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

Blood ◽  
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 .

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

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4562-4562
Author(s):  
Anne Bergeron ◽  
Sylvie Chevret ◽  
Regis Peffault De La Tour ◽  
Karine Chagnon ◽  
Cedric De Bazelaire ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cohort Study ◽  
Research Funding ◽  
Late Onset ◽  
Cox Model ◽  
Pulmonary Complications ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
History Of

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.

scholarly journals Myeloablative Conditioning for First Allogeneic Hematopoietic Stem Cell Transplantation in Children with ALL: Total Body Irradiation or Chemotherapy? - a Multicenter EBMT-PDWP Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 911-911
Author(s):  
Andre Manfred Willasch ◽  
Christina Peters ◽  
Petr Sedlacek ◽  
Jean-Hugues Dalle ◽  
Stelios Graphakos ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Research Funding ◽  
Cox Model ◽  
Univariate Analysis ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Donor Type ◽  
Total Body

Abstract Introduction: Most pediatric patients (pts) with ALL receive total body irradiation (TBI) for myeloablative conditioning of allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is unproven whether TBI can be replaced by chemotherapy (CHT). Methods: To compare the outcomes of TBI- versus (vs.) CHT-based conditioning, we performed a retrospective EBMT-registry based study. Children between 2 and 18 years of age (y.) after myeloablative conditioning for first allo-HSCT of bone marrow (BM) or peripheral blood SC (PBSC) from matched sibling (MSD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to consider the covariate "distribution of TBI recipients" for pts who did not receive TBI. Results: In total 3071 pts (CR1: 1504 (49%), CR2: 1567 (51%)) were included. CR1: 1045 pts (69%) received BM and 459 pts (31%) PBSC from MSD (760 (51%)) or UD (744 (49%)). CR2: 1067 pts (68%) received BM and 500 pts (32%) PBSC from MSD (675 (43%)) or UD (892 (57%)). Overall, conditioning was TBI- in 2647 (86%) and CHT-based in 424 pts (14%). Busulfan/Cyclophosphamide (Bu/Cy) and Bu/Cy/Etoposide (Bu/Cy/Eto) were the two most frequently applied CHT combinations in CR1 (68 (32%), 66 (31%)) and CR2 (68 (32%), 52 (25%)). The remaining conditionings included 5 different combinations of chemotherapeutics (other chemo). 1504 pts in CR1 were conditioned with TBI (1291), Bu/Cy/Eto (66) or other chemo (147) with a median follow-up of 4.4, 3.4 and 2.4 y. In weighted univariate analysis no significant differences were detected for LFS (5-y.-LFS, range: 62.4 to 67.5%) and relapse incidence (5-y.-RI, range: 24.0 to 29.0%). In pairwise testing, OS after Bu/Cy/Eto was significantly better compared with TBI (5-y.-OS, 78.7 vs. 66.8%, P=.006). Non-relapse mortality was significantly higher after other chemo (5-y.-NRM, 12.7%, P <.001) and TBI (12.5%, P <.001) compared with Bu/Cy/Eto (3.5%). Other significant influencing factors on LFS were age (5-y.-LFS, 2-11 y. 65.8 vs. 12-18 y. 58.0%, P=.009), y. of HSCT (2008-2012 65.9 vs. 2000-2007 59.6%, P=.035) and donor type (MSD 64.9 vs. UD 59.5%, P=.007). RI was influenced by y. of HSCT (5-y.-RI, 2008-2012 21.7 vs. 2000-2007 26.8%. P=.026). OS was influenced by age (5-y.-OS, 2-11 y. 72.7 vs. 12-18 y. 61.7%, P <.001) and donor type (MSD 70.1 vs. UD 65.0%, P=.002). NRM was influenced by age (5-y.-NRM, 2-11 y. 9.0 vs. 12-18 y. 18.0%, P <.001), donor sex (male 10.9 vs. female 16.6%, P=.007) and donor type (MSD 8.5 vs. UD 17.8%, P <.001). In weighted multivariable Cox model clustered on EBMT centers, TBI-based conditioning in CR1 was associated with lower RI (HR 0.70, P=.047), lower OS (HR 1.54, P=.017) and higher NRM (HR 3.97, P <.001). 1567 pts in CR2 were conditioned with TBI (1356), Bu/Cy (68) or other chemo (143) with a median follow-up of 3.9, 3.2 and 3.1 y. In weighted univariate analysis highly significant differences of survival were detected. TBI-based conditioning resulted in highest 5-y.-LFS of 52.2% (Bu/Cy 41.0%, other chemo 18.4%, P <.001), lowest 5-y.-RI of 33.2% (Bu/Cy 38.3%, other chemo 55.3%, P <.001), highest 5-y.-OS of 56.1% (Bu/Cy 43.6%, other chemo 23.6%, P <.001) and lowest 5-y.-NRM of 14.6% (Bu/Cy 20.8%, other chemo 26.2%, P <.001). Other significant influencing factors on LFS were age (5-y.-LFS, 2-11 y. 53.5 vs. 12-18 y. 43.0%, P <.001), y. of HSCT (2008-2012 53.3 vs. 2000-2007 47.3%, P=.009) and SC source (BM 53.3 vs. PBSC 42.5%, P <.001). RI was influenced by SC source (5-y.-RI, BM 33.1 vs. PBSC 36.6%, P=.024). OS was influenced by age (5-y.-OS, 2-11 y. 59.3 vs. 12-18 y. 46.8%, P <.001), y. of HSCT (2008-2012 58.6 vs. 2000-2007 52.0%, P=.005), donor type (MSD 58.5 vs. UD 52.6%, P <.024) and SC source (BM 58.4 vs. PBSC 47.5%, P <.001). NRM was influenced by age (5-y.-NRM, 2-11 y. 12.5 vs. 12-18 y. 22.3%, P <.001), donor type (MSD 10.2 vs. UD 19.8%, P <.001) and SC source (BM 13.6 vs. PBSC 20.8%, P <.001). In weighted multivariable Cox model clustered on EBMT centers, TBI-based conditioning in CR2 was associated with higher LFS (HR 0.48, P <.001), lower RI (HR 0.48, P <.001) and higher OS (HR 0.51, P <.001). Conclusion: Conditioning by TBI demonstrated clear superiority in comparison to CHT for children with ALL undergoing HSCT in CR2. For pts in CR1, TBI- and CHT-based conditioning showed similar results. This retrospective data is currently re-evaluated in a prospective, randomized, international trial (ALL SCTped 2012 FORUM). Disclosures Büchner: Novartis Pharmaceuticals Corporation: Consultancy; Pfizer: Consultancy. Veys: Bellicum: Research Funding; Servier: Research Funding. Bader: Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding.

scholarly journals Clinical Outcomes Following Treatment with Gilteritinib or Quizartinib in Patients with Relapsed/Refractory FLT3-ITD+ Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-43
Author(s):  
Alexander E. Perl ◽  
Qiaoyang Lu ◽  
Alan Fan ◽  
Nahla Hasabou ◽  
Erhan Berrak ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase 3 ◽  
Hematopoietic Stem ◽  
Travel Costs ◽  
Baseline Characteristics ◽  
Acute Myeloid

Background: Gilteritinib is approved for patients (pts) with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on findings from the phase 3 ADMIRAL trial (Perl AE, et al. N Engl J Med. 2019). A phase 3 trial, QuANTUM-R, demonstrated the benefit of quizartinib in pts with R/R AML with FLT3 internal tandem duplication (FLT3-ITD) mutations (Cortes JE, et al. Lancet Oncol. 2019). Although eligibility criteria across both studies were similar, QuANTUM-R was more stringent as to prior therapy intensity and remission duration, which potentially enriched for higher-risk pts. We sought to describe outcomes from ADMIRAL among pts who otherwise met eligibility for QuANTUM-R. Methods: In this post-hoc analysis, a subset of pts from ADMIRAL were matched with R/R FLT3-ITD+ AML pts from QuANTUM-R on the basis of baseline characteristics and prior treatment criteria. Matched pts were either refractory to initial anthracycline-based chemotherapy or had relapsed ≤6 mos after achieving composite complete remission (CRc) with an anthracycline-based regimen. Results: Overall, 218 pts with R/R FLT3-ITD+ AML in the ADMIRAL trial (gilteritinib, n=140; salvage chemotherapy [SC], n=78) were matched with the QuANTUM-R intention-to treat (ITT) population (N=367; quizartinib, n=245; SC, n=122). Proportions of pts preselected for high-intensity SC were 66% (n=143/218) in the matched ADMIRAL ITT population and 77% (n=281/367) in the QuANTUM-R ITT populations. Demographic and baseline characteristics of the matched ADMIRAL ITT population and QuANTUM-R ITT population were similar. Median durations of exposure to gilteritinib and quizartinib were 3.8 mos and 3.2 mos, respectively, and median number of treatment cycles received were five and four, respectively. Rates of hematopoietic stem cell transplantation (HSCT) were similar in pts treated with gilteritinib (35%; n=49/140) or quizartinib (32%; n=78/245), as were the proportions of pts who resumed gilteritinib (23%; n=32/140) or quizartinib (20%; n=48/245) therapy post-HSCT. Median overall survival (OS) in pts treated with gilteritinib or quizartinib was longer than that observed with SC. After a median follow-up of 17.4 mos, median OS was 10.2 mos with gilteritinib versus 5.6 mos with SC (hazard ratio [HR]=0.573 [95% CI: 0.403, 0.814]; one-sided nominal P=0.0008). After a median follow-up of 23.5 mos, median OS with quizartinib was 6.2 mos versus 4.7 mos with SC (HR=0.76 [95% CI: 0.58-0.98]; one-sided P=0.02). After censoring for HSCT, median OS was 9.3 mos with gilteritinib versus 5.5 mos with SC (HR=0.525 [95% CI: 0.356-0.775]; nominal one-sided P=0.0005), and 5.7 mos versus 4.6 mos with quizartinib versus SC, respectively (HR=0.79 [95% CI: 0.59, 1.05]; one-sided P=0.05). In both QuANTUM-R and matched ADMIRAL populations, the survival benefits of quizartinib and gilteritinib compared with SC were maintained across multiple subgroups, including high FLT3-ITD allelic ratio subsets. Compared with SC, high CRc rates were observed in pts treated with either gilteritinib (57%; n=80/140) or quizartinib (48%; n=118/245). The complete remission (CR) rate with gilteritinib was 23% (n=32/140), whereas the CR rate with quizartinib was 4% (n=10/245) (Table). Median time to achieve CRc was 1.8 mos with gilteritinib and 1.1 mos with quizartinib, median duration of CRc was 5.5 mos with gilteritinib and 2.8 mos with quizartinib. The safety profiles of gilteritinib and quizartinib were generally similar, though aspartate or alanine aminotransferase elevations (any grade) were more frequent with gilteritinib (41-44%) than quizartinib (≤13%), whereas neutropenia (14% vs 34%, respectively), fatigue (24% vs 39%, respectively), and prolonged QT intervals (9% vs 27%, respectively) were more frequent with quizartinib. Conclusions: In pts with R/R FLT3-ITD+ AML and similar baseline characteristics, both gilteritinib and quizartinib were generally well tolerated and associated with improved survival and treatment response compared with SC. Responses to gilteritinib and quizartinib, as measured by CRc, were similar; blood count recovery varied between the two FLT3 inhibitors. Although cross-study comparisons have substantial limitations, the findings suggest that while remission is achieved faster with quizartinib, response may be more durable and survival potentially longer with gilteritinib. Disclosures Perl: Syndax: Consultancy, Honoraria; Leukemia & Lymphoma Society, Beat AML: Consultancy; Novartis: Honoraria, Other, Research Funding; Agios: Consultancy, Honoraria, Other; Jazz: Honoraria, Other; FORMA Therapeutics: Consultancy, Honoraria, Other; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; New Link Genetics: Honoraria, Other; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; Biomed Valley Discoveries: Research Funding; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Takeda: Honoraria, Other: Travel costs for meeting; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Consultancy, Honoraria, Other. Lu:Astellas: Current Employment. Fan:Astellas Pharma: Current Employment. Hasabou:Astellas Pharma: Current Employment. Berrak:Astellas: Current Employment. Tiu:Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Astellas Pharma Global Development: Current Employment.

scholarly journals 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 ◽  
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.

scholarly journals JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F–positive essential thrombocythemia

Blood ◽  
2010 ◽  
Vol 116 (9) ◽  
pp. 1528-1538 ◽  
Author(s):  
Juan Li ◽  
Dominik Spensberger ◽  
Jong Sook Ahn ◽  
Shubha Anand ◽  
Philip A. Beer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Essential Thrombocythemia ◽  
Cell Function ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Jak2 V617f ◽  
Transgenic Models ◽  
Disease Phenotype ◽  
Hematopoietic Stem

The JAK2 V617F mutation is found in most patients with a myeloproliferative neoplasm and is sufficient to produce a myeloproliferative phenotype in murine retroviral transplantation or transgenic models. However, several lines of evidence suggest that disease phenotype is influenced by the level of mutant JAK2 signaling, and we have therefore generated a conditional knock-in mouse in which a human JAK2 V617F is expressed under the control of the mouse Jak2 locus. Human and murine Jak2 transcripts are expressed at similar levels, and mice develop modest increases in hemoglobin and platelet levels reminiscent of human JAK2 V617F–positive essential thrombocythemia. The phenotype is transplantable and accompanied by increased terminal erythroid and megakaryocyte differentiation together with increased numbers of clonogenic progenitors, including erythropoietin-independent erythroid colonies. Unexpectedly, JAK2V617F mice develop reduced numbers of lineage−Sca-1+c-Kit+ cells, which exhibit increased DNA damage, reduced apoptosis, and reduced cell cycling. Moreover, competitive bone marrow transplantation studies demonstrated impaired hematopoietic stem cell function in JAK2V617F mice. These results suggest that the chronicity of human myeloproliferative neoplasms may reflect a balance between impaired hematopoietic stem cell function and the accumulation of additional mutations.

Short-term follow-up of the nutritional status of children with Fanconi anemia undergoing hematopoietic stem cell transplant

2017 ◽  
Vol 26 (3) ◽  
pp. 895-903 ◽  
Author(s):  
Gisele Trennepohl da Costa Heinen ◽  
Daniella Schmit ◽  
Denise Johnsson Campos ◽  
Carmem Bonfim ◽  
Estela Iraci Rabito ◽  
...  
Keyword(s):  
Stem Cell ◽  
Nutritional Status ◽  
Fanconi Anemia ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Cell Transplant ◽  
Short Term ◽  
Hematopoietic Stem ◽  
Nutritional Status Of Children

Polycythemia Vera as a Predisposing Factor for Aortic Stenosis: Prevalence and Correlation with Blood Cells Count and Mutational Status

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5247-5247
Author(s):  
Ri ta Barone ◽  
Clementina Caracciolo ◽  
Rosario di Maggio ◽  
Giovanni Fazio ◽  
Luciana d’Angelo ◽  
...  
Keyword(s):  
Relative Risk ◽  
Aortic Stenosis ◽  
Blood Cell ◽  
Polycythemia Vera ◽  
Blood Cells ◽  
Jak2 V617f ◽  
Laboratory Findings ◽  
Mutational Status ◽  
Adhesive Molecules

Abstract The association between Polycythemia Vera (PV) and thrombosis is multi-factorial involving the complex interaction between activated leukocytes, platelets and endothelium. Recent reports have postulated that PV patients may over express adhesive molecules on red cell surface, likely by JAK2 mutation (Wautier M et al. Blood.2007;110(3):894–901). This process activates endothelium with production of vascular growth factors and other mechanisms leading to atherosclerosis. Aortic Stenosis (AS) is the commonest valvular heart disease in western countries; its pathogenesis is mainly related to a degenerative process sharing many characteristics with atherosclerosis. At the present is not known whether patients with PV are at high risk of developing AS. Objective of the study. We perform a case-control study for evaluating rate of AS and its correlation with blood cells count and mutational status in patients with PV. Materials and methods. Prevalence of AS among PV patients have been compared with control patients matched for age, cardiovascular risk factors (hypertension, hyperlipidemia, diabetes, smoke and alcohol abuse) and coexisting cardiac diseases (i.e. heart failure). Diagnosis of PV has been posted accordingly to PVSG criteria. Diagnosis and severity of AS has been posted by echocardiography: stenosis with a valve area <1.0 cm2 has been considered severe. Results. Over a period of 18 months we recruited 43 PV patients (28 males and 15 females) and 74 controls. No differences were found in regard of the above cited characteristics; median age was 66.7 among PV patients and 68.2 among controls. The average duration of PV was 5.7 years with an average follow-up of 2.5 years. Most of the PV patients were on antiplatelet/anticoagulant therapy (27/43, 62.7%) and have been treated with cytoreductive therapy. Twelve (27.9%) had a thrombotic event before PV diagnosis; 4 (9.3%) developed thrombosis during the follow-up (median 1.3 years). A moderate/severe AS was found in 11 PV patients (25.6%) in comparison to 4 (5.4%) in control group (P= 0.023), thus giving a Relative Risk of 4.7. Among PV patients, the multivariate analysis did not show any correlation regarding JAK2 V617F mutational status, duration of disease, previous thrombosis, cytoreductive therapy and other common cardiovascular factors. Comparison of laboratory findings is reported in Table 1; a not significant trend was demonstrated in favor of patients with elevated hematocrit (>55%). Conclusions. Our study clearly shows that PV patients carry a fourfold risk of developing AS, without a clear association with blood cell alterations or previous thrombosis. Whether high prevalence of AS may be related to expression of adhesive molecules on red cells or altered share stress is currently under investigation. Table 1. Comparison of laboratory findings between PV patients with and without AS Laboratory parameter* PV patients with AS (11) PV patients without AS (32) Relative Risk P value *At diagnosis Legend: PV (Polycythemia Vera), AS (Aortic Stenosis) White blood cell×109/L (mean± SD) 9520 ± 1230 12.900 ± 2120 0.73 .078 Hemoglobin, g/dL (mean ± SD) 17.5 ± 1.3 17.1 ± 1.2 1.02 .088 Hematocrit, % (mean ± SD) 56.2 ± 0.6 51.1 ± 0.8 1.1 0.06 Platelets × 109/L(mean ± SD) 415.9 ± 43 353 ± 55 1.1 0.76 JAK2 V617F, n/N (%) 11/11 (100%) 31/32 (97%) - -

Single-Cell Pharmacodynamic Monitoring of S6 Ribosomal Protein in AML Blasts During a Clinical Trial Combining the mTOR Inhibitor Sirolimus with Mitoxantrone, Etoposide, and Cytarabine Chemotherapy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 413-413
Author(s):  
Alexander E Perl ◽  
Kasner Margaret ◽  
Shank Doris ◽  
Selina Luger ◽  
Martin Carroll
Keyword(s):  
Flow Cytometry ◽  
Clinical Trials ◽  
Ribosomal Protein ◽  
Clinical Response ◽  
Whole Blood ◽  
Research Funding ◽  
Mtor Inhibitor ◽  
Off Label ◽  
Rapamycin Resistance

Abstract Abstract 413 The mammalian target of rapamycin (mTOR) is an emerging molecular target in cancer therapy, however the relationship between target activation in individual tumors as well as inhibition of target and clinical response is poorly defined. This is in large part due to the difficulty of real-time monitoring of mTOR activation in patient samples. mTOR is activated in acute myelogneous leukemia (AML) cells and the mTOR inhibitor rapamycin enhances cytotoxic effects of chemotherapy in vitro and in vivo. We therefore developed a new application of a recently-developed, whole blood fixation/permeabilization technique for intracellular flow cytometry (Chow, et al. Cytometry A 2005). Using this approach, we sought to serially monitor S6 ribosomal protein (S6) phosphorylation in peripheral blood leukemic blasts during clinical trials of mTOR inhibitors. S6 is a known target of mTOR and its phosphorylation is a surrogate marker for mTOR kinase activation. We applied this methodology during a recent pilot trial in which an oral mTOR inhibitor, sirolimus (rapamycin), was administered in sequence with intensive combination chemotherapy (mitoxantrone, etoposide, and cytarabine, or MEC) in patients with relapsed, refractory, or secondary AML. The whole blood fixation process sufficiently preserved surface epitopes and light scatter properties for immunophenotyping, allowing specific signaling analysis of leukemic blasts as well as non-malignant cell populations. Importantly, even leukopenic trial samples containing as few as 20% blasts provided robust signaling data in malignant cells. S6 phosphorylation was readily apparent in leukemic blasts prior to therapy and, consistent with prior reports, occurred only in a subset of blasts. Exposing aliquots of pre-treatment whole blood samples to increasing concentrations of rapamycin ex vivo determined that leukemic blasts from most samples showed inhibition of S6 phosphorylation at clinically achievable concentrations (between 10-20 nM). Notably, some subjects' leukemic blasts showed no inhibition to >50 nM rapamycin, which far exceeded trough concentrations measured on our studies. To examine rapamycin's in vivo biochemical effects, we performed a paired analysis of clinical samples drawn at study entry and after 72 hours of oral sirolimus. 10 subjects provided paired samples, of which 2 did not show baseline S6 phosphorylation, 6 showed baseline S6 phosphorylation that inhibited during therapy, and 2 showed baseline S6 phosphorylation but no inhibition. Trough rapamycin levels were similar among rapamycin responsive and resistant subjects. Considering the 6 subjects with in vivo mTOR inhibition, 3 subjects achieved complete or partial remissions from the regimen. Neither subject with in vivo rapamycin resistance had a clinical response. Overall, we conclude that effective inhibition of mTOR signaling in AML blasts occurs in the majority of subjects during sirolimus treatment at the dose studied. However, cell-intrinsic rapamycin resistance occurs in a minority of patients and requires further study to clarify its mechanism and effects upon concurrent chemotherapy response. These data demonstrate the feasibility of real-time, intra-tumoral pharmacodynamic monitoring of S6 phosphorylation by flow cytometry during clinical trials combining intensive chemotherapy and signal transduction inhibitors for leukemia. Our approach greatly clarifies pharmacokinetic/pharmacodynamic relationships and has broad application to pre-clinical and clinical testing of drugs whose direct or downstream effects disrupt PI3K/AKT/mTOR signaling. Such compounds include inhibitors of FLT3, c-KIT, BCR-ABL, JAK2, and ras/raf/MAPK. Multicenter/cooperative group phase II testing of sirolimus plus MEC in AML has been initiated to establish the regimen's response rate and test the extent to which our pharmacodynamic studies predict clinical response. Disclosures: Off Label Use: The use of sirolimus in the therapy of AML is investigational and off-label. Carroll:Cephalon consultancy: Consultancy; Sanofi Aventis Corporation: Research Funding; Kyowa Hakko Kirin Pharmaceutical: Research Funding.

Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia In Patients up to Age 75: Comparison of Survival In Patients with An Available Donor Compared to Patients without a Donor

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2381-2381
Author(s):  
Teresa Field ◽  
Janelle Perkins ◽  
Taiga Nishihori ◽  
Joseph Pidala ◽  
Hugo F. Fernandez ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Analysis ◽  
Myelodysplastic Syndrome ◽  
Cell Transplantation ◽  
Research Funding ◽  
Chronic Myelomonocytic Leukemia ◽  
No Donor ◽  
Hematopoietic Stem ◽  
Myelomonocytic Leukemia

Abstract Abstract 2381 Allogeneic hematopoietic cell transplantation (HCT) remains the only curative treatment strategy for patients with Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML). Recent reduction of the transplant related toxicity has permitted the expansion of empiric age limitations for HCT up to 75 years. There has been limited comparative data on HCT focusing on donor availability in patients with MDS/CMML. Between January 2004 and September 2009, a total of 255 new patients (NP) with a diagnosis of MDS or CMML were evaluated for HCT at Moffitt Cancer Center. This report describes the outcomes of these patients with emphasis on donor availability. Donor Search Results: Of the 255 NP, 58 did not undergo a donor search. Reasons for not proceeding were as follows: Medicare declined coverage due to age >65 (18), waiting as have low risk disease (15), patient declined (6), patient seen as second opinion only (7) and patient was not eligible for HCT (12). These patients were not included in the survival analysis. Of the 197 patients who had a donor search initiated, a sibling (SIB) matched unrelated (MUD) or single HLA antigen/allele mismatch (mMUD) unrelated adult donor was found in 173 patients. A suitable adult donor was not identified in the remaining 24 patients. To mitigate bias due to factors giving a survival advantage to patients who were stable enough to survive the donor and proceed to HCT, the survival analysis included only those patients alive 90 days after the donor search was initiated. We have been able to identify donors within this time frame for 99% of the patients who ever found one, although time to transplant is longer. At the 90 days landmark, there were 164 patient in the Donor cohort, and 19 patients in the No Donor cohort. Donor Cohort: The median age was 56.6 yrs (18.5 – 73.5). Ninety-seven patients (59%) were older than 55 yrs and 26 (16%) were above 65 yrs. At the time of the transplant consult, IPSS risk was Low (10), Int-1 (44), Int-2 (48), High (25), AML (21), CMML (13), or not evaluable (NE) (3). Donors included SIB (60), MUD (75) and mMUD (29). Median follow-up of surviving patients is 27.7months (7.2 – 70.7). No Donor Cohort: Median age was 57.4 yrs (32.6 – 68.1) with 12 patients (63%) older than 55 yrs and 3 (16%) patients older than 65 years of age. IPSS at initiation of the donor search was Int-1 (5), Int-2 (6), High (5), AML (1) and CMML (2). Median follow-up is 9.2 months (1.4 – 61.5). Of the 19 patients with no donor, 3 patients received an umbilical cord blood HCT elsewhere and were analyzed by intent to treat. Outcomes: Patients with a donor had significantly improved overall survival from time of donor search vs. patients with no donor (P=0.007) with 2 year OS of 48% vs. 23%, respectively. Median survival for the donor group was 22.2 months [95% CI 14.7 – 35.7] vs. 10.1 months for those without a donor [95% CI 2.3 – 14.7]. Transplant: Of the 164 patients with a donor, 121 (74%) patients received the planned allogenic transplants. The 2-year overall survival (OS) after transplantation is similar for SIB (51%), MUD (39%) or mMUD (68%) transplant recipients (P=0.4), and also similar by age below or above 55 years (P=0.7). These data demonstrate that most patients with MDS or CMML can have a suitable donor identified and proceed to HCT. Overall survival is significantly improved for those patients who have a suitable sibling or unrelated donor. Disclosures: Lancet: Eisai: Consultancy; Celgene: Honoraria. Alsina: Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. List: Celgene: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document