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  • 1
    In: Blood, American Society of Hematology, Vol. 122, No. 25 ( 2013-12-12), p. 4129-4139
    Abstract: Donor-derived anti-CD19-CAR T cells cause regressions of refractory malignancies after allogeneic transplantation.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
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  • 2
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 151-151
    Abstract: Progressive malignancy is a leading cause of death in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). To improve treatment of B-cell malignancies that persist despite alloHSCT, we conducted a clinical trial of allogeneic T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. Ten patients were treated on this trial. Four patients were recipients of human-leukocyte-antigen (HLA)-matched unrelated donor (URD) transplants and 6 patients were recipients of HLA-matched sibling transplants. T cells for genetic modification were obtained from each patient’s healthy alloHSCT donor. Patients received a single infusion of anti-CD19-CAR T cells. Cell doses ranged from 1x106 to 10x106 T cells/kg. A mean of 58% of the infused cells expressed the CAR. Patients did not receive chemotherapy or other anti-malignancy therapy with the CAR-T-cell infusions, so the responses observed in these patients are not confounded by the effects of chemotherapy. In contrast to other reports of successful treatment of B-cell malignancies with anti-CD19-CAR T cells, the patients on this study were not lymphocyte-depleted at the time of the CAR-T-cell infusions. Two patients with chronic lymphocytic leukemia (CLL) refractory to standard unmanipulated allogeneic donor lymphocyte infusions (DLIs) had regressions of large malignant lymph node masses after infusion of allogeneic anti-CD19-CAR T cells. One of these CLL patients obtained a complete remission that is ongoing 9 months after treatment with allogeneic anti-CD19-CAR T cells. This patient also had complete eradication of blood B cells within 9 days after her CAR-T-cell infusion. Another patient had tumor lysis syndrome requiring rasburicase treatment as his CLL dramatically regressed in lymph nodes, bone marrow, and blood within 2 weeks of his anti-CD19-CAR-T-cell infusion. A patient with mantle cell lymphoma obtained a partial remission that is ongoing 3 months after infusion of anti-CD19-CAR T cells. A fourth patient with diffuse large B-cell lymphoma has ongoing stable disease 11 months after infusion of anti-CD19-CAR T cells. The other 6 treated patients all had short periods of stable malignancy or progressive disease after their CAR-T-cell infusions. Specific eradication of blood B cells occurred after infusion of CAR T cells in 3 of 4 patients with measurable blood B cells pretreatment. None of the patients treated on this study developed GVHD after their anti-CD19-CAR-T-cell infusions, despite the fact that 6 of 10 treated patients had experienced GVHD at earlier time-points after their most recent alloHSCT. One patient, who had a history of cardiac dysfunction with prior acute illnesses, had temporary cardiac dysfunction after infusion of anti-CD19-CAR T cells. The most prominent toxicities experienced by patients were fever and hypotension; these peaked 5 to 12 days after CAR-T-cell infusions and resolved within 14 days after the T-cell infusions. Two patients had Grade 3 fever, and 2 patients had Grade 3 hypotension. No patients experienced Grade 4 toxicities that were attributable to the CAR-T-cell infusions. Elevated levels of serum interferon gamma were detected in 3 patients at the time that they were experiencing toxicities. We detected cells containing the anti-CD19-CAR gene in the blood of 8 of 10 patients. The peak blood levels of CAR T cells varied from undetec to 2.8% of peripheral blood mononuclear cells. The persistence of the CAR T cells in the blood of patients was limited to one month or less. When we assessed T cells from the blood of patients ex vivo, we found elevated levels of the T-cell inhibitory molecule programmed cell death protein-1 (PD-1) on CAR+ T cells compared to CAR-negative T cells. These results show for the first time that small numbers of donor-derived allogeneic anti-CD19-CAR T cells can cause regression of highly treatment-resistant B-cell malignancies after alloHSCT without causing GVHD. Malignancies that were resistant to standard DLIs regressed after anti-CD19-CAR-T-cell infusions. Future goals for improving this approach include enhancing the persistence of anti-CD19-CAR T cells and reducing toxicities. Infusion of allogeneic T cells genetically modified to recognize malignancy-associated antigens is a promising approach for treating residual malignancy after alloHSCT. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 3
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 16, No. 1 ( 2010-01), p. S106-S114
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2010
    detail.hit.zdb_id: 1474865-4
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  • 4
    In: Transfusion, Wiley, Vol. 54, No. 4 ( 2014-04), p. 1088-1092
    Abstract: Cryopreservation is often used to store cellular therapies, but little is known about how well CD 3+ or CD 34+ cells tolerate this process. Study Design and Methods Viable CD 34+ cell recoveries were analyzed from related and unrelated donor granulocyte–colony‐stimulating factor ( G ‐ CSF )–mobilized peripheral blood stem cell ( PBSC ) products and viable CD 3+ cell recoveries from G ‐ CSF –mobilized and nonmobilized apheresis products from related and unrelated donors. All products were cryopreserved with 5% dimethyl sulfoxide and 6% pentastarch using a controlled‐rate freezer and were stored in liquid nitrogen. Related donor products were cryopreserved immediately after collection and unrelated donor products greater than 12 hours postcollection. Results The postthaw recovery of CD 34+ cells from related donor PBSC s was high (n = 86; 97.5 ± 23.1%) and there was no difference in postthaw CD 34+ cell recovery from unrelated donor PBSC s (n = 14; 98.8 ± 37.2%; p = 0.863). In related donor lymphocyte products the postthaw CD 3+ cell recovery (n = 48; 90.7 ± 21.4%) was greater than that of unrelated donor products (n = 14; 66.6 ± 35.8%; p = 0.00251). All unrelated donor lymphocyte products were from G ‐ CSF –mobilized products, while most related donor lymphocyte products were from nonmobilized products. A comparison of the CD 3+ cell recovery from related donor G ‐ CSF –mobilized products (n = 19; 85.0 ± 29.2%) with that of unrelated donor products found no significant difference (p = 0.137). Conclusions The postthaw recovery of CD 34+ cells was high in both related and unrelated donor products, but the recovery of CD 3+ cells in unrelated donor G ‐ CSF –mobilized products was lower. G ‐ CSF –mobilized unrelated donor products may contain fewer CD 3+ cells than non– G ‐ CSF –exposed products upon thaw and, when indicated, cell doses should be monitored.
    Type of Medium: Online Resource
    ISSN: 0041-1132 , 1537-2995
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2014
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  • 5
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1245-1245
    Abstract: Abstract 1245 A clearly superior graft-versus-host disease (GVHD) prophylaxis regimen has not been established for patients undergoing reduced intensity allogeneic hematopoetic stem cell transplantation (HSCT) from matched unrelated donors (URD). Encouraging results have been reported with both the combination of alemtuzumab plus cyclosporine (AC) (Chakraverty R et al Blood 2002) and the regimen of tacrolimus, methotrexate, and sirolimus (TMS) (Antin JH et al, Blood 2003) in the URD setting. These two regimens work by biologically distinct mechanisms and may have markedly different effects upon engraftment and immune reconstitution. As part of a randomized pilot study, we prospectively assessed the effects of the AC and TMS regimens on GVHD, engraftment, and immune reconstitution in the setting of targeted lymphocyte-depleting chemotherapy and reduced-intensity allogeneic HSCT from HLA-matched URD. Twenty patients (median age 53 yrs; range 24–70) with high risk hematologic malignancies (median prior regimens = 4; chemo-resistant disease = 35%) received disease-specific induction chemotherapy (DA-EPOCH-FR or FLAG) prior to transplantation for disease control and lymphocyte depletion. All patients then received conditioning with fludarabine 30 mg/m2/day × 4 days and cyclophosphamide 1200 mg/m2/day IV × 4 days followed by a T-cell replete mobilized peripheral blood allograft from a 10/10 HLA-matched URD. Patients were randomized at the time of enrollment to receive either: AC (n=10): alemtuzumab 20 mg/day IV over 8 hours Days -8 to -4 and cyclosporine starting at Day -1 with a 10% per week taper starting at Day +100 or TMS (n=10): tacrolimus and sirolimus starting at Day -3 with a 33% taper at Day +63 and Day +119 and methotrexate 5 mg/m2 IV, days +1, +3, +6, and +11. Treatment related mortality at Day +100 and 1 year for all 20 patients was 5% and 17% respectively. Actuarial event free and overall survival at 1 year after transplantation were 70% and 85% respectively; cumulative incidence of relapse at 1 year was 15%. There were no graft rejections on either arm. Median CD3+ chimerism in the AC vs TMS group was 86% vs 99% at Day+14 (p=0.025), 100% vs 98% at Day+28 (p=0.63) and 100% in both groups at Day+100 (p=0.83). Median CD14+/15+ chimerism in the AC vs TMS group was 93% vs 100% at Day+14 (p=0.020), 99% vs 100% at Day +28 (p=0.12) and 100% in both groups at Day +100 (p=0.89). The overall incidence of acute GVHD in the AC arm was 30% (Grade II-IV = 20%; Grade III-IV = 10%) and 40% in the TMS arm (Grade II-IV = 20%, Grade III-IV = 10%). With a median follow-up of 18 months, chronic GVHD was seen in 70% of patients in the AC arm (mild =10%, moderate = 40%, severe = 20%) and 60% in the TMS arm (moderate = 40%, severe = 20%). Patients on the AC arm had significantly less T-lymphocyte recovery by Day +14 compared with the TMS arm (median CD3+ = 1 cells/μl vs 356 cells/μl; CD4+ = 0 cells/μl vs 243 cells/μl; CD8+ = 0 cells/μl vs 59 cells/μl; each p 〈 0.0001); this was less disparate at Day +28 (median CD3+ = 45 cells/μl vs 398 cells/μl; CD4+ = 36 cells/μl vs 218 cells/μl; CD8+ = 5 cells/μl vs 152 cells/μl; each p≤0.002). By Day +100, lymphocyte recovery was not appreciably different between the two groups (median CD3+ = 242 cells/μl vs 445 cells/μl CD4+ = 106 cells/μl vs 212 cells/μl, CD8+ = 72 cells/μl vs 135 cells/μl; each p 〉 0.03). NK-cell recovery was slightly less in the AC arm compared with the TMS arm at Day +14 (median NK = 14 cells/μl vs 70 cells/μl; p=0.01) and at Day +28 (median NK = 29 cells/μl vs 150 cells/μl; p=0.02). There was no difference by Day +100 (median NK = 124 cells/μl vs 88 cells/μl; p=0.31). B-cell reconstitution was negligible in both groups up through Day +100. At median 18 month follow-up, patients treated on the AC arm had experienced a total of 28 episodes of Grade III-IV infections compared with 23 episodes on the TMS arm. These initial data suggest that AC and TMS provide approximately equivalent GVHD prevention and comparable time to full donor chimerism. However, the AC regimen was associated with later lymphocyte and NK cell recovery and a higher number of infectious episodes, raising a potential concern for increased infection risk with the AC regimen. It is also notable that despite delayed lymphocyte recovery in the AC arm, there were still comparable rates of acute GVHD with the TMS arm. Based on these initial data, we have expanded patient accrual and extended enrollment to recipients of HLA-mismatched URD. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 6
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3451-3451
    Abstract: Abstract 3451 Relapse is the major cause of treatment failure and death following reduced-intensity (RI) allogeneic hematopoietic stem cell transplantation (HSCT) for non-Hodgkin's lymphoma (NHL), yet there are no reports that focus specifically on the natural history of relapse in this patient population. We assessed relapse risks and outcomes on 120 consecutive patients (median age = 52 years; range, 28–71 years) with NHL (indolent = 43; aggressive = 77) who all received a T-cell replete allograft from HLA-matched siblings following a reduced-intensity conditioning regimen (fludarabine/cyclophosphamide). All patients were assessed for disease status at 1, 3, 6, 12, 18, 24 months post-transplant, and annually thereafter or as clinically indicated. Median event-free survival (EFS) from transplant date for all 120 patients was 11.3 months (range, 0.5–105.5+ months) with a 5-year EFS = 35%. Median EFS (months) was assessed for the following pre-transplant characteristics: chemo-resistant vs. chemo-sensitive = 3.3 vs. 39.1, p = 0.0001; pre-transplant disease status - CR vs. PR vs. SD vs. PD = not reached (NR) vs. NR vs. 11.2 vs. 1.7, p 〈 0.0001; aggressive vs. indolent histology = 6.6 vs. 15.8, p = 0.13; number of disease sites: 0–1 vs. 2 vs. 3 vs. 4+ = 4.8 vs. 7.4 vs. 18.4 vs. 7.1, p = 0.85. Median overall survival (OS) from transplant date for all 120 patients was 71.1 months (range, 0.5–120+ months). We identified 55 patients (46%) who either relapsed or progressed post-transplant. Among those who have progressed/relapsed to date, median time to progression/relapse was 3 months (range, 0.5–46 months) with 72% of progressions/relapses occurring prior to 6 months post-transplant. The overall cumulative incidence (CI) probabilities for relapse/progression, adjusted for competing non-relapse mortality, at 3, 6, 12, 24 and 36 months were 0.169, 0.329, 0.394, 0.447, and 0.460, respectively. The association of 3-year relapse CI probabilities with pre-transplant characteristics were as follows: aggressive vs. indolent histology = 0.530 vs. 0.315; chemo-resistant vs. chemo-sensitive = 0.571 vs. 0.316; disease status prior to transplant – CR vs. PR vs. SD vs. PD = 0.210 vs. 0.217 vs. 0.597 and 0.627; number of prior treatments: 1–2 vs. 3 vs. 4 vs. 5+ = 0.375 vs. 0.418 vs. 0.613 vs. 0.450; sites of disease: 0–1 vs. 2 vs. 3 vs. 4+ = 0.458 vs. 0.516 vs. 0.331 vs. 0.579. Median OS from date of progression was 8.3 months (0.5 - 94+ months) with a 5-year OS = 32%. No patient who progressed/relapsed within 3 months post-transplant has survived beyond 12 months, with one patient still alive at 6 months. Median OS (months) from date of progression was assessed for the following characteristics: progression 〈 3 months vs. ≥ 3 months post-transplant = 2.6 vs. NR, p 〈 0.0001; progression 〈 6 months vs. ≥ 6 months post-transplant = 5.3 vs. NR, p = 0.0002; aggressive vs. indolent histology = 7.8 vs. 18.3, p = 0.53; number of disease sites: 0–1 vs. 2 vs. 3 vs. 4+ = 5.8 vs. 13.8 vs. 4.9 vs. 12.9, p = 0.75; number of prior treatments: 1–2 vs. 3 vs. 4 vs. 5+ = 8.4 vs. NR vs. 11 vs. 5.6, p = 0.27; response vs. no response to relapse/progression treatment = NR vs. 4.7, p = 0.0087 (determined by a landmark method, beginning 30 days after progression to allow time for determination of response to relapse treatment). These data demonstrate that a significant minority of NHL patients, who relapse after RI allogeneic HSCT, can achieve long-term survival, including patients with aggressive histology. These analyses, which utilized standard clinical characteristics, identified NHL patients at higher risk for relapse and poorer outcomes once relapse occurred. In particular, disease progression/relapse occurring less than 3 months post-transplant was associated with an extremely poor prognosis; novel strategies and trials are needed for such patients. These results need to be confirmed by other groups, and these analyses need to be performed in other transplant settings (e.g. unrelated donors and myeloablative conditioning). The use of these patient characteristics, alone or in combination, may ultimately lead to a method of estimating the risk for relapse and the subsequent prognosis, if relapse should occur, in NHL patients undergoing RI allogeneic HSCT. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 7
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2076-2076
    Abstract: Comorbid health conditions, both those present before transplant and those acquired as late effects of allogeneic hematopoietic stem cell transplantation (alloHSCT) and the treatment of chronic graft-versus-host disease (cGVHD), represent an important covariate. While the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) (Sorror et al. Cancer, 2008; 112(9):1992-2001) has been developed to predict non-relapse mortality and overall survival in allo-HSCT recipients, many of the chronic comorbid conditions that develop in the allogeneic post-transplant setting are not represented in the HCT-CI, and its predictive validity has had limited study in long-term transplant survivors. The objectives of this study were to: (i) establish a new measure of multimorbidity for the post-transplant setting (Post-Transplant Multimorbidity Index [PTMI]), and (ii) explore its content validity. Methods Based on a review of the literature and the most commonly used comorbidity measures, the PTMI was developed to reflect a broad and inclusive list of comorbid conditions that may arise in the post-transplant setting. Preliminary definitions to establish the presence of each of these conditions were developed. To enhance longitudinal comparisons, the conditions and definitions from the HCT-CI were nested within the PTMI. The conditions and definitions were iteratively refined (SM and DW) through application in a cohort of 30 post-transplant patients. Subsequently, the PTMI, HCT-CI, Charlson Comorbidity Scale (CCS), and the Functional Comorbidity Index (FCI) were comparatively evaluated in a cohort of 50 alloHSCT survivors referred for comprehensive cGVHD consultation. The evaluation cohort was a mean age of 42 (range 23-68) years and a median of 33.5 (range 13-208) months post-transplant. All but two (late acute GVHD n=1; no cGVHD n=1) had active cGVHD that had been present for a median of 27 (range 3-197) months. A majority had severe cGVHD (NIH global severity score 1 n=4; 2 n=8; 3 n=36) and 90% were currently receiving systemic immunosuppression. Results Applying the PTMI, HCT-CI, CCS and FCI to our evaluation cohort yielded a mean of 5 (SD±2.5), 1.5 (SD±1.23), 1.39 (SD±0.78), and 2.18 (SD±1.16) co-occurring conditions, respectively. On average the HCT-CI, CCS, and FCI missed the identification of one or more comorbidities 71%, 75%, and 43% of the time. Conditions that were prevalent in the cohort but missed by the other comorbidity measures included osteoporosis, avascular necrosis, hypertriglyceridemia, hypothyroidism, BMI 〈 22, and secondary solid malignancy (excluding nonmelanoma skin cancer) after transplant. Using the PTMI, the two most prevalent comorbid conditions were osteoporosis (64%) and underweight/sarcopenia (BMI 〈 22) (46%), whereas the FCI identified osteoporosis and depression as most prevalent, and the HCT-CI psychiatric disturbance and peptic ulcer, and the CCS history of malignancy and peptic ulcer disease, as the two most prevalent comorbidities, respectively. Conclusions Our results offer preliminary evidence that the PTMI improves the identification of chronic comorbid conditions in long-term transplant survivors with cGVHD, and demonstrate that the choice of a measure is an important methodologic issue in the design of epidemiologic studies of comorbidity in post-transplant survivors with cGVHD. Prospective studies evaluating the measurement properties of the PTMI are ongoing in post-transplant survivors with and without active chronic GVHD. With continued testing and refinement, we anticipate that this new measure will have utility for risk-adjustment and stratification in both observational studies and clinical trials in the post-transplant setting. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 8
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 211-211
    Abstract: Abstract 211 The adverse impact of chronic GVHD (cGvHD) on health and quality of life is especially critical in children because of their longer life expectancy and problems impacting growth and development. Although risk-factors for developing cGvHD in children are reported, little is known about risk factors for non-relapse mortality (NRM) in children with cGvHD. Identification of predictors for mortality in children with cGvHD could permit risk-adapted therapy, help plan for clinical trials and assist in counseling. We performed a multivariate analysis using data from CIBMTR to identify transplant- and cGvHD-related risk factors for NRM and survival in a cohort of 1117 subjects aged 0–20 years, transplanted from related donors, unrelated donors (URD), or unrelated cord blood (UCB) in 1995–2004 for acute myelogenous leukemia (AML), acute lymphoid leukemia (ALL), chronic myelogenous leukemia (CML) or myelodysplastic syndrome (MDS). Median age was 12 years. Characteristics of cGvHD at diagnosis were: progressive onset (49%), total bilirubin 〉 2 mg/dL (16%), thrombocytopenia (platelets 〈 100 × 109/L, 32%) and Karnofsky/Lansky (KPS/L) score 〈 80 (24%). Probabilities of NRM at 1, 3, and 5 years after diagnosis of cGvHD were 17% (95% CI: 14–19%), 22% (20-25%) and 24% (21-27%), respectively. Multivariate analysis indentified four factors significantly associated (p 〈 0.01) with higher NRM: (1) HLA-partially-matched or -mismatched URD; (2) peripheral blood cell graft; (3) KPS/L 〈 80 at cGVHD diagnosis; and (4) platelets 〈 100 × 109/L at cGVHD diagnosis. Survival after diagnosis of cGVHD at 1-, 3- and 5-years was 75% (72-77%), 63% (60-66%), and 59% (56-62%). Factors significantly associated with worse survival were: (1) age 〉 10 years; (2) transplant from an HLA-partially-matched or -mismatched URD; (3) advanced disease at transplant; (4) KPS/L 〈 80; and (5) platelets 〈 100 × 109/L. The cumulative incidence of NRM at 5 years was higher for children with KPS/L 〈 80 (46%; CI: 40–52%) than for those with a higher KPS/L score (15%; CI: 12–18%; p 〈 0.001). This translated to poorer survival of 42% (36-48%) vs. 66% (CI: 63–70%; p 〈 0.001), respectively. 5 year cumulative incidence of NRM was also higher in children with platelets 〈 100 × 109/L: 37% (32-43%) vs. 15% (CI: 12–18%; p 〈 0.001). This also resulted in poorer survival (47%, CI: 42–52%; vs. 67%, CI: 63–71%; p 〈 0.001). Cumulative incidence of discontinuation of systemic immune suppression (death and relapse treated as competing risks) at 1, 3 and 5 years after diagnosis of cGvHD were 22% (20-25%), 34% (31-37%), and 37% (34-40%). In conclusion, we identified several factors adversely correlated with NRM and survival children with cGvHD. The correlation between peripheral blood cell grafts and increased NRM without poorer survival may be explained by fewer relapses. This is the first large study elucidating factors affecting outcome after diagnosis of cGvHD in children. Our results may be useful for risk stratification.SurvivalNRMRelative Risk95% CIPRelative Risk95% CIPAge (baseline: 0–9 years)    10-191.321.091.600.005NSKPS/L (baseline: 80–100) 〈 .001 〈 .001     〈 801.891.522.34 〈 .0013.012.293.96 〈 .001    unknown1.341.001.780.051.641.122.430.015Platelets (x10e9/L) (baseline: ≥ 100) 〈 .001 〈 .001     〈 1001.631.322.01 〈 0.0012.321.763.07 〈 .001    Unknown1.330.991.780.061.731.182.520.005Donor (baseline: HLA-identical siblings)0.003 〈 0.001    Other related1.681.132.520.0111.670.962.960.07    HLA-well-matchedunrelated1.401.021.940.041.250.801.960.33    Partially matched unrelated1.691.232.310.0011.941.282.940.002    Mismatched unrelated1.751.272.42 〈 0.0012.311.493.59 〈 0.001No data1.020.641.620.941.220.602.130.71Disease State (baseline: Early) 〈 0.0010.005    Intermediate0.960.781.180.700.650.500.850.07    Advanced1.561.192.040.0010.920.631.350.68Graft (baseline: BM)0.002    BloodNS1.761.282.41 〈 0.001    Cord BloodNS1.070.671.700.78NS=Not SignificantCumulative Incidence of NRM by Platelets and KPS/L at Diagnosis of cGvHDCumulative Incidence of NRM by Platelets and KPS/L at Diagnosis of cGvHDSurvival and Cumulative Incidence of Discontinuation of Immune SuppressionSurvival and Cumulative Incidence of Discontinuation of Immune Suppression Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 9
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 4201-4201
    Abstract: Abstract 4201 Graft versus Host Disease (GvHD) is a potentially devastating complication of allogeneic hematopoietic cell transplantation (HCT) initiated in part due to donor-recipient disparities in immunoreactive proteins, or minor histocompatibility antigens (mHAgs). There are no established prognostic tools to predict which patients will get acute or chronic GvHD. Analysis of mHAg mismatch is a potential predictive tool for GvHD; however, previous studies attempting to establish a relationship between mHAg mismatch and GvHD have been largely equivocal. Here we tested the hypothesis that analysis of an expanded set of mHAgs for mismatch in the GvH direction can be predictive of acute or chronic GvHD by NIH criteria. We additionally analyzed event-free (EFS) and overall survival (OS) in the mHAg matched and mismatched subgroups. Recipient/donor pairs from 45 HLA-A, -B, -C, and DRB1 matched unrelated donor transplants from 2007–2011 were retrospectively typed for 19 mHAgs using an SSP-PCR typing kit (Minor Histocompatibility Antigen Typing Kit; Life Technologies, Carlsbad, CA). Genomic DNA was obtained from peripheral blood mononuclear cells. EFS and OS were estimated using the Kaplan-Meier method. The relationship between mismatch and acute or chronic GvHD was described using Fischer's Exact Test. Cumulative incidence of treatment related mortality (TRM) was calculated using the Gooley Method. Two patients expired of early TRM and were excluded from the GvHD analyses. The rate of acute GvHD grades II-IV was 6 of 14 in those without a mHAg mismatch and 21 of 29 in those with a mismatch (43% versus 72%, P = 0.062). The rate of chronic GvHD was 8 of 14 in those without a mismatch and 10 of 29 in those with a mismatch (53% versus 34%, P = 0.140). The presence of a mismatch did not significantly impact EFS (P = 0.42) or OS (P = 0.26). The cumulative incidence of TRM at 24 months post transplantation was greater in patients with a mismatch (36% versus 13%). Two year OS was superior in patients who were conditioned with alemtuzumab (N = 24) and had a lower degree of mismatch (0–1 mismatch = 72% versus 2+ mismatches = 38%, P = 0.038). This study suggests the possibility of a relationship between mHAg mismatch and acute GvHD and TRM. Further study using this expanded mHAg analysis on a larger cohort of individuals would more adequately define the potential benefit of mHAg mismatch analysis in the context of unrelated donor HCT. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 10
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 464-464
    Abstract: Abstract 464 Background: Assessing joint chronic GVHD needs to be accomplished reliably, simply and in a clinically meaningful way. To determine the optimal tool for assessing joint GVHD, we evaluated 2 NIH recommended joint tools (Table), a photographic range of motion (P-ROM) scale, and 7 other NIH recommended tools (Lee symptom scale, 10-point overall symptoms, FACT-G, SF36, Human Activities Profile, walk test and grip test). Methods: Patients ≥ age 2 with systemically treated chronic GVHD ≤ 3 years after hematopoietic cell transplantation were eligible for a prospective multicenter observational study. Incident and prevalent cases were included. At follow-up visits every 3–6 months, the clinician (MD) and patient (PT) rated separately their perception of change in joint GVHD on an 8-pt scale, which was collapsed into improved, stable or worse categories. Linear mixed models were used to correlate change in each tool with MD or PT-perceived change (improved vs. stable or worse vs. stable) in joint GVHD status. Results: Nine sites in the Consortium enrolled 567 participants through December 2011. Joint involvement, as defined by NIH joint/fascia score ≥1, was present at enrollment in 164 (29%) patients and included wrists (64%), ankles (47%), shoulders (35%) and elbows (30%). Joint involvement at enrollment was associated with longer duration of chronic GVHD, high-dose total body irradiation, higher symptom burden, lower quality of life (QOL), similar activity profile and similar physical function, compared to those without joint involvement. Change in joint GVHD status was examined for 652 paired visits when joint involvement was documented in the previous or current visit. In the later visits, both MDs and PTs more often reported improvement (44% and 45%) than worsening (5% and 11%). Tools that correlated with both MD and PT-perceived joint improvement were NIH joint/fascia score, Hopkins fascia score and SF36-PCS. Tools that correlated with both MD and PT-perceived joint worsening were P-ROM total score, NIH joint/fascia score, Hopkins fascia score, Lee muscle/joint subscale, Lee symptom overall score, 10-point overall symptoms and FACT-G. Among the 3 joint/fascia tools (Figure), for MD-perceived improvement, estimated change in the NIH score and P-ROM score was slightly larger than in the Hopkins score. For PT-perceived improvement, estimated change was similar for NIH and Hopkins scores. In contrast, for both MD and PT-perceived worsening, estimated change for the P-ROM score was significantly larger than in the other tools. Conclusion: Joint involvement with chronic GVHD is frequent and associated with increased symptom burden and decreased QOL. Our results support the combined use of NIH joint/fascia score and P-ROM scale to assess joint GVHD. The NIH score better reflects joint improvement and the P-ROM scale better reflects joint worsening. The more objective P-ROM scale is insensitive to PT-perceived joint improvement possibly because unlike the other two joint assessment tools, it does not incorporate tightness with or without activities of daily living. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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