significant increased risk of delayed engraftment, relapse, nonrelapse mortality (NRM), or survival with cryopreservation of BM grafts. In contrast, cryopreservation of related donor PBSC grafts was associated with decreased platelet recovery (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.68 to 0.78; P < .001) and an increased risk of grade II-IV (HR, 1.27; 95% CI, 1.09 to 1.48; P=.002) and grade III-IV (HR, 1.48; 95% CI, 1.19 to 1.84; P < .001) acute graft-versus-host disease. Cryopreservation of unrelated PBSC grafts was associated with delayed engraftment of neutrophils (HR, 0.77; 95% CI, 0.71 to 0.84; P < .001) and platelets (HR, 0.61; 95% CI, 0.56 to 0.66; P < .001) as well as an increased risk of NRM (HR, 1.4; 95% CI, 1.18 to 1.66; P < .001) and relapse (HR, 1.32; 95% CI, 1.11 to 1.58; P=.002) and decreased progression-free survival (HR, 1.36; 95% CI, 1.20 to 1.55; P < .001) and overall survival (OS) (HR, 1.38; 95% CI, 1.22 to 1.58; P < .001). Reasons for cryopreservation were not routinely collected; however, in a subset of unrelated donor HCT recipients, the reason was typically a change in patient condition. Products cryopreserved for patient reasons were significantly associated with inferior OS in multivariate analysis (HR, 0.65; 95% CI, 0.44 to 0.96; P=.029). We conclude that cryopreservation is associated with slower engraftment of PBSC grafts, which may be associated with inferior transplantation outcomes in some patient populations. However, the small numbers in the cryopreserved BM cohort and the lack of information on the reason for cryopreservation in all patients suggests that these data should be interpreted with caution, particularly in the context of the risks associated with unexpected loss of a graft during the pandemic. Future analyses addressing outcomes when cryopreservation is universally applied are urgently required.

Impact of Self-Reported Pre-Transplant Quality of Life (QOL) on Long-Term Survival after Allogeneic or Autologous Hematopoietic Cell Transplantation (HCT)

The role of pre-HCT self-reported QOL on long-term survival in autologous and allogeneic HCT recipients is not well understood. Although pre-HCT comorbidity is now a well-established indicator of post-HCT short-term outcome, patient-reported pre-HCT QOL may provide additional information for predicting long-term survival after HCT.This study examined the relationship between pre-HCT QOL scores and overall survival (OS), non-relapse mortality (NRM), and disease-related mortality (DRM) in patients who received their first allogeneic or autologous HCT at City of Hope between 2001 and 2005. Four domains of QOL (physical, psychological, social, and spiritual well-being; scale of 0 [worst] to 10 [best]) were assessed prior to HCT using the City of Hope-QOL instrument. Cox regression analysis was used to identify QOL domains associated with long-term survival, adjusted for demographic, clinical, and transplant-related variables. HCT-Comorbidity-Age Index (HCT-CAI) (Sorror et al. 2014) was also assessed in allogeneic HCT recipients. Vital status was determined using medical records and linkage with the National Death Index. OS probabilities were estimated using the Kaplan-Meier estimator. Analyses were conducted by stem cell source.The cohort comprised 103 allogeneic HCT recipients (median age at HCT, 42 years; 51% males; median follow-up since HCT, 7.6 years; 55 deaths) and 141 autologous HCT recipients (median age at HCT, 50 years; 56% males; median follow-up, 7.1 years; 59 deaths). The diagnoses included acute leukemia (n=45), chronic leukemia (n=20), lymphoma (n=14) and other hematologic conditions (n=24) in allogeneic HCT recipients and acute leukemia (n=24), lymphoma (n=76), myeloma (n=35), and other hematologic conditions (n=6) in autologous HCT recipients. All autologous and 81.5% of allogeneic HCT patients received myeloablative conditioning agents. OS: In allogeneic HCT recipients, OS adjusted for significant covariables increased with higher pre-HCT physical well-being score (Hazard Ratio [HR]=0.76 per point increase, p=0.003). Of note, HCT-CAI was not associated with OS in the multivariate model (HR=1.1, p=0.39). The hazard of death for physical well-being scores below the 75th percentile was 3.7 times that above this percentile (p=0.002). Survival rates at 5 and 10 years after HCT for physical well-being scores below the 75th percentile were 51% and 38%, respectively, compared to 72% (p=0.062) and 68% (p=0.018), respectively, above the 75th percentile. OS was also independently worse in males, unrelated donor HCT recipients, patients with acute leukemia vs. other diagnoses, absence of chronic GvHD, and pre-HCT income of $20K to $100K vs. <$20K or >$100K. In autologous HCT recipients, adjusted OS varied non-linearly with pre-HCT physical well-being score (p=0.03), with OS being significantly lower in the lowest (worst) quartile of pre-HCT physical well-being score (HR=2.4, p=0.004) compared to those with better scores. Survival rates at 5 and 10 years after HCT in the lowest quartile were 53% and 47%, respectively, compared to 70% (p=0.048) and 62% (p=0.065) for those with scores above the lowest quartile. Older age at HCT, other diagnoses vs. lymphoma, high risk of relapse at pre-HCT, cyclophosphamide as conditioning agent vs. no cyclophosphamide were also independently associated with worse OS. Other QOL domains were not significant for either HCT types. NRM: In allogeneic HCT recipients, NRM was not associated with HCT-CAI (HR=1.18, p=0.11) adjusted for chronic GvHD and stem cell donor relatedness. However, adjusted OS increased for higher pre-HCT physical well-being score (HR=0.8, p=0.06). NRM was higher for those with physical well-being score below the 75th percentile (HR=7.3, p=0.007) compared to those with scores above the 75thth percentile. In autologous HCT recipients, no QOL domains were significant. DRM: None of the QOL domains for either HCT types, or HCT-CAI in allogeneic HCT recipients were significant after accounting for salient clinical and demographic factors.This study shows that patient-reported pre-HCT physical well-being scores provide information not captured by medical factors that can aid in predicting long-term OS and NRM in allogeneic and OS in autologous HCT patients. Effort to incorporate such evaluation as part of the routine assessment preceding HCT may be useful in developing patient selection and intervention strategies. DisclosuresForman:Mustang Therpapeutics: Other: Construct licensed by City of Hope.

Physiologic Frailty Among Hematopoietic Cell Transplantation (HCT) Survivors Suggests Accelerated Aging and Is a Predictor for Premature Mortality: A Report from the Bone Marrow Transplant Survivor Study (BMTSS)

▪Background: Frailty is common in older adults in the general population; ~10% of >65y-olds are frail. Frail individuals are vulnerable to adverse health outcomes and early mortality. The high intensity therapeutic exposures and post-HCT complications can injure normal tissues and could possibly increase risk of frailty even among non-geriatric HCT recipients.Patients and Methods: We evaluated the risk of frailty among 18-64y-old HCT survivors (n=988) and siblings (n=297). Mean age at study was 42.5±11.6y (survivors) and 43.8±10.9y (siblings). HCT survivors had been transplanted at City of Hope or University of MN between 1974 and 1998; Stem cell source: allogeneic HCT (n=562, 56.3%); autologous (n=436, 43.7%); primary diagnoses: AML/ALL/CML (57.5%), NHL/HL (28.3%), and other (14.2%); Total body irradiation (TBI): 39.5%; chronic graft vs. host disease (cGvHD): 54% of allogeneic HCT recipients. HCT survivors and siblings completed a frailty survey (Pialoux T et al. Geriatr Gerontol Int. 2012;12:189-97) after a median of 7.2y (range, 2-28) from HCT. Survey addressed the following unique domains: low lean muscle mass, exhaustion, low energy expenditure, slow walking speed, and muscle weakness (frailty phenotype: >=3 conditions). Logistic regression was used to identify predictors of frailty. The "survivor-sibling" model included age at study, sex, race, SES, and CTCAE grade 3-4 chronic health conditions. The "within HCT survivor" comparison model included variables listed above, and cancer diagnosis, stem cell source, time since HCT, relapse risk at HCT, year of HCT, TBI, and cGvHD.Results:Survivor-sibling comparison: The prevalence of frailty in HCT survivors and siblings was 8.4% and 0.7%, respectively, p<0.001; HCT survivors were 10.8-fold more likely to be frail when compared with siblings (p=0.001, Table). Within HCT Survivor Comparisons: Compared with autologous HCT recipients, related donor HCT recipients were 2.7-fold more likely (p<0.0001) and unrelated donor HCT recipients were 6.5-fold more likely (p<0.0001) to report frailty. Autologous HCT: exposure to TBI (OR=5.0, p=0.03) was associated with an increased risk of frailty (Table). Allogeneic HCT: exposure to TBI (OR=6.7, p=0.01), active cGvHD (OR=9.1, p<0.001), and grade 3-4 chronic health conditions (OR=2.4, p=0.01) were associated with an increased risk of frailty. Subsequent Mortality: After a median of 10.3y (0.04-12.9) of follow-up from survey completion, 182 (18%) participants had died; 10y cumulative incidence of all-cause mortality (from survey completion) was 41% and 16% for patients with and without frailty (p<0.0001, Figure). Proportion of patients with relapse-related and non-relapse-related mortality did not differ by the frailty phenotype. Autologous HCT recipients: Cox regression analysis adjusted for existing chronic health conditions, year of HCT, TBI, sex and age at HCT revealed that frailty at survey completion was associated with a 5.4-fold increased risk of subsequent death (p<0.0001). Allogeneic HCT recipients: Adjusting for above variables and active cGvHD, frailty at survey completion was associated with a 2.1-fold increased risk of subsequent death (p=0.007).Conclusions: Young HCT survivors are 10.8 times as likely to be frail as compared to their siblings. Prevalence of frailty approaches that seen in the elderly general population, suggesting evidence of premature aging among HCT recipients. Frail HCT survivors are at increased risk of subsequent mortality when compared with non-frail survivors. The study identifies vulnerable populations among HCT survivors needing close monitoring to anticipate and manage morbidity and prevent mortality.TableSurvivors vs. SiblingsAutologous HCT recipientsAllogeneic HCT recipientsOR (95% CI)P-valueOR (95% CI)P-valueOR (95% CI)P-valueSiblings1.00.001Survivors10.8 (2.6-44.2)No Grade3-4 conditions1.0NA1.0Yes Grade 3-4 conditions2.1 (1.3-3.5)0.004NA2.4 (1.2-4.6)0.01Chemo-based conditioning1.01.0TBI-based conditioning5.0 (1.2-21.2)0.036.7 (1.5-30.5)0.01No cGvHD1.0Active cGvHD9.1 (4.3-19.0)<0.001Resolved cGvHD2.0 (0.9-4.9)0.11 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Superiority of Pediatric Chemotherapy over Allogeneic Hematopoietic Cell Transplantation for Philadelphia Chromosome Negative Adult ALL in First Complete Remission: A Combined Analysis of Dana-Farber ALL Consortium and CIBMTR Cohorts

▪Introduction: In adults with Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL), the optimal post-remission therapy remains uncertain. Although allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR1) has become a widely adopted curative strategy, the need for HCT may be supplanted by intensive, pediatric-style chemotherapy regimens. These two approaches have not previously been compared.Methods: We evaluated the outcomes of 422 related or unrelated donor HCT recipients aged 18-50 years with Ph-ALL in CR1 between 06/2002 and 12/2011 as reported to the CIBMTR. This was compared to a concurrent cohort of 108 Ph- ALL CR1 pts (18-50 years) who received a Dana Farber Cancer Institute (DFCI) ALL Consortium pediatric regimen consisting of intensive, non-HCT therapy. Primary outcome was disease-free survival (DFS). Patients in the DFCI chemotherapy cohort who received HCT in CR1 were censored at the day of HCT. Left-truncated analysis methods were used to adjust time from CR1 to transplant.Results: The HCT cohort was older (median age 34 vs. 30 years, p=0.001) and had higher diagnostic WBC counts (median 12x109/L [range <1-515) vs. 8x109/L [1-1424], p=0.001, respectively). The proportion of patients with T –ALL was lower in the HCT cohort (14% vs. 22%, p=0.03), while the incidence of t(4;11)/MLL was similar in both groups (8% vs. 10%, respectively). Of the HCT cohort 396 (94%) underwent myeloablative (MA) conditioning. Donor source was matched related donor in 176 (42%), 8/8 unrelated donors in 168 (40%), and 7/8 (18%) from 7/8 unrelated donors. In univariate analyses (Figure 1) cumulative incidence of relapse at 4 years was similar in both groups (HCT 25% [19-28] vs. chemo 23% [15-32] p=0.97). Two-year treatment-related mortality (TRM) was higher in the HCT cohort (HCT 33% [28-39] vs. chemo 4% [1-8], p<0.0001). At 4 years, DFS was superior in the chemo cohort (HCT 40% [35-45] vs. chemo 71% [60-79], p<0.0001). Four year OS also favored chemo (HCT 45% [40-50] vs. chemo 73% [63-81], p<0.0001). In multivariable analysis, independent factors predictive of treatment failure (relapse or death) were HCT (HR 3.11 [2.08 – 4.66], p<0.001) and the presence of CNS disease at diagnosis (HR 1.56 [1.03 – 2.38], p=0.04). The sole factor associated with poorer OS was the administration of HCT (HR 2.86 [1.88 – 4.34], p<0.0001). The favorable OS with chemo was maintained when restricting the HCT cohort to those recipients with related donors or fully matched (8/8) unrelated donors and those whose time from diagnosis to CR1 was <8 weeks (HR 2.14 [1.36-3.35], p=0.001). Similar outcomes were seen when restricting the HCT cohort to those who achieved CR1 < 8 weeks from diagnosis and received myeloablative conditioning.Conclusion: In this comparison of two cohorts of younger Ph- negative adults in CR1, post-remission therapy with an intensive, pediatric-inspired, chemotherapy-based regimen conferred a survival advantage when compared to allogeneic HCT. The high TRM associated with HCT is a major factor in determining outcomes after HCT. In an era of increasing adoption of pediatric regimens for adults with Ph- ALL, allogeneic HCT may no longer be required for the majority of patients who achieve CR1. These data support the need for randomized controlled studies in Ph- ALL comparing pediatric-inspired non-HCT regimens to allogeneic HCT-based therapy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Alternative Donor Transplantation For Adults With Lymphoma: Comparison Of Umbilical Cord Blood Versus 8/8 HLA-Matched Donor (URD) Versus 7/8 URD

Allogeneic donor hematopoietic cell transplantation (HCT) is increasingly used to treat relapsed lymphoma with curative intent; however, many patients will not have a suitable matched sibling donor. Transplant centers are investigating the use of alternative stem cell sources although data comparing outcomes by stem cell source are limited.We compared outcomes of 1593 non-Hodgkin and Hodgkin lymphoma patients who underwent alternative donor HCT from 2000-2010 and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Umbilical cord blood (UCB) (n=142), 8/8 (human leukocyte antigen [HLA] –A, B, C, and DRB1) matched adult unrelated donor (URD) (n=1176) and 7/8 HLA matched URD (n=275) HCT recipients were followed for a median of 25, 57 and 65 months, respectively.The median age in the 3 groups were UCB: 45 years (range 19-73 yrs), 8/8 URD: 50 (range 18-75 yrs) and 7/8 URD: 45 years (range 18-71yrs). Male gender and mantle cell lymphoma were more frequent in 8/8 URD recipients. 7/8 URD HCT recipients had lower Karnofsky performance scores, and UCB recipients were more likely to be non-Caucasian, have chemosensitive disease and to have undergone HCT in recent years.UCB recipients had inferior neutrophil and platelet engraftment rates at 100 days; however they were less likely to develop acute and chronic graft versus host disease (GVHD) compared to 7/8 URD and 8/8 URD (Table). The cumulative incidence of treatment related mortality (TRM) at 3 years was higher in 7/8 URD. There were no differences among the 3 groups in the 3-year relapse/progression, progression free survival (PFS) or overall survival (OS).TableOutcomesUCBURD 8/8URD 7/8% (95%CI)% (95%CI)%( (95%CI)P-valueTime to ANC>0.5 x 109/L at 28 days66 (57-73)94 (92-95)94 (90-96)<0.001Platelet recovery ≥ 20 x 109/L at 100 days68 (59-76)86 (84-88)85 (80-89)<0.001Acute GVHD (II-IV) at 100 days26 (19-34)37 (35-40)49 (43-55)<0.0013 years Chronic GVHD at 3 years22 (15-30)51 (48-54)48 (42-54)<0.0013 years Treatment related mortality38 (29-46)35 (32-37)46 (41-52)0.0023 years Relapse/Progression29 (22-37)32 (29-34)25 (20-31)0.1073 years Progression free survival33 (25-42)33 (31-37)29 (23-34)0.1863 years Overall survival44 (35-53)43 (40-46)34 (29-40)0.017In multivariate analysis stratified for performance status, lymphoma histology, GVHD prophylaxis, and disease status, no significant difference in OS was detected between UCB and 8/8 URD (HR 0.87 [95% CI 0.68-1.12]; p=0.29), UCB and 7/8 URD (HR 1.04 [95% CI 0.78-1.40]; p=0.77), and 8/8 and 7/8 URD (HR 1.19 [95%CI 0.97-1.45; p=0.08). Lower risk of treatment failure (death or relapse; inverse of PFS) was observed in transplants performed after 2007 (HR 0.79 [95% CI 0.66-0.96]; p=0.01) as compared to the time periods 2000-2003. Patients' age, time from diagnosis to HCT, race, history of prior HCT, and conditioning intensity did not influence OS or PFS.In conclusion, our results suggest that UCB and 7/8 URD grafts for patients with advanced lymphoma provide similar survival to 8/8 URD, extending allogeneic HCT to most patients with no suitable matched sibling donors. Graft source needs to be determined by availability, the clinical urgency of transplant, and transplant center experience. Disclosures:No relevant conflicts of interest to declare.

Human Papillomavirus (HPV)-Attributable Subsequent Neoplasms (SNs) After Hematopoietic Cell Transplantation (HCT) – a Potentially Preventable Outcome

AbstractAbstract ▪605▪This icon denotes a clinically relevant abstract Background:Centers for Disease Control estimate that 26,000 cancers diagnosed each year in the general population are attributable to HPV; oropharyngeal and female genital cancers account for 75% of these. We hypothesized that HCT recipients are at an especially increased risk of HPV-attributable SNs, because of exposure to high-intensity therapy, coupled with immune dysregulation. However, the magnitude of this risk and sub-populations at highest risk are not known. Clinically this information is important because of the ability to institute primary prevention (HPV vaccine) for the young (<26y-olds); and the need to develop targeted surveillance and intervention strategies across all age groups. Methods:We determined the risk of post-HCT oral/pharyngeal and female genital neoplasms in 5701 (2424 female, 3277 male) consecutive patients transplanted for hematologic malignancies (leukemia [49%], lymphoma [35%], myeloma [12%]) between 1976 and 2007 at a single institution. Near-complete ascertainment of SNs was accomplished by combining institutional follow-up with linkage of the cohort with California Cancer Registry, and National Death Index Plus programs. Results:Median age at HCT was 41y (0–78); 48% had received autologous HCT; 37% related and 15% unrelated donor HCT. Chronic graft vs. host disease (GvHD) developed in 44% of related and 66% of unrelated donor HCT recipients. Oral/pharyngeal cancer: After 34,621 p-y of observation, 25 patients developed oral cancer; 76% after allogeneic HCT. Squamous cell carcinoma (SCC) of tongue, lip, and mouth/alveolar ridge accounted for 84% of the oral SNs; 16% were salivary gland tumors. Pathology reports did not capture HPV status. Oral/cutaneous (adjacent to lip) chronic GvHD was present in 62% of SCC, and 6% of non-SCC oral cancers. Median latency from HCT to oral cancer was 7.7y (0.9–32); median age at diagnosis was 45y (24–69). While autologous HCT recipients were not at statistically significant increased risk (standardized incidence ratio [SIR] = 1.9 (p=0.12), related donor recipients were at a 9-fold (4.5–14.8, p<0.001) and unrelated donor HCT recipients at a 23-fold (10.7–43.4, p<0.001) increased risk of developing oral cancer compared with the age- and sex-matched general population. Multivariate Cox-regression analysis (adjusted for age at HCT, gender, race/ethnicity, conditioning, and year of HCT) revealed that unrelated donor HCT recipients with chronic GvHD were at a 10.8-fold increased risk of developing oral cancer (p=<0.001), compared with autologous HCT recipients. Female genital tract neoplasms: Evaluation of the 2424 female HCT recipients with 14,587 p-y of follow-up revealed 51 patients with genital tract neoplasms (premalignant and malignant lesions of the cervix, vagina, vulva and clitoris); 71% of the cases among allogeneic HCT recipients had chronic GvHD. Forty-nine of the 51 neoplasms were of squamous cell origin. Importantly, 39 of 41 (95%) evaluable cases had findings consistent with HPV infection. Median latency from HCT to genital tract SNs was 3.3y (0.2–16.5); median age at diagnosis was 42y (20–66). In an analysis restricted to SEER-reportable neoplasms, the cohort was at 5.8-fold (3.2–9.5, p<0.001) increased risk of developing genital tract neoplasms when compared with an age-matched general population. Autologous, allogeneic related and unrelated HCT female recipients were at 4.1- (1.5–8.7, p=0.002), 7.2- (2.9–14.6, p<0.001) and 10.8-fold (1.8–33.8, p<0.001) increased risk respectively, of developing genital tract neoplasms compared with the general population. Multivariate Cox-regression analysis (adjusted for age at HCT, race/ethnicity, conditioning, and year of HCT) revealed that unrelated donor HCT recipients with chronic GvHD were at a 2.5-fold increased risk of developing female genital tract neoplasms (p=0.04) when compared with autologous HCT recipients. Conclusion:Chronic GvHD significantly increases risk of oral and female genital tract neoplasms; populations at risk should be followed closely, with appropriate and aggressive management of suspicious lesions. Over 90% of post-HCT female genital tract neoplasms are attributable to HPV. The contribution of specific HPV strains to the development of post-HCT oral and female genital tract neoplasms is currently underway, as are studies examining immunogenicity/safety of HPV vaccine for the <26y-old HCT survivors. Disclosures:No relevant conflicts of interest to declare.

Anti-thymocyte globulin for conditioning in matched unrelated donor hematopoietic cell transplantation provides comparable outcomes to matched related donor recipients

Rabbit anti-thymocyte globulin (ATG) is used as prophylaxis against GVHD following allogeneic hematopoietic cell transplantation (HCT). At our institution, ATG is exclusively used in the conditioning of matched unrelated donor (URD) transplant recipients. A total of 50 URD HCT recipients who received ATG (ATG group) were retrospectively compared with 48 matched related donor (MRD) HCT recipients who did not receive ATG (no ATG group). There were no significant differences between the groups in rates of day 100 mortality, acute GVHD or relapse. Chronic GVHD incidence was significantly lower in the ATG group (P = 0.007). At a median follow-up of 36 months in the entire cohort, 50% patients are alive in the ATG group and 63% of the patients are alive in the no ATG group (P = 0.13). We conclude that the administration of ATG to patients undergoing URD HCT preserves the anti-leukemia benefit of the transplant, while reducing the risk of developing GVHD, resulting in OS rates that are comparable to MRD HCT recipients.

Late Effects in Hematopoietic Cell Transplant Recipients with Acquired Severe Aplastic Anemia: A Report from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR)

With improvements in hematopoietic cell transplantation (HCT) for severe aplastic anemia (SAA), there is a growing population of SAA survivors of HCT. However, there is a paucity of information regarding late effects in SAA HCT survivors. We analyzed the burden of malignant and non-malignant late effects in HCT survivors with acquired SAA. A descriptive analysis of 1,718 patients post-HCT for acquired SAA between 1995-2006 reported to the CIBMTR was conducted. Cumulative incidences (CI) of selected late effects are reported for among “condition-free” (i.e. survivors without a previous diagnosis of the specified late effect) HCT survivors with SAA. One-year overall survival for the recipients of related donor HCT was 83% (80-85) and 62% (58-66) for the recipients of unrelated donor HCT. Of the HCT recipients, 1176 (68.5%) patients with a median age at HCT of 20 years (<1-65) utilized a related donor and 542 (31.5%) patients with a median age at HCT of 20 years (<1-67) utilized an unrelated donor. The median interval from diagnosis to transplant was 3 months (<1-348) for related donor HCT and 14 months (1-318) for unrelated donor HCT. Radiation (of any type) was utilized in 6% and 78% of related and unrelated donor HCT cases; respectively. Cy-TBI (68%) was a commonly utilized conditioning regimen for unrelated donor HCT. The median follow-up is 70 months (1-160) and 67 months (3-182) for related and unrelated donor HCT; respectively. The 2-year CI of chronic GVHD was 20% (18-22) and 37% (32-41) in related and unrelated donor HCT; respectively. Table 1 demonstrates that among 1-year condition-free survivors, the CI of late effects is greater among unrelated donor HCT survivors and continues to increase. These findings suggest that HCT survviors with SAA are a robust and healthy group in general. However, subgroups of patients undergoing HCT for SAA are at-risk for late effects and must be educated about and should be monitored for late effects. Subgroups of survivors may be at-risk group for a greater burden of specific late effects. Ongoing analyses in our cohort will explore selected risk-factors for late effects after HCT for SAA.Table 1Interval specific cumulative incidence of select late effects among 1-year condition free survivors following related and unrelated donor HCT for acquired SAA between 1995 and 2006 reported to the CIBMTRHealth conditions post transplantN (at risk)Related DonorN (at risk)Unrelated DonorCumulative Incidence % (95% CI)Cumulative Incidence % (95% CI)Strokes/SeizuresOver next 2 years7071.7 (0.9-2.7)2831.3 (0.3-2.8)Over next 5 years4161.8 (1.0-2.9)1182.8 (1.2-5.1)Gonadal DysfunctionOver next 2 years7092.6 (1.6-3.8)2736.2 (3.8-9.1)Over next 5 years4193.0 (2.0-4.3)10810.5 (7.3-14.3)Renal FailureOver next 2 years7151.1 (0.5-1.9)2871.9 (0.7-3.6)Over next 5 years4251.4 (0.7-2.3)1272.4 (0.9-4.5)Avascular NecrosisOver next 2 years7241.4 (0.7-2.3)2763.2 (1.5-5.4)Over next 5 years4261.8 (1.0-2.8)1176.3 (3.6-9.7)CataractsOver next 2 years7340.6 (0.2-1.2)2842.2 (0.9-4.1)Over next 5 years4331.1 (0.5-1.9)1185.1 (2.9-8.0)Growth DisturbanceOver next 2 years7350.2 (0.0-0.7)2861.9 (0.7-3.6)Over next 5 years4330.5 (0.1-1.2)1137.2 (4.4-10.7)HypothyroidismOver next 2 years7310.7 (0.3-1.4)2860.6 (0.1-1.8)Over next 5 years4321.2 (0.5-2.1)1195.5 (2.8-9.0)Solid TumorsOver next 2 years8200.6 (0.2-1.1)2760.7 (0.1-1.9)Over next 5 years5280.7 (0.2-1.3)1211.4 (0.4-3.0) Open table in a new tab

ATG Prevents Severe Acute Graft-versus-Host Disease in Mismatched Unrelated Donor Hematopoietic Cell Transplantation

Severe acute graft-versus-host disease (aGVHD) remains a major source of morbidity and mortality following mismatched unrelated donor hematopoietic cell transplantation (HCT). Through a retrospective analysis, we investigated the efficacy of GVHD prophylaxis with rabbit anti-thymocyte globulin (ATG) 7.5 mg/kg (1 mg/kg given on day -3, then 3.25 mg/kg/day on days -2 and -1 before stem cell infusion) followed by standard tacrolimus plus methotrexate in a consecutive series of 45 HLA partially matched unrelated donor HCT recipients. The cumulative incidence of grade III-IV aGVHD was 11% by 100 days (95% confidence interval [CI] 5%-25%). Moderate to severe chronic GVHD (per NIH consensus criteria) was 19% (95% CI 10%-36%) at 1 year, and 28% (95% CI 16%-48%) at 2 years. With a median follow-up time for surviving patients of 12 months (range: 5-39 months), overall survival was 55% (95% CI 39%-71%) at 1 year, and 45% (95% CI 27%-63%) at 2 years. Nonrelapse mortality was 11% (95% CI 5%-25%) by 100 days post-HCT, 26% (95% CI 16%-44%) by 1 year, and 30% (95% CI 18%-50%) by 2 years. The cumulative incidence of primary disease relapse was 23% (95% CI 13%-41%) at 1 year, and 33% (95% CI 20%-56%) by 2 years after HCT. Cytomegalovirus (CMV) infection or reactivation varied according to recipient and donor CMV serostatus. Epstein-Barr Virus (EBV) reactivation occurred in 54% (95% CI 40%-71%) of patients. Preemptive rituximab therapy was administered for EBV reactivation, however, posttransplant lymphoproliferative disorder was diagnosed in 5 (11%) cases, and was fatal in 1. A regimen of ATG 7.5 mg/kg total ending on day -1 effectively decreased the occurrence of grade III-IV aGVHD and severe chronic GVHD.

Early Mortality After Hematopoietic Cell Transplantation (HCT) for Hematologic Malignancies Performed In the Recent Era

AbstractAbstract 902 Background:HCT is a curative option for patients with hematologic malignancies. However, the procedure carries a high risk of death in the immediate post-HCT period in part due to disease recurrence (relapse-related mortality [RM]), but also due to treatment-related mortality (TRM) resulting from the following: i) toxicity due to high intensity treatment; ii) graft vs. host disease (GvHD) and its management; and iii) infections. Previous studies utilizing data from HCTs performed in 1980s and 1990s indicate that the 1-yr cumulative incidence of TRM exceeds 20% for related donor and 30% for unrelated donor HCTs. However, gaps in knowledge remain related to the cause-specific cumulative incidence of TRM and RM after autologous and allogeneic HCT performed in the more recent eras. Methods:Between 2005 and 2008, a total of 1,673 consecutive patients received HCT at City of Hope at a median age of 50 years for AML (n=433), NHL (n=428), MM (n=369), ALL (n=176), and HL (n=154); 913 patients received autologous HCT; 382 allogeneic related donor; and 378 unrelated donor HCT. Reduced intensity conditioning was used for 268 patients. Early mortality was defined as death in the first year after HCT due to disease (RM) or treatment (TRM). Information regarding vital status and cause of death were obtained from medical records, supplemented with Social Security Death Index. Overall survival (OS) and cumulative incidence of TRM and RM were calculated for 30 d, 6 mo and 1 yr after HCT for i) the entire cohort, and by ii) diagnosis and iii) type of HCT. Multivariable models identified predictors of TRM and RM. Results:A total of 323 deaths (19.3% of the entire cohort) were observed within the first year after HCT; 55.5% attributed to TRM and 44.5% to RM. Among deaths due to TRM, 59% were attributed to infections, 12.9% to acute or chronic GvHD, and 9.5% to organ toxicity. Among autologous, related and unrelated donor HCT recipients, overall survival (OS) was 87.2%, 76.6% and 63.5% at 1 yr (p<0.001) (Figure 1A). Among autologous, related donor, and unrelated donor HCT recipients, 1-yr cumulative incidence of TRM was 1.6%, 12.1%, and 25.6% respectively (p<0.001) (Figure 1B), and cumulative incidence of RM was 8.2%, 6.9%, and 8.7% respectively (p=0.73) (Figure 1C). OS and cumulative incidence of TRM and RM by disease and type of HCT are summarized in Table. Predictors of increased RM included age at HCT 40–60 yr (HR: 1.6, p=0.04; referent group: <40 yr), and diagnosis of NHL (HR=2.0, p=0.008; referent group: AML); receipt of HCT in the later years was associated with decreased RM (2007: HR=0.5, p=0.02; 2008: HR=0.5, p=0.04; referent group: HCT in 2005). Of note, RM for NHL and AML did not differ by type of HCT (p=0.94). Predictors of TRM included allogeneic HCT (related: HR=4.3, p=0.0003; unrelated: HR=10.2, p<0.0001; referent group: autologous HCT). Among related and unrelated HCT recipients, use of reduced intensity conditioning did not have a significant impact on TRM (HR=1.2, p=0.6) or RM (HR=1.2, p=0.7). Conclusion:For patients with NHL and AML, cumulative incidence of RM does not differ by HCT type. Unrelated donor HCT continues to be associated with the highest risk of TRM. Infection is the most frequent cause of TRM, accounting for 62% of deaths due to TRM in unrelated donor, 52% in related donor, and 46% in autologous HCT recipients – reinforcing the need for aggressive measures for prevention and treatment of infections in this immune compromised population.Overall survivalCum incidence: TRMCum incidence RRM30 d6 mo1 yr30 d6 mo1 yr30 d6 mo1 yrEntire cohort (n=1673)98.7%88.8%79.1%1.2%6.7%9.7%0.1%3.7%8%Autologous HCT (n=913)99.6%94.8%87.2%0.5%1.1%1.6%02.9%8.2%Allogeneic HCT (n=382)98.7%87%76.6%0.8%8.2%12.1%0.6%4.3%6.9%URD HCT (n=378)96.6%77%63.5%3.6%17.9%25.6%0%5%8.7%Autologous (AML: n=67)98.5%95.2%85.3%1.5%4.8%6.4%0%0%8.2%Related donor (AML: n=175)98.9%85.3%72.4%0.6%10.1%14%0.6%4.4%8.3%URD HCT (AML: 191)97.4%75%62.9%2.7%19.3%25.1%05%9.1%Related donor (ALL: n=89)97.8%89.7%80.3%2.4%8.5%13.6%0%0%0%URD HCT (ALL: n=87)93.3%72.8%57.8%6.7%21.5%33.1%05.7%9.2%Autologous (NHL: n=313)100%91.2%82%0%0%0.4%0%6.6%13.7%Related donor (NHL: n=63)98.4%81.6%68.9%0%8.5%14.2%0%10.5%14.3%URD HCT (NHL: n=52)98.1%82.4%70.7%1.9%9.9%16.5%0%7.9%11.9%Autologous (HL: n=147)99.3%94.2%87.2%0.7%2.2%2.2%0%2.2%7%Autologous (MM: n=358)99.7%98.4%92.6%0.3%0.6%1.3%0%0.7%3.9% [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Comparison of Unrelated and Sibling Donor Allogeneic Hematopoietic Cell Transplantation (HCT) for Follicular Lymphoma (FL) - From the Lymphoma Working Party, European Group for Blood and Marrow Transplantation (EBMT) and Center for International Blood and Marrow Transplant Research (CIBMTR).

Abstract 874Allogeneic HCT is potentially curative in FL, but wide adoption of this treatment is limited by its toxicity and donor availability. Improvements in HLA-matching have improved the safety of unrelated donor (URD) HCT. We compared the outcomes of 702 recipients of allogeneic HCT for FL (198 URD and 504 sibling donors (sib)) from 171 centers world-wide reporting to the CIBMTR or EBMT between 1997 and 2005. Recipients of mismatched, cord blood or ex vivo T-cell depleted grafts were excluded. Overall and progression-free survival (OS and PFS), transplant-related mortality (TRM) and relapse/progression outcomes were analyzed using Cox proportional hazards regression models with donor type (sib vs. URD) as the main effect. URD HCT was performed more frequently after 2001. Comparing to the sib group, URD HCT recipients were more likely to receive reduced intensity conditioning (70% vs. 54%), antithymocyte globulin or alemtuzumab (in vivo T-cell depletion) or tacrolimus-based graft-versus host disease (GVHD) prophylaxis, and have a longer interval from diagnosis to HCT (median 49 vs. 32 months). URD HCT recipients had poorer risk FL with more pre-transplant chemotherapy, including previous autologous HCT (36% vs. 16%) and prior exposure to rituximab (66% vs. 43%) compared with sib HCT recipients. Adjusted probabilities for three-year PFS and OS were 49% vs. 60% (p=0.02) and 54% vs. 69% ( p<0.001) for URD and sib HCT, respectively. Cumulative incidence of acute GVHD (grade 2-4) at day 100 was 48% and 42% (p=0.3), whereas chronic GVHD at one year was 47% and 41% (p=0.3) for the URD and sib HCT respectively. Relative risks for TRM, relapse/progression, treatment failure and mortality, comparing URD to sib donors, are shown below. Significant risk factors associated with worse outcomes included poor performance status at transplantation and extensive pre-transplant therapy (> 4 lines of therapy or prior autologous HCT). Additionally, in vivo T-cell depletion was associated with a higher risk of relapse/progression and treatment failure. Reduced intensity conditioning was associated with lower TRM, but did not impact other outcomes. In conclusion, this study shows that URD HCTs are performed later in the treatment course for FL, in higher risk patients, most commonly with reduced intensity conditioning, and are associated with worse PFS and OS compared to sib HCT. Considerations for future studies include the use of URD allogeneic HCT earlier in the course of treatment for FL and avoiding T cell depleting agents in the conditioning regimen.Outcome#URD/SibURD vs. sib RR1 (95% CI)PTRM197/5002.04 (1.43 - 2.90)<0.0001Relapse/Progression197/5000.97 (0.61 - 1.52)0.8781Treatment Failure2197/5001.49 (1.11 - 2.01)0.0087All cause Mortality3198/5041.91 (1.40 - 2.61)<0.00011Relative Risk2Relapse/Progression or Death3Opposite of OS Disclosures:No relevant conflicts of interest to declare.

Obesity Adversely Affects Survival of Pediatric Patients with Severe Aplastic Anemia After Hematopoietic Cell Transplantation.

Abstract 652Prevalence of obesity in children has been rapidly rising in the last decade in the US and other industrialized countries (US prevalence, ages 2-19, 16%, NHANES, 2008) and it represents a serious health concern. The impact of recipient's weight on mortality after hematopoietic cell transplantation (HCT) for non-malignant diseases is not well characterized. We studied the effect of body mass (BMI) on transplant outcomes in 1,281 patients aged 2-19 years who underwent HCT for severe aplastic anemia from 1990-2005. The study population was divided in five groups based on age-adjusted BMI percentiles. Patients in the <5th, 5-25th, 26-75th, 76-95th and >95th percentile BMI were classified as underweight, at risk for underweight, normal weight, at risk for overweight, and overweight respectively. Cox proportional hazards regression models for survival and acute graft-versus-host disease grade III-IV (aGVHD) were performed using BMI groups as the main effect and the normal weight (26-75th percentile) as the baseline comparison. Two-year overall survival was lower for overweight children (p<0.001, table). The risk of death, adjusted for significant covariates was higher for overweight compared to normal weight children (p=0.001, table). BMI groups were not associated with excess risk for aGVHD. Other significant factors associated with mortality include race and region of US, donor type, performance score at HCT, recipient age, and year of transplant. Risk of death was higher in African American patients (1.84, p=0.009) compared to Caucasians in the US, donors other than HLA-matched sibling and patients who received HCT before 2002. Among recipients of HLA-matched sibling grafts, use of busulfan-containing regimens (3.13, p<0.001) or cyclophosphamide without antithymocyte globulin (ATG) (1.92, p=0.03) had a higher risk of death compared to recipients of cyclophosphamide and ATG. Conditioning regimens in recipients of unrelated donor HCT were not associated with mortality. Among the reported causes of death, organ failure and infections occurred more frequently in overweight patients compared to the other BMI groups. In conclusion, overweight children with severe aplastic anemia have a higher risk of death after HCT independent of other factors analyzed in the study.BMI percentileN100 day mortality Probability (95% CI)2-y OS Probability (95% CI)RR of death (95% CI)p26-75th152515 (10-20)76 (70-82)1.00-<5th10812 ( 7-19)77 (68-84)1.01 (0.65-1.57)0.975-25th19611 ( 9-14)77 (74-81)1.38 (0.99-1.91)0.0676-95th30417 (13-21)73 (68-78)1.22 (0.93-1.61)0.14>95th14229 (22-36)59 (51-67)1.71 (1.24-2.35)0.0011Baseline group Disclosures:No relevant conflicts of interest to declare.

Delayed Cytomegalovirus (cmv) Infection Following Hematopoietic Cell Transplantation (HCT): City of Hope (COH) Experience.

Patients undergoing HCT are at an increased risk of developing primary and/or reactivated CMV infection, although the magnitude of risk of CMV disease has decreased with the widespread use of preemptive ganciclovir. Most episodes of reactivation occur within the first year post-HCT and are associated with risk factors such as CMV serostatus of donor and recipient, development of acute graft vs. host disease (GVHD): and the immunosuppressive therapy used for its management. Because of prolonged periods of immunosuppression post-HCT, patients may be at risk for delayed CMV infection one or more years after HCT. However, the magnitude of risk of delayed CMV infection and characteristics of those at increased risk has not been described. Given the high morbidity and mortality associated with post-HCT CMV infection, identifying patients at high risk of delayed CMV could be useful for effective management. This report includes 2700 consecutive patients who survived more than one year after undergoing HCT at COH between 1976 and 2003; these included 1404 autologous HCT recipients and 1296 allogeneic HCT recipients (1043 related donor; 253 unrelated donor recipients). Median age at HCT was 38 years (range, 0.6 to 79 years) and 59% of the cohort was males. Median follow-up time from HCT until delayed CMV infection/disease, death, or end of study period (12/31/2006), whichever occurred first, was 4.3 years (range:1–26.6 years). Medical records from COH and/or outside facilities were the main source of data for CMV occurrences. In total, 33 patients (1%) developed delayed CMV infection after surviving at least one year post-HCT (1 autologous and 32 allogeneic [20 related donor and 12 unrelated donor HCT]) developed a total of 40 episodes of delayed CMV that included pneumonia (n=16), gastrointestinal disease (n=8), retinitis (n=2), hepatitis (n=1), concurrent pneumonia and hepatitis (n=1), and asymptomatic reactivation (n=12). The overall cumulative incidence of delayed CMV infection was 1.3% (95% Confidence Interval [CI], 0.9–1.8%) at 5 years from HCT. For autologous HCT recipients, the incidence was 0.07% at 1 year based on 1 event. Among allogeneic HCT recipients, the cumulative incidence at 5 years post-HCT was 2.1% [95%CI, 1.2–3.0%] for related donor HCT recipients; and 5.0% [95%CI, 2.2–7.7%] for unrelated donor HCT recipients. Among allogeneic HCT recipients, the risk factors for the development of delayed CMV infection included unrelated donor HCT (hazard ratio [HR] = 2.5, 95% CI, 1.1–5.7) and CMV seropositive status of the recipient (HR=7.7, 95% CI 1.0–57.0) (Figure). Interestingly, donor CMV status was not associated with increased risk of delayed CMV. All 32 allogeneic HCT recipients experienced chronic GVHD, with prolonged exposures to corticosteroids (median=494 days), and cyclosporine (median=380 days). Thirty patients with delayed CMV infection (94% of the allogeneic HCT recipients with delayed CMV) were receiving immunosuppressive therapy for management of chronic GVHD at onset of delayed CMV. A total of eight patients with delayed CMV did not have a history of CMV infection in the first year, and were characterized by the following clinical and demographic features: 6 (75%) were male; median age at HCT was 35 years; one was an autologous HCT recipient, who relapsed 10 months post-HCT for non-Hodgkin lymphoma, received further chemotherapy and radiation, including Rituximab and then developed late CMV, just over one year post-HCT. The seven allogeneic HCT recipients had chronic GVHD, and were CMV serostatus positive prior to HCT, with 4 also having CMV seropositive donors. Of the 33 patients with delayed CMV in this study, 26 expired; median survival after the development of delayed CMV was 46 days. This study describes the magnitude of risk of delayed CMV infection in autologous and allogeneic HCT recipients and identifies at risk patients as those who are seropositive for CMV, undergoing unrelated HCT, and those with prolonged exposures to immunosuppressive therapy for cGVHD (Figure), suggesting the need for a close surveillance of these patients at high risk. [Display omitted]

Hematopoietic cell transplantation for Chediak–Higashi syndrome

We reviewed outcomes after allogeneic hematopoietic cell transplantation (HCT) in 35 children with Chediak-Higashi syndrome (CHS). Twenty-two patients had a history of the life-threatening accelerated phase of CHS before HCT and 11 were in accelerated phase at transplantation. Thirteen patients received their allograft from an human leukocyte antigen (HLA)-matched sibling, 10 from an alternative related donor and 12 from an unrelated donor. Eleven recipients of HLA-matched sibling donor, three recipients of alternative related donor and eight recipients of unrelated donor HCT are alive. With a median follow-up of 6.5 years, the 5-year probability of overall survival is 62%. Mortality was highest in those with accelerated phase disease at transplantation and after alternative related donor HCT. Only four of 11 patients with active disease at transplantation are alive. Seven recipients of alternative related donor HCT had active disease at transplantation and this may have influenced the poor outcome in this group. Although numbers are limited, HCT appears to be effective therapy for correcting and preventing hematologic and immunologic complications of CHS, and an unrelated donor may be a suitable alternative for patients without an HLA-matched sibling. Early referral and transplantation in remission after accelerated phase disease may improve disease-free survival.

Impact of Activating Killer Immunoglobulin-like Receptor Genotype on Outcome of Unrelated Donor–Hematopoietic Cell Transplantation

Background In a previous study we demonstrated that incompatibility regarding ligands for inhibitory killer immunoglobulin-like receptors (KIRs) is associated with a survival advantage following unrelated donor–hematopoietic cell transplantation (URD-HCT). The goal of the present analysis was to evaluate whether genotype of activating KIRs of the donor may have an impact on the outcome of URD-HCT. Patients and Methods Twenty-five URD-HCT recipients with hematological malignancies, mean age 27 years (range, 14–43 years), were included in the analysis. The conditioning regimen was myeloablative and based on chemotherapy alone (n = 20) or total body irradiation (n = 5). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine, methotrexate, and pretransplant antithymocyte globulin. Patients were grouped according to their donors’ activating KIR genotype including two loci: KIR2DS1 and KIR2DS2. Results The presence of KIR2DS1 in the donor (n = 16/25) was not demonstrated to influence outcome. In contrast, the presence of KIR2DS2 (n = 13/25 donors) was associated with decreased probability of overall survival (0% vs 92%, P = .04) and disease-free survival (0% vs 92%, P = .046). The reason for failures in the KIR2DS2-positive group was chronic GVHD (n = 4), acute GVHD (n = 2), and relapse (n = 1). The cumulative incidence of nonrelapse mortality equaled 90% for the KIR2DS2-positive group and 8% for the KIR2DS2-negative group ( P = .09). Conclusion The presence of KIR2DS2 gene in the donor is associated with a high risk of mortality following URD-HCT, resulting mainly from the incidence of severe GVHD. Whether this effect is associated with the activity of natural killer cells or KIR-bearing T lymphocytes requires further investigation.

Predictors of Avascular Necrosis (AVN) of Bone after Long-Term Follow-Up of Allogeneic and Autologous Hematopoietic Cell Transplantation (HCT) for Malignant and Non-Malignant Disorders.

Patients undergoing allogeneic HCT are known to be at an increased risk of AVN. Chronic steroid use, to treat chronic graft vs. host disease (cGVHD) has been identified as a risk factor. Previous studies reporting AVN after allogeneic HCT are limited either due to small cohort size or reliance on registry data for passive reporting on outcomes such as AVN. Furthermore, little is known about the risk of AVN after autologous HCT. We report a retrospective chart review of 1595 consecutive patients undergoing HCT at City of Hope Cancer Center between 1976 and 1998, and surviving one or more years after HCT. The median age at HCT was 35 years (range, 0.6–71.5) and the median length of follow-up was 7.0 years (1–25.3). The cohort included 940 males (59%). In this cohort, 78 patients developed AVN of 163 joints, resulting in a mean of 2.1 affected joints per patient (range, 1 to 8). Diagnosis of AVN was confirmed by review of radiologic evidence of necrosis in the presence of clinical symptoms. The hip joint was the most common joint affected (70.5% of patients), followed by the knee (35%) and shoulder (26%). Symptoms developed a median of 38.7 months from HCT (12 to 199 months). The overall cumulative incidence was 6.2% at 15 years from HCT for the first reported AVN developing one or more years after HCT. Nineteen of 741 autologous HCT survivors developed AVN (cumulative incidence: 3.5% at 10 years), while 46 of the 746 allogeneic sibling donor HCT survivors (cumulative incidence, 6.2% at 10 years), and 12 of the 108 unrelated donor HCT recipients developed AVN (cumulative incidence 13.9% at 10 years, p<0.001). A multivariate analysis of the entire cohort identified exposure to cyclosporine, both for GVHD prophylaxis (relative risk (RR), 3.03, 95% confidence interval (CI), 1.4–6.5), and treatment of cGVHD (RR=4.1, 95% CI, 2.2–7.9), male sex (RR=2.1, 95% CI, 1.3–3.6), primary diagnosis of multiple myeloma (RR=7.5, 95% CI, 1.4–40.7) and Hodgkin disease (RR=10.8, 95% CI, 2.2–53.6) when compared with aplastic anemia to be independently associated with an increased risk of AVN after HCT. Among survivors of allogeneic HCT, presence of cGVHD (RR=4.2, 95% CI, 1.7–10.0), and treatment of cGVHD with a combination of systemic steroids, Cyclosporin, and Tacrolimus (RR=3.6, 95% CI, 1.7–7.7), compared to a combination of systemic steroids and Cyclosporin, were independently associated with an increased risk of AVN. Finally, no risk factors were identified for the development of AVN among autologous HCT recipients. AVN is a frequent and significantly debilitating consequence of HCT, frequently requiring surgical intervention, and potentially impacting the overall HRQL of the HCT survivors. This study describes the magnitude of risk in autologous and allogeneic HCT recipients and identifies cGVHD and use of immunosuppressive agents such as systemic steroids, Cyclosporin and Tacrolimus as risk factors, indicating the possible pathogenic role of Cyclosporin- and Tacrolimus-induced microangiopathy in the development of AVN in this population. Identification of genetic susceptibility and the role of interaction between therapeutic exposures and genetic susceptibility in handling these therapeutic exposures would further assist in identification of the populations at risk and the mechanistic pathways involved in the development of AVN in this population.