All-Trans Retinoic Acid and Gemtuzumab Ozogamicin as Adjunct To Salvage Therapy in Primary Refractory Acute Myeloid Leukemia: Results of Consecutive Phase II Studies of the AMLSG.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1849-1849
Author(s):  
Richard F. Schlenk ◽  
Konstanze Doehner ◽  
Martina Kerz ◽  
Frank Hartmann ◽  
Francesco del Valle ◽  
...  
Keyword(s):  
Salvage Therapy ◽  
Odds Ratio ◽  
Myeloid Leukemia ◽  
Response Rate ◽  
Liver Toxicity ◽  
Salvage Chemotherapy ◽  
Gemtuzumab Ozogamicin ◽  
All Trans Retinoic Acid ◽  
Phase Ii Studies ◽  
Refractory Aml

Abstract Introduction: Response to first induction therapy is one of the most important prognostic factors in patients with adult myeloid leukemia (AML). Induction of CR or PR is the primary aim in these patients. Methods: Between 1993 and 2005 225 consecutive patients (median age: 48.4 yrs, range 16–60 yrs) treated within the AMLHD93 (n=45), AMLHD98A (n=157) and AMLSG 05-04 (n=23, still active) trials were evaluated. All patients had primary refractory AML after one cycle of ICE. The different salvage therapies were as follows: AMLHD93 sequential-HAM (S-HAM) for patients <55 years of age [cytarabine 3g/m2 bid. days 1,2,8,9, mitoxantrone 10mg/m2 days 3,4,10,11], HAM for patients >=55 years of age [cytarabine 3g/m2 bid., days 1–3, mitoxantrone 12mg/m2 days 2,3]; AMLHD98A: A-HAM [HAM with ATRA 45mg/m2 days 3–5, 15mg/m2 days 6–28]; AMLSG 05-04: GO-A-HAM [A-HAM with gemtuzumab ozogamicin 3g/m2 day 1]. Results: The distribution of the different salvage therapies was HAM n=21, S-HAM n=22, A-HAM n=117, GO-A-HAM n=23, other n=31 no further therapy n=11. Response according to salvage therapy was as follows: response GO-A-HAM A-HAM S-HAM HAM CR 11 (48%) 40 (34%) 5 (23%) 3 (14%) PR 4 (17%) 33 (28%) 5 (23%) 4 (19%) RD 6 (26%) 36 (31%) 12 (54%) 12 (57%) death 2 (9%) 8 (7%) 0 2 (10%) No CTC-grade 3-5 liver toxicity was seen in patients receiving GO-A-HAM. Multivariable analyses revealed that regimens containing ATRA (odds ratio 2.5, p=0.01) and cytogenetic subgroup [t(11q23) odds ratio 4.2 p=0.04 (n=13), non-complex high risk aberrations odds ratio 4.2 p=0.007 (n=34)] were associated with a significantly better response rate (subsuming CR and PR). 119 of 225 patients have received stem cell transplantation. No case of veno occlusive disease was in 10 so far transplanted pts who have had GO-A-HAM. Median survival was 10.7 months. Conclusions: Although retrospective in nature our study suggests that ATRA as adjunct to salvage chemotherapy in primary refractory AML patients improves the response rate. The addition of GO in a dosage of 3mg/m2 results in promising response rates without increasing toxicity.

All-Trans Retinoic Acid and Gemtuzumab Ozogamicin as Adjunct To Salvage Therapy in Primary Refractory Acute Myeloid Leukemia: Results of Consecutive Phase II Studies of the AMLSG.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1949-1949
Author(s):  
Richard F. Schlenk ◽  
Konstanze Dohner ◽  
Martina Kerz ◽  
Francisco del Valle ◽  
Björn Heydrich ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Salvage Therapy ◽  
Odds Ratio ◽  
Gemtuzumab Ozogamicin ◽  
Prognostic Impact ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Significant Difference ◽  
The Impact ◽  
Refractory Aml

Abstract Background: In primary refractory patients the achievement of a response to salvage therapy is of enormous prognostic impact. Aims: To evaluate the impact of all-trans retinoic acid (ATRA) and gemtuzumab ozogamicin (GO) given as adjunct to high-dose cytarabine based intensive salvage therapy in primary refractory younger patients on clinical outcome. Methods: Between 1993 and 2006 264 consecutive patients (median age: 48 yrs) were evaluated. All patients had primary refractory AML after one cycle of ICE (idarubicine, cytarabine, etoposide). The different salvage therapies were as follows: from 1993–1998: S-HAM for patients <55 years of age [cytarabine 3g/m2 bid. days 1,2,8,9, mitoxantrone 10mg/m2 days 3,4,10,11] and HAM for patients >=55 years of age [cytarabine 3g/m2 bid., days 1–3, mitoxantrone 12mg/m2 days 2,3]; from 1998 to 2004 A-HAM [HAM with ATRA 45mg/m2 days 3–5, 15mg/m2 days 6–28]; from 2004 up to date: GO-A-HAM [A-HAM with gemtuzumab ozogamicin 3g/m2 day 1]. Results: The distribution of the different salvage therapies was HAM n=21, S-HAM n=22, A-HAM n=118, GO-A-HAM n=62, other n=31, or no further therapy n=10. CR-rate according to salvage therapy was GO-A-HAM 49%, A-HAM 34% S-HAM 23%, HAM 14%. Treatment related mortality did not differ between regimens. No CTC-grade 3–5 liver toxicity was seen in patients receiving GO-A-HAM. Logistic regression on the achievement of CR revealed that regimens containing ATRA (odds ratio 2.0, p=0.05) and GO (odds ratio 1.9 p=0.05) were associated with response. 151 of 264 patients have received a stem cell transplantation as consolidation therapy (n=59 MRD, n=79 MUD, n=6 haplo-identical donor, n=7 autologous). The rates of severe veno occlusive disease after transplant was identical (5%) for patients receiving a salvage therapy including GO and those who did not. Survival analysis revealed a significant difference (p= 0.00178) with a median survival of 16.2 months for GO+ATRA, 12.5 months for ATRA versus 7.2 months for the others. Conclusions: Although retrospective in nature our study suggests that ATRA and GO as adjunct to salvage therapy improves CR rates and survival in primary refractory AML patients.

All-Trans Retinoic Acid and Gemtuzumab Ozogamicin as Adjunct to High-Dose Cytarabine-Based Salvage Therapy in Primary Refractory Acute Myeloid Leukemia: Results of AMLSG 05-04 Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1837-1837
Author(s):  
Richard F. Schlenk ◽  
Konstanze Döhner ◽  
Jürgen Krauter ◽  
Daniela Späth ◽  
Francesco de Valle ◽  
...  
Keyword(s):  
Salvage Therapy ◽  
Myeloid Leukemia ◽  
Liver Toxicity ◽  
Gemtuzumab Ozogamicin ◽  
High Dose ◽  
Significant Variable ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
High Dose Cytarabine ◽  
Refractory Acute Myeloid Leukemia

Abstract Background: Patients with primary refractory acute myeloid leukemia (AML) have a dismal outcome. Only allogeneic stem cell transplantion (SCT) currently offers the chance of cure to these patients. In order to improve outcome after allogeneic SCT, one important prerequisite is to increase response rates prior to SCT. Aims: To evaluate the impact of all-trans retinoic acid (ATRA) and gemtuzumab ozogamicin (GO) given as adjunct to high-dose cytarabine-based salvage therapy in younger adult patients with primary refractory AML on achievement of response. Consecutive allogeneic SCT was intended in all patients. Methods: Main inclusion criteria of the AMLSG 05-04 trial (NCT00143975) were refractory AML following one cycle of ICE (idarubicin, cytarabine, etoposide); and age 18 to 60 years. Dose and schedule of the GO-A-HAM regimen were as follows: GO 3mg/m2, day 1; cytarabine 3g/m2 bid., days 1–3; mitoxantrone 12mg/m2, days 2,3; ATRA 45mg/m2, days 3–5, 15mg/m2 days 6–28. Primary endpoint of the study was CR rate. Safety endpoints comprised early / hypoplastic (ED/HD) death rate, liver toxicity CTC grade 3–5, and rate of veno occlusive disease (VOD) after allogeneic SCT. Results: Between September 2004 and June 2007, 94 patients (median age, 48 yrs; range, 22 to 62) were enrolled. Distribution of cytogenetics was as follows: adverse, n=29 [abn(3q), −5/5q-, −7/7q-, abn(12p), abn(17p), complex]; other n=57 [core binding factor (n=3), cytogenetically normal AML (n=37), various aberrations (n=18)]. FLT3-ITD was present in 18 (22%) of 82 analyzed patients. Response to GO-A-HAM was as follows: CR, n=28 (30%); CRi, n=19 (20%); PR, n=11 (12%); refractory disease (RD), n= 34 (36%); and ED/HD, n=2 (2%). In a logistic regression analysis for achievement of CR, the only significant variable was adverse cytogenetics (OR 0.34, p=0.02). The rate of severe liver toxicity was 0%, the incidence of neutropenic fever was 52%, platelet and neutrophil recovery times from start of treatment were 21 and 22 days, respectively. Following GO-A-HAM, allogeneic SCT was actually performed in 60 patients (64%): matched related (n=14) or unrelated donor (n=42); haploidentical related donor, n=4. All SCT were performed within 3 months after GO-A-HAM, intermediate/severe VOD developed in 5 patients after SCT (9%, 95%-confidence interval (CI) 4–19%), mild VOD in 3 patients. Survival analyses revealed that patients with adverse cytogenetics and/or FLT3-ITD (n=45) had a significantly (p=0.001) inferior overall survival after one year of 38% compared to all other patients (n=39) of 81%. The proportions of patients receiving an allogeneic SCT were similar in both groups (68% and 66%, respectively). Conclusions: The GO-A-HAM regimen is feasible and effective as salvage therapy. However, cytogenetics still remains the most significant variable for achievement of response. Allogeneic SCT after GO-A-HAM was not associated with an increased VOD-rate.

scholarly journals Comparison of Salvage Chemotherapy Regimens in Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2708-2708
Author(s):  
Muhammad Umair Mushtaq ◽  
Sibgha Gull Chaudhary ◽  
Laura C. Michaelis ◽  
Karen-Sue B. Carlson ◽  
Sameem Abedin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Salvage Therapy ◽  
Myeloid Leukemia ◽  
Salvage Chemotherapy ◽  
Regression Analyses ◽  
Salvage Regimen ◽  
Baseline Characteristics ◽  
Acute Myeloid ◽  
Refractory Aml

Abstract Background Induction therapy for acute myeloid leukemia (AML) with a cytarabine-anthracycline regimen (7+3) is well-established; however, there is no standard salvage therapy for patients with relapsed/refractory AML (RR-AML). There is a paucity of data regarding outcomes with salvage regimens in RR-AML that include cladribine, cytarabine, and filgrastim with mitoxantrone (CLAG-M) or without mitoxantrone (CLAG), and mitoxantrone, etoposide, and cytarabine (MEC). We compared outcomes of patients receiving CLAG-M, CLAG or MEC as salvage therapy for RR-AML. Methods A multi-center retrospective study was conducted, including 146 adult RR-AML patients who underwent salvage therapy at the University of Wisconsin and Medical College of Wisconsin from 2009 to 2018. Demographic, clinical and pathologic factors were ascertained at the time of RR-AML diagnosis. The Center for International Blood and Marrow Transplant Research (CIBMTR) response criteria were used. Refractory AML was defined as failure to achieve remission after one or more courses of induction chemotherapy. Minimal residual disease (MRD)-negative was defined by the absence of leukemic cells by morphology and flow cytometry (<0.01%). Data were analyzed using SPSS version 21 (SPSS Inc, Chicago, IL). Bivariate analyses, using chi-square and t-test, and logistic regression analyses were performed for baseline characteristics and response to salvage chemotherapy. Kaplan-Meier analyses, using the log-rank test, were conducted. Cox regression analyses were used to correlate factors with OS. Hazard ratios (HR) with 95% CI were obtained. Statistical significance was considered at P<0.05. Results The study included 146 patients with relapsed (57.5%, n=84) or refractory (42.5%, n=62) AML who received CLAG-M (51%, n=74), MEC (39%, n=57) or CLAG (10%, n=15) salvage chemotherapy. Baseline characteristics were similar between the three groups (all P>0.1). Median age was 60 years (range 22-77 years) and 59% patients were male. AML was classified according to WHO 2016 guidelines as AML with recurrent genetic abnormalities (23%), myelodysplasia (MDS)-related AML (25%), therapy-related AML (8%) and AML not otherwise specified (44%). Cytogenetics were good (5%), intermediate (60%) and poor (36%) with normal (41%), complex (25%), trisomy (8%) and monosomy 5 or 7 (5.5%) being common karyotypes. Among those who had molecular testing (n=119), NPM1 and FLT3-ITD were reported in 21% and 20% patients respectively. AML risk status was good (16%), intermediate (32%) and poor (52%), based on cytogenetic and molecular abnormalities as per ELN 2017 and NCCN 2018 guidelines. Extramedullary disease was present in 13% patients. Prior hematopoietic stem cell transplant (HSCT) was performed in 13% patients. Median lab values prior to salvage regimen were: hemoglobin 9.1 g/dL, platelets 49 K/uL, leukocytes 2.5 K/uL, LDH 231 U/L and bone marrow myeloblasts 28%. Overall response rate was 49% (CLAG-M 55%, n=41/74; MEC 44%, n=25/57, CLAG 40%, n=6/15) with complete remission (CR) rate of 46% (CLAG-M 54%, MEC 37%, CLAG 40%) [P=0.140]. Three percent patients (n=5; CLAG-M=1, MEC=4) had CR with incomplete hematologic recovery (CRi). MRD analysis was available for 83 patients and a trend was seen in MRD-negative CR rates favoring CLAG-M (44%) over MEC (25%) or CLAG (17%) [P=0.128]. Sixty-six patients (45%) received subsequent HSCT (CLAG-M 50%, n=37/74; MEC 44%, 25/57; CLAG 27%, n=4/15) [P=0.245]. At last follow-up, 34% patients were in CR (CLAG-M 42%, MEC 28%, CLAG 20%) [P=0.120]. Fifty (34%) patients were alive at last follow-up (CLAG-M 46%, MEC 23%, CLAG 20%) [P=0.010]. Median OS was 9.7 months (95% CI 6.8-12.6) that was significantly better with CLAG-M (13.3 months, 95% CI 2.4-24.3) compared to MEC (6.9 months, 95% CI 2.9-10.9) or CLAG (6.2 months, 95% CI 2.4-12.6) [P=0.025] Figure 1. In multivariate model adjusted for age, gender and refractory vs relapsed AML, MEC (HR 1.75, 95% CI 1.13-2.71, P=0.013) and CLAG (HR 1.97, 95% CI 1.02-3.79, P=0.043) regimens had worse OS compared to CLAG-M. After adjusting for age, gender, refractory vs relapsed AML and HSCT, CLAG-M remained independent predictor of better OS (HR 0.64, 95% CI 0.42-0.97, P=0.037). Conclusion CLAG-M compared to MEC or CLAG is associated with significantly better OS in RR-AML regardless of age, refractory vs relapsed AML and HSCT. Our findings support the use of CLAG-M as a preferred salvage regimen for RR-AML. Figure 1. Figure 1. Disclosures Atallah: Novartis: Consultancy; BMS: Consultancy; Jazz: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy.

scholarly journals Retrospective Analysis of the Outcomes of Patients with Relapsed/Refractory Acute Myeloid Leukemia Included in a Patient Named Program of Gemtuzumab Ozogamicin

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 876-876
Author(s):  
Juliette Lambert ◽  
Pierre Peterlin ◽  
Cecile Pautas ◽  
Emmanuel Raffoux ◽  
Denis Caillot ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Response Rate ◽  
De Novo ◽  
Gemtuzumab Ozogamicin ◽  
First Relapse ◽  
De Novo Aml ◽  
Grade 3 ◽  
Refractory Aml

Abstract Introduction: In 2010 the French Health Agency opened a compassionate patient named program of gemtuzumab ozogamicin (GO, Mylotarg®) in relapsed/refractory (R/R) patients with acute myeloid leukemia (AML). Of note, since 2012, it was recommended to use GO at the dose of 3 or 6 mg/m 2 in addition to chemotherapy. We conducted a retrospective trial (NCT03287128) to evaluate the efficacy and the safety of GO-based regimen in R/R adult AML patients. Patients and methods: We retrospectively collected data of patients older than 18 years treated with GO-based regimen for AML in first relapse or for refractory AML, defined by failure after a prior standard intensive chemotherapy, in 18 French centers between December 15, 2011 and November 10, 2016. The primary objective was to assess the response to GO-based regimen. Patients were considered in response if reaching complete remission (CR), CR without platelet recovery (CRp) or CR with incomplete hematological recovery (CRi). Secondary objectives were the cumulative incidence of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the safety of the use of GO-based regimen. Results: Three hundred and thirty-five adult patients with R/R AML were included. Median age was 58 years (20 to 80 years). At diagnosis, cytogenetics was favorable in 50 (17%) patients, intermediate in 173 (59%) and adverse in 60 (20%). ELN distribution was favorable: 35%, intermediate: 42% and unfavorable: 23%. NPM1 mutation was present in 29% of patients and FLT3 mutation in 23%. Most patients had de novo AML (84%). Two hundred and thirty-eight patients (79%) were in first relapse and 65 (21%) had a refractory AML. The time between first diagnosis of AML and treatment with GO-based regimen was 4 to 16 months (median 9.4 months). Most patients (88%) received GO in combination with various intensive chemotherapy scheme including "7+3" with anthracycline/cytarabine (n=39 patients), intermediate and high-dose cytarabine (n=68), cytarabine in continuous intravenous infusion (n=78), mitoxantrone/cytarabine (n=49) and fludarabine/cytarabine and/or amsacrine and/or etoposide chemotherapy (n=35). Median follow-up time was 11 months. Among the 305 patients, 191 responded to GO-based regimen: 110 (36%) were in CR, 62 (20%) were in CRp and 19 (6%) in CRi for an overall response rate (CR+CRp+CRi, ORR) of 63%. In multivariate analysis, response was associated with age &lt;50 years, de novo AML and relapse status. Among the 191 responders, 110 received additional courses of chemotherapy, 69 with GO. Main reason to not receive additional course (with or without GO) was allo-HSCT project. In the whole population, median overall survival (OS) after day 1 of treatment with GO was 11.2 months. In the population of responders, median OS after response was 20.4 months. In multivariate analysis, longer survival was associated with age &lt; 50 years, de novo AML and favorable ELN group. Cumulative incidence of relapse at 24 months after response was 46%. One hundred and forty-seven patients received allo-HSCT, including 122 responders after GO-based regimen and 25 patients in treatment failure. Cumulative incidence of allo-HSCT at 18 months was 48%. Four-year OS was 48% in transplanted patients versus 19% in non-transplanted patients (Figure 1). Regarding safety of GO-based regimen, early deaths occurred within &lt;30 days after the first dose of GO in 14 patients, and within &lt;60 days in 35 patients. Myelosuppression was observed in all patients. Mean duration of thrombocytopenia &lt;100 G/L was 35 days in responders. Bleeding grade 3 or more was observed in 22 patients (7%). Infection grade 3 or more was observed in 112 patients (30%). Sinusoidal obstruction syndrome (SOS) after GO treatment was reported in 6 patients, resolving in 4 of them. Four cases of fatal SOS were reported after allo-HSCT. Toxic deaths, i.e., not related to worsening leukemia, were reported in 20 patients after the first course of chemotherapy, 3 after additional courses and 33 after allo-HSCT. Conclusion. Our study is the first to report efficacy data in the real-world setting of R/R AML adult patients treated with GO-based regimen. In our cohort of 305 patients, response rate was 63% and GO-based regimen appears as a valuable bridge-to-transplant option. Safety analysis showed toxicities consistent with the known safety profile of GO and chemotherapy. Figure 1 Figure 1. Disclosures Lambert: ASTELLAS: Consultancy; CELGENE/BMS: Consultancy. Pautas: PFIZER: Consultancy; ABBVIE: Consultancy. Raffoux: ASTELLAS: Consultancy; PFIZER: Consultancy; ABBVIE: Consultancy; CELGENE/BMS: Consultancy. Legrand: Servier: Consultancy. Gastaud: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; GSK: Consultancy. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Mathilde: SERVIER: Consultancy; ABBVIE: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Castaigne: PFIZER: Consultancy.

Decitabine and Gemtuzumab Ozogamicin In Patients with Advanced Myelofibrosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5061-5061
Author(s):  
Ali Al-Ameri Al-Ameri ◽  
Hagop Kantarjian ◽  
Asifa Malik ◽  
Xavier Badoux ◽  
Michael Andreeff ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Response Rate ◽  
Myeloproliferative Disorders ◽  
Gemtuzumab Ozogamicin ◽  
Infectious Complications ◽  
Myelogenous Leukemia ◽  
Hypomethylating Agents ◽  
Acute Myelogenous ◽  
Clinically Significant ◽  
Splenic Size

Abstract Abstract 5061 Background: While hypomethylating agents, azacitidine and decitabine, are approved for use in treatment of myelodysplastic syndromes (MDS), their role in treatment of myeloproliferative disorders is evolving. The modified dosing schedule of decitabine (20 mg/m2 IV for 5 days) in MDS has shown overall response rates of approximately 40%. A clinical study of azacitidine in myelofibrosis (MF) has shown a response rate of 32%. We investigated the activity of the combination of decitabine and gemtuzumab ozogamicin (GO) (anti-CD33 antibody), a combination with activity in patients with MDS and acute myelogenous leukemia (AML), in patients with advanced myelofibrosis. Patients and Method: We reviewed the records of patients with MF treated with the combination of decitabine and GO. Result: Seven patients were treated till the decisions by FDA to withdraw GO from the market. Age ranged from 60–69 years (median 65 years), 5 patients were male and no of prior therapies ranged 0–4 (median2). Three patients had MF progressed to acute myeloid leukemia. Prior treatments included, hydroxyura, thalidomide, prednisone, pomolidamide etc. All patients were positive for JAK 2 V617F mutation. Cytogenetic abnormalities were seen in 4 patients (hyperdiploid, complex or -5/-7) and 3 were with diploid cytogenetics. Five patients received 3 cycles of Decitabine plus myelotarg while 2 patients had only one cycle. Four patients had stable disease, one had clearance of marrow blasts (40%>0%), two had no response. Three patients showed decreases in splenic size. Clinically significant infectious complications were encountered in 4 patients. Conclusions: The combination of decitabine and GO showed early signs of activity in patients with MF but future investigation of this combination will be limited due to lack of access to GO. Disclosures: Borthakur: eisai: Research Funding.

scholarly journals Low-Dose Azacitidine, Pioglitazone and All-Trans Retinoic Acid Versus Standard-Dose Azacitidine in Patients ≥ 60 Years with Acute Myeloid Leukemia Refractory to Standard Induction Chemotherapy (AMLSG 26-16/AML-ViVA): Results of the Safety Run-in Phase I

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1382-1382 ◽  
Author(s):  
Daniel Heudobler ◽  
Sebastian Klobuch ◽  
Florian Lüke ◽  
Joachim Hahn ◽  
Matthias Grube ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Low Dose ◽  
Advisory Committees ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Refractory Aml

Introduction: Patients (pts) with acute myeloid leukemia (AML) who are refractory to intensive frontline treatment have a dismal outcome. In case of ineligibility for allogeneic stem cell transplantation (HSCT), the median survival of chemo-refractory AML is about 2 months and less than 5% of these pts are alive after 1-year (retrospective analysis from the AMLSG database). To date, there is no universally accepted standard approach for the treatment of chemo-refractory AML in older pts. Several retrospective studies have assessed the role of hypomethylating agents in this patient group, but complete remission (CR) rates were disappointingly low (≤10%) when compared to first line treatment. The presented study represents a novel approach focusing on hematopoietic tissue reprogramming (i.e. anakoinosis) (ClinicalTrials.gov Identifier: NCT02942758). Methods: The initial dose-finding phase I of the study evaluated the combination of azacitidine (AZA) 75 mg/d s.c. for 7 days, repeated every 28-days, pioglitazone 45 mg/d p.o. continuously from day 1 and all-trans retinoic acid (ATRA). A modified 3+3 design has been used to establish the maximum-tolerated dose of ATRA. Patients have been enrolled at an ATRA dose of 45 mg/m²/d from day 1 to day 28 and 15 mg/m²/d continuously thereafter if no dose limiting toxicity (DLT) occurred until start of next cycle on day 29. The safety DLTs were defined as toxicities attributable to ATRA, expected or unexpected, except if these are likely associated with another cause. Eligible patients had confirmed diagnosis of AML refractory to induction therapy and were not eligible for further intensive induction therapy or were not immediate candidates for allogeneic HSCT. The severity of adverse events was graded using the Common Terminology Criteria for Adverse Events (CTCAE) V. 4.03. The response to treatment was evaluated using standard criteria defined by the expert panel on behalf of the European LeukemiaNet and international working group (IWG) response. Results: Ten pts were enrolled in the safety-run-in phase I (one pt withdrew informed consent on day 9 of cycle 1). Among all treated pts, the median age was 67 years (range, 62-76 years), and the majority of pts (70%) had an ECOG PS of 1 (see table 1). Two pts had secondary AML; another two pts had therapy-related AML (t-AML). Eight pts had a complex karyotype. Concerning safety, hematological adverse events (AEs) were the most common toxicities observed. Because pts with baseline cytopenia were included (leukopenia n=8; 80%; thrombocytopenia n=9; 90%), occurrences of many hematological AEs began before study drug initiation and were attributed to underlying hematologic disease. Common 3°/4° AEs included neutropenia (50%), anemia (50%), thrombocytopenia (30%), and infections (40%). 50% of pts experienced a serious AE; one 5° AE (gastric hemorrhage) occurred. No DLTs were observed. Five pts discontinued the study, with progressive disease (PD) or relapse being the most common reason for discontinuation. Concerning efficacy, 3 pts (30%) achieved a CR and one pt a long-lasting stable disease (14 months). Morphologic review showed signs of differentiation of blasts in responding pts, which has already been shown in in-vitro analysis. In line with this observation, one pt demonstrated resolution of fungal pneumonia during the study. Conclusions: In summary, the low-intensity, biomodulatory regimen of low-dose AZA, pioglitazone, and ATRA demonstrated a tolerable safety profile and encouraging signals for efficacy in pts with AML refractory to standard induction chemotherapy warranting further investigation. S.T. and A.R. contributed equally to this abstract as senior co-authors. Disclosures Paschka: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Abbvie: Other: Travel expenses; Amgen: Other: Travel expenses; Otsuka: Membership on an entity's Board of Directors or advisory committees; BMS: Other: Travel expenses, Speakers Bureau; Astex: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Other: Travel expenses; Takeda: Other: Travel expenses; Sunesis: Membership on an entity's Board of Directors or advisory committees. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AROG, Bristol Myers Squibb, Pfizer: Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria. Thomas:Celgene: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Medigene AG: Consultancy, Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Other: Travel support; Janssen: Other: Travel support.

Dexabeam versus ICE salvage regimen prior to autologous transplantation for relapsed or refractory aggressive peripheral T-cell lymphoma: A retrospective evaluation of parallel patient cohorts of one center.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8548-8548
Author(s):  
Jan-Henrik Mikesch ◽  
Mareike Kuhlmann ◽  
Angela Demant ◽  
Utz Krug ◽  
Eva Schmidt ◽  
...  
Keyword(s):  
T Cell ◽  
Salvage Therapy ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Autologous Transplantation ◽  
Salvage Chemotherapy ◽  
T Cell Lymphoma ◽  
Remission Induction ◽  
Peripheral T Cell Lymphoma ◽  
Salvage Regimen

8548 Background: High-dose chemotherapy (HDT) followed by autologous stem-cell transplantation (ASCT) is considered standard in the treatment of patients with relapsed or refractory aggressive peripheral T-cell lymphoma (PTCL). However, the optimal salvage regimen before ASCT has not yet been established. Methods: We retrospectively analyzed 31 patients with relapsed or refractory aggressive PTCL after anthracycline based first-line chemotherapy who received either DexaBEAM (n=16) or ICE (n=15) regimen as first salvage chemotherapy followed by HDT and ASCT between 1996 and 2009. The median patient age was 46 years (range, 18-66) in the DexaBEAM group and 40 years (range, 17-59) in the ICE group. Patients were included independent of WHO stage and IPI score. Results: The overall response rate (OR) was significantly higher for patients treated with DexaBEAM (69%) as compared to the ICE group (20%; P=0.01), with higher complete response (CR; 38% vs. 7%) as well as partial response (PR; 31% vs. 13%) rate. Changing regimen due to failure of the first salvage therapy, 12 patients initially receiving ICE still achieved an OR of 58% (33% CR, 25% PR) with DexaBEAM as second salvage therapy, whereas in 3 patients receiving ICE after DexaBEAM failure only 1 patient achieved an OR (1 PR). Median progression-free survival (PFS) was significantly higher in the DexaBEAM group (6.4 vs. 2 months; P=0.01). Median overall survival (OS) was not different between the two groups (22.8 vs. 29.8 months; P=0.72), most likely due to the good response rate of patients to DexaBEAM as 2nd salvage regimen after failure of ICE chemotherapy. Major adverse event in both groups was myelosuppression with higher but tolerable treatment-related toxicity for patients in the DexaBEAM group. Conclusions: In this retrospective comparison DexaBEAM salvage chemotherapy was superior to ICE for patients with relapsed or refractory aggressive PTCL for remission induction prior to autologous transplantation, with higher but manageable treatment-related toxicity.

Gemtuzumab Ozogamicin Is an Acceptable Alternative to Anthracyclines in Combination with Standard Dose Infusional Cytarabine as Induction Therapy for Elderly Patients with Acute Myeloid Leukemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1856-1856 ◽  
Author(s):  
Gail J. Roboz ◽  
Ellen K. Ritchie ◽  
Michael W. Schuster ◽  
Tsiporah Shore ◽  
Tania J. Curcio ◽  
...  
Keyword(s):  
Single Dose ◽  
Overall Response Rate ◽  
Response Rate ◽  
Liver Toxicity ◽  
Single Agent ◽  
Gemtuzumab Ozogamicin ◽  
Left Ventricular ◽  
Historical Cohort ◽  
Secondary Aml ◽  
Overall Response

Abstract Gemtuzumab ozogamicin (GO), a humanized IGG4 anti-CD33 antibody conjugated to calicheamicin, has demonstrated single agent efficacy in relapsed AML. Combination with other anti-leukemic drugs has required a significant dose reduction of GO to avoid excess liver toxicity. The maximally tolerated dose of GO in combination with cytarabine 100 mg/m2 by 24 hr infusion for 7 days, was established at 6 mg/m2 day 1 and 4 mg/m2 day 8 in a phase I trial involving relapsed patients as well as untreated adults with AML above the age of 60. From 7/03 to 7/05, 31 adults (M-17, F-14) with a median age of 70 (range 60–83) were treated with this regimen on a phase II trial. Patients with residual disease on day 14 were given cytarabine 100 mg/m2 by 24 hr infusion daily for 5 days without GO. Post remission therapy, generally included repetitive cycles of cytarabine 50 mg/m2 twice daily by subcutaneous injection in combination with rotating cycles of 6-thioguanine, cyclophosphamide, or daunorubicin. Patients with an antecedent hematological disorder (AHD) or secondary AML were not excluded, and prior treatment for myelodysplastic syndrome was allowed. An AHD was documented in 13/30 (43%) of patients and 3/30 (10%) had secondary AML. Unfavorable cytogenetics (−5, −7, 11q2,3 abnormalities and complex karyotypes) were present in 17/30 (56%) patients. Of the first 7 patients treated, 4 developed severe and fatal hyperbilirubinemia in conjunction with ascites, fluid retention and encephalopathy consistent with sinusoidal occlusion syndrome (SOS). Subsequent patients were treated with 6 mg/m2 of GO without the day 8 dose. Of these 24 patients, 4 developed grade 3 hyperbilirubinemia which was transient and not associated with SOS. Apart from this toxicity, other non-hematologic effects, including infusional reactions, mucositis, diarrhea, nausea, vomiting and anorexia were mild to moderate. No cardiac toxicity was observed in any patients including 3 patients with reduced left ventricular function documented prior to treatment. Overall 9/31 (29%) patients achieved a complete response (CR) and 1 achieved a CRp for an overall response rate of 32%. Of the 24 patients who received 1 dose of GO (6 mg/m2), the overall response rate was 9/24 (36%). The induction mortality rate in these 24 patients was 5/24 (21%). The median duration of response is 10.5 months (range 6 to 12 months) with 2 patients in ongoing CR at 12 months and 18 months respectively. This data demonstrates that GO administered on day 1 and day 8 leads to unacceptable liver toxicity in unselected patients with AML above the age of 60 yrs. However, in patients receiving a single dose of GO (6 mg/m2) in combination with cytarabine, the overall response rate and toxicity profile is comparable to a historical cohort of similarly unselected elderly AML patients treated with daunorubicin and cytarabine at our institution. We conclude that a single dose of GO (6mg/m2) is an equally safe and effective alternative to anthracycline in combination with standard doses of infusional cytarabine in adults with AML above the age of 60.

Decitabine-Based Salvage Therapy in Adults with Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2063-2063 ◽  
Author(s):  
Ellen K Ritchie ◽  
Jon Arnason ◽  
Eric J. Feldman ◽  
Usama S Gergis ◽  
Sebastian A Mayer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Median Survival ◽  
Salvage Therapy ◽  
Myeloid Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
Myelogenous Leukemia ◽  
Rank Test ◽  
Off Label ◽  
Acute Myeloid

Abstract Abstract 2063 Poster Board II-40 Introduction: Adults with primary refractory or relapsed acute myeloid leukemia (AML) have a poor prognosis with complete responses to salvage therapy from 13-15% and a median survival of 1.5-6 months[1, 2]. From 2006-2009, 79 patients with relapsed or refractory acute myeloid leukemia were given salvage chemotherapy with decitabine 20mg/m2 daily for 10 days or decitabine 20mg/m2 × 5 days with gemtuzumab ozogamicin (GO) 3mg/m2 on day 5 at Weill Cornell Medical Center. Methods: Medical records of 79 patients who received decitabine-based salvage therapy were reviewed from September 2006 through July 2009 at Weill Cornell Medical College. Survival was calculated by the Kaplan Meir method and differences in survival calculated by the log-rank test using STATA software. Results: Twenty-five patients received decitabine-based therapy as first salvage, 32 patients as second salvage, and 22 patients as third or greater salvage. Fifty-one patients were treated with decitabine/GO and 29 patients received decitabine alone. Median age of patients was 65.5 years with a range of 24 -89 years (first salvage 75 years, second salvage 62 years, and third or greater salvage 64 years). Median survival of all patients was 205 days, range 7-732 days. Overall 34% patients responded: 16% CR (<5% blasts in bone marrow, recovery ANC >1000 and Plts > 100,000) with median survival not yet reached; 5% CRp (< 5% blasts in bone marrow, ANC >1000 and plts < 100,000) with median survival 223 days; 13% PR (blasts 6-11%) with median survival 205 days; and 66% no response with median survival 118 days. Patients receiving first salvage had median survival 181 days with CR 13%, CRp 6%, PR 17%. Patients receiving second salvage had median survival 207 days with CR 9%, CRp 4%, PR 9%. Patients with third or greater salvage had median survival 209 days with CR 23%, CRp 0%, PR 14%. Patients receiving decitabine alone had a median survival of 209 days and those receiving decitabine/GO had a median survival of 177 days but the difference was not significant. Median survival for normal, favorable, intermediate and unfavorable cytogenetics was 282, 224, 157 and 176 days respectively (p=0.06). Conclusions: Decitabine-based treatment for relapsed and refractory AML is a low intensity alternative that has activity rivaling more intensive regimens. This retrospective study suggests that further investigation of decitabine-based salvage is warranted. 1. Sievers, E.L., et al., Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol, 2001. 19(13): p. 3244-54. 2. Giles, F., et al., Outcome of patients with acute myelogenous leukemia after second salvage therapy. Cancer, 2005. 104(3): p. 547-54. Disclosures: Off Label Use: Phase I trial of decitabine in AML is off-label .

Sign in / Sign up

Export Citation Format

Share Document