Encoraging Results after Alternative Donor Transplantation for Myelodysplastic Syndrome.

Abstract Hematopoietic stem cell transplantation (HSCT) remains the treatment of choice for children with myelodysplastic syndromes (MDS). Umbilical cord blood (UCB) represents an alternative source of hematopoietic stem cells for transplantation in children without a HLA-matched sibling. We examined risk factors influencing outcomes after UCB transplantation (UCBT) in 70 children (40 males and 30 females; median age 7 years, range 0.8–18) with MDS reported to the European Working Group of MDS in Childhood, the Center for International Blood and Marrow Transplant Research or the Eurocord-European Blood and Marrow Transplant Group. Excluded were patients who had received prior autologous/allogeneic HSCT and those with Down syndrome, Fanconi anemia, or MDS that evolved to AML prior to HSCT. Patients had refractory cytopenia (RC, n=31), refractory anemia with excess blasts (RAEB, n=30), and RAEB in transformation (RAEB-t, n=9). All patients received a single UCB unit and myeloablative preparatory regimen. Karyotype analysis (available for 68 of 70 patients) was normal in 22 patients, while the remaining 46 had cytogenetic abnormalities, the most frequent being monosomy 7 (n= 23). In all pairs but one, donor-recipient histocompatibility was determined by serology (low-resolution typing) for HLA-A and -B and allele-level typing for DRB1. UCB units were HLA matched (A, B, DRB1) in 4 cases, 1-locus, 2-loci and 3-loci mismatched in 34, 26 and 5 cases, respectively. The day-60 probability of neutrophil recovery was 76%; in multivariate analysis, transplantation of HLA matched or 1-locus mismatched UCB, irradiation-containing preparatory regimen, cell dose ≥ 6x107/kg (pre-cryopreservation) and monosomy 7 were associated with faster neutrophil recovery. The 100-day probability of grade II-IV acute graft-versus-host disease (GVHD) was 30% (95% CI, 20–41). The 3-year cumulative incidence of chronic GVHD was 23% (95%CI 14–33). Five of 16 patients with chronic GVHD had limited and 11 extensive chronic GVHD. Twenty-nine patients died from transplantation-related complications, the 3-year cumulative incidence of transplantation-related mortality (TRM) was 41% (95% CI 29–52). Three deaths were related to GVHD. In multivariate analysis, TRM was lower when transplants were performed after 2001 (HR 0.41, 95%CI 0.20–0.84, p=0.015). Thirteen patients had recurrent disease and 11 were dead at last follow up. No variable predicted disease recurrence. With a medium follow-up of 39 months (range 10 – 105), the 3-year probability of disease-free survival (DFS) for the entire cohort was 39%; it was 50% when transplantation was performed after 2001 compared to 27% in the earlier period (p=0.02). After 2001, patients received UCB containing higher cell doses and the interval from diagnosis to transplantation was shorter. The 3-year DFS was 61% for the 23 patients with monosomy 7 compared to 30% for patients with other karyotypes (p=0.042). In multivariate analysis, year of transplantation (prior to 2001) and cytogenetic abnormalities other than monosomy 7 were independent risk factors predicting treatment failure, HR 2.38, (95% CI: 1.14–5.0, p=0.02) and HR 2.04,(95% CI: 1.11–3.70, p=0.02), respectively. The 3-year DFS was not influenced by MDS variant. Given the relatively small sample size the influence of MDS variant on transplant-outcome requires validation in a larger series. These data indicate that UCBT is an acceptable alternative in children with MDS without a HLA-matched related or unrelated adult bone marrow donor. The results of UCBT have improved in recent years and monosomy 7 does not confer an unfavourable outcome.

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Risk Factors and Outcome of Chronic GVHD: Analysis of 5,660 Patients Undergoing Unrelated Bone Marrow Transplantation through the Japan Marrow Donor Program.

Blood ◽

10.1182/blood.v106.11.139.139 ◽

2005 ◽

Vol 106 (11) ◽

pp. 139-139

Author(s):

Chiaki Nakaseko ◽

Miki Nishimura ◽

Shinnichi Ozawa ◽

Ryuko Cho ◽

Chikako Ohwada ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Cumulative Incidence ◽

Hematological Malignancies ◽

Chronic Gvhd ◽

Post Transplant ◽

Risk Of Death ◽

Significant Difference ◽

Late Morbidity

Abstract Background: Chronic GVHD (cGVHD) remains the major cause of late morbidity and mortality after allogeneic stem cell transplantation. However, there are limited data available on cGVHD after unrelated BMT (UR-BMT). We retrospectively analyzed the data of 5,660 patients who underwent UR-BMT through the Japan Marrow Donor Program (JMDP) between January 1993 and June 2004. Methods: Data were collected by the JMDP using a standard report form. Follow-up reports were submitted at 100 days, 1 year, and then annually after transplantation. Overall survival (OS) was estimated by the Kaplan-Meier method and patients surviving beyond day 100 after transplant were analyzed for the development of cGVHD. The log-rank test was used for univariate analysis and time-dependent Cox proportional hazards modeling was used for multivariate analysis. The cumulative incidence of cGVHD and of relapse was calculated using the Gray method considering death without cGVHD and death without relapse as respective competing risks. Results: The median age of all patients was 28 years and the median follow-up was 433.5 days after transplant. Estimated 5-year OS of all patients and those with hematological malignancies was 47.4% and 45.5%, respectively. A total of 3,974 patients survived beyond day 100 after transplant and their cumulative incidence of cGVHD was 43.2% at day 500 and 44.9% at day 2,000 post-transplant. The cumulative incidence of extensive cGVHD was 28.8% at day 2,000 post-transplant. In multivariate analysis, variables predicting cGVHD were recipient age (p=0.000), donor age (p=0.002), diagnosis of hematological malignancy (HR=1.99, p=0.000), HLA class I mismatch by either serology or DNA typing (HR=1.24, p=0.020), acute GVHD (I: HR=1.50, p=0.000; II: HR=2.07, p=0.000; III and IV: HR=2.25, p=0.000) and no platelet recovery over 50,000/mm3 before day 100 (HR=1.36, P=0.002). There was a significant difference between patients <20 and ≥20 years old (HR=1.27, p=0.000). However, there were no significant differences between any adults grouped by age decade (p=0.894). OS at 5 years in patients surviving >100 days post-transplant was 62.4% without cGVHD, 68.0% with limited cGVHD, and 55.4% with extensive cGVHD (p=0.000). In the patients with hematological malignancies, OS at 5 years was 58.8%, 67.3% and 55.8%, respectively (p=0.000). Cumulative incidence of relapse of hematological malignancies at day 2,000 in patients surviving >100 days post-transplant was 17.6% with limited cGVHD, 18.4% with extensive cGVHD and 27.1% without cGVHD (P=0.000). Conclusions: This study provides strong evidence of risk factors for developing cGVHD after UR-BMT and suggests that limited cGVHD provides a survival benefit to patients with hematological malignancies by reducing the risk of relapse without increasing the risk of death from cGVHD. There was a significant difference in occurrence of cGVHD between patients <20 and ≥20 years old but no differences comparing any age ≥20 years.

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Risk Factors for Late Infections after Allogeneic Hematopoietic Stem Cell Transplantation from a Matched Related Donor.

Blood ◽

10.1182/blood.v108.11.2848.2848 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2848-2848

Author(s):

Marie Robin ◽

Raphaël Porcher ◽

Renato De Castro Araujo ◽

Régis Peffault de Latour ◽

Agnès Devergie ◽

...

Keyword(s):

Risk Factors ◽

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Viral Infection ◽

Cumulative Incidence ◽

Chronic Gvhd ◽

First Year ◽

Hematopoietic Stem ◽

Cmv Status

Abstract After allogeneic hematopoietic stem cell transplantation (HSCT), late infections represent a major cause of morbidity and mortality but little has been previously reported. In a retrospective cohort study, late infections incidence was determined in 196 long-term survivors after matched related HSCT. Only patients transplanted for aplastic anemia, chronic myeloid leukemia (CML) and acute myeloblastic leukemia (AML) were included in this study. Median follow-up was 8 years. Among 30 patients who died beyond the first year, 9 patients died from graft-versus-host disease (GVHD) and 10 from infections. Bacterial late severe infections occurred in 30 patients, yielding an 8-year cumulative incidence of 15%. Late invasive fungal infection occurred in 8 patients corresponding to a cumulative incidence of 3.6%. Most viral infections were hepatitis C and VZV and overall late viral infection incidence was 35%. We identified 3 risk factors for bacterial infections in multiple analysis: CMV status (positive recipient and negative donor), irradiation based conditioning regimen and extensive chronic GVHD within the first year. Extensive chronic GVHD was the only risk factor of non-HCV viral infection in patients transplanted for AML or CML. Thus, late life threatening infections may occur in nearly a fourth of late survivors even after matched related transplantation and are associated not only with chronic GVHD but also with irradiation and to CMV status prior to transplantation.

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Risk Factors for Major Transplant Related Outcomes In Pediatric Patients with Chronic Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v116.21.211.211 ◽

2010 ◽

Vol 116 (21) ◽

pp. 211-211

Author(s):

David A. Jacobsohn ◽

Mukta Arora ◽

John P. Klein ◽

Joseph H. Antin ◽

Brian J. Bolwell ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Blood Cell ◽

Immune Suppression ◽

Peripheral Blood ◽

Cumulative Incidence ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Peripheral Blood Cell ◽

Myelogenous Leukemia

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.

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Comparison of Autologous and Allogeneic Transplantation As Therapy of First Relapse in Patients with Multiple Myeloma - Long-Term Follow up Analysis,

Blood ◽

10.1182/blood.v118.21.4124.4124 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4124-4124

Author(s):

Ute Hegenbart ◽

Stefan O Schonland ◽

Axel Benner ◽

Christina Wunder ◽

Thomas M. Moehler ◽

...

Keyword(s):

Multiple Myeloma ◽

Multivariate Analysis ◽

Chronic Gvhd ◽

High Dose ◽

Two Stage ◽

Hematopoietic Stem ◽

Number Of Patients ◽

First Relapse ◽

First Diagnosis

Abstract Abstract 4124 BACKGROUND: Most patients (pts) undergoing high-dose therapy with melphalan 200 mg/m2 (HDM) and autologous transplant for multiple myeloma (MM) develop disease recurrence. The optimal salvage treatment including autologous (auto-) and allogeneic (allo-) hematopoietic stem cell transplantation (SCT) as consolidation therapy for these patients is not yet defined. METHODS: We performed a retrospective analysis of 116 pts with MM treated in our institution between 1999 and 2005. Inclusion criteria were relapse after auto-SCT (n=88) or failure of induction treatment (n=28) and age ≤ 65 years. Re-induction was performed with TCED (thalidomide, cyclophosphamide, etoposide and dexamethasone (Möhler et al, Blood 2001). Seventy-one pts (median age, 59 yrs) received auto-SCT (auto-group) after HDM followed by maintenance therapy with thalidomide or interferon-alpha in 42 pts. Forty-five pts (allo-group, median age, 53 yrs) underwent a reduced-intensity allo-SCT (related in 24 pts), mostly using conditioning with 2 Gy total body irradiation and fludarabine. Thirty-eight pts received an auto-allo-tandem-SCT (Maloney, Blood 2003) and 7 pts have been directly transplanted after TCED. Statistical analysis was done using the two-stage test of Qiu & Sheng (JRSS Ser. B 2008) to compare two possibly crossing survival curves. Extended Cox proportional hazards regression models were applied to allow for time-varying differences between the two SCT groups. RESULTS: Estimated median follow-up after start of TCED was 95 months. All pts received a median number of 3 TCED cycles for re-induction therapy. 64 of 116 pts (55%) showed at least a PR after TCED chemotherapy (CR in 3 pts). TRM was 17% after 2 years in the allo-group and differed significantly from the auto-group (3%, p=0.02). More CR were achieved after allo-SCT compared to auto-SCT (17 vs. 4 pts., p<0.001). Median overall survival (OS) was 26 months for the auto group and 23 months for the allo group (Figure 1, p=0.16). Median progression-free survival (PFS) was 12 months for both groups but crossing hazards were observed (Figure 2, p=0.03, two-stage test of Qiu & Sheng). The results of multivariate regression analysis for OS and PFS including age at relapse-SCT, response to TCED, time between first diagnosis until first relapse-SCT and primary progression are shown in table 1. In the allo group, there was no OS or PFS difference between related and unrelated donors (multivariate analysis). Cumulative incidence of chronic GvHD was 73% (53% extensive). Patients with chronic GvHD showed a better OS and PFS than pts without (univariate analysis, both p<0.01). CONCLUSIONS: To our knowledge, this is the first analysis in a large number of patients with a long follow-up comparing allo with auto SCT in 1st myeloma relapse which were treated uniformly with TCED therapy for re-induction. Main problem was MM recurrence. However, younger pts with disease response after TCED and longer time from first diagnosis to first SCT after relapse profit best from TCED and this transplant approach. Most interestingly, disease control is better after allo compared to auto SCT in univariate and multivariate analysis leading to a PFS of about 20% after 4 years. In our opinion, allo SCT is a valuable clinical option for patients with 1st relapse after HDM and auto SCT. Disclosures: No relevant conflicts of interest to declare.

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Second Malignancies After Autologous Hematopoietic Cell Transplantation (AHCT) for Multiple Myeloma (MM): A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis

Blood ◽

10.1182/blood.v120.21.591.591 ◽

2012 ◽

Vol 120 (21) ◽

pp. 591-591

Author(s):

Girindra Raval ◽

Anuj Mahindra ◽

Xiaobo Zhong ◽

Ruta Brazauskas ◽

Robert Peter Gale ◽

...

Keyword(s):

Risk Factors ◽

At Risk ◽

Multivariate Analysis ◽

General Population ◽

Cumulative Incidence ◽

Incidence Rates ◽

High Dose ◽

Risk Of Death ◽

Age And Sex

Abstract Abstract 591 Background: Survival of patients with MM has improved over the past two decades, in part due to the use of AHCT. Increasingly, second primary malignancies (SPMs) are observed in MM survivors. Determining the baseline incidence and risk factors associated with SPMs after AHCT is important to assess risk and to evaluate the risk-benefit ratio of newer therapies. Methods: We analyzed the incidence of SPMs in 3784 MM patients receiving (“upfront”) AHCT for MM within 18 months of diagnosis between 1990 and 2010 and reported to the CIBMTR. Cumulative incidence rates of SPMs were estimated taking into account the competing risk of death. For each transplant recipient, the number of person-years at risk was calculated from the date of transplantation until date of last contact, death, or diagnosis of SPM, whichever occurred first. Incidence rates for all invasive cancers in the general population were obtained from the SEER database. Age-, sex-, and race- specific incidence rates for overall SPMs and particular anatomical sites were applied to the appropriate person-years at risk to compute the expected numbers of cancers. Observed–to –expected (O/E) ratios were calculated, and Poisson distribution 99% confidence intervals (CIs) were generated. Poisson regression model was used to analyze risk factors for overall SPMs and AML/MDS. Results: Pre-transplant therapy included novel agents in 56% including thalidomide (35%), lenalidomide (9%), bortezomib (16%) or their combinations (11%). Majority (80%) received high dose melphalan conditioning. Post-transplant maintenance therapy included thalidomide (16%), lenalidomide (8%), bortezomib (9%) and interferon (6%). Median follow-up of survivors was 52 months (range 3 to 192 months).With 12707 person years of follow up, 153 new malignancies were reported with a crude rate of 1.2 SPM per 100 person years of follow up. Observed/Expected [O/E] ratio for all SPMs was 0.99 (99% CI, 0.80–1.22). Cumulative incidence of SPM overall was 2.48% (95% CI, 1.96–3.05) at 3 years and 6.0% (95% CI, 4.96–7.10) at 7 years [Figure 1]. Individual SPMs observed significantly more frequently than expected are summarized in Table 1. The cumulative incidence of MDS/AML was 0.5% (95% CI, 0.28–0.78) at 3 years and 1.3 (95% CI, 0.85– 1.9%) at 7 years. Majority had MM progression prior to diagnosis of SPM (65 of 102 patients overall and 15 of 23 patients for MDS/AML). In multivariate analysis, significant risk factors for development of SPMs included: obesity [Hazard ratio = HR 1.89(95%CI, 1.21–2.93), p=0.0047 for BMI>30 vs. BMI<25], older age: [HR10.53 (95%CI, 1.46–75.82), p=0.0195] for 60–69 year olds and HR14.4 (95%CI, 1.89–109.75), p=0.01 for 70+ year olds compared to the 18–39 year old group. Specific conditioning regimens did not correlate with the risk of SPM. The low number of MDS/AML (33 events out of 3784 cases) limited the power of multivariate analysis. Increasing age was significantly associated with development of MDS (HR10.77, (95%CI,92.09–55.51), p=0.004 for 70+ year old vs. 40–49 year olds). Conclusion: In this large cohort of AHCT recipients for MM, the incidence of MDS/AML, melanoma and other skin cancers was significantly higher compared to age and sex matched general population. However the overall risk of SPM was similar to that expected for age and sex matched population. It was also similar to the placebo arms of recent reports by McCarthy Pl et al and Attal M et al (N Engl J Med. 10; 366(19):1770–91). Lenalidomide (8%) or thalidomide maintenance (16%) used in a small subset of patients with comparatively short follow up, was not associated with risk of SPM in the analysis of the overall cohort. Disclosures: Gale: Celgene: Employment. Brandenburg:Celgene: Employment, Equity Ownership. Lonial:Millennium, Celgene, Novartis, BMS, Onyx, Merck all Consultancy. Krishnan:Celgene and Millennium: Consultancy, Speakers Bureau. Dispenzieri:Celgene and Millennium: Research Funding. Hari:Celgene: Consultancy, Honoraria.

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Impact of Serum Ferritin Levels on the Incidence of Chronic Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v116.21.1248.1248 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1248-1248

Author(s):

Soichiro Sakamoto ◽

Hiroshi Kawabata ◽

Junya Kanda ◽

Tatsuki Uchiyama ◽

Chisaki Mizumoto ◽

...

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Serum Ferritin ◽

Relapse Rate ◽

Cumulative Incidence ◽

Acute Gvhd ◽

Proportional Hazards ◽

Ferritin Level ◽

Chronic Gvhd ◽

Hematopoietic Stem

Abstract Abstract 1248 Background: Iron overload is an important adverse prognostic factor in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). Many studies have shown that elevated pre-transplant serum ferritin levels are associated with an increased risk of morbidity and mortality after allo-SCT. Conversely, a couple of other studies have suggested that elevated pre-transplant ferritin levels are associated with a low incidence of the chronic graft-versus-host disease (GVHD). To verify these apparently paradoxical findings, we analyzed the association between pre-transplant serum ferritin levels and clinical outcomes of allo-SCT. Patients and methods: We retrospectively studied 161 consecutive patients (age, 16–65 years; median age, 46 years) who underwent their first allo-SCT for hematologic diseases at the Kyoto University Hospital between September 2004 and April 2010. The primary diseases were myeloid (n = 87) and lymphoid malignancies (n = 68), and non-malignant diseases (n = 6). Patients with acute leukemia in complete remission, untreated MDS, CML in the chronic phase, or non-malignant diseases were considered to have standard-risk diseases (n = 96), whereas those with any other hematologic disease status were considered to have high-risk diseases (n = 65). Stem cells were obtained from the bone marrow (BM) or peripheral blood (PB) of HLA-matched related donors (n = 56) and partially matched related donors (n = 18), BM of unrelated donors (n = 65), and cord blood of unrelated donors (n = 22). Conventional myeloablative regimens were used in 99 patients while reduced-intensity regimens were used in 62. The primary endpoint was the cumulative incidence of chronic GVHD, which is defined according to the Seattle criteria, while the secondary endpoints were overall survival, acute GVHD, treatment-related mortality (TRM), and relapse rate. For statistic analyses, cumulative incidence curves were used in a competing-risks setting to determine the incidence of GVHD, TRM, and relapse rate, whereas the Kaplan–Meier method was used to determine survival rate. The Fine and Gray proportional-hazards model for the sub-distribution of a competing risk and the Cox proportional-hazards regression model were used as appropriate. Factors evaluated in the analysis included the recipient's age, sex, diagnosis, disease status at the time of transplant, source of stem cells, conditioning regimen, GVHD prophylaxis, serum ferritin levels (<900 vs. ≥900 ng/mL), and serum CRP levels (<0.2 vs. ≥0.2 mg/dL). Only ferritin levels, CRP levels (which is associated with ferritin levels), and those factors with P-values of <0.10 in the univariate analysis were included in the multivariate analysis. Result: There was no significant difference in patient characteristics between the low-ferritin group (n = 105) and the high-ferritin group (n = 56). The median follow-up period among survivors was 38 months (range, 2–113 months). The cumulative incidence of chronic GVHD was lower in the high-ferritin group (32%) than in the low-ferritin group (49%) (P = 0.080) (Figure 1). In the multivariate analysis, serum ferritin level was significantly associated with the incidence of chronic GVHD (hazard ratio, 0.59; P = 0.045). Even when the serum ferritin level was treated as a continuous variable, this association remained significant. A trend toward a higher incidence of grade 3–4 acute GVHD was observed in the high-ferritin group; however, this association was not statistically significant. TRM was significantly higher in the high-ferritin group, but the relapse rate was not different between the 2 groups. High serum ferritin levels, the male sex, and high-risk diseases were significantly associated with a lower overall survival in the multivariate analysis. Conclusion: In our cohort, elevated pre-transplant ferritin levels were significantly associated with a lower incidence of chronic GVHD. Conversely, patients in the high-ferritin group tended to have a high incidence of severe acute GVHD. These patients had lower overall survival probably due to a higher incidence of TRM. Further clinical and biological studies on the immunomodulatory effects of iron or iron-related molecules, such as ferritin, may provide clues on the prophylaxis and management of acute and chronic GVHD. For this purpose, studies on post-transplant iron status in association with acute and chronic GVHD should also be conducted. Disclosures: No relevant conflicts of interest to declare.

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Hyperlipidemia After Allogeneic Stem Cell Transplantation: Prevalence, Risk Factors and Impact on Prognosis.

Blood ◽

10.1182/blood.v116.21.3458.3458 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3458-3458

Author(s):

Yuki Kagoya ◽

Sachiko Seo ◽

Yasuhito Nannya ◽

Mineo Kurokawa

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Relapse Rate ◽

Allogeneic Stem Cell Transplantation ◽

Cumulative Incidence ◽

Chronic Gvhd ◽

Calcineurin Inhibitors

Abstract Abstract 3458 Introduction: Hyperlipidemia is one of the late complications after allogeneic stem cell transplantation (SCT). Although intrahepatic cholestasis caused by chronic graft-versus host disease (GVHD) or calcineurin inhibitors has been considered to be one of the etiologies, its prevalence, risk factors, and the impact on prognosis have not been investigated well. Methods: We performed a retrospective analysis of 194 adult patients who underwent allogeneic SCT between 1995 and 2008 in our institute, and survived more than 100 days after SCT. Hypercholesterolemia or hypertriglyceridemia was defined as more than 240 mg/dl or 200 mg/dl, respectively, at two successive tests at least one week apart after the first 100 days after SCT. Cumulative incidence of hypercholesterolemia or hypertriglyceridemia was analyzed. The time to the development of hypercholesterolemia or hypertriglyceridemia was calculated and the multivariate analysis of pre- and posttransplant variables was performed by a Cox proportional hazards model. Chonic GVHD, chronic liver dysfunction (CLD; defined as more than twice the upper limit of normal for aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase, or total bilirubin >3 mg/dl over 3 months) and administration of calcineurin inhibitors were studied as posttransplant factors, which were assessed as time-dependent variables. To analyze the prognosis of patients who developed persistent hyperlipidemia, the multivariate analysis of overall survival (OS), relapse rate, and non-relapse mortality (NRM) was carried out by a landmark approach. Persistent hyperlipidemia was defined as hypercholesterolemia or hypertriglyceridemia continuing more than 3 months. Results: Overall, 83 (42.8%) and 98 (50.5%) patients developed hypercholesterolemia and hypertriglyceridemia, respectively. The median follow-up period of serum cholesterol and triglyceride values in surviving patients was 44 months. The cumulative incidence of each abnormality at 3 years after SCT was 38.1% (95% confidence interval [CI]: 31.0–45.1%), and 46.0% (95% CI: 38.8–52.9%), respectively. In a multivariate analysis, the development of chronic GVHD was independently associated with both hypercholesterolemia (hazard ratio [HR] 2.05, 95% CI: 1.23–3.43, P<0.01) and hypertriglyceridemia (HR 2.04, 95% CI: 1.30–3.18, P<0.01). Besides, CLD was significantly associated with hypercholesterolemia (HR 2.20, 95% CI: 1.39–2.50, P<0.01). Administration of calcineurin inhibitors was not an independent risk factor for the development of hypercholesterolemia (HR 1.23, 95% CI: 0.73–2.08, P=0.43) or hypertriglyceridemia (HR 1.03, 95% CI: 0.61–1.54, P=0.89). Among pretransplant factors, prior hypercholesterolemia and hypertriglyceridemia were associated with posttransplant hypercholesterolemia (HR 2.76, 95% CI: 1.07–7.17, P=0.04) and hypertriglyceridemia (HR 2.04, 95% CI: 1.27–3.27, P<0.01), respectively. Persistent hyperlipidemia was found in 49 patients (25.3%), of which 35 patients (71.4%) developed hyperlipidemia within one year. The median interval to the occurrence of hyperlipidemia of the patients was 180 days after SCT. In univariate analysis, patients with persistent hyperlipidemia had a tendency of better 3-year OS (77.3% vs 64.7%, P=0.23). Multivariate analysis showed that the development of persistent hyperlipidemia was independently associated with better OS (HR: 0.49, P=0.049). Further, although not statistically significant, patients with persistent hyperlipidemia had a tendency of lower 3-year cumulative relapse rate (15.7% vs 20.3%). There were no significant differences in 3-year NRM between patients with or without hyperlipidemia (12.3% vs 13.9%). Conclusions: Both hypercholesterolemia and hypertriglyceridemia are very common complications after SCT. Patients with persistent hyperlipidemia, however, have significantly better OS. Considering a strong association between the development of hyperlipidemia and chronic GVHD, and a tendency of lower relapse rate in patients with persistent hyperlipidemia, hyperlipidemia is regarded as one of the symptoms accompanied with chronic GVHD. Unless severe, its incidence indicates a better control of the primary disease and an improved prognosis. Disclosures: No relevant conflicts of interest to declare.

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Clostridium Difficile Infections After Allogenic Hematopoietic Stem Cell Transplantation: Comparison of Cord Blood to Other Grafts

Blood ◽

10.1182/blood.v118.21.4573.4573 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4573-4573

Author(s):

Kohei Hosokawa ◽

Masanori Tsuji ◽

Hideki Araoka ◽

Kazuya Ishiwata ◽

Shinsuke Takagi ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Stem Cell ◽

Clostridium Difficile ◽

Stem Cell Transplantation ◽

Cord Blood ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Cumulative Incidence ◽

Hematopoietic Stem

Abstract Abstract 4573 Background: Clostridium difficile, a gram-positive sprore-forming anaerobic bacillus, associated diarrhea (CDAD) is a major cause of nosocomial antibiotic-associated diarrhea. Hematopoietic stem cell transplant (HSCT) recipients are at increased risk of developing CDAD during the early posttransplant period due to prolonged exposure to broad-spectrum antibiotics and immunosuppressive agents. The incidence of CDAD has been increasing up to as high as 20% in allogeneic bone marrow (BMT) and peripheral blood stem cell transplantation (PBSCT). Although cord blood transplant (CBT) recipients are subjected to delayed immune constitution and high incidence of infectious complications to be risk factors for CDAD, the frequency of CDAD after CBT is unclear. We therefore retrospectively investigated the incidence and clinical features of CDAD in patients receiving CBT. Objectives/Methods: During the 2-yr retrospective period (2007–2008), 201 allogeneic HSCT were performed at the Department of Hematology of Toranomon Hospital: 135 CBT, 39 BMT and 27 PBSCT. The median age of the patients was 56 yr (range, 19–82 yr). All patients with diarrhea had a minimum of one diarrheal stool sample evaluated for the presence of toxin A. A patient found to have toxigenic Clostridium difficile by ELISA was diagnosed as CDAD. The cumulative incidence of CDAD was calculated using the Gray method considering death without CDAD as a competing risk. Overall survival (OS) was estimated by the Kaplan-Meier method. The time-dependent Fine and Gray proportional hazards model was used for multivariate analysis. Results: CDAD developed within 100 days in 11 out of 135 CBT recipients at a median onset of day 18 (range, 3–56 days). The cumulative incidence of CDAD after CBT was 9% at day 100 (Fig 1), which was similar to that after BMT (6%, P= 0.55) and to that after PBSCT (16%, P=0.27). All 17 patients who developed CDAD were successfully treated with using oral metronidazole or oral vancomysin. Of the 17 patients with CDAD, 7 (41%) died within 100 days after transplant, and the direct cause of death was irrelevant to CDAD in the 7 patients. The 1-yr survival after diagnosis of CDAD was 58%, which was comparable to that in patients without developing CDAD (59%, P=0.98). The univariate analysis failed to identify any significant risk factors for CDAD as well as the multivariate analysis. Conclusions: The current study showed that CDAD developed early after CBT at the incidence similar to BMT or PBSCT, and that prompt treatment for CDAD may work in improving its prognosis. It is therefore essential to recognize CDAD as one of the differential diagnosis of diarrhea because it is treatable complication after HSCT. Disclosures: No relevant conflicts of interest to declare.

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Long-Term Follow-up of a Randomized Trial of Two Dose Levels of Antithymocyte Globulin in Haploidentical Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2020-139063 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 20-20

Author(s):

Yu Wang ◽

Ren Lin ◽

Lan-Ping Xu ◽

Kai-Yan Liu ◽

Xiao-Hui Zhang ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Randomized Trial ◽

Late Effects ◽

Cumulative Incidence ◽

Antithymocyte Globulin ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Free Survival

Background The optimal dose of antithymocyte globulin (ATG) with respect to the prevention of graft-versus-host disease (GVHD) following haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is under investigation. In our previous single-center randomized study, as compared with 6 mg/kg ATG, 10 mg/kg ATG was found to be associated with better GVHD prevention and superior GRFS, but an increase in infection-related deaths. Later on, in our multi-center randomized trial, 7.5 mg/kg ATG for GVHD prophylaxis was associated with reduced EBV and CMV infections without increased incidence of GVHD in comparison with 10.0 mg/kg ATG in haplo-HSCT. Methods We reanalyzed and updated the prospective, randomized trial (clinicaltrials.gov, NCT01883180) identifying the influence of 7.5mg/kg versus 10.0 mg/kg of ATG on clinical outcomes in haplo-HSCT with extended follow-up (N=145. Seventy-six patients received 7.5 mg/kg ATG (ATG-7.5), whereas the remaining patients received 10 mg/kg ATG (ATG-10). Results The median follow-up period was 1702 days (range, 23-2036 days). The rate of infection-related deaths in ATG-10 arm was double that of the ATG-7.5 arm (20.0% vs 11.8%; P=0.024). The 5 year cumulative incidence of relapse was not significantly different between the ATG-7.5 and ATG-10 groups (16.8% vs. 5.7%, P = 0.053). The 5 year cumulative incidence of non-relapse mortality was comparable between the ATG-7.5 and ATG-10 groups (27.6% vs. 28.7%, P = 0.938). The 5 year cumulative incidence of chronic GVHD (46.7% vs. 48.3%, P = 0.913), moderate-to-severe chronic GVHD (32.8% vs. 25.3%, P = 0.248), and severe chronic GVHD (17.1% vs. 13.3%, P = 0.505) were comparable between the ATG-7.5 and ATG-10 groups. The 5 year probabilities of disease-free survival (DFS) in the ATG-7.5 and ATG-10 groups were 55.6% and 65.7%, respectively (P = 0.281). The 5 year probability of GVHD-free/relapse-free survival (GRFS) in the ATG-10 group was significantly higher than that in the ATG-7.5 group (48.1% vs. 29.5%, P = 0.020). The 5 year cumulative incidence of late effects of grades 1-5 (67.2% vs. 71.2%, P = 0.695) and multiple late effects (26.2% vs. 25.4%, P = 0.920) were comparable between the ATG-7.5 and ATG-10 groups. In multivariate analysis, ATG-7.5 was associated with a significantly lower GRFS compared to ATG-10 (hazard ratio, 1.819; 95% confidence interval, 1.106-2.994; p=0.019). Conclusion it appears that 10 mg/kg ATG was found to be associated with superior GRFS and comparable GVHD and late effects, but an increase in infection-related deaths as compared with 7.5 mg/kg ATG for haplo-HSCT. Figure Disclosures No relevant conflicts of interest to declare.

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Lost to Follow-up Rates Are Higher in Pediatric Than Adult Survivors, but Not By Transplant Type: A Report from the Center for International Blood and Marrow Transplant Research

Blood ◽

10.1182/blood-2018-99-116531 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2260-2260 ◽

Cited By ~ 1

Author(s):

David K. Buchbinder ◽

Ruta Brazauskas ◽

Khalid Bo-Subait ◽

Karen K. Ballen ◽

Theresa E. Hahn ◽

...

Keyword(s):

Risk Factors ◽

Health Insurance ◽

Cumulative Incidence ◽

Insurance Coverage ◽

Marrow Transplant ◽

Allogeneic Hct ◽

Autologous Hct ◽

Pediatric Recipients

Abstract Introduction Follow-up is an integral part of hematopoietic cell transplant (HCT) care which ensures accurate characterization of HCT-related outcomes as well as surveillance and intervention for complications. Despite the importance of follow-up of all HCT recipients at transplant centers, they may be lost to follow-up (LTFU). HCT recipients who are LTFU may be demographically or clinically distinct from HCT recipients who maintain regular center follow-up. Using population-based data from 17,550 adult and 4,279 pediatric HCT recipients from United States centers reported to the Center for International Blood and Marrow Transplant Research (CIBMTR), we characterize the incidence of, and predictors for, becoming LTFU. Methods The study included 2-year (yr) survivors of first allogeneic (10,367 adults and 3,865 children) or autologous (7,183 adults and 414 children) HCT for malignant and non-malignant disorders in the United States from 2002-2013 reported to the CIBMTR. LTFU was defined as a patient having missed 2 consecutive follow-up reporting periods. CIBMTR follow-up forms are collected annually for the first 6 yrs post-HCT and bi-annually thereafter. The cumulative incidence of LTFU HCT recipients was calculated. Marginal Cox models allowing adjustment for center effect were fit to evaluate risk factors for becoming LTFU among adults and pediatric allogeneic and autologous HCT survivors. Risk factors evaluated included: sociodemographic (age at HCT, sex, performance status, race, distance to center, income, health insurance, marital status) and disease/HCT-related (disease type, yr of HCT) factors. Results Among 2-yr allogeneic HCT survivors, the median age at the time of HCT was 49 yrs (range, 18-81) and 7 yrs (range, <1-18) for adult and pediatric recipients, respectively. Corresponding median follow-up was 75 months (mos) (range, 12-173) and 74 mos (range, 3-173). Health insurance coverage was public (23%) or private (64%) for adult recipients, and public (40%) or private (43%) for pediatric recipients. For 2-yr autologous HCT survivors, the median age at the time of HCT was 58 yrs (range, 18-82) and 4 yrs (range, <1-18) for the adult and pediatric recipients, respectively. Corresponding median follow-up was 76 mos (range, 3-174) and 73 mos (range, 6-173). Health insurance coverage was public (27%) or private (57%) for adult recipients, and public (48%) or private (39%) for pediatric recipients. The 10-year cumulative incidence of becoming LTFU among adult and pediatric allogeneic HCT recipients was 13% (95% CI, 12-14) and 25% (95% CI, 24-27), respectively. Among autologous HCT recipients, the 10-year cumulative incidence of becoming LTFU among adults and children was 15% (95% CI, 14-16) and 23% (95% CI, 19-28), respectively. (Figure 1) Among pediatric allogeneic HCT survivors, older age, non-white race, public or no insurance (referent: private), and earlier yr of HCT were significantly associated with increased LTFU risk. However, in adult allogeneic HCT survivors, younger age, non-malignant disease, public or no insurance (referent: private), living farther from the HCT center, and unmarried were significantly associated with higher risk of LTFU (Table 1). In pediatric autologous HCT survivors, males and Non-Hodgkin lymphoma (NHL)/Hodgkin lymphoma patients (referent: central nervous system tumors) were significantly associated with higher risk of becoming LTFU (Table 1), whereas for adult autologous HCT survivors, older age and multiple myeloma (referent: NHL) were significantly associated with decreased risk of LTFU. Conclusions The incidence of LTFU is significantly higher in pediatric than adult patients, with no difference between autologous and allogeneic HCT patients, regardless of age. We identified risk factors for LTFU that differed by age and HCT donor type. A national, comprehensive, risk-based approach to long-term follow-up focusing on minimizing the attrition in high-risk groups such as adolescent and young adult-aged HCT survivors and HCT survivors with non-private health insurance is needed. Future studies incorporating patient reported outcomes may help describe reasons for lack of long-term follow-up. Collection of accurate and meaningful epidemiologic and clinical data from all survivors can help develop and refine strategies to improve long-term outcomes of this population. Disclosures Parsons: Seattle Genetics: Research Funding.

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