Use of Clofarabine in the Treatment of Relapsed or Refractory Acute Myeloid Leukemia in Adults: The French Experience

Abstract Abstract 2623 Introduction. Relapsed or refractory acute myeloid leukemia (AML) patients (pts) have a dismal outcome and conventional chemotherapy offers almost no chance of cure. Consequently, allogeneic transplantation (alloSCT) has been widely used for these patients, but outcome is limited by a high relapse rate. There is no generally established standard for reinduction of remission. Clofarabine is a second-generation purine nucleoside analogue mainly evaluated in older adults with untreated AML, but there are limited data in relapsed/refractory AML. The aim of the present study was to establish the role of clofarabine in a large series of adults with relapsed/refractory AML. Methods. Eighteen French centers participated in this retrospective study. Eligibility criteria were as follows: confirmed diagnosis of AML, pts >18 years (yrs) old at clofarabine treatment, and clofarabine used outside of a clinical trial. Relapses after alloSCT were included, but use of clofarabine as part of the conditioning regimen of alloSCT was not included. Data were collected regarding patient demographics, leukemia characteristics, previous treatments and the use of clofarabine including the regimen used and the outcome following treatment. Results. Between January 2007 and June 2011, 100 pts were treated with clofarabine for relapsed/refractory AML. At first diagnosis of AML, median age was 58 yrs, male:female ratio was 60:40, 86% of pts had performance status 0–1, 57% had white blood cells < 10000/mm3, 37% had secondary AML (prior myelodysplastic syndrome 54%), 39% had unfavorable cytogenetics, 58% had intermediate cytogenetics and 3% had favorable cytogenetics, 14/55 had NPM1 mutation, 19/69 had FLT3 internal tandem duplication. At clofarabine treatment, median age was 59 yrs (range 18–77), 42 pts were in first relapse, 35 in relapse >1, and 23 had primary refractory AML. Anthracycline was previously used in 92 pts. Twenty three relapses occurred after alloSCT. Clofarabine was used as single agent (n=22) or in combination with low-dose cytarabine (LDAC, 20–40 mg/m2/d for 4–14 days, n=18) or intermediate-dose cytarabine (IDAC, 1000–2000 mg/m2/d for 3–5 days, n=56) or other drugs (n=4). The dose of clofarabine at cycle 1 was 20 mg/m2/d (n=26), 30 mg/m2/d (n=32), 40 mg/m2/d (n=40) or other (n=2) for a median number of 5 days (mean 4.9, range 3–5). Among all pts, 30 achieved complete remission (CR), and 9 achieved CR with incomplete recovery (CRi), for an overall response rate of 39%. Six pts died during cycle 1, all of infection. Responding pts received a median number of 2 cycles (mean 2.1, range 1–6). Thirteen pts underwent subsequent alloSCT and four pts proceeded to donor lymphocyte infusion. No predictive factor of response was found in univariate analysis among age (cut-off at 60 yrs), sex, de novo vs secondary AML, cytogenetics (unfavorable vs intermediate), molecular genetics, line of treatment (first relapse vs relapse>1 vs refractory AML), relapse after alloSCT vs other relapse (for patients < 65 yrs with equally distributed cytogenetics), regimen (monotherapy vs LDAC vs IDAC) or dose of clofarabine (20 vs 30 vs 40 mg/m2/d). The median disease-free survival (DFS) was 17 months (mo). No factor significantly influenced DFS in univariate analysis, even though DFS tended to be better in relapse after alloSCT than in other relapse (for patients < 65 yrs with equally distributed cytogenetics) with 1-yr DFS being 100% vs 60% (p=0.1). Median overall survival (OS) was 19 mo for responding pts (CR+CRi) vs 3 mo in treatment failure (p<0.0001). In univariate analysis, median OS was better in male than in female (6.8 mo vs 4.1 mo, p=0.03), and in intermediate vs unfavorable cytogenetics (5.4 mo vs 4.1 mo, p=0.04); median OS tended to be better in relapse after alloSCT than in other relapse (for patients < 65 yrs with equally distributed cytogenetics) with median OS being 21 mo vs 4 mo (p=0.09). In multivariate analysis, cytogenetics was the only prognostic factor for OS (p=0.02). Conclusion. This study suggests that clofarabine-based salvage regimen is safe and can be effective in the treatment of relapsed/refractory AML. Durable remissions were achieved, especially in AML relapsed after alloSCT, allowing pts the option of (second) transplantation with the potential of long term cure. Disclosures: Off Label Use: clofarabine is approved for relapsed ALL in children.

Download Full-text

Allogeneic Stem Cell Transplantation for Refractory Acute Myeloid Leukemia in Pediatric Patients: The UK Experience

Blood ◽

10.1182/blood.v126.23.4404.4404 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4404-4404

Author(s):

Patricia M O'Hare ◽

Giovanna Lucchini ◽

Michelle Cummins ◽

Paul Veys ◽

Mike Potter ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Allogeneic Stem Cell Transplantation ◽

Myeloid Leukemia ◽

Pediatric Patients ◽

Refractory Disease ◽

Free Survival ◽

Refractory Acute Myeloid Leukemia ◽

Acute Myeloid ◽

Refractory Aml

Abstract INTRODUCTION The prognosis for children with refractory acute myeloid leukemia (AML) treated with chemotherapy is dismal and data on the outcome after allogeneic haematopoietic stem cell transplant (SCT) are scanty with reported leukemia free survival (LFS) rates of 10-20%. Thus there is significant controversy about whether SCT is appropriate in such patients (pts). We performed a retrospective, national study to analyse outcomes and prognostic factors for children undergoing SCT for refractory AML in the UK. METHODS A retrospective analysis of all pts <18 years of age reported to the BSBMT registry who received their first allogeneic SCT between 2000-2012 for refractory AML (ie >5% blasts in the bone marrow (BM) or proven extramedullary disease (EM) was performed. Source data verification (SDV) was performed to ensure pts were indeed refractory. The primary end-point was 5 year LFS. Secondary end-points were Relapse Rate (RR), Treatment Related Mortality (TRM), Graft Versus Host Disease (GVHD) and Overall Survival (OS). The Kaplan Meyer method was used to estimate survival data and Fisher's exact and Mantel-Cox Log Rank tests were used to compare disease- transplant- and survival-related variables. RESULTS Following SDV, a total of 44 pts from 13 centres were included in the study. The median age at SCT was 11.5 yrs and the median number of prior lines of chemotherapy was 3. The median time from diagnosis to SCT was 197 days. 23 pts had primary refractory AML and 21 had relapsed refractory AML. 12 pts showed adverse risk cytogenetics, 26 standard risk and 6 favourable. EM disease was documented in 5 pts. 42 children had >5% myeloid blasts in the BM immediately prior to conditioning and refractory disease was confirmed by cytogenetics/molecular genetics in 23. 2 pts were in BM remission but had frank EM disease. 38 pts (86%) received myeloablative conditioning (14 TBI based) and 6 (14%) had reduced intensity conditioning (RIC). In vivo T cell depletion was used in 25 pts. 15 pts (35%) were transplanted from an HLA identical family donor, 15 from a matched unrelated donor and 14 (32%) a mismatched donor. BM was used as the stem cell source in 18 (41%), peripheral blood in 20 (46%) and cord blood in 6 cases (14%). Median follow up was 4 years 10 months. 5 pts never achieved engraftment and had disease progression. The remaining 39 pts engrafted at a median of 15 days post-SCT. 30 pts (68%) achieved a complete remission (CR) following SCT. TRM at 1 year was 18% (5 infections, 1 cardiac failure, 1 GVHD-related). Acute GVHD occurred in 23 pts and was severe (grade ≥III) in 8 (19%). The incidence of chronic GvHD was low (1 limited, 2 extensive). Relapse was the major cause of treatment failure and occurred in 17 pts (39%) at a median 2.3 months post SCT. At last follow-up, 18 pts remain alive and in continuous complete remission (CCR). In this cohort, the 5 year OS and LFS were both 43% (95%CI 31-61%) (Figure1). Outcomes in pts with primary refractory disease (9/23, 39% in CCR) and those with relapsed refractory AML (9/21, 43% in CCR) were equivalent. Outcome for pts with cytogenetic confirmation of refractory disease was not statistically different (7/23, 30% in CCR) from the overall group. Pts transplanted with ≤30% blasts in the BM had improved outcomes (5-year LFS 52% vs 27%, p= 0.05). Likewise, the development of aGVHD of any grade was associated with a significantly better LFS (5-year LFS 56% vs 30%, p= 0.05). Cytogenetics including monosomy 7 (n=7) and molecular risk classification did not translate into a significant prognostic factor for relapse. Since RIC was used in only 6 pts, the impact of the intensity of conditioning cannot be determined. CONCLUSIONS This is the largest series of outcomes for SCT for refractory paediatric AML reported to date. Our data indicate that for selected pts, particularly those with a lower disease burden, SCT offers a realistic chance of salvage in both primary refractory and relapsed refractory AML (5 year LFS 43%) with acceptable toxicity. The association of aGVHD with improved LFS suggest a possible role in engineering a graft-versus-leukemia effect in this patient group. Figure 1. Leukemia-free survival for pediatric patients with refractory acute myeloid leukemia undergoing allogeneic stem cell transplantation. Figure 1. Leukemia-free survival for pediatric patients with refractory acute myeloid leukemia undergoing allogeneic stem cell transplantation. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Retrospective Comparison between MEC and FLAG-Ida Regimens for Refractory or Relapsed Acute Myeloid Leukemia in Adults

Blood ◽

10.1182/blood-2019-127202 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1354-1354

Author(s):

Wellington F Silva ◽

Lidiane Inês Da Rosa ◽

Fernanda S Seguro ◽

Douglas R. A. Silveira ◽

Luciana Nardinelli ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Univariate Analysis ◽

Multivariable Analysis ◽

High Dose ◽

Npm1 Mutation ◽

Baseline Characteristics ◽

One Year ◽

Relapsed Acute Myeloid Leukemia ◽

Acute Myeloid

Introduction: There is no consensus regarding the best salvage regimen for refractory or relapsed acute myeloid leukemia (r/rAML), with classic regimens traditionally based on high-dose cytarabine in a changeable combination with anthracyclines, purine analogs, and etoposide. Outcomes of r/rAML patients in developing countries are underreported, even though the same regimens are widely used. Methods: This is a retrospective single-center study, conducted in an academic center in Brazil. Local research ethics committee approved this analysis. All patients above 16 years of age who received MEC (mitoxantrone, etoposide and cytarabine) or FLAG-IDA (fludarabine, cytarabine, filgrastim and idarubicin) as originally reported (Amadori, S. et al. and Steinmetz, H. T. et al.) for r/rAML between December/2009 and January/2019 were included. Only patients with refractory or relapsed disease following standard upfront therapy ("7+3" regimen) were included in this analysis, being divided among refractory (less than partial response after one cycle of "7+3"), early relapsed (relapse within one year from first complete response [CR]) and late relapsed (relapse after one year of CR). Only the first salvage was considered for this study. Results: Sixty patients were included in the final analysis, with a median age of 45 years (range, 17 - 69). There were no cases of therapy-related AML. Four AML cases (7%) were secondary to myeloproliferative neoplasm (MPN) or myelodysplastic syndrome (MDS). All FLT3-ITD positive cases had an associated NPM1 mutation. Two patients had chronic human immunodeficiency virus infection and received antiretroviral therapy. Baseline characteristics of the whole cohort are summarized in Table 1. Three patients had undergone SCT in first CR and were post-SCT relapses. Twenty-eight patients received MEC and 32 received FLAG-IDA. By comparing the baseline characteristics of both groups, no difference statistically significant was found except for the indication for salvage treatment, in which there were more refractory cases in FLAG-IDA group (56 vs. 28%, p=0.029) (Table 2). Overall, 17/60 achieved CR and 12/60 CRi, with a total CR rate (CR+CRi) of 48.3% (95% confidence interval [CI], 35.4 - 61.5). Sixteen patients (27%) early died before a response assessment. By univariate analysis, only age affected the CR rate (p=0.045). No difference in CR rate was found between the two protocols (MEC 53.5 vs. FLAG-IDA 43.7%, p=0.447). Looking into this data, it can be seen that there were more refractory patients in FLAG-IDA arm (37.5 vs. 4%, p=0.02) but more patients early-died in MEC arm (35.7 vs. 18.7%, p=0.137), even though the latter was not statistically significant. After correcting the initial differences between the two groups regarding indication for salvage through a propensity score calculation, a post-matching cohort with 44 subjects was found. In this cohort, no difference in refractoriness rate could be detected (p=0.077). In the whole cohort, 17 patients proceeded to allogeneic SCT - 15 in CR/CRi and 2 with active disease, with no difference in SCT execution rate between the two groups (p=0.470). 4/17 transplanted patients were alive. Median follow-up was 48 months. Median survival for total cohort was 4 months (95% CI, 2.7 - 9.2), with a 3-year OS of 9.7% (95% CI, 4 - 23.7) and a 3-year EFS of 7.5% (95% CI, 2.5 - 22.4). In the univariate analysis for OS, age (p=0.04), FLT3 status (p<0.001) and SCT procedure (p=0.002) were statistically significant. Chosen regimen did not influence OS or EFS as well as the genetic risk, colonization or time of relapse (Figure 1). In a multivariable model for EFS including age, FLT3 status and SCT procedure, only the last two indicators remained significant: FLT3-ITD mutation (Hazard ratio [HR] = 4.6 [95% CI 1.9 - 11.4], p<0.001) and SCT procedure (HR = 0.43 [95% CI 0.22 - 0.82], p=0.01). Conclusion: In this analysis, there was no difference concerning the chosen regimen for r/rAML, even though a possible higher refractoriness rate could be seen in FLAG-IDA arm. High early toxicity was found, emphasizing the role of supportive care and judicious selection of patients to intensive salvage therapy in our setting. FLT3-ITD mutation and SCT remained as significant factors for survival in a multivariable analysis, which is in line with previous studies. Disclosures No relevant conflicts of interest to declare.

Download Full-text

A Retrospective Observation of Treatment Outcomes Using Decitabine-Combined Standard Conditioning Regimens Before Transplantation in Patients With Relapsed or Refractory Acute Myeloid Leukemia

Frontiers in Oncology ◽

10.3389/fonc.2021.702239 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yuhang Li ◽

Longcan Cheng ◽

Chen Xu ◽

Jianlin Chen ◽

Jiangwei Hu ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Low Dose ◽

High Dose ◽

Hematopoietic Stem ◽

Hematopoietic Reconstitution ◽

Conditioning Regimens ◽

Refractory Acute Myeloid Leukemia ◽

Acute Myeloid ◽

Refractory Aml

Hypomethylating agents, decitabine (DAC) and azacitidine, can act as prophylactic and pre-emptive approaches after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a non-intensive bridging approach before allo-HSCT. However, they are rarely used as a part of conditioning regimens in patients with relapsed or refractory acute myeloid leukemia (AML). This retrospectively study included a total of 65 patients (median, 37; range, 13–63) with relapsed or refractory AML who were treated by allo-HSCT after myeloablative conditioning regimens without or with DAC (high-dose DAC schedule, 75 mg/m2 on day −9 and 50 mg/m2 on day −8; low-dose DAC schedule, 25 mg/m2/day on day −10 to −8). DAC exerted no impact on hematopoietic reconstitution. However, patients who were treated with the high-dose DAC schedule had significantly higher incidence of overall survival (OS, 50.0%) and leukemia-free survival (LFS, 35.0%), and lower incidence of relapse (41.1%) and grade II–IV acute graft versus host disease (aGVHD, 10.0%) at 3 years, when compared with those treated with standard conditioning regimens or with the low-dose DAC schedule. In conclusion, high-dose DAC combined with standard conditioning regimens before allo-HSCT is feasible and efficient and might improve outcomes of patients with relapsed or refractory AML, which provides a potential approach to treat these patients.

Download Full-text

FLAG-IDA Regimen (Fludarabine, Cytarabine, Idarubicin and G-CSF) in the Treatment of Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndromes.

Blood ◽

10.1182/blood.v110.11.2866.2866 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2866-2866

Author(s):

Pau Montesinos ◽

Javier de la Rubia ◽

Guillermo Orti ◽

Jaime Sanz ◽

David Martinez ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Term Outcome ◽

Long Term Outcome ◽

First Relapse ◽

Subsequent Relapse ◽

Acute Myeloid ◽

Refractory Aml

Abstract Background: Preliminary results with the combination of fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor (G-CSF) (FLAG-IDA), reported complete response (CR) rates of 47–95% in patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), with acceptable toxicity. These results lead to a generalized use of FLAG-IDA regimen in this set of patients. However, these studies have been made in small series and the long-term outcome of patients have not been described. Objectives: Analyze the results of FLAG-IDA regimen, in terms of CR rate and long-term outcome, in a large series of patients with high-risk AML and MDS treated in a single institution. Methods: From 1997 to 2007, 158 adult patients (median age 60 years, range 16–79) received FLAG-IDA regimen (Fludarabine, 30 mg/m2 intravenous (iv) for 4 days, cytarabine 2 g/m2 iv for 4 days, idarubicin 10 mg/m2 iv for 3 days and glycosylated G-CSF at a daily dose of 300 mcg/m2, from day -1 until day 5). Post-remission therapy consisted of allogeneic transplantation (Allo-HSCT) in eligible patients, or consolidation (idarubicin, 10 mg/m2 iv for 3 days and cytarabine, 200 mg/m2 iv for 5 days), followed by intensification with Auto-HSCT or one cycle of carboplatin (300 mg/m2 for 4 days, as a 24 h continuous infusion). Patients were diagnosed with high-risk MDS (11%), treatment related AML (10%), AML secondary to MDS (29%), primary refractory AML (17%), AML in first relapse (27%), and AML in second or subsequent relapse (6%). Median follow-up of the cohort was 40 months (range 2–104). We calculated the Kaplan-Meier estimates curves for overall survival (OS), disease-free (DFS) and relapse-free survival (RFS). Results: CR and partial remission (PR) was achieved in 84 patients (53%) and in 19 patients (12%), respectively. Twenty-three patients (15%) died during induction, mostly due to infection (19 patients). The CR rates according to the disease status were the following: high-risk MDS 61%, treatment related AML 73%, AML secondary to MDS 52%, primary refractory AML 54%, AML in first relapse 49%, and AML in second or subsequent relapse 30%. Post-remission therapy consisted of Allo-HSCT in 16 patients (8 related and 8 unrelated), Auto-HSCT in 15 patients, and chemotherapy alone in 53 patients. The 1 and 5 year OS, DFS and RFS of the entire cohort were 36% and 11%, 40% and 11%, and 51% and 23%, respectively. The 1 and 5 year OS in patients achieving CR, PR and resistance were 64% and 22%, 26% and 7%, and 4% and 0%, respectively (p<0.0001). The 5 year RFS of patients treated with chemotherapy alone, Auto-HSCT and Allo-HSCT were 13%, 16% and 64%, respectively (p=0.09). The 5 year RFS of patients aged >55 years and ≤55 years were 4% and 53%, respectively (p=0.0005). The 5 year DFS of patients treated with chemotherapy alone, Auto-HSCT and Allo-HSCT were 7%, 13% and 35%, respectively (p=0.22). Conclusion: Our results confirm the acceptable toxicity and high response rate observed with FLAG-IDA regimen in this very high-risk subgroup of patients. This regimen can be a bridge towards Allo-HSCT, that appear to be the most curative therapy in this setting.

Download Full-text

A Prospective Monocentric Study of Fractionated Gemtuzumab Ozogamicin (GO) Combined to Standard-Dose Cytarabine in Older Patients with Acute Myeloid Leukemia (AML) in First Relapse,

Blood ◽

10.1182/blood.v118.21.3603.3603 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3603-3603

Author(s):

Sylvain Pilorge ◽

Sophie Rigaudeau ◽

Clémentine Sarkozy ◽

Anne L Taksin ◽

Hassan Farhat ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Median Duration ◽

Myeloid Leukemia ◽

Standard Dose ◽

Gemtuzumab Ozogamicin ◽

Molecular Profile ◽

Molecular Response ◽

Npm1 Mutation ◽

First Relapse ◽

Acute Myeloid

Abstract Abstract 3603 Aim. Gemtuzumab Ozogamicin (GO) is a potent antibody-directed chemotherapy against CD33 antigen. We have previously conducted a phase 2 study evaluating fractionated infusion of GO 3 mg/m2 on day 1, 4 and 7 combined to standard 3+7 DNR/cytarabine in patients aged 50 to 70 years with relapsed acute myeloid leukemia (AML) (Farhat et al., AJH, accepted). We decided to determine whether the omission of daunorubicin may retain the efficacy of fractionated GO combined to standard-dose cytarabine. Methods. GO was proposed to patients (pts) with CD33 positive AML in relapse according to the French Temporary Authorization (ATU) program. All consecutive pts from our center were eligible if they were in first relapse and aged of 50 years or more. Refractory patients and patients with a first CR of less than 6 months were excluded. Induction consisted of cytarabine 200 mg/m2/d CI on day 1–7 with GO at 3 mg/m2/d on day 1, 4 and 7. Pts achieving CR/CRp received two consolidation courses with cytarabine 1 g/m2/12h on day 1–2 with GO at 3 mg/m2/d on day 1. A maintenance phase with low-dose cytarabine was allowed. Minimal residual disease (MRD) monitoring based on NPM1 mutation or WT1 expression was assessed in informative and evaluable patients. Results. From October 2007 to June 2011, 22 pts (median age, 67 years) were recruited. All pts received an intensive regimen as part of their first line therapy (3+7 schedule or more intensive). Median duration of first CR was 16 months (6 to 33). Cytogenetic analysis at relapse was successfully assessed in all pts and karyotype was classified as favorable in 3 pts (t(8;21); t(16;16); t(15;17)), intermediate in 18 pts and adverse in 1 pt. Molecular profile analysis of intermediate-risk patients revealed the presence of a FLT3 internal tandem duplication (FLT3 -ITD) in 3 pts, a NPM1 mutation in 8 pts (including 2 cases with a concomitant FLT3 -ITD), a single CEBPA mutation in 1 pt, a EVI1 hyperexpression in 2 pts, and a MLL rearrangement in 1 pt. CR+CRp was achieved in 17/22 pts (77.3%) including 2 CRp. The 5 primary resistant pts corresponded to 1 pt with complex karyotype, 1 pt with a MLL rearrangement, 1 pt with EVI1 hyper expression, 1 pt with FLT3 -ITD, and 1 pt without any identified genetic alteration. There were 2 (9%) induction deaths including one patient that experienced veino-occlusive disease (VOD) and one patient with severe sepsis. A second case of reversible grade 2 VOD was documented during induction. Four patients (18.1%) experienced G3-4 infections and only one severe mucositis was observed. Median duration of G3-4 neutropenia and thrombocytopenia was 24 days (16–30) and 30 days (20–60), respectively. Prolonged grade ≥ 3 thrombocytopenia was observed in 2 patients. With a median follow-up of 22 months, median DFS was 17.2 months and estimated at 66.3% at 18 months. To date, the duration of CR2 was superior to that of CR1 in 5 non transplanted patients. Median overall survival was 22.6 months. Four pts who received a reduced intensity allogeneic stem cell transplantation in CR2, and one of them subsequently died. We were able to compare the molecular response obtained after CR2 and after CR1 using the same MRD marker in 6 patients that achieved CR2. In 5 out of 6 paired samples, MRD levels after CR2 were found equal or inferior to MRD levels after CR1 (see fig 1). Conclusion. Fractionated doses of GO (3 mg/m2/d on day 1, 4, and 7) combined to standard-dose cytarabine in older pts with AML in first relapse is associated with a high CR rate, a prolonged survival and a low rate of toxic deaths. A gain in MRD levels was noted in paired CR1 and CR2 samples. Disclosures: Castaigne: Pfizer/Wyeth: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Azacitidine and lenalidomide as an alternative treatment for refractory acute myeloid leukemia: a case report

Sao Paulo Medical Journal ◽

10.1590/1516-3180.2012.6790006 ◽

2014 ◽

Vol 133 (3) ◽

pp. 271-274 ◽

Cited By ~ 2

Author(s):

Juliana Todaro ◽

Patrícia Weinschenker Bollmann ◽

Edna Terezinha Rother ◽

Auro del Giglio

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Therapeutic Option ◽

Monosomy 7 ◽

Refractory Acute Myeloid Leukemia ◽

Third Line ◽

Line Chemotherapy ◽

Monosomal Karyotype ◽

Acute Myeloid ◽

Refractory Aml

CONTEXT:Refractory acute myeloid leukemia (AML) is a difficult disease to control with second or third-line chemotherapy regimens. In this report, we describe using azacitidine in combination with lenalidomide as salvage therapy.CASE REPORT:52-year-old female was diagnosed with refractory AML and high-risk cytogenetics: complex monosomal karyotype consisting of t (3, 3) in association with monosomy 7 and del 5q. Morphological remission associated with maintenance of the cytogenetic abnormality of chromosome 3 and disappearance of the abnormalities relating to chromosomes 5 and 7 was achieved after three cycles of combination therapy with azacitidine and lenalidomide.CONCLUSION:Azacitidine plus lenalidomide can be a therapeutic option for patients with refractory AML, as illustrated in this case.

Download Full-text

Enasidenib, an Oral Therapy in Mutant IDH2 Relapsed/Refractory Acute Myeloid Leukemia: A Real-Life Single Center Experience

Blood ◽

10.1182/blood-2020-141987 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 20-21

Author(s):

Marta Riva ◽

Lorenzo Rizzo ◽

Valentina Mancini ◽

Rosa Greco ◽

Giambattista Bertani ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Target Therapy ◽

Real Life ◽

Median Number ◽

Intensive Chemotherapy ◽

Unfit Patients ◽

Refractory Acute Myeloid Leukemia ◽

Acute Myeloid

Background: The treatment for relapsed or refractory acute myeloid leukemia (R/R AML) has minimal chances and a low impact on improving survival. One of the most important goal is to treat unfit patients who are often intolerant to intensive chemotherapy and are not eligible for allogeneic stem cell transplantation. Most patients with AML, including nearly all patients older than 60 years, present multiple, sequentially acquired, somatic mutations. Isocitrate dehydrogenase 2 (IDH2) mutations are present in approximately 8-19% of cases (Buege MJ, Cancers 2018). IDH2 mutations occur early in the leukemogenesis and accumulate an oncogenic product (R-2-hydroxyglutarate) that arrests the histone demethylation pathway, thereby stopping haematopoietic differentiation (Rakheja D, Hum Pathol. 2012). Enasidenib (ENA) is a selective, powerful oral inhibitor of the oncogenic activity of the IDH2 mutant enzyme, that decreases R-2-hydroxyglutarate levels in vitro and in vivo. Interestingly, phase I/II trials showed an overall response rate (ORR) of 40.3% in R/R disease, with 19.3% of complete remission (CR) and with 6.8 % of CR with incomplete haematological recovery (CRi). Moreover, the reported median overall survival was 9.3 months, with 19.7 months (mo) for patients who achieved CR (Stein E, Blood 2017). Aims: To study retrospectively the efficacy and safety of ENA, as single agent, in improving overall survival (OS) and progression-free survival (PFS) in IDH2 mutated R/R AML patients (pts), unfit for intensive chemotherapy. Furthermore, to compare outcomes with a cohort of patients with R/R AML IDH2 wild-type (wt). Methods: Since 2018 we have retrospectively collected and analyzed data of unfit IDH2 mutated R/R AML patients, treated with ENA, thanks to the expanded access program of this drug. The dose was 100 mg/day for all pts. PFS and OS were estimated using the Kaplan-Meier product limit method. Therefore, we considered, as historical comparison, a sample of 28 pts with R/R IDH2 wt AML, treated with the best available therapy at our Institution in the same time frame and matched for clinical features. OS and PFS were compared using the log-rank test. Results: Nine IDH2 mutated pts were considered for analysis: 4 (44%) cases were de novo AML, while 5 (56%) were secondary (1 myelodysplasia and 4 myeloproliferative neoplasms). Median age at relapse was 71 years (range 47-79). Median number of previous therapies was 2 (range 1-3). All pts completed at least one cycle of ENA with a median number of 5 cycles (range 1-16). Median OS from AML diagnosis and from the beginning of ENA was 28 mo (range 3-65), and 15 mo (range 1-27) respectively; median PFS was 13 mo (range 1-14). Among the 28 patients of the control group, with a median age at relapse of 74 years (range 65-86) we recorded a median OS of 14 mo (range 7-62) and an OS from the last relapse of 2 mo (range 0,5-26). The ENA pts group showed a significantly better OS than the control population (p = 0,0419) (Figure 1). The most prominent toxicities were hyperbilirubinemia in 2 pts (22,2%) and IDH-differentiation syndrome (IDH-DS) in 3 (33,3%); though the drug was generally well tolerated. Therefore, patients were treated as outpatients in most cases. Conclusions: In the era of precision medicine, molecular target therapy is the most promising strategy to increase the probability of treatment success with limited side effects. Our experience confirms the efficacy of the IDH2 inhibitor ENA to treat unfit patients with R/R AML in the real life, showing significantly better outcome in terms of survival for the pts treated with target therapy, compared to pts treated with standard therapy. Disclosures Veronese: Janssen Cilag:Honoraria;Bayer:Honoraria;Novartis:Other: Travel Expenses;AstraZeneca:Other: Travel Expenses.

Download Full-text

Determination of the Maximum Tolerated Dose of Panobinostat in Combination with Cytarabine and Mitoxantrone As Salvage Therapy for Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v118.21.423.423 ◽

2011 ◽

Vol 118 (21) ◽

pp. 423-423 ◽

Cited By ~ 2

Author(s):

Richard F. Schlenk ◽

Jürgen Krauter ◽

Markus Schaich ◽

Didier Bouscary ◽

Hervé Dombret ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Febrile Neutropenia ◽

Dose Escalation ◽

Salvage Therapy ◽

Myeloid Leukemia ◽

Maximum Tolerated Dose ◽

Refractory Acute Myeloid Leukemia ◽

Grade 3 ◽

Acute Myeloid ◽

Refractory Aml

Abstract Abstract 423 BACKGROUND: Relapsed/refractory acute myeloid leukemia (AML) is characterized by poor prognosis, with low complete remission (CR) rates after salvage therapy and low overall survival. A major challenge is to improve the CR rate, thereby increasing allogeneic hematopoietic stem cell transplantation (alloHSCT) rates. Panobinostat is a pan-deacetylase inhibitor that increases acetylation of proteins involved in cancer. Preclinical studies in AML demonstrated that panobinostat potentiates the activity of cytarabine (ara-C) and fludarabine and has synergistic activity in combination with doxorubicin in vitro. Single-agent panobinostat has induced CR in patients (pts) with AML. The addition of panobinostat to an active chemotherapeutic regimen in pts with relapsed/refractory AML has the potential to improve therapeutic outcomes in this setting. AIMS: This phase Ib, multicenter, open-label dose-escalation study was designed to determine the maximum tolerated dose (MTD) of panobinostat in combination with a fixed dose of ara-C and mitoxantrone in pts with relapsed/refractory AML. The secondary objectives were to characterize safety and tolerability during the dose-escalation phase and at the MTD and to evaluate anti-leukemic activity. METHODS: Successive cohorts of at least 3 pts with confirmed relapsed or refractory AML were treated with oral panobinostat (starting with 20 mg, escalated in 10-mg steps) thrice weekly on days 1, 3, 5, 8, 10, and 12, in combination with intravenous ara-C (1 g/m2) on days 1–6 and mitoxantrone (5 mg/m2) on days 1–5 of a 28-day cycle. The MTD was determined on the basis of the observed dose-limiting toxicities (DLTs), safety assessment, and tolerability during the first 28 days after starting panobinostat. A DLT was defined as any adverse event (AE) or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications with the following criteria: neutropenia lasting > 28 days after cycle 1 for hematologic DLTs; grade 4 AST/ALT or grade 3 AST/ALT for > 7 days; grade 3/4 bilirubin, vomiting, diarrhea, or any non-hematologic toxicity for non-hematologic DLTs. Safety and tolerability were described as type, duration, frequency, relatedness, and severity of AEs according to CTCAE v3.0. The adaptive Bayesian logistic regression model was used to guide dose escalation with overdose control. RESULTS: Of 5 dose levels, 40 pts (median age, 55 years; range, 19–73 years) were treated at panobinostat dosages of 20 to 60 mg, with 5 pts at 20 mg, 8 at 30 mg, 10 at 40 mg, 11 at 50 mg, and 6 at 60 mg. Of 6 DLTs observed, 1 was at 40 mg (sepsis and tachyarrhythmia), 2 were at 50 mg (vomiting/nausea; diarrhea), and 3 were at 60 mg (neutropenic colitis; 2 hypokalemic events). Frequent AEs of all grades, regardless of causality, included nausea (32 [80%]), diarrhea (31 [78%]), vomiting (26 [65%]), hypokalemia (25 [63%]), thrombocytopenia (24 [60%]), abdominal pain (22 [55%]), decreased appetite, and febrile neutropenia (21 each [53%]). The most frequent grade 3/4 treatment-related AEs were thrombocytopenia (20 [50%]), anemia (9 [23%]), leukopenia, and neutropenia (7 each [18%]). Serious AEs, regardless of causality, were reported in 23 pts, with febrile neutropenia (12 [30%]) being the most common. The MTD was determined to be 50 mg of panobinostat on the basis of observed DLTs and safety and tolerability in cycle 1 of the dose-escalation phase. Clinical responses were observed in 22 pts (55%), including 13 CR, 5 morphological CR, and 4 partial remissions. In pts receiving 40- and 50-mg doses of panobinostat, the preliminary efficacy was promising, with a response in 11 of 21 pts (52%). An alloHSCT was performed in 8 pts after the start of salvage therapy. CONCLUSIONS: The combination of panobinostat, ara-C, and mitoxantrone showed no unexpected toxicities and promising anti-leukemic activity in pts with relapsed/refractory AML. The MTD was determined to be 50 mg of panobinostat; enrollment at this dose is ongoing for the dose-expansion phase to further assess safety, tolerability, and activity. Thrombocytopenia and anemia were the principal treatment-related hematologic AEs. Treatment-related non-hematologic AEs were primarily gastrointestinal toxicities and fatigue. Disclosures: Krauter: Novartis: Consultancy, Honoraria. Winiger:Novartis AG: Employment, Equity Ownership, Honoraria. Squier:Novartis Corporation: Employment. Zahlten:Novartis AG: Employment. Wang:Novartis Corporation: Employment. Ottmann:Novartis Corporation: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding.

Download Full-text

Outcome Of Dose-Adjusted Decitabine Regimen Compared With FLAG Regimen In The Treatment Of Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v122.21.5031.5031 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5031-5031

Author(s):

Qian Wu ◽

Guangsheng He ◽

Wu Depei ◽

Aining Sun ◽

Huiying Qiu ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Therapeutic Effects ◽

Survival Times ◽

Overall Response ◽

Refractory Acute Myeloid Leukemia ◽

Group 5 ◽

Acute Myeloid ◽

Refractory Aml

Abstract Background The salvage therapy in patients with relapsed/refractory acute myeloid leukemia still poses a highly unmet clinical need. Given the established activity and toxicity profiles of hypomethylating agents such as 5-aza-2'-deoxycytidine (decitabine, DAC) in patients with untreated acute myeloid leukemia (AML), we explored the therapeutic effects of dose adjusted DAC in patients with relapsed / refractory AML, and compared treatment outcome with the conventional FLAG regimen. Patients and Methods 27 patients with relapsed/refractory AML were included in this analysis. Twelve patients were treated with DAC 20 mg/m2 per day as 1-hour intravenous infusion for consecutive five days, with additional 1-3 doses of DAC added based on response and tolerability (Table 1). Another group of 15 patients received a course of FLAG regimen as controls. Results Although the overall response rates (ORR) were similar in DAC group (5/12) and FLAG group (9/15)£¨41.7 % versus 60 %, P=0.449£©, the complete remission (CR) rate plus CRi was lower in DAC group (2/12) than in FLAG group(10/15)£¨16.7 %versus 66.7 %, P=0.047£©. Induction mortality was 0 (0% at 8 weeks) and toxicities were manageable in both groups. Toxicities were predominantly hematologic. The most common drug-related adverse events (AEs£© were grade 4 myelosuppression which were comparable for DAC and FLAG., DAC group hadfewer infections£¨DAC, 6/12£»FLAG£€n=14/15, P=0.024£©. The 2-year survival rate was similar in the two groups: 25.0% in the DAC versus 26.7% in the FLAG group£¨P=0.574£©, while median survival times of the two groups were 4 and 12 months, respectively. Conclusion Dose-adjusted DAC achieved similar overall response rate with lower infection risk compared to FLAG regimen in patients with relapsed / refractory AML. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Phase I/II Study of Continuous-Infusion Troxacitabine in Refractory Acute Myeloid Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2006.06.6209 ◽

2007 ◽

Vol 26 (1) ◽

pp. 10-15 ◽

Cited By ~ 15

Author(s):

Gail J. Roboz ◽

Francis J. Giles ◽

Ellen K. Ritchie ◽

Sandra Allen-Bard ◽

Tania J. Curcio ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Steady State ◽

Continuous Infusion ◽

Myeloid Leukemia ◽

Serum Drug Concentration ◽

Significant Activity ◽

Platelet Recovery ◽

Refractory Acute Myeloid Leukemia ◽

Acute Myeloid ◽

Refractory Aml

Purpose Troxacitabine is a non-natural nucleoside analog with unique structural and metabolic features. Bolus intravenous (IV) troxacitabine regimens have shown significant activity in patients with refractory acute myeloid leukemia (AML) and preclinical data suggest that administration via continuous infusion may result in enhanced antitumor activity. Patients and Methods Patients with refractory AML initially received troxacitabine 10.1 mg/m2 by continuous IV infusion (CIVI) for 48 hours. Infusion duration and daily dose were increased in subsequent patient cohorts. Results Forty-eight patients, median age 58 years (range, 21 to 81 years), were treated. Dose-limiting toxicities were mucositis and hand-foot syndrome, and 12.0 mg/m2/d for 5 days was established as the maximum-tolerated dose. Seven patients (15%) achieved complete remission (CR) or CR with incomplete platelet recovery (CRp), with a median survival among responders of 12 months. Steady-state concentrations of troxacitabine were found to be linearly and inversely proportionally related to calculated creatinine clearance at doses of 10.1 and 12.0 mg/m2/d. All patients responding to troxacitabine had steady-state serum drug concentration of more than approximately 80 ng/mL. In 27 patients achieving target troxacitabine plasma concentrations (ie, approximately 80 ng/mL) the CR + CRp rate was 26%. Conclusion Troxacitabine administered as a CIVI allows a significant increase in dose-intensity in comparison to IV bolus regimens, has antileukemic activity, and warrants additional investigation in patients with refractory AML. The recommended phase II study dose is 12.0 mg/m2 daily CIVI for 5 days.

Download Full-text