To evaluate the benefit of a precision medicine based strategy (targeted therapeutic options (TTOs)) for patients with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) (in terms of composite remission).

Inclusion Criteria:

1. Patients aged 15y or more (under 18y only for France)

2. Signed informed consent for patients aged ≥ 18 years and signed informed consent from both parents for patients aged between ≥ 15 years and < 18 years (only for France).

3. Patients with T-cell acute lymphoblastic leukemia in first or second relapse or in the refractory phase.

   1. Patients with first relapses are eligible if relapse occurred within 24 months post complete remission achievement and if nelarabine is not considered as appropriate salvage therapy.
   2. Patients with second and all subsequent relapses are eligible.
   3. Refractory patients are defined as patients not responding after at least 2 lines of chemotherapy (induction + salvage).
   4. Patients with relapses post-transplant and post CART-cells treatments are eligible.

4. Blast cells in blood and/or bone marrow to allow the shipment to one of the 3 reference laboratories in France, Spain and The Netherlands or An informative biological assessment already performed within 10 days prior to inclusion in one of the three reference laboratories in France, Spain or The Netherlands with at least one targeted therapeutic option validated (TTO1, venetoclax + tofacitinib; TTO2, venetoclax+ everolimus + enrylaze; TTO3, venetoclax + 5-azacytidine) by one of the three National Validation Committees.

5. Adequate ECOG score (0-3).

6. Patients must be affiliated to a National Health systems (see country-based specificity).

7. Patients must not have a contra-indication for venetoclax, tofacitinib, everolimus, glutaminolytic agents (enrylaze) or 5-azacytidine.

8. Willingness of women of child-bearing potential (WOCBP) or of male patients whose sexual partners are WOCBP to use an effective form of contraception during the study and at least 6 months thereafter.

Exclusion Criteria:

1. Patients in palliative care.

2. Patients with late relapses after the first complete remission (> 24 months post complete remission).

3. Patients with extramedullary only relapses or with clinically symptomatic central nervous system (CNS) involvement.

4. Pregnant or lactating women.

5. Participation in another clinical trial with an investigative drug at the time of study enrolment.

6. Individuals with another active uncontrolled malignancy.

7. Known active HBV-, HCV and HIV related diseases.

8. Patient under curatorship or deprived of liberty (except for minors).

9. Patients with contra-indication to chemotherapy except if considered related to the ALL:

   • ASAT (SGOT) and/or ALAT (SGPT) > 5 x ULN
   • Total bilirubin ≥ 2.5 x ULN
   • Estimated glomerular filtration rate (GFR) < 50 mL/mn using the MDRD equation