Study of Decitabine Alone or in Combination With Valproic Acid and All-trans Retinoic Acid in Acute Myeloid Leukemia

AML of the older patient constitutes a major unmet clinical need since the large majority will not be found eligible for induction chemotherapy. Reasons for this decision include host factors (comorbidities, reduced performance status, functional limitations due to age), leading to often poor tolerance of repeated chemotherapy courses and the unfavorable biology underlying this disease in older patients. Low dose Decitabine has shown very promising efficacy in high-risk MDS and is therefore a very promising approach also in older AML patients. Preliminary results from several centres have demonstrated excellent feasibility and good efficacy of this treatment. Therefore the investigators intend to investigate the effects of two drugs added onto low-dose Decitabine which have shown very promising synergistic effects in vitro and for which preliminary results indicate that the combination with low-dose Decitabine is very feasible.

Sex

All

Minimum age

60 Years

Inclusion Criteria:

1. Written informed consent obtained according to international guidelines and local law;
2. Male or female patients aged \> 60 years without upper age limit;
3. Patients with primary or secondary AML according to WHO (≥ 20% blasts in the peripheral blood (pB) or bone marrow (BM)) who are not expected to benefit from standard remission-induction chemotherapy;
4. Patients with \< 30 000 leukocytes/μl;
5. Performance status ECOG 0, 1, 2;
6. Creatinine \< 2.0 mg/dl (unless leukemia-related);
7. Ability to understand the nature of the study and the study related procedures and to comply with them.

Exclusion Criteria:

1. AML of FAB subtype M3;
2. Previous remission-induction chemotherapy for MDS or AML, previous allografting;
3. Previous treatment with DAC, 5-azacytidine, VPA or another HDAC inhibitor, or ATRA;
4. "Low-dose" chemotherapy (e.g. hydroxyurea, cytosine arabinoside (Ara-C), melphalan, clofarabine etc.) within 4 weeks prior to DAC treatment, except for cytoreduction of leukocytosis ≥ 30 000/μl with hydroxyurea or Ara-C as proscribed by the study protocol (section 7.3 and 7.4); the patient must have recovered from all clinically relevant reversible non-hematologic toxicities;
5. Treatment with tyrosine kinase inhibitors, immunomodulating agents (IMIDS) or other investigational AML treatment within the last 4 weeks or in a time period of drug half-life x 5 (whatever is shorter) before the first administration of DAC;
6. Treatment with cytokines within previous 4 weeks;
7. Concomitant therapy which is considered relevant for the evaluation of efficacy or safety of the trial drug (i.e. other chemo- or immunotherapy);
8. Other malignancy requiring treatment (previous chemotherapy for other malignancies is not an exclusion criteria);
9. Cardiac insufficiency NYHA IV;
10. Insufficient hepatic function (bilirubin, AST or ALT \> = 2.5 x Upper Limit of Normal (ULN)) (unless leukemia-related);
11. Fatal hepatic function disorder during treatment with valproic acid in siblings;
12. Hepatic porphyria;
13. Manifest serious pancreatic function disorder;
14. Plasmatic coagulation disorder not related to AML;
15. Known active hepatitis B or C;
16. Known HIV infection;
17. Other uncontrolled active infections;
18. Known allergy against soy beans or peanuts;
19. Psychiatric disorder that interferes with treatment;
20. Patient without legal capacity who is unable to understand the nature, significance and consequences of the study;
21. Known hypersensitivity to, or intolerance of, one of the trial drugs, another retinoid or the excipients of the trial drugs;
22. Concomitant use of any other investigational drug or participation in a clinical trial within the last thirty days before the start of this study; simultaneous participation in registry and diagnostic trials is allowed;
23. Female patients who are pregnant or breast feeding;
24. Fertile patients refusing to use safe contraceptive methods during the study (for details see clinical trial protocol section 5.3);
25. Known or persistent abuse of medication, drugs or alcohol.

• DERIVEDBresser H, Schmoor C, Grishina O, Pfeifer D, Thomas J, Rehman UU, Crysandt M, Jost E, Thol F, Heuser M, Gotze KS, Schlenk RF, Salih HR, Schittenhelm MM, Heil G, Schwaenen C, Muller-Tidow C, Brugger W, Kundgen A, de Wit M, Giagounidis A, Scholl S, Neubauer A, Krauter J, Bug G, May AM, Wasch R, Duyster J, Dohner K, Ganser A, Dohner H, Hackanson B, Becker H, Lubbert M. Impact of TP53 Mutation Status in Elderly AML Patients When Adding All-Trans Retinoic Acid or Valproic Acid to Decitabine. Eur J Haematol. 2025 Feb;114(2):231-237. doi: 10.1111/ejh.14304. Epub 2024 Oct 13. PMID 39400388
• DERIVEDThomas J, Rehman UU, Bresser H, Grishina O, Pfeifer D, Sollier E, Dohner K, Plass C, Becker H, Schmoor C, de Wit M, Lubbert M. Continued decitabine/all-trans retinoic acid treatment: extended complete remission in an elderly AML patient with multi-hit TP53 lesions and complex-monosomal karyotype. Clin Epigenetics. 2024 Sep 11;16(1):126. doi: 10.1186/s13148-024-01737-4. PMID 39261919
• DERIVEDDuque-Afonso J, Veratti P, Rehman UU, Herzog H, Mitschke J, Greve G, Eble J, Berberich B, Thomas J, Pantic M, Waterhouse M, Gentile G, Heidenreich O, Miething C, Lubbert M. Identification of epigenetic modifiers essential for growth and survival of AML1/ETO-positive leukemia. Int J Cancer. 2024 Dec 1;155(11):2068-2079. doi: 10.1002/ijc.35134. Epub 2024 Aug 15. PMID 39146497
• DERIVEDJavorniczky NR, Grishina O, Hund I, Pantic M, Pfeifer D, Schmoor C, Thomas J, Duyster J, Becker H, Lubbert M. Long-term decitabine/retinoic acid maintenance treatment in an elderly sAML patient with high-risk genetics. Clin Epigenetics. 2023 Nov 28;15(1):185. doi: 10.1186/s13148-023-01596-5. PMID 38012682
• DERIVEDLubbert M, Grishina O, Schmoor C, Schlenk RF, Jost E, Crysandt M, Heuser M, Thol F, Salih HR, Schittenhelm MM, Germing U, Kuendgen A, Gotze KS, Lindemann HW, Muller-Tidow C, Heil G, Scholl S, Bug G, Schwaenen C, Giagounidis A, Neubauer A, Krauter J, Brugger W, De Wit M, Wasch R, Becker H, May AM, Duyster J, Dohner K, Ganser A, Hackanson B, Dohner H; DECIDER Study Team. Valproate and Retinoic Acid in Combination With Decitabine in Elderly Nonfit Patients With Acute Myeloid Leukemia: Results of a Multicenter, Randomized, 2 x 2, Phase II Trial. J Clin Oncol. 2020 Jan 20;38(3):257-270. doi: 10.1200/JCO.19.01053. Epub 2019 Dec 3.