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.

Combined Analysis of Treatments for Pediatric T-ALL in KYCCSG Protocols, ALL-96 and ALL-02.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4102-4102
Author(s):  
Yasuhiro Okamoto ◽  
Yoshihisa Nagatoshi ◽  
Akinobu Matsuzaki ◽  
Aiko Suminoe ◽  
Hideki Nakayama ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cranial Irradiation ◽  
High Dose ◽  
Costal Margin ◽  
Hematopoietic Stem ◽  
Combined Analysis

Abstract Abstract 4102 Background Previously we reported the result of Kyushu-Yamaguchi Children's Cancer Study Group (KYCCSG) protocol, ALL-96, for pediatric acute lymphoblastic leukemia (ALL) (ASH meeting in 2005). The 7-year event-free survival (EFS) and overall survival (OS) rates were 72% (95% CI; 68 - 76 %) and 85 % (95% CI; 80 - 90 %), respectively. Following protocol, ALL-02, was aimed to assess the usefulness of polymerase chain reaction (PCR)-based minimal residual disease (MRD) in the same context as ALL-96 protocol. Purpose In this combined analysis, we analyzed the outcome and risk factors for relapse/survival in children with T-ALL who were treated with the ALL-96/ALL-02 protocols. Study Design and Treatment A total of 42 patients (22 of 218 in ALL-96 and 20 of 165 in ALL-02, 26 males and 16 females) with median age of 8 years (range 1 - 14) were treated. Patients were classified into 2 groups, standard risk (SR) and high risk (HR). HR patients had one of the followings: high white blood cell (WBC) counts more than 50,000/μl, T-cell immunophenotype, central nervous system (CNS) disease at diagnosis, organomegaly (hepatomegaly or splenomegaly more than 5 cm below costal margin), M2/3 marrow at day 15 of induction therapy. Both protocols consisted of induction, early intensification, consolidation, late intensification and maintenance therapy. Predonisolone (PSL), weekly vincristine (VCR), 4 doses of daunorubicin (DNR), 8 doses of L-asparaginase (L-asp) and 2 or 4 doses of intrathecal (IT) methotrexate (MTX) depending on the CNS status, were given during induction. In early intensification, DNR, cytarabine (CA), etoposide and 6-mercaptopurine (6-MP) were given. Consolidation consisted of intermediate dose of MTX, combination of cyclophosphamide(CPM), CA and 6-MP, and high dose CA. Late intensification similar to induction included 2 weeks of dexamethasone (DEX), weekly VCR, 2 doses of pirarubicin, single dose of CPM, 5 doses of L-asp and IT-MTX followed by combination of CA, 6-MP, IT-MTX along with 18 Gy cranial irradiation in 12 fractions. In ALL-96 protocol, patients were randomized to receive maintenance therapy of either combination of 6-MP/MTX and DEX/ VCR pulse (A-arm) or LSA2L2-type therapy (B-arm). In ALL-02 protocol, A-arm was chosen as a maintenance therapy based on result of ALL-96. No patient underwent hematopoietic stem cell transplantation (SCT) in 1st complete remission (CR). Results Median follow-up periods were 96 and 38 months in ALL-96 and ALL-02, respectively. Two patients were off-protocol before achieving CR because of toxicity and chromosome abnormality with t(4;11). Induction rate in 40 patients was 95%. All 14 events were relapses and TRM rate was 0%. Last event occurred at 40 months. The sites of relapse were isolated BM in 9, isolated testis in 2, isolated CNS in 1 and combined sites in 2. Nine died from disease progression and 2 died from toxicity after SCT in 2nd CR. The 4-year EFS and OS rates in all patients were 55 % (95 % CI; 39 – 71 %) and 71 % (95 % CI; 56 -86 %), respectively. EFS of ALL-96 and ALL-02 were 50 %[95 % CI; 29 -71 %]) and 65 % [95 % CI; 45 - 85 %]), respectively. OS of ALL-96 and ALL-02 were 59 % [95 % CI; 39 – 80 %]) and 90 % [95 % CI; 77 - 103 %]), respectively (p = 0.063). EFS of patients treated in A and B arm were 60 % [95 % CI; 41 -71 %]) and 55 % [95 % CI; 25 - 84 %]), respectively. None of age, sex, organomagaly, WBC, chromosomal abnormalities, CNS status, protocol, and maintenance arm was identified as a risk factor for relapse or survival. Two of 10 (ALL-96) and 3 of 4 (ALL-02) relapsed patients have survived with allogeneic SCT. Conclusion Although T-ALL patients received an intensified treatment including cranial radiation, the outcome was unsatisfactory. One possible explanation for better OS in ALL-02 protocol is that the majority of relapsed patients in ALL-02 were salvaged by SCT in 2nd CR. Disclosures: No relevant conflicts of interest to declare.

High-Risk AML, Including Flt3ITD+, Exhibits Resistance To Conventional Cytarabine Induction Associated With Diminished ENT1 and p16INK Expression: Evidence For Epigenetic Repression and HDAC Inhibitor Modulated De-Repression

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2525-2525 ◽  
Author(s):  
H. Scott Boswell ◽  
Sushil Gupta ◽  
Rui Gao ◽  
Katie J Sargent ◽  
Larry D. Cripe ◽  
...  
Keyword(s):  
Hdac Inhibitor ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
Trisomy 13 ◽  
Epigenetic Mechanism ◽  
Remission Induction ◽  
High Dose ◽  
Event Free Survival ◽  
Free Survival ◽  
Poor Risk

Abstract Resistance to conventional induction chemotherapy involving continuous infusion cytarabine, 100mg/m2 X 7 days, has been observed in several poor-risk AML phenotypes including normal karyotype with Flt3ITD or DNMT3A mutations (JP Patel, NEJM; 2012). However, escalated anthracycline dosing along with conventional cytarabine was determined to confer superior survival among certain subgroups, including mDNMT3A, in the randomized E1900 trial. We asked whether optimal therapy among other AML molecular subgroups, where the former combination may be inferior, might preferentially require intermediate/high-dose cytarabine within induction regimens containing conventional anthracycline. This hypothesis was generated in recognition of diminished cytosine analog (cytarabine, azacytidine) transport by the rate-limiting equilibrative nucleoside transporter (ENT1) in poor-risk groups (J Hummel-Eisenbeiss, Mol Pharm, 2013) and observation of disparate cytarabine LC50’s among known AML subgroups: normal karyotype (NK), =/> 10 micromolar; CBF+ve, 1-4 micromolar. In an attempt to identify an impact of diminished ENT1 expression on successful remission induction at day+14 of conventional “7+3” therapy and/or associated severe limitation of event-free survival, an unselected group of 20 AML patients’ blasts were comparatively studied for ENT1 by immunoblot and/or quantitative RT-PCR, and as well were subjected to parallel analysis of p16INK4a transcripts, whose diminution, accompanying an epigenetic mechanism, is also implicated in poor treatment outcomes (HJ DeJonge, Blood; 2009). Median follow-up of the 20 patients exceeded 12 months. Among patients with high ENT1 expression by immunoblot (50kd species) were included CBF+ve and NK AMLs, of whom 7/8 pts. overall (2 CBF+ve, 1 NK-mNPM1, 1 NK-absent Flt3ITD, 2 NK Flt3ITD+, 1 complex/trisomy 13) had no evidence of leukemia on a day +14 marrow, and the event-free survival exceeded the 12 month mark. By contrast, among patients with 2-5-fold lower blast cell ENT1 expression were included a higher fraction of poor-risk (complex) karyotype or normal karyotype with Flt3ITD mutation (62%). These patients either had persistent disease at day +14, or had less than 3-month event-free survival. There was correspondence for differing ENT1 protein expressions with transcript quantity, and coupling between low/nondetection or high/detection of both ENT1/p16INK4, respectively, predicted divergent outcome of therapy from usual prognostic groups. Because the mechanism of repressed ENT1 transcriptional expression resulting from transduction of Flt3ITD gene in model AML systems is linked to transfactor c-jun interaction on the ENT1/SLC29A1 promoter, we tested the activity of tyrosine kinase/FLT3 inhibitor or HDAC inhibitor (SAHA), or their combination, on upmodulation of ENT1 in cultured primary blasts. In patient blasts in which phospho-c-jun expression was associated with diminished ENT1 expression, application of inhibitor(s) yielded downregulation of p-jun and upregulation of ENT1. This result supports an initiative to introduce both epigenetic agent(s) along with intermediate-dose cytarabine into induction therapy of certain poor-risk AML subgroups, including Flt3ITD+. Disclosures: No relevant conflicts of interest to declare.

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.

scholarly journals The Molecular Basis of Long First Remissions in Normal Karyotype AML Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3827-3827
Author(s):  
Francesca Ferraro ◽  
Christopher A Miller ◽  
Amy Abdalla ◽  
Nichole Helton ◽  
Nathan Salomonis ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Somatic Mutations ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
High Dose ◽  
Intermediate Risk ◽  
The Mean ◽  
Cebpa Mutations

Currently, it is not clear why some patients with acute myeloid leukemia (AML) can be "cured" with chemotherapy alone; are they living with small amounts of disease that is held in check by immunologic (or other) mechanisms, or is their disease really eradicated? The percentage of cytogenetically normal AML patients who have long (>5 years) first remissions (LFRs) after chemotherapy alone is low (about 9.1% in patients <60 years and 1.6% in >60 years1). For this reason, most intermediate risk patients are offered allogeneic transplantation to decrease their risk for relapse. To better understand mechanisms of chemotherapy sensitivity in AML, we performed an analysis of the mutation landscape and persistence, using samples from 8 normal karyotype LFR patients (without CEBPA mutations) who received standard "7+3" induction and high dose cytarabine consolidation as their only therapy. The mean age at diagnosis was 43.5 years, and the mean follow up in first remission is 7.6 years; none of these patients has relapsed to date. For each case, we performed enhanced exome sequencing at diagnosis (235x coverage of the entire exome, and ~1008x coverage of recurrently mutated AML genes). Each case had at least one documented AML driver mutation, with a median of 29 somatic mutations in the exome space. We created probes for 225 mutations (mean 28 per case), and performed error-corrected sequencing (Haloplex) for all available remission samples. The mean depth of Haloplex coverage was 1607x, and each sample had at least one AML-specific mutation assayed, with a sensitivity of 1 cell in 1,750 (0.06%). 7/8 patients demonstrated complete clearance of all mutations in all remission samples tested, which was confirmed with digital droplet PCR for 5 cases, with a sensitivity of detection of 1 cell in 100,000. In one case, we detected a persistent ancestral clone harboring DNMT3AR882H, which can be associated with long first remissions for some patients2. Strikingly, the founding clone in all 8 cases had one or more somatic mutations in genes known to drive cell proliferation (e.g. MYC, FLT3, NRAS, PTPN11, Figure 1 top panel). These are usually subclonal mutations that occur late during leukemic progression, suggesting that the presence of a "proliferative hit" in the founding clone might be important for chemotherapy clearance of all the AML cells in a given patient. To support this hypothesis, we analyzed the mutational clearance of 82 AML cases with paired diagnosis and day 30 post-chemotherapy bone marrow samples. We observed that, whether present in the founding clone or in subclones, mutations in MYC, CEBPA, FLT3, NRAS, and PTPN11 cleared after induction chemotherapy in all samples, while other mutations were often persistent at day 30 (e.g. DNMT3A, IDH1, IDH2, NPM1, TET2; Figure 1 bottom panel). Compared to other published sequencing studies of AML, MYC and NRAS mutations were significantly enriched in this small cohort (MYC p= 0.002, and NRAS p= 0.034), with MYC enrichment being particularly striking (37.5% versus 1.8%). All MYC mutations were canonical single base substitutions occurring in the highly conserved MYC Box 2 domain at the N-terminus of MYC (p.P74Q or p.T73N). Overexpression of MYCP74Q in murine hematopoietic progenitors prolonged MYC half life (89 min vs. 44 min for wild type), and enhanced cytarabine sensitivity at all concentrations tested (range 10-1000 nM, p=0.0003), both in vitro and in a MYC-driven leukemia model in vivo. MYC expression measured with flow cytometry in the blasts of the LFR samples was significantly higher (p=0.045) compared to unfavorable risk (complex karyotype) or other intermediate risk categories, but similar to good risk AML (biallelic CEBPA mutations, core binding factor fusion-associated AML, and AML with isolated NPMc), suggesting that activation of the MYC pathway may represent a shared feature of chemosensitive patients. Taken together, these data suggest that some intermediate patients who are effectively "cured" with chemotherapy alone may not have persistent subclinical disease, nor retained ancestral clones that could potentially contribute to relapse. Importantly, these patients often have mutations driving cell proliferation in the founding clone, indicating that the presence of specific mutations in all malignant cells may be critical for complete AML cell clearance with chemotherapy. 1. Blood Adv. 2018 Jul 10; 2(13): 1645-1650 2. N Engl J Med 2018; 378:1189-1199 Disclosures No relevant conflicts of interest to declare.

scholarly journals P179 Glucocorticoid exposure and link to serious adverse events in patients with ANCA-associated vasculitis

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Philip Spearpoint ◽  
Cormac Sammon ◽  
Antonio Ramirez de ◽  
Arellano Serna ◽  
Peter Rutherford
Keyword(s):  
Cardiovascular Disease ◽  
Adverse Events ◽  
Renal Disease ◽  
Real World ◽  
Low Dose ◽  
Remission Induction ◽  
High Dose ◽  
Anca Associated Vasculitis ◽  
Increased Risk ◽  
New Onset

Abstract Background Remission induction in ANCA-associated vasculitis (AAV) is with high dose glucocorticoids (GC) and immunosuppressants. Patients are exposed to high GC dose and/or prolonged low dose. EULAR/EDTA guidelines target 7.5-10mg at 3 months but acknowledge this is often achieved later. This study used UK real world practice data to examine the scale of GC exposure and associated clinical risks in AAV. Methods The study utilised the Clinical Practice Research Datalink (CPRD) - Hospital Episode Statistics (HES) linked database. AAV patients were identified using specific READ and ICD codes and followed between 01/01/1997 and 01/01/2018. GP prescriptions were used to describe periods of continuous GC use, stop and restart and when high dose (&gt; 30mg/day) and low dose (&lt;30mg/day) was prescribed. Diagnostic codes indicative of infections and adverse events linked to GCs were used to estimate rates in the AAV population using a generalized linear model with a Poisson distribution. Results 450 AAV patients with at least one GC prescription were analysed. The median dose decreased to 9.3 mg (IQR 5.0 - 17.0) at 6 months and 5.1 mg (0.00 - 10.0) at 12 months,50% patients were taking &gt; 10mg at 5 months and 25% were still &gt; 10mg at 12 months. However, within 6 months of achieving 10mg/day, 50% relapse to needing dose &gt;10mg, 75% within 2 years and 90% within 6 years. In adjusted Poisson model (age, gender, year of diagnosis before/after 2013) the rate of infection in AAV patients taking high dose was 2.59 times (CI95 1.95, 3.45) that of those on low dose and lower in those not taking GCs (IRR 0.27 (0.22-0.34)). Increased risk of new onset cardiovascular disease (IRR 2.55 (0.92, 7.04)) and new onset renal disease (IRR 3.4 (1.29-8.96)) were higher in patients receiving high dose. Conclusion AAV patients have significant exposure to high dose GCs and in real world practice, GC dose remains higher than recommended in current clinical guidelines. High dose GCs are associated with high risk of infection and new cardiovascular disease and renal disease. This creates a significant patient burden and has implications for healthcare resource use. Disclosures P. Spearpoint: Corporate appointments; Employee of Vifor Pharma. C. Sammon: Corporate appointments; Employee of PHMR. A. Ramirez de Arellano Serna: Corporate appointments; Employee of Vifor Pharma. P. Rutherford: Corporate appointments; Employee of Vifor Pharma. Shareholder/stock ownership; Vifor Pharma.

Cyproterone acetate as initial treatment and maintenance therapy for hirsutism

1985 ◽  
Vol 109 (4) ◽  
pp. 522-529 ◽  
Author(s):  
I. M. Holdaway ◽  
M. S. Croxson ◽  
H. K. Ibbertson ◽  
A. Sheehan ◽  
B. Knox ◽  
...  
Keyword(s):  
Growth Rate ◽  
Side Effects ◽  
Maintenance Therapy ◽  
Cyproterone Acetate ◽  
Hair Growth ◽  
Low Dose ◽  
Sex Hormone Binding Globulin ◽  
Plasma Testosterone ◽  
High Dose ◽  
Dose Therapy

Abstract. Thirty-four patients with hirsutism were treated for 9 months with 100 mg cyproterone acetate (CA) given on days 5–15 of the menstrual cycle together with a combination oral contraceptive containing 2 mg CA and 50 μg ethinyloestradiol (Diane®) given on days 5–25 of the cycle. After 9 months treatment patients were randomised to a 12 month double-blind cross-over trial comparing Diane® plus 25 mg CA with Diane® plus placebo, to test the efficacy of low-dose CA as maintenance therapy. Thirty-one patients (92%) experienced moderate or good subjective improvement in hirsutism on high-dose CA, associated with a 40% mean overall improvement in objective hirsutism grade and 13% overall reduction in hair growth rate measured by a photographic technique. Minor or moderate side effects were experienced by 64% of patients and severe side effects by 11% at this dosage. There was a mean subjective relapse rate of 33% when patients were changed to low dose CA, and relapse rates were not significantly different between the two regimens with 28% relapsing on 25 mg CA + Diane® and 48% on placebo and Diane® (P < 0.05). Despite significant subjective relapse with low-dose treatment there was no significant deterioration in objective hirsutism grade or hair growth rate determined photographically. Levels of plasma testosterone, sex hormone binding globulin, free testosterone (derived) and androstenedione fell significantly on high dose CA and this reduction was maintained during low dose therapy. Cyproterone acetate at high dosage thus appeared an effective agent in the treatment of hirsutism, but 33% of patients considered they deteriorated when changed to low-dose therapy despite maintenance of androgen suppression and lack of change in objective measurements. Maintenance therapy after remission with high-dose CA appears justified since 60% of patients underwent subjective relapse when all treatment was stopped.

Low Dose Thalidomide for the Treatment of Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5146-5146
Author(s):  
Rosane Bittencourt ◽  
Andreia D. Almeida ◽  
Joao R. Friederich ◽  
Flavo Fernande ◽  
Laura Fogliatto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Maintenance Therapy ◽  
Marrow Transplantation ◽  
Low Dose ◽  
Bone Marrow Microenvironment ◽  
Immunoglobulin M ◽  
Remission Induction ◽  
Immunoglobulin Level

Abstract In the last two decades, we have seen a radical change in the therapy and prognosis of Multiple Myeloma (MM). Recent research on the role of the bone marrow microenvironment as integrant part of the biology of MM and the possible therapeutic interference at this level are leading to control and regression of the malignant plasma cell clone with a recognized clinical impact. Thalidomide, an old drug thought to interfere on the bone marrow microenvironment, is active not only for the treatment of refractory patients but also, as was recently shown, for induction and/or remission maintenance therapy. Most of the side effects (somnolence, constipation, fatigue, tremor, bradycardia, edema, and neuropathy) can be managed by reducing the dose and most patients need a dose reduction. The appropriate dose of thalidomide in myeloma is unknown. We treated thirty-five patients with MM with low-dose thalidomide (200mg or less). Twenty four patients were on maintenance therapy (13 after bone marrow transplantation, and 11 after chemotherapy with VCAP/VMCP); 5 patients were treated after relapse, 4 with refractory disease and 2 for remission induction as a first line therapy. Patients were treated at the Hematology and Bone Marrow Transplantation Service of the Hospital de Clínicas de Porto Alegre, RS, Brazil, from march/2001 to December/2003. The response as measured by hemoglobin level, immunoglobulin (M component) or urinary light chain concentration and bone marrow examination was evaluated before, 3, 6, and 12 months after the beginning of thalidomide. Results: All patients are alive and well. Fifty one percent are on 100mg schedule; of the patients on maintenance therapy 90% are on complete remission or on a sustained plateau. A Wilcoxon ranks test for the immunoglobulin level before and after 6 months for the entire group showed p=0.001 (25–75%). Conclusion: Low dose thalidomide is tolerable and effective.

A Maintenance Therapy with Differentiating Agents and Low-Dose Chemotherapy Increases Remission Duration and Survival in High Risk AML and MDS Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4614-4614
Author(s):  
Dario Ferrero ◽  
Chiara Dellacasa ◽  
Margherita Bonferroni ◽  
Mariella Grasso ◽  
Elisabetta Campa ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Maintenance Therapy ◽  
Maintenance Treatment ◽  
Low Dose ◽  
Normal Karyotype ◽  
Intensive Chemotherapy ◽  
Actuarial Survival ◽  
Maintenance Program ◽  
Low Dose Chemotherapy

Abstract Acute myeloid leukemia (AML) patients above the age of 60 or with secondary AML generally have an unfavourable outcome. The same is true for high risk myelodysplastic syndrome (MDS) patients ineligible to bone marrow transplantation. Indeed, in spite of an improved CR rate after intensive chemotherapy (about 60–65%), median CR duration and survival remain short (9–12 months in most studies), due to early relapses. (Sekeres MA et al.: Curr Opin Oncol2002;14:24–30. Verbeek W et al.: Ann Hematol2001;80:499–509). On the basis of our previous clinical trials with differentiative agents + low dose chemotherapy in MDS/AML patients unsuitable to intensive treatments, (Ferrero D et al.: Leuk Res1996;20:867–876; Haematologica2004;89:619–620), we adopted the same strategy as a post-remission maintenance therapy to patients with AML or MDS at high risk of relapse and ineligible to allogeneic transplant. Thirty-six patients (27 AML and 9 high risk MDS) who had obtained a CR after different schemes of intensive chemotherapy were scheduled to receive the maintenance treatment with 13-cis-retinoic acid (20–40 mg/day) + 1,25-di-hydroxy-vitamin D3 (1 microgram /day) in association to intermittent, low dose chemotherapy: 6-thioguanine 40 mg/day x 21 days every 5 weeks, alternated every 2–3 months, in 24 patients, to a 14 day course of ARA-C 8 mg/m2 s.c. x 2/day + 6-mercaptopurine 50 mg/day. Patients’ median age was 64 years (range 27–76), with only 9 below the age of 60. Cytogenetic analysis was performed successfully in 27 cases, and an unfavourable karyotype was found in 10. All patients presented at least one poor prognosis determinant, including age >60 (27), previous AML relapse after autologous BMT (1), therapy-related disease (5), AML secondary to MDS (7), resistance to 1st induction therapy (4), hyperleukocytosis (8), RAEB-2 (8), abnormal karyotype (10). Twenty six had received 1 - 4 courses of consolidation treatment, including autologous stem cell transplantation in 2 MDS patients, before starting the maintenance program. Three patients underwent a very early relapse before maintenance start and 1 patient refused to prosecute the therapy after the first 2 months. The other 32 patients received the treatment as outpatients, with good tolerance and no major toxicity, until relapse, death or 4 years of continuous CR. After a median follow up for alive patients of 23 months (6–76), median disease-free (dfs) and overall survival, based on "intention to treat analysis" are 22 (1–74+) and 23 (5–76+) months, respectively, with a 28% 4 year actuarial survival. Inclusion of ARA-C in the maintenance treatment did not significantly prolong CR duration. The 17 patients with a normal karyotype enjoyed better median dfs (43 months) and overall survival (50,5 months) compared to the 10 patients with abnormal cytogenetics (12,5 and 15,5 months respectively); however, the differences are not significant, probably due to sample exiguity. In conclusion, our patients evidenced quite longer dfs and overall survival than expected from literature data on AML/MDS patients with similar features. However some late relapses (after 3–4 years) occurred. Therefore, our maintenance program seems worthy to be evaluated on larger casistics in randomised trials.

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