APR-246 COMBINED WITH AZACITIDINE IN TP53 MUTATED MYELODYSPLASTIC SYNDROMES (MDS) AND ACUTE MYELOID LEUKEMIA. A PHASE 2 STUDY BY THE GROUPE FRANCOPHONE DES MYÉLODYSPLASIES (GFM)
Author(s): ,
Thomas Cluzeau
Affiliations:
Hematology,Universitary Hospital of Nice,Nice,France
,
Marie Sebert
Affiliations:
Hematology,Saint Louis Hospital,Paris,France
,
Ramy Rahmé
Affiliations:
Hematology,Saint Louis Hospital,Paris,France
,
Stefania Cuzzubo
Affiliations:
Neurology,Saint Louis Hospital,Paris,France
,
Anouk Walter-Petrich
Affiliations:
SBIM,Saint Louis Hospital,Paris,France
,
Jacqueline Lehmann-Che
Affiliations:
Pharmacy,Saint Louis Hospital,Paris,France
,
Isabelle Madeleine
Affiliations:
Pharmacy,Saint Louis Hospital,Paris,France
,
Pierre Peterlin
Affiliations:
Hematology,CHU de Nantes,Nantes,France
,
Blandine Bève
Affiliations:
GFM,Paris,France
,
Habiba Attalah
Affiliations:
GFM,Paris,France
,
Fatiha Chermat
Affiliations:
GFM,Paris,France
,
Elsa Miekoutima
Affiliations:
Hematology,Saint Louis Hospital,Paris,France
,
Odile Beyne Rauzy
Affiliations:
Hematology,IUCT Oncopole,Toulouse,France
,
Christian Recher
Affiliations:
Hematology,IUCT Oncopole,Toulouse,France
,
Aspasia Stamatoullas
Affiliations:
Hematology,Centre Henri Becquerel,Rouen,France
,
Lise Willems
Affiliations:
Hematology,Cochin Hospital,Paris,France
,
Emmanuel Raffoux
Affiliations:
Hematology,Saint Louis Hospital,Paris,France
,
Celine Berthon
Affiliations:
Hematology,CHU de Lille,Lille,France
,
Bruno Quesnel
Affiliations:
Hematology,CHU de Lille,Lille,France
,
Antoine Carpentier
Affiliations:
Neurology,Saint Louis Hospital,Paris,France
,
David Sallman
Affiliations:
Moffitt Cancer Center,Tampa,United States
,
Sylvie Chevret
Affiliations:
SBIM,Saint Louis Hospital,Paris,France
,
Lionel Ades
Affiliations:
Hematology,Saint Louis Hospital,Paris,France
Pierre Fenaux
Affiliations:
Hematology,Saint Louis Hospital,Paris,France
EHA Library. Cluzeau T. 06/12/20; 295001; S181
Thomas Cluzeau
Thomas Cluzeau
Contributions
Abstract

Abstract: S181

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Novel treatments for MDS I

Background

TP53 mutated (TP53m) MDS and AML have very poor outcomes irrespective of the treatment received, including 40% responses (20% CR) with azacitidine (AZA) with short response duration and a median overall survival (OS) of about 8 months. APR-246 leads to p53 protein reconformation and reactivates its proapoptotic and cell cycle arrest functions and has received Breakthrough Therapy Designation in MDS from FDA.

Aims

We report current results of a GFM phase 2 study of AZA+APR-246 in TP53m MDS and AML.

Methods

The study included hypomethylating agent naïve and not previously allografted intermediate, high or very high IPSS-R TP53m MDS and AML adult patients. Patients received APR-246 4500 mg IV/d (6-hour infusions, days 1-4) followed by AZA 75 mg/m²/d (days 4-10) in 28 day cycles. Response (primary endpoint, assessed by IWG 2006 for MDS and ELN criteria for AML) was evaluated after 3 and 6 cycles in the intent to treat (ITT) population, ie all patients who had received any protocol treatment, and in patients who had at least a blood and bone marrow evaluation after cycle 3 (evaluable population). Allo-SCT, when possible, was proposed after 3 to 6 cycles and treatment with reduced doses of APR 246 and AZA could be continued after allo-SCT.

Results

52 patients were consented and enrolled between Sept 2018 and July 2019 in 7 GFM centers, with a median age of 74 years (range 44-87), and M/F: 27/25. 34 patients had MDS (including 74% very high IPSS-R) and 18 had AML (including 7 with >30% blasts). IPSS-R cytogenetic risk was very poor in 88% MDS, unfavorable in 94% AML, and complex in 94% of all patients. Median baseline TP53m VAF was 21% (range 3-76).

As of March 1, 2020, all 52 patients had received at least one treatment cycle, and no increased myelosuppression, compared with AZA alone, was apparent. Treatment related AEs observed in ≥ 20% of patients were febrile neutropenia in 19 (36%) and neurological AEs in 21 (40%) of patients (ataxia (n=13) associated with cognitive impairment (n=4), acute confusion (n=4), isolated dizziness (n=3) and facial paresthesia (n=1)).  Neurological AEs reached grade III only in 3 cases (1 acute confusion, 2 ataxia). Occurrence of neurological AEs was correlated with lower glomerular filtration rate at treatment onset (p<0.01) and higher age (p=0.05). Neurological symptoms spontaneously resolved with temporary drug interruption and no recurrence was observed after APR 246 dose reductions.

At data cutoff, 38 patients received at least 3 cycles and were considering as evaluable per protocol. The response rate was 76%, including 53% CR/CRi, 11% marrow CR, 3% PR and 11% stable disease + hematological improvement (SD+HI). In the subset of 28 evaluable MDS patients the response rate was 75% (21/28), including 57% (16/28) CR. The response rate in ITT population (including >30% blast AML) was 56%, including 38% CR/CRi, 8% marrow CR, 2% PR and 8% SD+HI. To-date, 4 patients have received allo-SCT and 1 started maintenance therapy. With a median follow up of 8.5 months, median overall survival has not been reached.

Conclusion

In this very high-risk elderly population of TP53m MDS and AML, a promising 64% CR/CRi/mCR rate was reached in the evaluable population with AZA+ APR 246 combination, including 57% CR rate in MDS patients. We observed manageable neurologic AEs, mainly in elderly patients with reduced renal function, who therefore require close monitoring and dose reduction if necessary. A phase III international trial comparing AZA vs AZA+ APR-246 in TP53m MDS is ongoing.

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): Azacitidine, Clinical trial, Myelodysplasia

Abstract: S181

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Novel treatments for MDS I

Background

TP53 mutated (TP53m) MDS and AML have very poor outcomes irrespective of the treatment received, including 40% responses (20% CR) with azacitidine (AZA) with short response duration and a median overall survival (OS) of about 8 months. APR-246 leads to p53 protein reconformation and reactivates its proapoptotic and cell cycle arrest functions and has received Breakthrough Therapy Designation in MDS from FDA.

Aims

We report current results of a GFM phase 2 study of AZA+APR-246 in TP53m MDS and AML.

Methods

The study included hypomethylating agent naïve and not previously allografted intermediate, high or very high IPSS-R TP53m MDS and AML adult patients. Patients received APR-246 4500 mg IV/d (6-hour infusions, days 1-4) followed by AZA 75 mg/m²/d (days 4-10) in 28 day cycles. Response (primary endpoint, assessed by IWG 2006 for MDS and ELN criteria for AML) was evaluated after 3 and 6 cycles in the intent to treat (ITT) population, ie all patients who had received any protocol treatment, and in patients who had at least a blood and bone marrow evaluation after cycle 3 (evaluable population). Allo-SCT, when possible, was proposed after 3 to 6 cycles and treatment with reduced doses of APR 246 and AZA could be continued after allo-SCT.

Results

52 patients were consented and enrolled between Sept 2018 and July 2019 in 7 GFM centers, with a median age of 74 years (range 44-87), and M/F: 27/25. 34 patients had MDS (including 74% very high IPSS-R) and 18 had AML (including 7 with >30% blasts). IPSS-R cytogenetic risk was very poor in 88% MDS, unfavorable in 94% AML, and complex in 94% of all patients. Median baseline TP53m VAF was 21% (range 3-76).

As of March 1, 2020, all 52 patients had received at least one treatment cycle, and no increased myelosuppression, compared with AZA alone, was apparent. Treatment related AEs observed in ≥ 20% of patients were febrile neutropenia in 19 (36%) and neurological AEs in 21 (40%) of patients (ataxia (n=13) associated with cognitive impairment (n=4), acute confusion (n=4), isolated dizziness (n=3) and facial paresthesia (n=1)).  Neurological AEs reached grade III only in 3 cases (1 acute confusion, 2 ataxia). Occurrence of neurological AEs was correlated with lower glomerular filtration rate at treatment onset (p<0.01) and higher age (p=0.05). Neurological symptoms spontaneously resolved with temporary drug interruption and no recurrence was observed after APR 246 dose reductions.

At data cutoff, 38 patients received at least 3 cycles and were considering as evaluable per protocol. The response rate was 76%, including 53% CR/CRi, 11% marrow CR, 3% PR and 11% stable disease + hematological improvement (SD+HI). In the subset of 28 evaluable MDS patients the response rate was 75% (21/28), including 57% (16/28) CR. The response rate in ITT population (including >30% blast AML) was 56%, including 38% CR/CRi, 8% marrow CR, 2% PR and 8% SD+HI. To-date, 4 patients have received allo-SCT and 1 started maintenance therapy. With a median follow up of 8.5 months, median overall survival has not been reached.

Conclusion

In this very high-risk elderly population of TP53m MDS and AML, a promising 64% CR/CRi/mCR rate was reached in the evaluable population with AZA+ APR 246 combination, including 57% CR rate in MDS patients. We observed manageable neurologic AEs, mainly in elderly patients with reduced renal function, who therefore require close monitoring and dose reduction if necessary. A phase III international trial comparing AZA vs AZA+ APR-246 in TP53m MDS is ongoing.

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): Azacitidine, Clinical trial, Myelodysplasia

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