Azacitidine Use in a Low Income Country, Effectiveness of a 100mg Fixed Dose

Abstract Azacitidine, a pyrimidine nucleoside analog of cytidine, causes hypomethilation of DNA. Currently FDA approved for treatment of low and intermediate MDS with complete responses around 50%. And Acute myeloid leukemia (AML) in the eldery In the CALGB studies, the usual dose is 75mg/m2 in 28 day cycles, with dose modifications according to toxicity. In low income countries such as Mexico, one course of Azacitidine is around 500 dollars, median income in Mexico is 4,910 PPP (purchasing power parity); vs 30,616 in the USA. So, azacitidine treatment is far from reach for most of the common population, particularly those who do not have insurance. This is a retrospective observational study, of a compassionate use program of a fixed dose of Aza at 100mg. We analyzed data from patients that were treated with Aza between 2012 and 2016, and collected data in 2016. The aim of the study was to assess the effectivity of the fixed dose. For that purpose, we collected information from the physical and electronic file. We analyzed: Hemoglobin level before and after treatment, independence of transfusion, ANC recovery, number of courses, and overall survival. We conducted our research in a public institution in Mexico (Instituto Nacional de Cancerología) and a private institution (Medica Sur). We included acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients, regardless of age, previous treatment and comorbidities (we included patients with renal failure, hypertension etc.) We included 8 patients in our study, 6 males and 2 females, with a mean age of 69.9 years (49-87). We had 2 AML and 6 MDS. We had 2 high risk AML and according to IPSS-R: 1 very low, 2 low, 1 intermediate, 1 high and 1 very high risk MDS. As for the Karyotype we had 1 complex KT, 4 normal KT and 1 Del 7q Del 5q +8. All patients received at least one dose of Aza, with mean number of cycles of 4. We have a mean survival of 439 days (110-1385). 6/8 patients achieved transfusion independency within 3 doses of Aza. 6/8 patients achieved ANC but lost eventually lost response. 5/8 patients are alive in follow up. 3 patients died of infectious complications. 2 patients never achieved transfusion independence or ANC. The information recovered suggests that a fixed dose of 100mg is as feasible as a higher dose, at least when no other treatment or higher dose can be administered. We still are analyzing the survival data in order to find other bad prognosis factor within this population. Disclosures No relevant conflicts of interest to declare.

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Patterns of Infection in Patients with Myeloid Malignancies Receiving 5-Azacytidine: identification of Candidates for Antifungal Prophylaxis

Blood ◽

10.1182/blood.v120.21.4955.4955 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4955-4955

Author(s):

Cristina Calderón ◽

Jose F Falantes ◽

Francisco Márquez-Malaver ◽

Jose González ◽

Maria Luz Martino ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myelodysplastic Syndrome ◽

Fungal Infection ◽

Myeloid Leukemia ◽

Hospital Admissions ◽

Conflicts Of Interest ◽

Infectious Complications ◽

Febrile Episodes ◽

Acute Myeloid

Abstract Abstract 4955 Introduction Infectious complications are among the most recurrent causes of mortality in patients (pts) with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) undergoing intensive chemotherapy (IC). These pts routinely receive anti-infective prophylaxis (AIP) with flourquinolones and antifungals. 5-azacytidine has recently been incorporated to treatment options for AML and MDS. However, the evidence of the effectiveness of AIP in patients treated with 5 azacytidine (AZA) is limited [1–3]. Objectives To analyze the incidence of episodes of infectious fever (IF), type of microbiological isolation and clinical relevance of infectious complications in AML and MDS pts treated with AZA who did not received prophylaxis. Identification a subgroup of pts who may benefit from AIP in this setting. Material/methods We retrospectively analyzed 48 pts with AML and MDS who received AZA from 2008, with a total of 365 cycles administered. Median age was 68 years (29–83y). Distribution: LMA (n=17) and MDS (n=31). One third of these pts had an absolute neutrophil count (ANC)<0. 5×10e9/L at time of starting AZA. Another 33% of pts had received prior IC, being all refractory to previous treatment. Baseline characteristics in table 1. Results Forty-eight febrile episodes were recorded (13% of IF/cycles of AZA). There was no difference in IF in pts with ANC<0. 5×109/L vs ANC>0. 5×10e9/L (p=0. 53). A total of 17 pts suffered at least one episode of IF (35% of the pts). Hospital admission was required in 14 of these 17 pts with a median time of hospitalization of 14 days (4–80). Mortality attributed to infectious complications ocurred only in 3/48 pts (6%). Twelve microbiological isolations were documented, the most common being: Gram negative bacilli (E Coli=4) and aspergillus reported as probable (n=4) and shown in table 1. Upon comparing pts who received prior IC (n=16; 33%) vs AZA as first line treatment, a higher risk for IF per cycle was observed in first group (18% vs 11. 5%; p=0. 06). Double of these pts developed fever (56% vs 25%; p=0. 03), required more hospital admissions (44% vs 22%; p=0. 21) and had longer duration of hospital stay (22 vs 14 days; p=0. 71). Finally, the group of patients that underwent previous IC, had higher rate of fungal infection by aspergillus and candida (5/9 isolations; 55% vs 0/5; 0%. P <0. 001), although no difference was observed in terms of mortality attributed to infection (6% each group) because of the reduced number of pts who died of this complication overall (3/48). Conclusions To our knowledge, this is the first study to evaluate the frequency and impact of IF in pts treated with AZA not receiving routinely AIP. Overall, the incidence of IF is lower than the reported in similar series. These results allow to identify pts that previously were treated with IC as those at highest risk of fungal infection. Thus, prophylaxis should be considered in this group. Prospective studies are needed to assess the requierement of prophylaxis during treatment with 5 azacytidine. Jain N et al. Benefit of Anti-infectious Prophylaxis in Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome receiving Frontline “Targeted Therapy”. Blood (ASH) 2007, 110:Abstract 2858 Je-Hwan Lee et al. Decreased incidence of febrile episodes with antibiotic prophylaxis in the treatment of decitabine for myelodysplastic syndrome. Leuk Res 35 (2011):499–503 Merkel D et al. Predictive Parameters for Infections During Azacitidine Therapy in High Risk MDS Patients. Blood (ASH) 2011, 118:Abstract 3811 Disclosures: No relevant conflicts of interest to declare.

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Adoptive Immunotherapy with Haploidentical Kir Ligand-Mismatched Natural Killer Cells In Elderly High Risk Acute Myeloid Leukemia Patients: Biological and Clinical Results of A Pilot Study

Blood ◽

10.1182/blood.v116.21.4287.4287 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4287-4287

Author(s):

Antonio Curti ◽

Loredana Ruggeri ◽

Alessandra D'Addio ◽

Andrea Bontadini ◽

Valeria Giudice ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Nk Cells ◽

Natural Killer ◽

Myeloid Leukemia ◽

Nk Cell ◽

Conflicts Of Interest ◽

Interleukin 2 ◽

Active Disease ◽

Acute Myeloid

Abstract Abstract 4287 Purpose: To evaluate safety, feasibility and anti-leukemia potential of haploidentical KIR-L mismatched natural killer (NK) cell infusion in elderly high risk acute myeloid leukemia (AML) patients. Patients and Methods: Thirteen patients (5 active disease, 2 molecular relapse and 6 complete remissions) with median age 62 years (range 53–73) received NK cell infusion after immunosuppressive chemotherapy (fludarabine/cyclophosphamide), followed by interleukin-2. Highly purified CD56+CD3- NK cells from haploidentical KIR-L mismatched donors were used. The median number of infused NK cells was 2.74 × 106/Kg. T cells were less than 105/Kg. NK cell chimerism, phenotyping, and functional assays were performed. Results: No significant toxicity, including graft versus host disease, related to NK cell infusion was observed. Among patients with active disease, 1/5 obtained transient complete remission (CR), whereas 4/5 patients had no clinical benefit. Both patients in molecular relapse obtained CR, which lasted 9 and 4 months. Three/6 patients in morphologic CR are disease-free after 34, 32 and 18 months. Donor NK cells were demonstrated in the peripheral blood (PB) of all evaluable patients with a peak at day 10 after infusion and, in some cases, also in the bone marrow (BM). NK alloreactivity was demonstrated in vivo by the detection of donor-derived postinfusion NK clones capable of killing recipient targets. Conclusion: Infusion of purified CD56+CD3- NK cells is feasible and safe in elderly high risk AML patients. Adoptively transferred NK cells, which can be detected in PB and BM after infusion, are alloreactive against recipient cells and may induce an anti-leukemic activity. Disclosures: No relevant conflicts of interest to declare.

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Unmanipulated, G-CSF-Primed Bone Marrow Transplantation From Haploidentical Donor for Patients with High-Risk Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v120.21.3122.3122 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3122-3122

Author(s):

William Arcese ◽

Raffaella Cerretti ◽

Stella Santarone ◽

Gottardo De Angelis ◽

Pasqua Bavaro ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Acute Gvhd ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Disease Free Survival ◽

Unrelated Donor ◽

Acute Myeloid

Abstract Abstract 3122 The outcome of high-risk acute myeloid leukemia (AML) patients not undergoing an allogeneic transplantation is extremely poor. Therefore transplantation from haploidentical donor represents an alternative option for these patients on urgency to be transplanted. We report the results of a study on unmanipulated, G-CSF primed, haploidentical bone marrow (BM) transplantation in patients with high-risk AML lacking a suitable HLA-identical donor. Materials and methods: Between August 2005 to December 2011 58 patients (median age: 44 yrs, range 5–71) with very high-risk AML (CR1=32; CR2=16; advanced stage=10) underwent BM transplant from haploidentical donor. As pretransplant regimens, 43 patients were conditioned with a myeloablative regimen (MAC), while 15 patients received a reduced intensity conditioning (RIC). Of the 58 patients, 43 received the chemotherapy based regimen consisting of Thiotepa, i.v. Busulphan and Fludarabine (TBF MAC or RIC protocol). All 42 patients received an identical GvHD prophylaxis consisting of pretransplant ATG combined with CSA, MTX, MMF and Basiliximab, an anti-CD25 monoclonal antibody. Donors were primed with G-CSF at 4 microgr/Kg/d for 7 consecutive days. BM was harvested on day 0 and infused unmanipulated. Results: The median number of total nucleated, CD34+ and CD3+ cells infused was 7.2 (1–28)x108/kg, 2.04 (0.8–11)x106/Kg and 2.9 (0.9–6.7)x107/Kg, respectively. Five patients died early. All 53 evaluable patients engrafted at a median of 21 (13–29) days and the cumulative incidence (CI) of neutrophil engraftment was 100% at 30 days. For 53 evaluable patients, acute GVHD was absent or just grade I in 25 (47%). The 100-day CI of II-IV and III-IV grade acute GVHD was 34+/−0.4% and 12+/−0.2% respectively. Extensive chronic GVHD occurred in 4 (8%) out of 49 evaluable patients and the 2-year CI of extensive chronic GVHD was 13+/−0.4%. The 1 and 5-year CI of transplant-related mortality (TRM) was 32+/−0.4% and 34+/−0.4% respectively. The overall CI of relapse was 20+/−0.4% at 1-year and 34+/−0.7% at 5-year. The overall and disease-free survival probability was 61+/−6% and 54+/−7% at 1 year, 49+/−7% and 42+/−7% at 5 years. For patients in early stage of disease (CR1+CR2: n=48) the 1 and 3-year probability of overall survival was 70+/−7% and 58+/−8%. Conclusions: Haploidentical transplant using G-CSF primed, unmanipulated BM is correlated with high engraftment rate, low incidence of acute and chronic GVHD, acceptable TRM and favorable outcome. This approach represents a valid and feasible alternative to transplant from matched unrelated donor or cord blood for high-risk AML patients particularly on urgency to be transplanted. Disclosures: No relevant conflicts of interest to declare.

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Second Bacteremia During Antibiotic Treatment In Children With Acute Myeloid Leukemia: A Report From The Canadian Infections In AML Research Group

Blood ◽

10.1182/blood.v122.21.1415.1415 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1415-1415

Author(s):

Thai Hoa Tran ◽

Rochelle Yanofsky ◽

Donna Johnston ◽

David Dix ◽

Biljana Gillmeister ◽

...

Keyword(s):

Risk Factors ◽

Acute Myeloid Leukemia ◽

High Risk ◽

Antibiotic Treatment ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Gram Positive ◽

Hematopoietic Stem ◽

Gram Negative ◽

Acute Myeloid

Abstract Background The risk of second bacteremia during antibiotic treatment for initial bacteremia is unknown in high-risk populations. Objectives were to describe the prevalence of second bacteremia during treatment and identify risk factors in children with acute myeloid leukemia (AML). Methods We conducted a retrospective, population-based cohort study that included children and adolescents with de novo, non-M3 AML who were diagnosed and treated between January 1, 1995 and December 31, 2004 at 15 Canadian centers. Patients were monitored for bacteremia during chemotherapy until completion of treatment, hematopoietic stem cell transplantation, relapse, refractory disease, or death. Results There were 290 episodes of bacteremia occurring in 185 (54.3%) of 341 children. Eighteen (6.2%) had a second bacteremia while receiving antibiotic treatment. Two episodes of second bacteremia were complicated by sepsis; there were no infection-related deaths. Eleven episodes (61.1%) had either an initial Gram-positive and subsequent Gram-negative bacteremia or initial Gram-negative followed by Gram-positive bacteremia. Days receiving corticosteroids (odds ratio (OR) 1.09, 95% confidence interval (CI) 1.07-1.12; P<0.0001), cumulative dose of corticosteroids (OR 1.04, 95% CI 1.00-1.08; P=0.035) and days of neutropenia from start of course to initial bacteremia (OR 1.07, 95% CI 1.02-1.12; P=0.007) were significantly associated with second bacteremia. Conclusion In pediatric AML, 6% will experience a second bacteremia during antibiotic treatment; duration of corticosteroid exposure and neutropenia are risk factors. These patients remain at high risk for second bacteremia after identification of the initial bacteremia and warrant continued broad-spectrum treatment during profound neutropenia. Abbreviations CONS: coagulase negative Staphylococcus ; VGS: viridans group Streptococcus; Amp: ampicillin; Cz: ceftazidime; Cef: cefotaxime; Cipro: ciprofloxacin; Clin: clindamycin; Clox: cloxacillin; G: gentamicin; Metro: metronidazole; Mero: meropenem; O: oxacillin; Pip: piperacillin; Ta: piperacillin/tazobactam; Tm:ticarcillin/clavulanate; To: tobramycin; V: vancomycin. Disclosures: No relevant conflicts of interest to declare.

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Treatment of Acute Myeloid Leukemia with the NOPHO-AML 2004 Study in Chinese Children: A Single Center Study

Blood ◽

10.1182/blood.v124.21.5270.5270 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5270-5270

Author(s):

Xiaoqin Feng ◽

Chunfu Li

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Risk Group ◽

High Risk Group ◽

Low Risk ◽

Chinese Children ◽

Hematopoietic Stem ◽

Acute Myeloid

Abstract Objectives: The objective of the present study was to investigate the therapeutic efficacy and feasibility of NOPHO-AML 2004 study in the treatment of acute myeloid leukemia (AML; excluding acute promyelocytic leukemia) in Chinese children. Methods: Thirty-one children with novo AML treated with the NOPHO-AML 2004 study were recruited from Jan. 2010 to Dec. 2013, and the clinical data were retrospectively analyzed. Among 31 AML children, their age were from 2-14 years old (median age 8 years old). There were 12,15 and 4 children classified in low risk group, intermediate risk group and high risk group by cytogenetic risk classification respectively. Eight children received concomitant hematopoietic stem cell transplantation. Kaplan Meier method with Log-Rank testing was employed for survival analysis. Results: Follow-up was for a median 24 months (range: 5–50 months). The complete remission rate was 83.8%. The predicted 3-year leukemia free survival (LFS) rate was 53.8%. The LFS rate of low, intermediate and high risk group were 55.6%, 52.5% and 50.0% respectively. There was no significance in risk groups. The LFS rate of chemotherapy and chemotherapy concomitant HSCT were 42.7% and 87.5%, P<0.05. There were 2 cases of treatment related mortality including one case of sepsis and one case of ARDS. Conclusions: NOPHO-AML 2004 study is clinically efficacious for the treatment of AML in Chinese children. HSCT treatment had better outcome than only chemotherapy in childhood with non low risk AML in CR1 phase. Disclosures No relevant conflicts of interest to declare.

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Molecular Screening of 28 Genes in Mexican Patients with Acute Myeloid Leukemia a Series of 70 Patients from the Instituto Nacional De Cancerologia, Mexico

Blood ◽

10.1182/blood-2018-99-115300 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5197-5197

Author(s):

Nidia Zapata ◽

Espinoza Ramiro ◽

Eduardo Cervera ◽

Judith Cruz ◽

Diana Arcos ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

The Elderly ◽

Mexican Population ◽

Population Characteristics ◽

First Line ◽

Monosomy 7 ◽

Acute Myeloid

Abstract Introduction: Acute Myeloid Leukemia is a clonal heterogeneous disease, where age is an important risk factor to develop theses disease, PCR studies and next generation sequence have proven the diversity of these disease. A lot of genes mutations have been identifying to play a role in the DNA metilation, epigenetics a transcription. We initiate a screening to all acute myeloid leukemias that where the novo or relapse with a 28 gene panel of HEMAVISION a 28q; DNA diagnostic, for the detection al ARN gene fusion and alternatives of the: PML-RAR ALFA (bcr2,V), CBF-MYH11, RUNX1-RUNX1T1, PML-RAR alfa(bcr1,L), KMT2A-MLT3, PML-RAR alfa (bcr3,S), KMT2A-ELL, FUS-ERG, ETV6-MN1, DEK-NUP214, KMT2A-EPS15, KMT2A-AFDN, TCF3-PBX1, ETV6-RUNX1, KMT2A-MLLT1, KMT2A-AFF1, TCF3-HLF, STIL-TAL1, BCR/ABL(p190), SET-NUP214, BCR/ABL(p210), BCR/ABL(p230), ZBTB16-RARalfa, ETV6-ABL1, ETV6-PDGFRB, KMT2A-MLLT10, KMT2A-MLLT11,KMT2A-FOXO4, KMT2A-MLLT6, RUNX1-MECON, NPM1-RAR alfa, NMP1-MLF1, RUNX1-MECON. FLT3 ITD mutation and D385 by PCR electrophoresis by Invivoscribe was also perform. And the regular cytogenetics and FISH mutations for BCR/ABL, PML/RAR alfa, Inv16, MLL, +8, ETO, BCR, ABL, monosomy 7, monosomy8 Objectives The main objective is the know the mutation in the Mexican population and the prognostic in these group of patients Results These study was perform at Instituto Nacional de Cancerologia, Mexico, randomized patient from 2016-2018 where screen. A total of 70 patients, 37 females and 33 males, ages from 18-85years old, 54 patients where newly diagnosis of acute myeloid leukemia, 4 where relapses and 12 where secondary leukemias, the most frequent FAB morphologic classification where M4:22 cases, M2:15 cases, M3:8 cases, M1:4cases, M0 and M5:3 cases each. Of the 70 patients: 56 patients where negative to all of the panel screen, FLT3 where only perform in 14 patients 12 where negative and 2 where insufficient to perform the test, the most common FISH translocation was PML/RAR alfa, follow by MLL, ETO and +8. For the cytogenetics we had 21 cases that didn´t have enough metaphases, 7 normal, 28 cases with more than 2 cytogenetics alterations and 9 with only 1. With a Cytogenetics risk: high risk 44, intermedium:10 and low12. Of the 70 patient, 14 have some genes mutations +: t(9;11)(p22;q23) KMT2A-MLLT3, t(6;11)(q27;q23) KMT2A-AFDN, t(5;12)(q33;p13) ETV6-PDGFRB, t(8;21)(q22;q22) RUNX1RUNX1T1, inv16(p13q;22q) CBFB-MYH11, t(6;11)(q27;q23) KMT2A-AFDN, t(3;21)(q26:q22) RUNX1-MECOM, inv16(p13q;22q) CBFB-MYH11, t(15;17)(q24;q21) PML-RARA (bcr2,V) t(15;17)(q24;q21) PML-RARA (bcr1,L) t(15;17)(q24;q21) PML-RARA (bcr3,S), t(8;21)(q22;q22) RUNX1RUNX1T1, t(8;21)(q22;q22) RUNX1RUNX1T1, t(15;17)(q24;q21) PML-RARA (bcr3,S) Out of 70 patients: 38 receive 7+3 (cytarabine + Daunorubicin) for first line of treatment, 41 received high doses of cytarabine at 3g /m2. Our first option for relapse treatment is MEC (mitoxantrone, cytarabine and etoposide) because of costs and the second line of rescued treatment is Flag- Ida (idarubicin, fludarabine and cytarabine) and not all patient can afford it. For the elderly patients the first line of treatment is low dose of cytarabine and only in those who can pay azacytidine it is use. The correlation between high risk cytogenetics with mortality is 12 cases out 70. And genes with morality only 4 patients with: t(9;11)(p22;q23) KMT2A-MLLT3, t(6;11)(q27;q23) KMT2A-AFDN, t(5;12)(q33;p13) ETV6-PDGFRB, t(6;11)(q27;q23) KMT2A-AFDN Conclusion We need to know our population characteristics, we don´t have the incidence and prevalence of the gene mutation in the Mexican population. In the market there are several screening panels with different genes. We need to have more genes and more patient to be analyzed to learn our molecular risk, to have a better approach to these patients and better techniques. There is no paper publish with the genetics and gene alteration in the Mexican Population, it is important to continuing working and to use panels with genes as ASXL1, FLT-TKD, CEBPA, KIT, KRAS, IDH1,2, TET2 and others. And other important issue that we found is the high number of patient that abandon treatment 4 cases, because of money issues. And the time of these population 24 patient where death. The incidence of FLT3 mutation ITD and D385 is low in theses population but it was performed only 14/70 patients, we need a large number of patient to know the real incidence. Table. Table. Disclosures No relevant conflicts of interest to declare.

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Pembrolizumab and Decitabine for Refractory or Relapsed Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-115097 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1437-1437 ◽

Cited By ~ 7

Author(s):

Katherine E Lindblad ◽

Julie Thompson ◽

Gege Gui ◽

Janet Valdez ◽

Tatyana Worthy ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Adverse Events ◽

Male Patient ◽

Stable Disease ◽

Survival Data ◽

Myeloid Leukemia ◽

Hematopoietic Stem ◽

Myeloid Neoplasm ◽

Acute Myeloid

Abstract Background: The powerful "graft versus leukemia" effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic stem cell transplantation in reducing relapse of high-risk acute myeloid leukemia (AML) provides the rationale for the investigation of immune-based therapy in those with relapsed or refractory AML. There is considerable pre-clinical evidence for potential synergy between PD-1 checkpoint blockade and hypomethylating agents. Aims: To determine the feasibility of a novel combination of pembrolizumab and decitabine in relapsed/refractory adult AML patients. Methods: 17-H-0026, (PD-AML, NCT02996474) was an investigator sponsored, single-institution, single-arm open-label ten subject study approved by the NHLBI IRB and conducted in accordance with the Declaration of Helsinki (FDA IND: 131826). Pembrolizumab 200 milligrams was administered intravenously on day 1 of every three-week cycle, with decitabine 20 milligrams per meter squared administered on days 8-12 and 15-19 (i.e.: total of 10 days) of alternative cycles starting with cycle 1. Up to eight cycles (24 weeks) of therapy were given. Results: Ten high-risk patients (median age 62, range 30-81) were enrolled, seven with refractory disease (including two with therapy-related myeloid neoplasm) and three with early relapse (less than 6 months from completion of last therapy). This novel combination therapy was well tolerated, with a toxicity profile largely consistent with that expected from decitabine. No grade 5 adverse events occurred. Most grade 4 adverse events were hematological. Non-hematological grade 4 events were seen in only two subjects; febrile neutropenia, hypotension and sepsis in one, and sepsis in the other. Two patients suffered from hypothyroidism as an immune-related adverse event (after 2 and 4 cycles respectively) and a third patient developed central diabetes insipidus thought possibly associated with pembrolizumab. In summary, 4 of the 10 patients had stable disease at the end of 8 cycles (24 weeks), 4 progressed prior to cycle 8, 1 patient was taken off study due to grade 4 toxicity (sepsis) in cycle 5 in a morphological leukemic free state (MLFS) and 1 patient achieved an MRD negative complete response at the end of 8 cycles. Specifically, a 74 year-old male patient, enrolled at second relapse, achieved a CR3 lasting 337 days (compared with prior CR2 of 185 days) which was MRD negative at the end of eight cycles, and was still alive 14 months from start of treatment. A 81 year old male patient, with refractory treatment related myeloid neoplasm achieved a MRD-negative MLFS but was removed from study early due to grade 4 toxicity. The 4 patients with stable disease at the end of planned eight cycles included a 71 year-old male patient in early first relapse who decreased blasts from 4.4% at enrollment to 0.1% at the end of 8 cycles. Median overall survival for patients on this study was 7 months (range 2 to ongoing at 14 months) with a median time of follow-up in survivors of 13 months (range 7-14 months). Updated survival data will be reported at the meeting. Additional planned laboratory correlates include assessment of changes in leukemic clonality, T-cell receptor repertoire diversity and bone marrow-resident immune cell profiles during therapy. Conclusion/summary: This first proof of principle study demonstrates the feasibility of the combination of pembrolizumab and decitabine in relapsed/refractory adult AML patients. . Table. Table. Disclosures No relevant conflicts of interest to declare.

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Indoleamine 2,3-Dioxygenase (IDO) Is Associated with High Incidence of Chemorefractory Disease in Acute Myeloid Leukemia (AML) Patients

Blood ◽

10.1182/blood.v120.21.4787.4787 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4787-4787

Author(s):

Sarah Parisi ◽

Sara Trabanelli ◽

Darina Ocadlikova ◽

Stefania Paolini ◽

Cristina Papayannidis ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Significant Proportion ◽

Age At Diagnosis ◽

Indoleamine 2,3 Dioxygenase ◽

Tryptophan Degradation ◽

Acute Myeloid

Abstract Abstract 4787 Indoleamine 2,3-dioxygenase (IDO) is a heme-containing enzyme that catalyzes the first and rate-limiting step in tryptophan degradation along the kynurenine pathway. IDO is able to inhibit T-cell function and to induce the transformation of T-cells into regulatory T-cells. Several studies demonstrated that IDO expression is involved in immune tolerance induction during pregnancy, infection, transplantation, autoimmune diseases and neoplasias, including acute myeloid leukemia (AML). In particular, our and other groups demonstrated that IDO is expressed in a significant proportion of AML patients and that it increases along with disease progression. Here, we addressed the correlation between IDO expression by AML cells, risk factors at diagnosis and patients' outcome. Adult AML patients from the Hematology Institute “L. and A. Seràgnoli” in Bologna were analyzed for risk characteristics at diagnosis and for IDO expression by RT-PCR and by Western-Blot analysis. Patients were stratified according to age at diagnosis, de novo or secondary disease (pre-existing myelodysplastic syndrome or radio-chemotherapy), leucocytosis, cytogenetics (on the basis of cytogenetic characteristics patients were divided into low, intermediate and high risk groups) and FLT3 and NPM mutational status. Fifty-two patients with AML at diagnosis were analyzed for IDO expression both at gene and protein level. According to IDO transcript levels, patients were divided into IDO-negative (21%) and IDO positive (79%). Positive patients were further subdivided into three different subgroups according to IDO level: IDO-low expression (78%), IDO-intermediate expression (10%) and IDO-high expression (12%) patients. When IDO protein was assessed, we found a correlation between IDO mRNA level and the detection of IDO protein. In particular, IDO protein was detectable only in IDO-high-expressing patients. No statistically significant differences in the recurrence of prognostic characteristics at diagnosis among the groups considered were observed, even though IDO-negative and IDO-low expressing patients showed a higher median age at diagnosis than IDO-intermediate and IDO-high expressing patients and an increased frequency of high-risk cytogenetics was found in IDO-high expressing patients. Response to induction chemotherapy regimen was then analyzed among the four groups of patients. Only patients who received cytotoxic chemotherapy were evaluated for response. Intriguingly, we found that refractory patients were 60% among patients who express IDO at high level and 27% among IDO-negative patients. In conclusion, IDO-high expressing patients show an increased proportion of refractory disease than IDO negative patients. To support our preliminary findings, a multivariate analysis on a larger cohort of patients is currently ongoing. Disclosures: No relevant conflicts of interest to declare.

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Maintenance Therapy with Decitabine after Allogeneic Hematopoietic Stem Cell Transplantation to Prevent Relapse of High Risk Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-124033 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3306-3306

Author(s):

Yunju Ma ◽

Changju Qu ◽

Haiping Dai ◽

Jia Yin ◽

Zheng Li ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Maintenance Therapy ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Median Number ◽

Control Group ◽

Post Transplantation ◽

Hematopoietic Stem ◽

Acute Myeloid

Background: Relapse remains the main cause of treatment failure post transplantation. Relapse prevention is an important strategy for acute myeloid leukemia (AML) patients. M ethods: We retrospectively analyzed the results of21 high risk AML patients who received a median number of 3 courses (range, 2 - 8) of decitabine (DAC) maintenance treatment (20mg/m2/d ×5d every 3 months for 1 year). Meanwhile, another 63 high risk AML patients without any prophylactic treatment after transplantation were included as a control group for 1:3 pair matched study. Results: With median follow-up of 23 months, 20 out of 21 (95.2%) patients maintained complete molecular remission (CMR) in DAC group, while 35 out of 63 (55.6%) patients maintained CMR in control group. Comparing with control group, the patients of DAC group had higher 3-year overall survival (OS) rates and 3-year leukemia free survival (LFS) rates (92.9% vs 51.8%, P =0.003; 94.1% vs 54.7%, P=0.002 respectively). Moreover, DAC maintenance was well tolerated in all patients and grade 3/4 or 4/4 hematological toxicities were observed in 11 of 21 (52.4%) patients. Conclusion: Our results suggested that DAC maintenance therapy was an effective and safe treatment option to prevent relapse after transplantation for high risk AML patients. Disclosures No relevant conflicts of interest to declare.

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Genome-Wide Genotype-Based Risk Model for Survival in Acute Myeloid Leukemia Patients with Normal Karyotype.

Blood ◽

10.1182/blood.v120.21.2526.2526 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2526-2526

Author(s):

Hyeoung-Joon Kim ◽

Hangseok Choi ◽

Yeo-Kyeoung Kim ◽

Sang Kyun Sohn ◽

Joon Ho Moon ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Risk Model ◽

Conflicts Of Interest ◽

Snp Array ◽

Normal Karyotype ◽

P Value ◽

Genome Wide ◽

Acute Myeloid

Abstract Abstract 2526 Introduction: Single nucleotide polymorphism (SNP) is an inter-individual genetic variation which could explain inter-individual differences of response/survival to chemotherapy. The present study was attempted to build up risk model of survival for acute myeloid leukemia (AML) patients with normal karyotype (AML-NK). Methods and materials: A total of 247 patients with AML-NK was included into the study. Genome-wide SNP array (Affymetrix SNP-array 6.0) was performed in the discovery set (n=118), and genotypes were analyzed for overall survival (OS). After identifying significant SNPs for OS in single SNP analyses, risk model was constructed. Replication was performed in an independent validation cohort (n=129). Results: Out of 632,957 autosomal SNPs meeting genotype data filtration criteria, a total of 82 SNPs were selected and passed into the next step of validation in an independent cohort. In the risk model generation step, finally 4 SNPs (rs2826063, rs12791420, rs11623492 and rs2575369) were meeting stringent criteria for SNP selection as follows: 1) p-value < 0.10 from Cox proportional hazards regression model in adjustment with age and WBC counts at diagnosis; 2) minor allele frequency > 0.05; 3) call rate > 95.0%; 4) high linkage disequilibrium r2 < 0.8. These 4 SNPs were introduced into the risk model, and patients was grouped into 2 groups according to the number of deleterious variables including 4 SNPs and 2 clinical variables (i.e. age and WBC counts at presentation): risk score 0–2 as a low risk (n=80) and 3–6 as a high risk (n=38). The risk model could stratify the patients according to their OS in discovery (p=1.053656•10−4) and in validation set (p=5.38206•10−3). The risk model showed a higher AUC than those being incorporated only clinical or only 4 SNPs, suggesting improved prognostic stratification power of combined model. Conclusion: Genome-wide SNP based risk model obtained from 247 patients with AML-NK can identify high risk group of patients with poor survival using genome wide SNP data. (Clinicaltrials.govIdentifier:NCT01066338) Disclosures: No relevant conflicts of interest to declare.

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