Incidence, Risk Factors and Outcome of Late Onset Noninfectious Pulmonary Complications after Allogeneic Hematopoietic Stem Cell Transplantation: A Prospective Cohort Study

Abstract Introduction: Late onset noninfectious pulmonary complications (LONIPCs) occurring beyond the third month following allogeneic hematopoietic stem cell transplantation (HSCT) are various and are associated with a poor outcome. Bronchiolitis obliterans (BO) is the most frequent LONIPC. Available epidemiological data are conflicting and exclusively come from retrospective studies. Methods: We conducted a prospective observational cohort study where all consecutive patients who were scheduled to receive an allogeneic HSCT between January, 31, 2006 and December, 31, 2008 at the university-teaching Saint Louis Hospital (Paris, France) were prospectively screened for inclusion in the study. Those allogeneic HSCT recipients surviving at day 100 were included in the cohort. They were followed-up for at least three years after HSCT. Clinical outcomes were the 3-year incidence and mortality of LONIPC, and the identification of early risk factors for LONIPC and specifically BO. This study is registered with ClinicalTrials.gov, number NCT 01219972. Results: 198 patients were included after a median of 101 [IQR: 99-106] days following HSCT, from a total of 243 screened patients. The actual median follow up of the 198 included patients was 72.3 months [IQR: 15.2-88.5]. 68 patients died within the first 36 months resulting in a 3-year overall survival after inclusion of 65.4% (95%CI: 59.1-72.4%). Fifty five episodes of LONIPC were diagnosed in 43 patients. These 55 LONIPC were diagnosed as BO (n=22), interstitial lung disease (n=12), and others. Ten patients had more than one LONIPC during the follow-up. At 36 months after inclusion, the estimated cumulative incidence of LONIPC was 19.8% (95%CI: 14.2-25.3%). The 36 months cumulative incidence of BOS was 10.7%, (95%CI: 6.3-15.1%). 18 patients with a LONIPC died during the follow up with an estimated median survival of 78.5 months (95%CI: 20.0-not reached) after the diagnosis of LONIPC. The occurrence of LONIPC was associated with an increased hazard of death (HR=2.18, 95%CI= 1.14; 4.15; p= 0.0181). Based on a multivariable Cox model, a chest irradiation prior to HSCT, a history of pneumonia within the 100 days post HSCT and a low FEF 25-75 at day 100 were associated with the development of LONIPC. The use of PBSC was predictive for BOS based on a multivariable Cox model both after multiple imputation and on the complete cases whereas both a history of post transplantation pneumonia and bronchial abnormalities on CT scan at day 100 were also identified as predictive factors after multiple imputation and a 10% FEV1 decline from baseline to day 100 was a predictive factor for BOS on the complete cases. Conclusion: our data give clues to identify high-risk patients for developing LONIPC/BO. These patients should be targeted for close monitoring, and so offer earlier treatment of LONIPC or prophylactic treatment to improve the outcome. Funding: The study was supported by an institutional grant from the French Ministry of Health (CRC 04118). Disclosures Peffault De La Tour: PFIZER: Consultancy, Honoraria, Research Funding; ALEXION: Consultancy, Honoraria, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding.

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Efficacy and Safety of a FLAG-Sequential Regimen Followed By Hematopoietic Stem Cell Transplantation for Myelodysplasia or Acute Leukemia in Fanconi Anemia: A Franco-Brazilian Report

Blood ◽

10.1182/blood-2019-122007 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2498-2498

Author(s):

Pierre-Edouard Debureaux ◽

Flore Sicre de Fontbrune ◽

Carmem M. S. Bonfim ◽

Jean-Hugues Dalle ◽

Nimrod Buchbinder ◽

...

Keyword(s):

Cumulative Incidence ◽

Research Funding ◽

Bone Marrow Failure ◽

Clonal Evolution ◽

Infectious Complications ◽

Hematopoietic Stem ◽

Free Survival ◽

History Of ◽

Syncytial Virus

Background: Fanconi anemia (FA) is the most frequent genetic cause of bone marrow failure (BMF) due to a DNA repair mechanism defect. The natural history of FA is marked by progressive BMF during early childhood. Throughout life, the hematopoietic situation may change by clonal evolution toward myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for bone marrow failure in FA patients. The role of HSCT for FA patients with AML or advanced MDS is less defined. Currently, HSCT first line result offers 50% Overall Survival (OS) for patients with cytogenetic abnormalities only and 30% OS for patients with advanced MDS or AML in FA (Ayas et al., JCO 2013; Mitchell et al., BJH 2014). We previously reported a FLAG-sequential approach in 6 patients with FA (5 AML and 1 advanced MDS), all alive at a median follow-up of 28 months (Talbot et al., Hematologica 2014). We update here those patients and report 12 more patients treated by FLAG-sequential since then. Materials & Methods: This retrospective study (2006-2019) was conducted in 7 centers in France and Brazil on behalf of the French Reference Center for Aplastic Anemia to evaluate FLAG-sequential in FA patients with morphological clonal evolution (no patients with cytogenetic abnormalities only). The study was conducted in accordance with the Declaration of Helsinki. Anonymous data collection was declared to the appropriate authorities. The FLAG-sequential treatment consisted of FLAG, Fludarabine 30 mg/m²/d for five days and Cytarabine 1 g/m²x2/d with G-CSF for five days, which was followed three weeks later by Cyclophosphamide 10 mg/kg/d for four days, Fludarabine 30 mg/m²/d for four days and TBI 2 Gy (Fig 1A). In a haploidentical setting, Cyclophosphamide at 30 mg/kg/d was performed only in post-transplantation, at Days +4 and +5 (Fig 1B). Results: Eighteen patients were included with 14 AML, 1 acute lymphoblastic leukemia (ALL), and 3 RAEB-2 (Table 1). The median age at the time of HSCT was 22 years (4-37 years). Fifteen patients (83%) were older than 10 years at the time of HSCT. The median follow-up was 31 months (3- 153 months). Eight patients (44%) had complex karyotype. None of the included patients had a history of solid malignancies before HSCT. All patients engrafted. The cumulative incidence of neutrophil engraftment at Day 60 was 94% (95% CI 63-100%) with a median of 18 days (12-343 days). The cumulative incidence of platelet engraftment at Day 60 was 83% (95% CI 50%-96%) with a median of 25 days (17-245 days). The donor chimerism was complete at Day +100 for 15 patients. The three patients without full donor chimerism at Day +100 either had a relapse (n=1) and 2 early deaths before Day+100 from steroid-refractory aGVHD (n=1) or septic shock (n=1). None of the patients received a second HSCT. Non-relapse mortality (NRM) at 3 years was 32% (95% CI 6-58%) (Fig 2). Cumulative incidence of grades II to IV aGVHD was 56% (35% grades III to IV). Cumulative incidence of extensive cGVHD was 16%. Infectious complications during HSCT include the following: CMV (n=8), EBV (n=2), adenovirus (n=4), BK virus (n=7), respiratory syncytial virus (n=1), candidaemias (n=2) and invasive aspergillosis (n=3). Progression free survival (PFS) and OS at 3 years were 53% (95%CI 32-89%) and 53% (95%CI 32-89%), respectively (Fig 2). Cumulative incidence of relapse at 3 years was 13% (95%CI 0-31%) (Fig 2). Seven patients died during the study. Causes of death were relapse (n=2), aGVHD (n=2), cGVHD (n=1), septic shock (n=1), and respiratory syncytial virus associated with invasive aspergillosis (n=1). GVHD-relapse free survival (GRFS) at 3 years was 48% (95%CI 29-78%). One patient had anal epidermoid carcinoma at 4 years after HSCT, which required multiple surgical ablations. Conclusion: With almost 3 years follow-up, which is long enough for our results to be considered robust, we report an OS and PFS of 53%, which compares favorably to historical controls since all of our 18 patients were treated with florid disease at time of HSCT (and not with cytogenetic abnormality only, known to be associated with a better prognosis). Toxicity is still a concern in this particular population of FA patients with notably a high rate of infectious complications. Future well designed prospective clinical trials will refine this sequential strategy, which appears promising in this particular difficult clinical situation. Disclosures Socie: Alexion: Consultancy. Peffault de Latour:Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

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Different Contributions of Dyslipidemia and Obesity to the Natural History of Type 2 Diabetes: 3-Year Cohort Study in China

Journal of Diabetes Research ◽

10.1155/2019/4328975 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Lu Liu ◽

Xiaoling Guan ◽

Zhongshang Yuan ◽

Meng Zhao ◽

Qiu Li ◽

...

Keyword(s):

Risk Factors ◽

Type 2 Diabetes ◽

Cohort Study ◽

Natural History ◽

Glucose Tolerance ◽

Serum Triglyceride ◽

Glycemic Status ◽

History Of

Aim. It is known that different stages of type 2 diabetes represent distinct pathophysiological changes, but how the spectrum of risk factors varies at different stages is not yet clarified. Hence, the aim of this study was to compare the effect of different metabolic variables on the natural history of type 2 diabetes. Methods. A total of 5,213 nondiabetic (normal glucose tolerance (NGT) and prediabetes) Chinese older than 40 years participated this prospective cohort study, and 4,577 completed the 3-year follow-up. Glycemic status was determined by standard oral glucose tolerance test both at enrollment and follow-up visit. Predictors for conversion in glycemic status were studied in a corresponding subcohort using the multiple logistic regression analysis. Results. The incidence of prediabetes and diabetes of the cohort was 93.6 and 42.2 per 1,000 person-years, respectively. After a 3-year follow-up, 33.1% of prediabetes patients regressed to NGT. The predictive weight of body mass index (BMI), serum triglyceride, total cholesterol, and systolic blood pressure in different paths of conversions among diabetes, prediabetes, and NGT differed. Specifically, BMI was the strongest predictor for regression from prediabetes to NGT, while triglyceride was most prominent for onset of diabetes. One SD increase in serum triglyceride was associated with a 1.29- (95% CI 1.10–1.52; P=0.002) or 1.12- (95% CI 1.01–1.27; P=0.039) fold higher risk of diabetes for individuals with NGT or prediabetes, respectively. Conclusion. Risk factors for different stages of diabetes differed, suggesting personalized preventive strategies for individuals with different basal glycemic statuses.

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Prophylactic Use of a Combination of an Anticoagulant and Ursodeoxycholic Acid for Sinusoidal Obstruction Syndrome after Allogeneic Myeloablative Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v128.22.5755.5755 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5755-5755

Author(s):

Hiroshi Okamura ◽

Mitsutaka Nishimoto ◽

Takahiko Nakane ◽

Hideo Koh ◽

Yasuhiro Nakashima ◽

...

Keyword(s):

Risk Factors ◽

Research Funding ◽

Gemtuzumab Ozogamicin ◽

Adult Patients ◽

Allogeneic Hsct ◽

History Of ◽

Group 3 ◽

Group 2 ◽

Prophylactic Use ◽

Group 1

Abstract Introduction: Sinusoidal obstruction syndrome (SOS) is one of the potentially fatal complications of hematopoietic stem cell transplantation (HSCT). In particular, severe SOS frequently leads to multiple organ failure, and a worse prognosis. Thus, prophylaxis against development of SOS could contribute improved survival after HSCT. Previous reports demonstrated the effectiveness of the prophylactic use of ursodeoxycholic acid (UDCA) or certain anticoagulants, including unfractionated and low-molecular-weight heparin, for SOS. In two randomized controlled trials and two meta-analyses it was reported that UDCA, a hydrophilic bile acid, was an effective and safe drug for prophylaxis against SOS. The usefulness and feasibility of prophylactic use of anticoagulants after allogeneic HSCT are however still controversial. In addition, to our knowledge no study has evaluated the feasibility of usage of UDCA combined with an anticoagulant for SOS prevention after allogeneic HSCT in adult patients. To assess the efficacy and safety of use of UDCA combined with an anticoagulant as SOS prophylaxis, we performed a retrospective cohort study to examine the occurrences of SOS and hemorrhagic events in patients who underwent myeloablative allogeneic HSCT at our institution. We examined use of any anticoagulant together with simultaneous administration of UDCA, in comparison with UDCA alone for the prevention of SOS. Patients and methods: We reviewed the charts of consecutive adult patients in whom myeloablative allogeneic HSCT was performed at our hospital from November 1994 to May 2014, and who received either unfractionated heparin or dalteparin (low-molecular-weight heparin) with UDCA (group 1), danaparoid with UDCA (group 2), or UDCA only (group 3), used for prophylaxis against SOS. Results: A total of 280 patients (group 1: n=52; group 2: n=33; and group 3: n=195) were investigated. The proportions of patients with risk factors for SOS-including non-remission at the time of HSCT, a second or subsequent HSCT, high aspartate aminotransferase (AST) levels before HSCT, high ferritin levels before HSCT, a history of receiving gemtuzumab ozogamicin, and HLA disparity-were similar across the three groups. In group 1, a conditioning regimen containing busulfan was used less frequently (P = 0.002). SOS occurred in seven patients (13.7%) in group 1, five patients (15.2%) in group 2, and 28 patients (14.4%) in group 3, all meeting the Seattle criteria. None of the patients in group 1, two (6.1%) in group 2, and nine (4.6%) in group 3 had SOS diagnosed according to the Baltimore criteria. There was no significant difference in the incidence of SOS among the three groups. In addition, with regard to the cumulative incidence of severe SOS, no statistically significant difference was present among the three groups. The incidence of hemorrhagic events within 30 and 100 days following allogeneic HSCT was not significantly different across the three groups (30 days; 5.8%, 3.0%, 5.1%, P = 0.843, 100 days; 17.6%, 15.2%, 14.4%, P=0.843, respectively). Furthermore, the probabilities of OS and NRM until day 100 after allogeneic HSCT were similar among the three groups (P = 0.733 and P = 0.637, respectively). In a univariate model, a history of gemtuzumab ozogamicin treatment, high serum ferritin levels before HSCT, an HLA mismatched donor, and non-complete remission of disease at the time of allogeneic HSCT were found to be significant risk factors for SOS. Multivariate analysis revealed that a history of gemtuzumab ozogamicin therapy, a mismatched HLA donor, and non-complete remission of disease at the time of allogeneic HSCT were significant and independent risk factors for SOS. In the multivariate as well as univariate analyses, combined administration of UDCA and any anticoagulant for SOS prophylaxis did not have a significant effect on the incidence SOS, when compared to prophylaxis with UDCA alone. Conclusion: Our study results suggest that the combined use of UDCA and an anticoagulant for SOS prophylaxis after myeloablative allogeneic HSCT in adult patients was not beneficial. Establishment of an optimal strategy for prophylaxis against SOS after HSCT is still needed. Disclosures Nakane: Mundipharma KK: Research Funding. Koh:Pfizer: Consultancy, Honoraria. Hino:Pfizer: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Speakers Bureau; Alexion: Honoraria, Research Funding. Nakamae:Mochida Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis Pharma KK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation/meeting expenses, Research Funding.

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Risk Factors and the Therapeutic Efficacy for Thrombotic Microangiopathy in Patients after Allogeneic Hematopoietic Stem Cell Transplantation - Results of the Multicenter Retrospective Cohort Study

Blood ◽

10.1182/blood-2019-123252 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4554-4554

Author(s):

Hiroharu Imoto ◽

Hiroyuki Matsui ◽

Yasuyuki Arai ◽

Tadakazu Kondo ◽

Yasunori Ueda ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Cohort Study ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Research Funding ◽

Therapeutic Interventions ◽

Post Transplantation ◽

Hematopoietic Stem

[Introduction] Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication after allogeneic hematopoietic stem cell transplantation (HSCT). However, given its relatively low incidence, no large cohort-based study has determined TA-TMA risk factors and its impact on overall survival (OS) or the most effective therapeutic interventions. Recombinant human soluble thrombomodulin (rTM) is a promising therapeutic option; with dual antithrombosis and anti-inflammation activities, a single-center small cohort study in Japan reported rTM to be effective against TA-TMA. This study aimed to clarify risk factors for TA-TMA development and the efficacy of various TA-TMA therapies in a multicenter large cohort. [Methods] This retrospective cohort study conducted by the Kyoto Stem Cell Transplantation Group enrolled adult patients (age ≥ 16 years) with hematological diseases who underwent allogenic HSCT after 2000. Cumulative TA-TMA incidence was calculated using Gray's test; death from any cause was a competing risk. We evaluated OS in patients with or without TA-TMA using the Simon-Makuch method and compared it using the Cox proportional hazard model with TA-TMA development as a time-dependent covariate. Correlations were analyzed between each pre- or post-transplant factor and TA-TMA development using Gray's test. Factors significant in the univariate analysis were subjected to the multivariate analysis using the Fine-Gray proportional hazards model. We evaluated the effect of each therapeutics on response using a logistic regression model. [Results] We enrolled 2,430 patients [median age at HSCT, 50 (range: 16-74) years] from 14 institutes. Overall, 1,234 patients were transplanted for acute myeloid leukemia or myelodysplastic syndrome, followed by acute lymphoblastic leukemia (n = 381) and non-Hodgkin lymphoma (n = 351). Overall, 1,219 patients (50.2%) had advanced disease (non-remission status) at HSCT. The HCT-CI score was higher (≥3) in 213 patients (8.8%), and 360 (14.8%) were transplanted at poorer performance statuses (PS 2-4). In total, 471 patients (19.4%) received related bone marrow transplantation (BMT), 423 (17.4%) received related peripheral blood stem cell transplantation (PBSCT), 871 (35.8%) unrelated-BMT, and 665 (27.4%) unrelated cord blood transplantation. HLA was mismatched in 1,461 (60.1%) patients. After HSCT, TA-TMA was observed in 123 patients; the cumulative incidence of TA-TMA 12 months after HSCT was 5.0%; TA-TMA occurred at a median of 36 days (range: 3-482) (Figure 1). TA-TMA was correlated with a remarkably inferior OS [hazard ratio (HR), 4.93; 95% confidence interval (CI), 4.03-6.02; P < 0.001] when treating TA-TMA as a time-dependent covariate. In the multivariate analysis, poorer PS [HR, 1.64; 95% CI, 1.05-2.58; P = 0.03], higher HCT-CI [HR, 1.70, 95% CI, 1.02-2.83; P = 0.04], and HLA-mismatch [HR, 2.06; 95% CI, 1.34-3.17; P = 0.001] were significant pre-transplantation risk factors for TA-TMA. Post-transplantation factors (acute GVHD (Grade 3-4) [HR, 2.51; 95% CI, 1.64-3.85; P < 0.001] and veno-occlusive disease (VOD/SOS) [HR, 3.70; 95% CI, 2.05-6.70; P < 0.001]) were also significant risk factors for TA-TMA in the multivariate analysis. No infections (bacterial, viral, or fungal) were significantly related to TA-TMA incidence. Regarding therapeutic interventions, 36 (29.3%) patients received rTM-including treatment, 6 (5%) were treated with rTM alone, and 30 (24.4%) were treated with rTM and FFP (14; 11%), PE (5; 4%), or both FFP and PE (11; 9%). No significant differences in response rate [OR, 0.99; 95% CI, 0.39-2.52; P = 0.98] and OS [HR, 0.93; 95% CI, 0.58-1.49; P = 0.77] between the groups treated with or without rTM were identified. The results showed similar trends in other therapeutic interventions. [Conclusion] This study clarified the incidence of TA-TMA, its impact on clinical outcomes, risk factors including post-transplantation factors, and therapy efficacies. Patients with poor PS, high HCT-CI scores, and HLA-mismatched donors were high-risk patients; the development of severe acute GVHD and VOD/SOS also increased the risk of TA-TMA. rTM administration or other treatments did not improve patient outcomes. Therefore, strategies to avoid TA-TMA are essential. Intensification of the GVHD and VOD/SOS prophylaxis or treatment for these high-risk patients may reduce TA-TMA and improve HSCT outcomes. Figure 1 Disclosures Imada: Novartis Pharma K.K.: Honoraria; Takeda Pharmaceutical Co.,LTD.: Honoraria; Celgene K.K.: Honoraria; Bristol-Meyer Squibb K.K.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Nippon Shinyaku Co.,Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria. Takaori-Kondo:Kyowa Kirin: Research Funding; Chugai: Research Funding; Takeda: Research Funding; Ono: Research Funding; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Honoraria; Pfizer: Honoraria.

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Mesenchymal Stem Cells Vs. Mesenchymal Stem Cells Combined With Cord Blood For Treating Engraftment Failure Following Autologous Hematopoietic Stem Cell Transplantation: A Pilot Prospective Study

Blood ◽

10.1182/blood.v122.21.3693.3693 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3693-3693 ◽

Cited By ~ 1

Author(s):

YiYing Xiong ◽

Fan Qian ◽

Fen Huang ◽

Yu Zhang ◽

Yu Wang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Research Funding ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Significant Difference ◽

Engraftment Failure

Abstract Background Engraftment failure (EF) is a formidable complication after autologous hematopoietic stem cell transplantation (auto-HSCT). Mesenchymal stem cells (MSCs) and cord blood (CB) have been found to support hematopoiesis. Thus, we designed a multicenter randomized clinical trial to investigate the effects and safety of MSCs alone or combined with CB infusion for patients with EF. Methods Twenty-two patients were randomly assigned to receive the treatment with MSCs alone (MSCs group, n=11) or MSCs combined with CB (CB group, n=11). MSCs were administered once every 2 weeks (2 doses were a cycle) in both groups, and single-unit CB was administered at the same day with the first application of MSCs in CB group; After one cycle of treatments (within 28 days), the patients who did not response to MSCs would receive the therapeutic schedule in CB group, and those patients with partial response (PR) in MSCs group and those without complete response (CR) in CB group would continue another cycle of MSCs treatment. If patients did not obtain CR after two cycles of treatments (within 56 days), they would receive other treatments including allogeneic HSCT. Results After the first treatment cycle, the effect rates were not significant difference in MSCs and CB groups (7/11 vs. 9/11, P=0.635), and the median time of hematopoietic reconstruction was 22 (18-28) and 17 (13-22) days, respectively (P=0.036) in MSCs and CB group. There was statistically significant difference regarding neutrophil engraftment, with 17 (range 9-28) and 8 (range 6-14) days respectively (P=0.030), but no difference regarding platelet engraftment, with 21 (range 18-28) and 18 (range 11-21) days respectively (P=0.092) between MSCs and CB groups. After two cycles of treatments, 17 patients obtained CR, 2 PR and 3 NR. CB chimerisms were not detected by short tandem repeat (STR) at +15 and +30 days after CB infusion. None of the patients experienced any adverse events of grade 3/4 with the Common Terminology Criteria for Adverse Events v3.0 (CTCAE v3.0) and acute GVHD or chronic GVHD during the period of study treatment and follow-up. One patient with PR in MSCs group and 1 NR in CB group received allogeneic HSCT at +249 and +273 days after auto-HSCT because of EF and primary disease relapse, respectively. At a median follow-up time of 345 (range 129–784) days post-transplantation, 16 patients remained alive, 3 died of relapse of primary diseases and 1 died of CMV pneumonia following allo-HSCT. None of patients developed EBV-DNA viremia and EBV-associated diseases in two groups. The 2-year overall survival, disease-free survival and tumor relapse post-transplantation were 75.2% (95% CI, 63.2-87.2%), 79.5% (95% CI, 70.1-88.9%) and 20.5% (95% CI, 11.1-29.9%) respectively. Conclusions Our data suggest that ex-vivo-expanded MSCs derived from HLA-mismatched BM alone or combined with unrelated CB are effective to EF after auto-HSCT. CB can facilitate the effect of MSCs to EF. Both two strategies do not result in GVHD or increase the risk of primary diseases relapse in patients with EF. This trial was registered at www.clinicaltrials.govas#NCT01763099. Disclosures: Liu: It was supported by 863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation (Grant No. 201202017).: Research Funding; It was supported by National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174). : Research Funding.

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Incidence and Risk Factors for Secondary Autoimmune Diseases (AD) After Hematopoietic Stem Cell Transplantation (HSCT) for a Severe Autoimmune Disease-A Retrospective EBMT WP AD Study

Blood ◽

10.1182/blood.v116.21.2322.2322 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2322-2322

Author(s):

Thomas Daikeler ◽

Myriam Labopin ◽

Massimo di Gioia ◽

Mario Abinun ◽

Tobias Alexander ◽

...

Keyword(s):

Risk Factors ◽

Antiphospholipid Syndrome ◽

Cumulative Incidence ◽

Significant Risk ◽

Data Management System ◽

Type I ◽

Acquired Hemophilia ◽

Hematopoietic Stem ◽

Allogeneic Hsct

Abstract Abstract 2322 New onset of AD have been reported after autologous and allogeneic HSCT and AD patients (pt) treated by HSCT may be at higher risk for developing a secondary AD. A single US centre study showed that more profound T cell depleting conditioning with antithymocyte globulin (ATG) or alemtuzumab enhanced the risk of secondary AD after HSCT for primary AD. We therefore aimed at specifying the incidence, nature and risk factors for secondary AD after autologous or allogeneic HSCT for a primary AD. Methods: Retrospective analysis of AD pts treated by HSCT as reported to the EBMT data management system ProMISe until November 2009. Each EBMT participating centre was asked to identify all pts having developed at least one AD and those not having developed AD after HSCT as controls with complete detailed information on HSCT and outcome of original disease and treatment and outcome of secondary AD for cases. Cumulative incidence curves were used to estimate incidence of AD considering death as a competing event. Associations of patients and graft characteristics with secondary AD were evaluated by multivariate analyses, using Cox proportional hazards. All tests were two-sided. The type I error rate was fixed at 0.05 to determinate factors associated with time to event outcomes. Results (median, extremes): Out of 338 patients from 26 centres in 12 European countries, 33 developed at least one secondary AD within 569 (19-1489) days after HSCT, 305 pts without secondary AD served as controls. Characteristics of both groups are in table 1. The cumulative incidence of secondary AD after HSCT for primary AD was 6.5 (±1) % after 3 years and 11.1 (±2) % after 5 years. Diagnoses of secondary AD were thyroiditis (n=13), autoimmune hemolytic anemia (AIHA) (n=4), autoimmune thrombopenia (n=3), acquired hemophilia (n=3), Graves' disease, rheumatoid arthritis, sarcoidosis, antiphospholipid syndrome and psoriatic arthritis in 2 pts each and myasthenia gravis and vasculitis in 1 pt each. Two pts developed two secondary AD. After multivariate analysis age younger than 33 years p=0.016 (overall median age at HSCT), primary systemic lupus erythematosus (SLE) p= 0.003, ex vivo manipulation p= 0.015 and HSCT performed after the year 2002 p=0.02 remained as risk factors for secondary AD. At last follow-up within 5.9 years (0.25-15 years) after HSCT, 28/33 pts with secondary AD were alive and 257/305 nonAD pts. 0ne Systemic Sclerosis pt and one Multiple Sclerosis transplanted pt died from secondary embolic antiphospholipid syndrome and acquired hemophilia respectively. 26 primary AD pts received specific therapy after HSCT for their secondary AD. The pts with acquired hemophilia received steroids plus cyclophosphamide and additional Rituximab or ivIG or plasmapheresis, those with immune thrombocytopenia responded to steroids. One pt with thrombocytopenia followed by AIHA needed additional immunosuppression and Rituximab. Two pts with AIHA received steroids, cyclophosphamide and additional Rituximab, and one case also ivIG and ultimately allogeneic HSCT for secondary AID. At last follow-up, 12 pts remained in remission of secondary AD without treatment, 15 pts needed ongoing therapy, 3 pts had persistent secondary AD without therapy. This first multicenter study after HSCT for primary AD showed that secondary AD occurred in 10% of 338 pts after HSCT and led to death in 2 pts. Younger age and SLE as primary AD were significant risk factors for secondary AD, but contrary to previous single centre US experience, conditioning with ATG or alemtuzumab did not increase the secondary AD risk. Secondary AD after HSCT should be added to the post transplant follow up clinical parameters. Disclosures: Lenhoff: Celgene: Honoraria.

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The Natural History of Fanconi Anemia: A Report from the Italian Fanconi Anemia Registry (RIAF)

Blood ◽

10.1182/blood.v126.23.1208.1208 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1208-1208

Author(s):

Serena Marotta ◽

Antonio M Risitano ◽

Rita Calzone ◽

Oriana Catapano ◽

Adriana Zatterale

Keyword(s):

Overall Survival ◽

Natural History ◽

Fanconi Anemia ◽

Research Funding ◽

Disease Course ◽

Hematopoietic Stem ◽

History Of ◽

Hematological Manifestations

Abstract Fanconi anemia (FA) is a rare inherited syndrome characterized by chromosomal instability, eventually resulting in a number of manifestations affecting the hematopoietic system and other organs. The phenotype of FA patients is largely heterogeneous, and encompasses different clinical manifestations that may be present at birth, or rather develop later during the disease course. Thus, even due to the rarity of the disease, the natural history of FA remains hard to be established in its details. To accomplish the need of a large disease registry, in 1994 we have established at the local health unit "ASL Napoli 1" a National Database named as "Registro Italiano Anemia di Fanconi " (RIAF): here we report on a 20-year experience of the Italian FA Registry. Patients were enrolled prospectively at diagnosis or later on, after signature of the informed consent form; epidemiological, genetic and clinical data were recorded at registration, with these latter information eventually collected periodically to assess the clinical course, possible complications and long-term survival. The main endpoint of the study was the description of the natural history, looking for the following variables: family history, disease presentation, development of hematological manifestations, development of malignancies, occurrence of hematopoietic stem cell transplantation (HSCT) and survival. Between 1994 and 2014 a total of 180 patients were included in the RIAF, belonging to 151 distinct families; all diagnoses were based on standard chromosome DEB (diepoxybutane) - or MMC (mytomicin C) - breakage test confirmed at specialized centers. The median age at diagnosis was 3170 days, and it was lower in patients born in the more recent periods; the median follow up of enrolled patient was 15.6 years. For the majority of patients the diagnosis was suspected based on the typical morphological abnormalities and/or growth retardation; congenital abnormalities (mostly skin pigmentation and skeletal abnormalities) were demonstrated in 90% of patients. The majority of patients (77%) exhibited some hematological abnormalities at diagnosis, which in most cases was a mild-to-moderate cytopenia. Looking at the subsequent disease course, a total of 172 (96%) FA patients developed some hematological manifestations, typically progressive cytopenia due to bone marrow failure. The cumulative incidences (CI) of any hematological disorder were 62%, 88% and 94% at 10, 20 and 30 years, respectively, whereas those of a hematological malignancy were 5%, 8% and 22% at 10, 20 and 30 years. Hematological manifestations led to an allogeneic hematopoietic stem cell transplantation (HSCT) in more than half of the patients (57%), with a CI of HSCT of 33%, 64% and 72%% at 10, 20 and 30 years, respectively; patients born in the most recent years were transplanted earlier. The presence at diagnosis of a solid tumor was quite rare; nevertheless, solid tumors were the most significant complication in the long-term period, with a CI of 1%, 15% and 32% at 10, 20 and 30 years respectively; head and neck were the most common cancer sites. Eighty-eight of the 180 FA patients enrolled in the RIAF died during their follow up; in non-transplanted patients, the main causes of death were related to the underlying disease (infections, bleeding, and solid tumors), whereas in transplanted patients graft versus host disease and other transplant-related complications played a major role. The median survival of this large cohort was 22.5 years; overall survival at 10, 20 and 30 years were 88%, 56% and 37%, respectively, with no improvement over the past decades. These data confirm the poor long-term prognosis of FA patients, irrespective of earlier diagnosis and improved treatment options achieved in the most recent years. Figure 1. Overall survival of the 180 patients enrolled in the RIAF Figure 1. Overall survival of the 180 patients enrolled in the RIAF Disclosures Risitano: Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Consultancy, Research Funding; Rapharma: Consultancy, Research Funding; Novartis: Research Funding; Pfizer: Consultancy.

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Hematopoietic Stem and Progenitor Cell Fitness As a Novel Prognostic and Monitoring Biomarker for JAK2 V617F Myeloproliferative Neoplasms (MPNs)

Blood ◽

10.1182/blood-2021-153003 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 627-627

Author(s):

Ghaith Abu-Zeinah ◽

Silvana Di Giandomenico ◽

Tatiana Cruz ◽

Daniel Choi ◽

Elwood Taylor ◽

...

Keyword(s):

Clinical Trials ◽

Relative Risk ◽

Clinical Response ◽

Research Funding ◽

Cox Model ◽

Myeloproliferative Neoplasms ◽

Jak2 V617f ◽

Short Term ◽

Hematopoietic Stem

Abstract Introduction: MPNs are chronic malignancies associated with significant morbidity and mortality due to cardiovascular events (CVE) and progression to more aggressive myeloid neoplasms (progression). CVE, progression, and survival are not feasible clinical trial endpoints due to the long follow-up required for analysis, leading to use of short-term measures. A reliable biomarker linking MPN biology with these important outcomes would facilitate development of new agents that can meaningfully reduce these risks and improve survival. Ultimately, MPNs result from hematopoietic stem cell (HSC) acquisition of highly recurrent driver mutations, most commonly JAK2 V617F. Here, we study MPN fitness - the competitive advantage of mutated hematopoietic stem and progenitor cells (HSPC) over their normal counterparts- as a prognostic and monitoring biomarker in MPNs, and compare it to whole blood (WB) mutation allele frequency (MAF). Methods: We measured fitness by sorting peripheral blood (PB) specimens from MPN patients (pts) at Weill Cornell Medicine (WCM) into 11 well-defined and strictly validated immunophenotypic HSPC and mature cell compartments and measured MAF in each and in WB (Fig 1A). The study was approved by WCM institutional review board. Pt age, sex, diagnosis (Dx), duration of disease (Dur), symptoms, blood counts, mutations, spleen size, treatment, follow-up, and events (CVE, progression, death) were tabulated. Principal component (PC) analysis was used for unsupervised hierarchical clustering of 11-population MAFs to identify predominant patterns of fitness. Event-free survival (EFS) was assessed using Kaplan-Meier (KM) methods and log-rank test. Cox multivariable analysis (MVA) of EFS was used to assess the independent prognostic value of baseline MPN fitness, compared to WB MAF. A Cox model was used to translate change in fitness (PCs 1-3, Fig 1E) from serial samples into a relative risk of events. A Fisher's test was used to determine if changes in fitness were associated with events and/or IWG-MRT/ELN response (Barosi et al. & Tefferi et al. Blood 2013). Results: A total of 212 PB samples from 93 JAK2 V617F MPN pts with essential thrombocythemia (ET, n = 20, 22%), polycythemia vera (PV, n = 39, 42%), myelofibrosis (MF, n = 32, 34%) or unclassified MPN (MPNU, n = 2, 2%) were prospectively collected between 7/2017-7/2021 and analyzed. Median age was 68 years (yr) (range 28-90) and median Dur was 6 yr (0-45). The majority were females (n=58, 62%). Unsupervised PC clustering at baseline revealed 4 major fitness levels (FLs): F1, F2, F3, and F4 (Fig 1B). The pattern of JAK2 V617F propagation from HSPC to mature lineages differed across FLs (Fig 1C). EFS was strongly (KM, p<0.001, Fig 1D) and independently (Cox MVA) associated with FL when covariates of age, sex, Dx, Dur, and WB MAF were considered (F2, 3, 4, versus F1: HR of 7 [p=0.15], 31 [p=0.009], and 92 [p=0.009], respectively). In contrast, EFS was not statistically linked to WB MAF quartiles in KM analysis (p=0.06) and was not associated with WB MAF in MVA (HR 0.97, p=0.06). We developed a Cox model to predict relative risk of events from serial fitness measures and tested the model in 25 pts. Pts with increased fitness were more likely to experience an adverse event (33% vs 0%, p=0.047) and were less likely to achieve clinical response (13% versus 75%, p=0.007) than pts with decreased fitness. Change in WB MAF did not correlate with change in fitness (r 2=0.0116) and did not predict events (p=1) nor clinical response (p=0.23). Discussion: Reliable biomarkers are needed to efficiently identify disease-modifying treatments mitigating the risk of progression and other adverse events. Our study offers a feasible approach to monitor risk by tracking MPN fitness in clinically accessible PB specimens. In this large study, MPN fitness outperformed WB MAF as a biomarker and was highly prognostic of EFS. Fitness dynamics were strongly predictive of events and clinical response whereas changes in WB MAF were unreliable. Methods to simplify routine measurement of MPN fitness are being developed to support clinical trials. Updated validation of MPN fitness as a biomarker in clinical trials will be presented. Conclusion: MPN fitness may serve as both a prognostic biomarker identifying MPN pts at high risk of disease-related events and a monitoring biomarker for use as a short-term surrogate of long-term outcomes in clinical trials. Figure 1 Figure 1. Disclosures Abu-Zeinah: PharmaEssentia: Consultancy. Ritchie: ARIAD Pharmaceuticals: Ended employment in the past 24 months, Speakers Bureau; Protaganist: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Research Funding; NS Pharma: Research Funding; Astellas: Consultancy, Research Funding; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Other: travel support, Speakers Bureau; Abbvie: Consultancy, Honoraria; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Silver: Abbvie: Consultancy; PharamEssentia: Consultancy, Speakers Bureau. Scandura: MPN-RF (Foundation): Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Research Funding; CR&T (Foudation): Research Funding; European Leukemia net: Honoraria, Other: travel fees .

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Risk Factors of Thrombosis in Adults with Primary Immune Thrombocytopenia. a French Nationwide Cohort Study

Blood ◽

10.1182/blood-2018-99-112506 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3745-3745

Author(s):

Guillaume Moulis ◽

Bérangère Baricault ◽

Charlotta Ekstrand ◽

Margaux Lafaurie ◽

Christian Fynbo Christiansen ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Additional Risk Factor ◽

Discharge Diagnosis ◽

Additional Risk ◽

Icd 10 ◽

History Of

Abstract Background: Immune thrombocytopenia (ITP) is associated with an increased risk of venous and arterial thrombosis (VT and AT, respectively) as compared with the general population. However, the impact of thrombosis risk factors and of ITP treatments, particularly of thrombopoietin-receptor agonists (TPORAs), is not well known in the routine clinical practice. Aim: The objective of this cohort study was to assess the risk factors of VT and AT in adults with primary ITP, including ITP treatments. Methods: The population was the cohort of all incident primary ITP adults in France during 2009-2015 built within the national health insurance database (French Adult Immune Thrombocytopenia - FAITH - cohort; NCT03429660). Incident ITP patients were identified using a validated algorithm combining drug exposures and diagnosis codes according to the international classification of diseases, version 10 (ICD-10). Risks of first hospitalization with a validated primary discharge diagnosis code of VT and AT (coded with the ICD-10) were assessed separately. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Variables included in multivariable models were: age, sex, history of AT and of VT, diabetes, cardiovascular disease, chronic kidney disease, chronic liver disease, cancer; exposures to antihypertensive, lipid-lowering, antiplatelet, anticoagulant drugs and ITP treatments including splenectomy were modeled as time-dependent variables. Results: The cohort included 7225 adult patient with incident primary ITP: 3807 (52.7%) were ≥60 year-old, 3199 (44.3%) were males, 692 (9.6%) had a history of cardiovascular disease, 937 (13.0%) had diabetes. During the follow-up, 5737 (79.4%) were exposed to corticosteroids, 3364 (46.6%) to intravenous immunoglobulin (IVIg), 995 (13.8%) to TPORAs, and 755 (10.4%) were splenectomized. During the follow-up (23 852 patient-years in total; mean follow-up: 39.5 months), 174 patients had a hospitalization with a primary discharge diagnosis of VT and 333 of AT, leading to incidences of 7.4 (95% CI: 6.4-8.6) and 14.4 (95% CI:12.9-16.0)/1000 patient-years, respectively. In multivariable Cox models, the most important risk factors for VT were higher age (≥60 years vs. <40 years: HR: 2.22, 95% CI: 1.39-3.53), a history of VT (HR: 4.38, 95% CI: 1.07-18.02), splenectomy (HR: 3.22, 95% CI: 2.06-3.03), exposure to IVIg (HR: 2.30, 95% CI: 1.41-3.75), corticosteroids (HR: 3.29, 95% CI: 2.39-4.53) and TPORAs (HR: 3.16, 95% CI: 2.04-4.88). All classical baseline cardiovascular risk factors listed above as covariables were associated with the risk of AT. The HRs for AT were 0.97 (95% CI: 0.59-1.61) for splenectomy, 1.05 (95% CI: 0.80-1.40) for corticosteroids, 2.35 (95%CI: 1.58-3.50) for IVIg, 1.25 (95%CI: 0.46-3.37) for danazol and 1.31 (95%CI: 0.84-2.06) for TPORAs. It is of note that among the 25 patients who had a VT while treated by TPORA, 18 (72.0%) were>50 year-old, 14 (56.0%) were women, 6 (24.0%) were splenectomized, 9 (36.0%) were concomitantly exposed to corticosteroids and 3 (12.0%) to IVIg; only 3 women aged<50 years had no additional risk factor. Among the 21 patients who had an AT while treated by TPORA, 18 (85.7%) were>50 year-old, 15 (71.4%) were men, 8 (38.1%) were splenectomized, 5 (23.8%) were concomitantly exposed to corticosteroids and one to IVIg; only one 48-year-old man had no additional risk factor for AT. Conclusions: Baseline risk factors for VT and AT were highly associated with VT and AT occurrence in adults with primary ITP. Splenectomy, corticosteroids, IVIg and TPORAs were risk factors for VT. Most patients who had a thrombosis while treated by TPORA had additional risk factors. These findings help choosing a tailored treatment strategy for a given patient depending on his/her risk profile for VT and AT. Disclosures Christiansen: Amgen: Research Funding. Bahmanyar:Amgen: Research Funding.

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Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation

Blood ◽

10.1182/blood-2006-10-054080 ◽

2007 ◽

Vol 110 (9) ◽

pp. 3463-3471 ◽

Cited By ~ 126

Author(s):

André Tichelli ◽

Christoph Bucher ◽

Alicia Rovó ◽

Georg Stussi ◽

Martin Stern ◽

...

Keyword(s):

Risk Factors ◽

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Autologous Hsct

Abstract We assessed incidence and risk factors of cardiovascular events in 265 patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT) between 1980 and 2000 and who survived at least 2 years. Results were compared with a cohort of 145 patients treated during the same period with autologous HSCT. The median age of patients with allogeneic HSCT at last follow-up was 39 years, and median follow-up was 9 years. Eighteen (6.8%) patients after allogeneic and 3 (2.1%) patients after autologous HSCT experienced an arterial event. The cumulative incidence of first arterial event after allogeneic HSCT was 22.1% (95% CI, 12.0-40.9) at 25 years. The cumulative incidence 15 years after allogeneic HSCT was 7.5% as compared with 2.3% after autologous HSCT. Adjusting for age, risk of an arterial event was significantly higher after allogeneic HSCT (RR 6.92; P =.009). In multivariate analysis, allogeneic HSCT (RR: 14.5; P =.003), and at least 2 of 4 cardiovascular risk factors (hypertension, dyslipidemia, diabetes, obesity) (RR: 12.4; P =.02) were associated with a higher incidence of arterial events after HSCT. Thus, long-term survivors after allogeneic HSCT are at high risk for premature arterial vascular disease. HSCT might favor the emergence of established risk factors, such as hypertension, diabetes, and dyslipidemia.

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