scholarly journals Epigenetic Priming with Decitabine Followed By Low-Dose Idarubicin Plus Cytarabine in AML Evolving from MDS or Higher Risk MDS: A Multicentre Phase 2 Single-Arm Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2594-2594
Author(s):  
Hongyan Tong ◽  
Xinping Zhou ◽  
Chen Mei ◽  
Jin Zhang ◽  
Ying Lu ◽  
...  
Keyword(s):  
Complete Remission ◽  
Dna Methyltransferase ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Treatment Plan ◽  
Refractory Anemia ◽  
Remission Induction ◽  
Phase 2 ◽  
Hematopoietic Stem ◽  
Major Response

Background: DNA methyltransferase inhibitors sensitize leukemia cells to chemotherapeutics. Previous studies have indicated decitabine sequentially combined with idarubicin was an effective treatment for myeloid neoplasms. We therefore conducted a phase 2 study of combination of decitabine followed by low-dose idarubicin plus cytarabine in acute myeloid leukemia (AML) evolving from myelodysplastic syndrome (MDS) and higher risk MDS. Methods: The study was a single-arm, prospective, multicenter study. Patients with AML evolving from MDS and refractory anemia with excess blasts (RAEB-2) high-risk MDS based on the 2008 WHO classification were included. The treatment plan consisted of decitabine 20 mg/m2 daily for 3 consecutive days on days 1-3, followed by idarubicin 6mg/m2 for 3 consecutive days on days 4-6, and cytarabine 25mg/m2 every 12 hours for 5 days on days 4-8. Granulocyte colony stimulating factor ( G-CSF) was given from day 4 and discontinued when neutrophil count increased to 1.0 × 109/L. In case remission was achieved after the first course, a similar second remission-induction course was given, to be followed by either an allogeneic hematopoietic stem cell transplantation (allo-HSCT) or subsequent consolidation courses, which was at the investigator's discretion. Results: A total of 71 patients were enrolled and treated, among whom 44 (62.0%) had AML evolving from MDS, 55 (77.5%) were previously untreated, 12 (16.9%) had an adverse karyotype, and 6 (10.0%) had TP53 mutations. 40 (56.3%) patients achieved a major response, including 20 (28.2%) patients with complete remission (CR) and 20 (28.2%) patients with complete remission with incomplete blood count recovery (CRi). The major response (CR+CRi) rate was 63.6% in AML patients and 44.4% in MDS patients (p=0.142). The median overall survival (OS) was 22.4 months (95% confidence interval (CI) ,17.8-27.0). The median OS was 24.2 months (95% CI 18.0-30.4) and 20.0 months (95% CI 11.2-28.7) for patients with AML and MDS (p=0.347), respectively. The median progress free survival (PFS) for the entire cohort was 12.1 months (95% CI 3.9-20.4). The median PFS was 17.6 months ( 95% CI 13.3-22.0) and 6.8 months (95% CI 0.1-13.6) for patients with AML and MDS (p=0.151), respectively. Patients who achieved CR/CRi had superior OS: 26.4 months ( 95% CI 17.6-35.2) vs. 20.0 months (95% CI 6.2-33.8) in non CR/CRi patients (p=0.042). Also patients who achieved CR/CRi had prolonged PFS: 17.8 months (95% CI 8.6-27.0) vs. 8.6 months (95% CI 3.5-13.8) in those not achieving CR. Patients with platelet doubling achieved significantly higher CR/CRi rate (24/24(100%) vs. 16/47(34.0%), p<0.01) and OR rate (24/24(100%) vs.36/47(76.6%), p=0.012) than those without platelet doubling. Also, patients with platelet doubling after the first cycle of therapy achieved prolonged OS (31.2 months with 95% CI not reached vs. 20.0 months with 95% CI of 15.0-25.0, p=0.029) and PFS (17.6 months with 95% CI of 3.4-31.9 vs. 10.6 months with 95% CI of 7.1-14.0, p=0.018) than patients without platelet doubling. The regimen was well tolerated, with one (1.4%) death within the first 6 weeks. Grade 3 or 4 hematological toxicities were reported in all of the cases. The hematopoietic recovery of patients who achieved CR/CRi was shown by the median recovery of neutrophils to 0.5×109/L of 21 days (range:8-53) and of platelets to >50×109/L of 25 days (range: 8-41). Conclusions: The regimen of decitabine priming followed by low-dose idarubicin plus cytarabine appears to be highly effective and has an acceptable safety profile in patients with AML evolving from MDS or RAEB-2. Further controlled studies are needed to confirm the activity of this regimen, and could help to provide an alternative option for induction therapy in this population. Disclosures No relevant conflicts of interest to declare.

Sorafenib Is Contributing to Salvage Chemotherapy and Is Effective Given Alone for Maintenance in AML FLT3 ITD Patients Relapsing Post Allo Hematopoietic Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5265-5265 ◽  
Author(s):  
Emilia Jaskula ◽  
Janusz Lange ◽  
Mariola Sedzimirska ◽  
Andrzej Lange
Keyword(s):  
Maintenance Therapy ◽  
Low Dose ◽  
Liver Toxicity ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
Salvage Chemotherapy ◽  
Remission Induction ◽  
Comparative Genomic ◽  
High Dose ◽  
Hematopoietic Stem

Abstract Normal karyotype AML patients with FLT3 ITD have a higher risk of relapse than those lacking this mutation (Estey EH, Am J Hematol. 2013). Our comparative genomic hybridization study (77 patients) showed that AML cases with as compared to those without FLT3 ITD had significantly lower number of amplifications or deletions (number of total CNV aberrations: 18±4 vs 51±8, p=0.003). The latter observation in concert with that of others (Thiede, Blood 2002) suggest that FLT3 ITD mutation if present in normal karyotype patients is a key player in the pathogenesis of leukaemia and targeting this mutation may be used successfully in FLT3 ITD positive patients relapsing post HSCT. This was also the case in the two patients presented in this study. Patient UPN 952, male, 53 years old, AML M4 (FAB), normal karyotype, received alloHSCT in 2 CR after completion of two lines of remission induction therapies (first: DA3+7 (Daunorubicin, Ara-C), HAM, high dose Ara-C; second: ICE (IDA, Ara-C, VP-16)) and then promptly transplanted. He relapsed 56 days after transplantation. Patient UPN 938, female, 50 years old, AML, normal karyotype, received as an induction DA 3+7, and for consolidation HAM and high dose Ara-C and completed only one course of the maintenance therapy and transplanted in CR. Both cases were transplanted from unrelated donors (10/10 HLA A, B, C, DR and DQ alleles matched), they received myeloablative conditioning (i.v. Busulfan and Cyclophosphamide) and Cyclosporin A as GvHD prophylaxis. At relapse they received salvage chemotherapy tailored to their biological performance (UPN 938 having Age Adjusted Charlson Comorbidity Index 3 received FLAG and UPN 952 with the index 9, ECOG 3, DA2+5). Both cases received in addition Sorafenib (two times 400 mg per day). The response was prompt and the marrow was free from blasts beginning from 11 day post chemotherapy. UPN 952 received as a maintenance only one course of 6-TG with low dose of Ara-C. Due to the substantial comorbidity and liver toxicity WHO3 further chemotherapy treatment was terminated. The patient was left only on Sorafenib (2 times 200 mg per day). UPN 938 was receiving the maintenance therapy (AML protocol) in 6 – 8 weeks intervals based on low dose Ara-C with 6TG or DNR and also Sorafenib (2 times 200 mg per day). In both cases FLT3 signalling pathway (FLT3 Pathway Mutation PCR Array, SABiosciences, Qiagen) revealed a lack of any additional mutation at the check points in FLT3, KRAS, HRAS, NRAS, MEK1, PIK3CA, BRAF and PTEN genes. UPN 938 had in addition to FLT3 ITD mutation c.1807_1808insATGAATATGATCTCAAAT (p.K602_W603insYEYDLK) insertion which relevance was not so far describe. Sorafenib resistance mutations were not found. The patients were on Sorafenib for 8 (UPN 938) and 9 months (UPN 952). The course of UPN938 was uncomplicated. The second case showed mild aGvHD symptoms evolving into cGvHD (skin lesions and dry eye) slowed down with rapamicine. Up to now the patients are in CR and free from FLT3 ITD. The main observation points: - Sorafenib with chemotherapy tailored to the biologic performance of patients contributes to the efficient salvage in patients with relapsing FLT3 ITD positive AML post HSCT and is also effective given alone as a maintenance. - Side effects were seen in one out of two patients likely associated with the blocking of VEGFR signalling transmission (hand foot skin rash, von Willebrandt factor activity – 388%). Conclusion: The use of multikinase inhibitor (Sorafenib) contributes effectively to salvage therapy in FLT3+ AML patients relapsing post alloHSCTSorafenib given alone is able to maintain long-lasting remissionSide effects are individually dependent Supported by NBiR CellsTherpy grant and Byer Health Care Disclosures No relevant conflicts of interest to declare.

scholarly journals Ripk3 Signaling Regulates Hematopoietic Stem Cell Number and Function during Stress

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3714-3714
Author(s):  
Lei Zhang ◽  
Huacheng Luo ◽  
Jing Li ◽  
Hong-Min Ni ◽  
Mark Sellin ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Low Doses ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Leukemia Development ◽  
Serial Transplantation

Background: Among all tissues, bone marrow (BM) is the most sensitive tissue to ionizing radiation (IR)-induced acute tissue damage (ATD) and chronic long-term residual damage (LT-RD). BM failure and a significant reduction in blood cells (pancytopenia) often occurs within days after exposure to IR due to the massive death of proliferative hematopoietic progenitor cells (HPCs). However, due to their quiescent cell cycle status and reduced fidelity of DNA repair feature, many hematopoietic stem cells (HSCs) cannot fully eliminate such damage and enter senescence; this results in LT-RD. Abnormal dysplastic hematopoiesis is the most common LT-RD in most victims of IR, followed by an increased risk of leukemia/lymphoma development. Thus IR exposure is an established cause of BM failure and leukemia. A significant increase in the production of inflammatory cytokines is induced by IR which contributes to the pathogenesis of both ATD and LT-RD. Such inflammatory cytokines induce the activation of Ripk3-Mlkl-mediated necroptotic signaling in HSCs. However, the role of Ripk3-Mlkl signaling in IR-induced damage has not studied. Experimental procedures: The self-renewal capacity of HSCs among Ripk3-/-, Mlkl-/- and WT mice were examined and compared by serial transplantation assay. The phenotypes of ATD and LT-RD induced by different dosages of IR were compared among Ripk3-/-, Mlkl-/- and WT mice. The mechanism by which Ripk3 signaling prevents IR-induced leukemia development was studied. Results: Ripk3-Mlkl signaling is not required for hematopoiesis during homeostatic condition. However, during serial transplantation, inactivation of such signaling prevents stress-induced loss of HSCs. Interestingly, Ripk3 signaling also induces an Mlkl-independent ROS-p38-p16-mediated senescence in HSCs. Thus Ripk3-/- HSCs showed better competitive hematopoietic ability compared to Mlkl-/- and WT HSCs during serial transplantation. A sub-lethal dosage of IR (6Gy) induces Ripk3-dependent NF-κB activation and pro-survival gene expression in HSCs, which is necessary for the survival of damaged HSCs. After 6Gy IR, although DNA damage is repaired in most HSCs within 2 days, a proportion of HSCs in WT and Mlkl-/- mice fail to fully repair the damage and undergo p53-p21-dependent senescence. However such cells in Ripk3-/- mice die from apoptosis. Thus the remaining HSCs in Ripk3-/- mice should be functionally normal, while a proportion of the remaining HSCs in Mlkl-/- and WT mice remain damaged but senescent, all as demonstrated by competitive hematopoietic reconstitution assay. Multiple low-doses of IR (1.75Gy once week × 4) induce HSC exhaustion in WT mice but not in Ripk3-/- and Mlkl-/- mice. Interestingly, almost all Ripk3-/- mice develop acute lymphoblastic leukemia within 200 days after such low dose IR, while 45% of WT and 60% of Mlkl-/- mice develop thymomas within 360 days (see Figure). Mechanistically, such low-dose IR stimulates chronic inflammatory cytokine production. Such cytokines induce Ripk3-Mlkl-mediated necroptosis in response to HSC exhaustion observed in WT mice. These cytokines also induce Ripk3-ROS-p38-p16-mediated senescence in response to impaired HSC functioning observed in both WT and Mlkl-/- mice. In Ripk3-/- mice, due to the lack of both necroptotic and senescent signaling, mutant HSCs accumulate and leukemia development is accelerated. Conclusion: Ripk3 signaling plays distinct roles in HSCs in response to different doses of IR. High-dose IR induces Ripk3-dependent NF-κB/survival signaling, which is required for the survival of HSCs which fail to repair the damage. Thus temporal inhibition of Ripk3-NF-κB signaling might help to remove the damaged HSCs thus preventing the occurrence of LT-RD. However multiple low-doses of IR induces Ripk3 activation in HSCs which represses leukemia development by inducing both ROS-p38-p16-mediated senescence and Ripk3-Mlkl-mediated necroptosis. Induced activation of Mlkl-necroptosis might help to repress leukemia development by removing damaged HSCs. Disclosures No relevant conflicts of interest to declare.

Clinical and Biological EFFECTS of 5-Azacitidine FIVE Days/Monthly Schedule IN Symptomatic LOW-RISK (IPSS: 0-1) Myelodisplastic Patient.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4851-4851
Author(s):  
Carla Filí ◽  
Marco Gobbi ◽  
Giovanni Martinelli ◽  
Carlo Finelli ◽  
Ilaria Iacobucci ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Biological Effects ◽  
Treatment Plan ◽  
Low Risk ◽  
Refractory Anemia ◽  
Hematologic Toxicity ◽  
Polymorphism Analysis ◽  
Cytokine Network ◽  
Who Grade ◽  
Biological Studies

Abstract Abstract 4851 Background Nucleoside 5-Azacitidine (5-Aza) administered at a dose of 75mg/mq/day subcutaneously for 7 days, every 28 days, induces high hematologic response rates, reduces progression to acute myeloid leukaemia (AML) and increases overall survival in the high risk MDS patients. Aim The use of 5-Aza in the earlier phases of MDS could reduce the proliferative advantage of MDS clone and favours the regrowth of normal hematopoiesis. In the setting of low-risk MDS patients lower doses of 5-Aza could be enough to induce hematologic responses. We attempted to use an alternative schedule, 75 mg/mq subcutaneous daily for 5 consecutive days every 28 days, for a total of 8 courses, to evaluate its efficacy and tolerability in low risk MDS patients. Pharmacogenomic studies (gene expression profile and single nucleotide polymorphism analysis), cytokine network and phosphatidylinositol-phospholipase C – β1 (PI-PLC - β1) expression, before and after 5-Aza treatment, were planned to identify new biological markers to predict the response. Methods From September 2008 to August 2009, 25 patients were enrolled into the study. According to WHO criteria 12 patients had refractory anemia (RA), 5 patients refractory cytopenia with multilineage dysplasia (RCMD), 7 patients refractory anemia with excess blasts-1 (RAEB-1) and 1 patient refractory anemia with ringed sideroblasts (RARS). All patients were classified as Low Risk (IPSS score 0-1). Age at diagnosis ranged between 56 and 84 years. All patients failed previously EPO therapy and were in chronic red blood cell (RBC) supportive care with a median transfusions requirement of 4 units/monthly. The response treatment criteria was according to IWG 2006. Results 9/25 (36%) patients completed at least 4 courses of therapy and only 6/25 (24%) patients finished the treatment plan (8 courses). Five patients obtained an hematologic improvement (3 erythroid response and 2 neutrophil response) whereas 4 patients maintained a stable disease. The others 16 patients are ongoing. The drug was very well tolerated. WHO grade III hematologic toxicity consisted in neutropenia (1 case) and thrombocytopenia (1 case) was observed in only two patients, but it was transitory and no delay of treatment was necessary. Conclusion Our preliminary results show that the 5-Aza five days/monthly schedule is very well tolerated and it appears to induce hematologic improvements as well as the seven days/monthly schedule, at least in the low-risk MDS setting. Biological studies will be useful to elucidate the genetic bases of sensititvity or resistance to 5-AZA and to optimise the therapy.Acknowledgments: this work was supported by MIUR 2008. Disclosures No relevant conflicts of interest to declare.

Analysis of TCR Vgamma and Vdelta Repertoire and Clonality of T Cells in MDS Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4833-4833
Author(s):  
SuXia Geng ◽  
Xin Du ◽  
Yangqiu Li ◽  
Jianyu Weng ◽  
Liye Zhong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Clonal Expansion ◽  
Refractory Anemia ◽  
Rt Pcr ◽  
Hematopoietic Stem ◽  
Discriminative Value ◽  
Skew Distribution

Abstract Abstract 4833 Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis and frequent progression to acute myeloid leukemia. The pathophysiology of these syndromes remains poorly explained. The immune system also seems to contribute to the progressive cytopenias observed in MDS in some cases. We investigated the frequency and the discriminative value of TCR gamma and delta CDR3 clonality using RT-PCR and genescan technique in 40 MDS patients (24 male, 16 female),which included refractory anemia(n=1), refractory anemia with with ringed sideroblasts(n=6), refractory anemia with excess of blasts I (n=16)and II (n=17) respectively. The median age was 60 years (range 15-84).The results showed that 35(87.5%) MDS patients expressed all three TCR Vgamma subfamilies. Four(10%) and one(2.5%) MDS patients expressed two and one TCR Vgamma subfamilies respectively. Clonal expansion of T cells in some Vgamma subfamilies could be identified in 31 patients. The clonal expansion of Vgamma2 subfamily were identified most frequently. All the Vdelta subfamilies were absent in 2 MDS patients. The remaining 38 (95%) MDS cases expressed 0-6 Vdelta subfamilies. Vdelta1 and Vdelta2 were expressed most frequently followed by Vdelta8. While only 3(7.5%) patients expressed Vdelta5 subfamilies. Clonal expansion of Vdelta T cells were found in all MDS patients. The most frequent clonal expansion T cell was Vdelta3. In addition, 12 patients expressed monoclonal T cell Vdelta subfamily. Monoclonal expanded T cells were found in Vdelta3, Vdelta4, Vdelta6, Vdelta7 and Vdelta8 subfamilies. In summary,we found that MDS patients showed TCR Vgamma and delta skew distribution and clonal expansion. The absent of TCR Vdelta subfamily was more evident than TCR Vgamma subfamily. These findings provided further evidence that T cell mediated immune processes were a feature of MDS. Disclosures No relevant conflicts of interest to declare.

DNMT3A Mutation Leads to Hematopoietic Dysregulation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2382-2382
Author(s):  
Jie Xu ◽  
Wei-na Zhang ◽  
Tao Zhen ◽  
Yang Li ◽  
Jing-yi Shi ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Epigenetic Modification ◽  
Hematopoietic Cells ◽  
In Vitro Assays ◽  
Clinical Samples ◽  
Hematopoietic Stem

Abstract Abstract 2382 Epigenetic modification process is required for the development of hematopoietic cells. DNA methyltransferase DNMT3A, responsible for de novo DNA methylation, was newly reported to have a high frequency of mutations in hematopoietic malignancies. Conditional knock-out of DNMT3A promoted self-renewal activity of murine hematopoietic stem cells (HSCs). However, the role of mutated DNMT3A in hematopoiesis and its regulative mechanism of epigenetic network mostly remain unknown. Here we showed that the Arg882His (R882H) hotspot locus on DNMT3A impaired the normal function of this enzyme and resulted in an abnormal increase of primitive hematopoietic cells. In both controlled in vivo and in vitro assays, we found that the cells transfected by R882H mutant promoted cell proliferation, while decreased the differentiation of myeloid lineage compared to those with wild type. Analysis of bone marrow (BM) cells from mice transduced by R882H reveals an expansion of Lin−Sca-1+C-kit+ populations and a reduction of mature myeloid cells. Meanwhile, a cluster of upregulated genes and downregulated lineage-specific differentiation genes associated with hematopoiesis were discovered in mice BM cells with R882H mutation. We further evaluated the association of mutated DNMT3A and HOXB4 which was previously detected to be highly expressed in clinical samples carrying R882 mutation. Compared with wildtype DNMT3A, R882H mutation disrupted the repression of HOXB4 by largely recruiting tri-methylated histone 3 lysine 4 (H3K4). Taken together, our results showed that R882H mutation disturbed HSC activity through H3K4 tri-methylation, and transcriptional activation of HSC-related genes. Disclosures: No relevant conflicts of interest to declare.

Final Results of a Phase 2 Open-Label, Monotherapy Efficacy and Safety Study of Quizartinib (AC220) in Patients ≥ 60 Years of Age with FLT3 ITD Positive or Negative Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 48-48 ◽  
Author(s):  
Jorge E. Cortes ◽  
Alexander E Perl ◽  
Hervé Dombret ◽  
Sabine Kayser ◽  
Björn Steffen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Complete Remission ◽  
Qt Interval ◽  
Median Overall Survival ◽  
Phase 1 ◽  
Phase 2 ◽  
Interval Prolongation ◽  
Hematopoietic Stem ◽  
Qt Interval Prolongation ◽  
Duration Of Response

Abstract Abstract 48 FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib (AC220) is an oral FLT3 receptor tyrosine kinase inhibitor that is active against both ITD mutant and wild type FLT3, and has shown promising activity in a Phase 1 study of patients (pts) with AML. This Phase 2 study was conducted to assess the efficacy and safety of quizartinib monotherapy in FLT3-ITD positive (+) and FLT3-ITD negative (-) pts with a total of 333 pts included in two cohorts. Cohort 1 included pts aged ≥ 60 yrs with AML relapsed in <1 yr or refractory to 1st-line chemotherapy. A total of 134 pts were included in this cohort and constitute the basis for this analysis. Data through 31 January 2012 from 134 pts in this cohort were analyzed. These pts included 92 (69%) who were FLT3 ITD(+), 41 (31%) who were FLT3-ITD(-), and 1 (1%) whose FLT3-ITD status was unknown. Half the 92 FLT3-ITD(+) pts and 46% of the 41 FLT3-ITD(-) pts were male. The FLT3-ITD(+) pts had a median age of 70 yrs (range 54 to 85 yrs), and the FLT3-ITD(-) pts had a median age of 69 yrs (range 60 to 78 yrs). Pts received quizartinib at a starting dose of 90 mg/day (females) or 135 mg/day (males and 1 female), and were treated continuously during 28-day cycles. The composite complete remission (CRc) rate included complete remission (CR), complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete hematologic recovery (CRi). For FLT3-ITD(+) pts the CRc rate was 54% (0 CR, 3% CRp, and 51% CRi), with a median duration of response of 12.7 weeks and median overall survival of 25.3 weeks. Of those refractory to their last AML therapy, 39% achieved a CRc with quizartinib. For FLT3-ITD(-) pts the CRc rate was 32% (2% CR, 2% CRp, and 27% CRi), with a median duration of response of 22.1 weeks and median overall survival of 19.0 weeks. Of those refractory to their last AML therapy, 44% achieved a CRc with quizartinib. Efficacy Results in Relapsed/Refractory AML Pts ≥ 60 Yrs FLT3-ITD(+) (N = 92) FLT3-ITD(−) (N = 41) Cumulative CRc, n (%) 50 (54) 13 (32) CRc + PR, n (%) 66 (72) 17 (41) Prior nonresponders achieving CRc to quizartinib, n (%) 12/31 (39) 8/18 (44) Subjects discontinuing quizartinib because of HSCT, n (%) 9 (10) 1 (2) Median CRc duration, weeks 12.7 22.1 Median overall survival, weeks 25.3 19.0 CRc = composite complete remission; HSCT = hematopoietic stem cell transplantation; PR = partial remission. The most common (≥20%) treatment-related adverse events (AEs) were nausea (40%), fatigue (31%), anemia (28%), QT interval prolongation (25%), diarrhea (23%), vomiting (23%), dysgeusia (22%), and febrile neutropenia (20%). The most common (≥10%) Grade 3 or 4 treatment-related AEs were anemia (25%), febrile neutropenia (20%), QT interval prolongation (13%), and thrombocytopenia (12%). An AE of QT interval prolongation occurred in 33/134 pts (25%) and was Grade 3 or 4 in 17 pts (13%). There was 1 occurrence of Grade 4 QT prolongation with torsade de pointes. QT interval prolongations were transient, and none were fatal. A total of 17 pts (13%) experienced a treatment-related AE resulting in discontinuation of quizartinib. The final data from this Phase 2 study for elderly relapsed/refractory AML pts with few other available therapy options confirm the high degree of activity of quizartinib monotherapy in FLT3-ITD(+) pts and also suggest activity in FLT3-ITD(-) pts. These data represent the highest level of single agent activity observed to date for FLT3-targeted therapy in elderly pts with relapsed/refractory FLT3-ITD(+) AML. Of clinical significance in this elderly population, a number of pts refractory to prior therapy responded to quizartinib, with some pts (8%) able to bridge to potentially curative hematopoietic stem cell transplantation. Safety findings were manageable, and were primarily myelosuppression and QT prolongation that was mitigated with dose modifications. Results from the total study population will be presented. Further Phase 1 and 2 studies investigating lower doses of quizartinib as monotherapy and in combination with other agents in FLT3-ITD(+) and FLT3-ITD(-) AML are being planned/ongoing. Disclosures: Cortes: Novartis: Consultancy. Perl:Ambit Biosciences: Consultancy. Dombret:Celgene: Consultancy. Steffen:Novartis: Travel/accommodations/meeting expenses Other. Rousselot:Ambit Biosciences: Consultancy. Martinelli:BMS, Novartis; Pfizer, Roche: Consultancy. Estey:Ambit Biosciences: Consultancy. Burnett:Ambit Biosciences: Consultancy. Gammon:Ambit Biosciences: Employment. Trone:Ambit Biosciences: Employment. Leo:Ambit Biosciences: Employment. Levis:Ambit Biosciences: Consultancy.

A 5-Day Cytoreductive Chemotherapy Followed By Haplo-Identical HSCT (FA5-Bucy) As a Tumor-Ablative Regimen Improved the Survival of Patients with Advanced Hematological Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4674-4674
Author(s):  
Ting Yang ◽  
Jinhua Ren ◽  
Qiaoxian Lin ◽  
Xiaohong Yuan ◽  
Xiaofeng Luo ◽  
...  
Keyword(s):  
Complete Remission ◽  
Hematological Malignancies ◽  
Conflicts Of Interest ◽  
Severe Infection ◽  
Salvage Chemotherapy ◽  
Tumor Burden ◽  
Hematopoietic Stem ◽  
Entire Study ◽  
Gvhd Prophylaxis ◽  
Reduce Tumor Burden

Abstract Background: Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has been used when HLA-matched siblings are not available. Conditioning regimens aim to reduce tumor burden prior to HSCT and provide sufficient immunoablation. Patients and Interventions: We report the outcome of haplo-HSCT in 63 consecutive patients (19 females/44 males) with high-risk or relapsed/refractory hematological malignancies (n=29-AML; 8-sAML; 19-ALL; 5-advanced-MDS; 2-CML-BC), followed at our Center from 2/2013 to 12/2015. Median age was 20 years (range: 1.1-49). Twenty-one patients achieved remission prior to transplant, while 42 did not (7%-98% BM blasts). No patient had severe infection or organ failure before HSCT. Patients received FA5-BUCY registered on http:// ClinicalTrials.gov (NCT02328950), i.e., 5-day salvage chemotherapy (Fludarabine/Ara-C) and conditioning (Busulfan/Cyclophosphamide). GvHD prophylaxis included ATG, CsA, MMF and short-term MTX. Results: All patients received stem cells from bone marrow and peripheral blood, and achieved successful engraftment, except two who died before. With a median follow-up of 269 days (120-1081), 42/63 patients are still alive and disease-free. Two-year OS and RFS were similar in patients not in remission and in those in complete remission (61.3% vs 56.3%, p=0.88; 58.3% vs 56.3%, p=0.991). Non-relapse mortality and relapse incidence were 22.2% and 11.1%, respectively. Severe acute-GvHD occurred in 4/63 patients. Transplant-related mortality was low at day+100 (17.5%) and for the entire study period (20.6%). Unexpectedly, few patients experienced mild-to-moderate toxicity, and main causes of death were infection and GvHD. BM blast counts, age,and donor-recipient gender-pairs did not affect the outcome. Less chemotherapy cycles prior to HSCT might result in more favorable outcome. Conclusions: Thus, haplo-HSCT with FA5-BUCY appears promising for advanced disease, especially when TBI and amsacrine, used for FLAMSA, are not available and in pediatric patients for whom TBI is not recommended. Two-year OS and RFS in patients not in remission prior to HSCT compared to those in complete remission. The two-year OS and RFS in patients not in remission were similar to those from patients in complete remission (61.3% vs 56.3%, p=0.88; 58.3% vs 56.3%, p=0.991). Two-year OS and RFS in patients not in remission prior to HSCT compared to those in complete remission. / The two-year OS and RFS in patients not in remission were similar to those from patients in complete remission (61.3% vs 56.3%, p=0.88; 58.3% vs 56.3%, p=0.991). Disclosures No relevant conflicts of interest to declare.

scholarly journals Efficacy and Safety of Decitabine in Combination with G-CSF, Low-Dose Cytarabine and Mitoxantrone in Pediatric Refractory and Relapse Acute Myeloid Leukemia and MDS-Raebt

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5175-5175
Author(s):  
Liyan Fan ◽  
Aili Chen ◽  
Yixin Hu ◽  
Peifang Xiao ◽  
Jun Lu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Pediatric Patients ◽  
Efficacy And Safety ◽  
Hematopoietic Stem ◽  
Grade Ii ◽  
Acute Myeloid

Abstract Background: It is difficult for pediatric refractory and relapse acute myeloid leukemia (RR-AML) and MDS-RAEB/RAEBT patients to achieve complete remission (CR) and these patients develop recurrence and die of either disease progression or associated complications. The CAG regimen (cytarabine, aclarubicin and G-CSF) has been widely used in treating patients with MDS-EB and AML-MRC in Asia. Likely, Short term CAG derived regimens called low dose induction therapy, MAG regimen (Mitoxantrone for 3 doses, cytarabine and G-CSF for 10 days) also showed efficacy in De Novo AML. However, MAG regimen showed less efficacy in RR-AML and MDS-5(5q-). Purpose: To evaluate the clinical efficacy and safety of low-dose decitabine in combination with low-dose MAG regimen (D-MAG regimen) in the treatment of RR-AML and MDS-RAEB/RAEBT. Method A total of 17 patients with MDS-RAEB/RAEBT and RR-AML((2 cases of MDS-RAEB, 3 cases of MDS-RAEBT, 10 cases for refractory AML, and 2 cases for relapse AML) from June 2017 to April 2018 in our center were included in the retrospective study. All the patients were treated with decitabine of 20 mg/m2 for 5 days and followed by 10 days of MAG regimen (cytarabine of 10mg/m2 q12h for 10 days, mitoxantrone of 5 mg/ m2.d for 3 days, and G-CSF of 5μg/kg.d for 10 days),called D-CAG regimen. After two cycles of induction chemotherapy, the patients who obtained CR received consolidation chemotherapy or hematopoietic stem cell transplantation (HSCT). Results Among a total of 17 patients, the median age was the median age was 102 months (32-200 months) and 64.71 % of them were male. Characteristic features of these patients were illustrated in Table 1. Only 2 cases died of severe lung infection due to continuous agranulocytosis who had been received high dose induction therapy (Daunorubicin of 50mg/M2.d for 3 days, cytarabine of 100mg/m2 q12h for 10 days, and Etoposide of 150mg/m2.d for 5 days) for 2 cycles with poor physical condition before D-MAG. In the other 15 cases, 10 of them had complete remission (CR) after the first course of treatment, 4 cases were partial remission (PR), 1 case with a high blast cells at 25% indicated a poor response to D-MAG, and the effective rate was 93.3%. Among 4 children with PR, one case reached CR after the second courses of treatment. The most common adverse reactions in all children were hematological toxicity, grade III-IV. Liver damage was found in 2 cases, grade I and grade II respectively. There were 3 cases of oral side reactions, 1 case in grade I and 2 cases in grade II. The gastrointestinal reactions in all children were grade I - II. By July 2018, the median follow-up was 11 months (7-16months). Among 15 patients after D-MAG, 11 patients received HSCT. The twelve-month survival rate was 88.24% and the median leukemia-free survival (LFS) was 11 months. Conclusion The low-dose decitabine in combination with Low-dose MAG regimen improved CR rate for pediatric patients with MDS-RAEB and RR- AML, and is a promising treatment for pediatric patients with MDS/RR-AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals The First Experience of Treatment of Patients with Primary Mediastinal Lymphoma Using the R-m-NHL-BFM-90/R-EPOCH Protocol

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5391-5391
Author(s):  
Nelly Gabeeva ◽  
Daria Koroleva ◽  
Anastasya Belyaeva ◽  
Anna Smolyaninova ◽  
Natalia G. Chernova ◽  
...  
Keyword(s):  
Complete Remission ◽  
Treatment Plan ◽  
Hematologic Toxicity ◽  
Hematopoietic Stem ◽  
Number Of Patients ◽  
Mediastinal Lymphoma ◽  
Pet Ct ◽  
Mediastinal Disease ◽  
Primary Mediastinal Lymphoma

Abstract Background: Primary mediastinal lymphoma (PML) is an aggressive, but curable disease. Given the rarity of disease there is no consensus on the most effective program. The most encouraging results with R-DA-EPOCH program (Dunleavy K. et al, 2013) demonstrated high response rate and improved long-term event-free (EFS) and overall survival (OS) without radiotherapy. However, in the real world setting we still face a very difficult treatment decision: on the one hand, due to increasing treatment-related toxicities about 20% of patients (pts) didn`t complete the treatment plan, on the other, approximately 10% of patients had disease progression or relapse. Based on our own successful experience of treating aggressive B-cell lymphomas by using the previously published R-m-NHL-BFM-90 protocol, we used a strategy of intensive induction of remission (blocks A, B), followed by de-escalation of therapy with 2 or 4 courses of R-EPOCH depending of interim PET/CT (iPET/CT) results. Here we report the first results of the toxicity and efficacy assessment of the response-adapted program R-m-NHL-BFM-90/R-EPOCH for patients with untreated primary mediastinal lymphoma. Methods: Eleven previously untreated patients (pts) with PML underwent R-m-NHL-BFM-90/R-EPOCH treatment between October 2004 and July 2015 in Federal State Budgetary Organization «National Research Center for Hematology of Russian Federation Ministry of Healthcare»; median age 34 years old (range 24-50); M\F=2\9; Ann Arbor stage >I in 11 (100%). All the patients had one or more adverse factors (bulky mediastinal disease>10 cm in 10 pts, soft tissues involvement in 7 pts, breast in 4 pts; elevated lactate dehydrogenase level in 7 pts, pleural effusion in 5 pts). The treatment plan consisted of: (i) pre-phase (dexamethasone and cyclophosphamide); (ii) induction of remission (courses A and B of NHL-BFM-90 program that was modified in the following way: the dose of methotrexate was reduced to 1500mg/m2 (12 h) in course A, doxorubicin in dose 50mg\m2 was added on the third day of course A); (iii) consolidation with R-EPOCH without dose escalation (2 courses in pts with negative iPET/CT (DS1-3) and 4 courses in pts with positive iPET/CT (DS 4-5)). Results: All the patients completed the treatment plan. Hematologic toxicity grade 3-4 was observed only during the induction therapy, mainly after block A. After the induction with R-m-NHL-BFM-90 8 out of 11 patients (72%) were iPET/CT-negative and received 2 additional courses of R-EPOCH; 3 out of 11 patients (28%) were iPET/CT-positive and received 4 additional courses of R-EPOCH. Only 1 patient`s response was assessed as DS4 at the end-of-treatment PET/CT. She received autologous transplantation of hematopoietic stem cells and has now been in complete remission for 12 months. With a median follow-up of 10 months (range 1-29) all the patients are alive in complete remission. Conclusions: Despite a small number of patients and a short follow-up period, our results suggest that the response-adapted strategy of treatment is a reasonable option for PML patients, even in high risk of treatment failure. Disclosures No relevant conflicts of interest to declare.

scholarly journals FoxM1 Haploinsufficiency Drives Clonal Hematopoiesis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 726-726
Author(s):  
Chunjie Yu ◽  
Yue Sheng ◽  
Zhijian Qian
Keyword(s):  
Cell Cycle ◽  
Progenitor Cells ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Clonal Expansion ◽  
Brdu Incorporation ◽  
Quiescent State ◽  
Dapi Staining ◽  
Hematopoietic Stem ◽  
Increased Risk

Hematopoiesis is an orchestrated process in which hematopoietic stem cells (HSCs) can self-renew and produce all lineages of blood cells. Majority of HSCs are in a quiescent state with a low growth rate. However, some genetic mutations that occur in HSCs impel HSCs to exit the quiescent state and to proliferate excessively, which enables mutant HSCs to outcompete normal HSCs and leads to clonal expansion of mutant HSCs. Myelodysplastic syndromes (MDSs) as a clonal disease, arise from the expansion of mutant HSCs and are characterized by morphologic dysplasia, ineffective hematopoiesis and an increased risk of transformation to acute myeloid leukemia. FoxM1 is one of transcription factors in the family of Fox ('Forkhead box') proteins. Analysis of public database revealed that the expression level of FOXM1 was decreased significantly in CD34 + cells from a subset of patients with MDS as compared to healthy individuals. Thus, we sought to determine whether haploinsufficiency of FOXM1 contributes to the development of MDS in mice. Our study showed that haploinsufficiency of Foxm1 led to an expansion of hematopoietic stem/progenitor cells in mice. Since FoxM1 has previously been implicated in regulation of cell cycle, we determined the cell cycle status of Foxm1 heterozygous HSCs. By BrdU incorporation assay, we showed that Foxm1 heterozygous HSCs have an increased S phase and G2/M phase as compared to control HSCs from wildtype mice. Additional analysis with Hochest33342/Pyronin-Y staining and Ki67/DAPI staining showed a significant decrease in the number of quiescent (G0) cells in Foxm1 heterozygous HSCs as compared to control HSCs. These results suggest that FoxM1 haploinsufficiency promotes HSCs to exit quiescence and to enter cell cycle, thereby leading to exhaustion of HSCs. To further assess the function of Foxm1 heterozygous HSCs in vivo, we performed competitive repopulation assay. We found that Foxm1 haploinsufficiency HSCs exhibited competitive repopulation advantage in the first and secondary recipient mice, but displayed significantly decreased capacity of repopulation in tertiary recipient mice as compared to control HSCs, suggesting that Foxm1 haploinsufficiency promoted clonal expansion of HSCs, which leads to an exhaustion of HSCs eventually. HSC proliferation can be induced by some specific immune effectors such as Toll-like receptor 4 (TLR4). Lipopolysaccharide (LPS) stimulates HSC proliferation by activating TLR4 signaling pathway. Low dose of LPS treatment over time accelerated the development of MDS in mice. Interestingly, low dose of LPS injection chronically induced defects in hematopoiesis in Foxm1 haploinsufficient mice but not the control wildtype mice. Recipient mice transplanted with Foxm1 heterozygous BM cells but not the control BM cells developed MDS-like disease with cytopenia and a decreased number of hematopoietic stem/progenitor cells after LPS stimulation. Moreover, we found that nearly half of aged Foxm1 haploinsufficient mice (20 months) developed splenomegaly. Analysis of histologic sections in Foxm1 haploinsufficient mice showed that the mice developed hematopoietic dysplasia including dysplastic megakaryocytes with bizarre-shaped nuclei in bone marrow and extramedullary hematopoiesis with accumulation of myeloid cells in spleen. RNA-seq analysis indicated that haploinsufficiency of Foxm1 perturbed multiple stem cell-maintenance mechanisms especially in metabolic processes. Taken together, our studies suggest that Foxm1 haploinsufficiency in mice causes clonal expansion of HSCs and promotes MDS-like disease, which underscores the significant role of FOXM1 downregulation in the initiation and development of human MDS. Disclosures No relevant conflicts of interest to declare.

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