Daratumumab in VHR T-ALL Treated According to the ALL National Treatment Program

Inclusion Criteria:

1. Age 18-65 years.

2. A diagnosis of T-ALL according to the 2022 International Consensus Classification (ICC) is required, either de novo or secondary to chemo-radiotherapy for anothercancer. Pre-treatment with low-dose corticosteroids +/- cyclophosphamide in patientspresenting with hyperleukocytosis is allowed.

3. Availability of fresh bone marrow (BM) (or peripheral blood (PB) in patients withhyperleukocytosis) samples to perform diagnostic procedures. ).

4. Bone marrow blast percentage at diagnosis ≥20%.

5. CD38 positivity on ALL blasts (any level of positivity).

6. ETP and near ETP at diagnosis according to internationally accepted criteria (appendix G) at diagnosis or other VHR T-ALL subtypes (WBC count >100 x109/L;complex karyotype with ≥5 unrelated anomalies; other CD1a-negativeimmunophenotypes). T-Myeloid MPAL according to the 2022 ICC of Acute Leukemias ofAmbiguous Lineage (appendix H) can also be eligible and considered as VHR.

7. Availability of full cytological, cytochemical, immunophenotypic, cytogenetic andmolecular disease characterization according to the EGIL and WHO classifications.

8. An ECOG performance status 0-2, unless a performance of 3 is unequivocally caused bythe disease itself, (and not by pre-existing comorbidities,) and is consideredand/or documented to be reversible following the application of anti-leukemictherapy and appropriate supportive measures.

9. For females of childbearing potential, a negative pregnancy test must be documented.Female and male patients who are fertile must agree to use an effective form ofcontraception with their sexual partners from enrollment through 12 months after theend of treatment.

10. Signed written informed consent according to ICH/E U/GCP and national local laws.

Exclusion Criteria:

1. Diagnosis of B-lineage ALL, and Ph+ ALL.

2. Down's syndrome.

3. Prior systemic chemotherapy for ALL (excluding cyclophosphamide during pre-phase).

4. Pre-existing, uncontrolled pathology such as heart failure (congestive/ischemic,acute myocardial infarction within the past 3 months, untreatable arrhythmias, NYHAclasses III and IV), severe liver disease with serum direct bilirubin >3 mg/dL (unless attributable to Gilbert' syndrome or ALL) and/or ALT >5x upper normal limit (unless attributable to ALL), kidney function impairment with serum creatinine >2mg/dL (unless attributable to ALL), and severe neuropsychiatric disorder thatimpairs the patient's ability to understand and sign the informed consent, or tocope with the intended treatment plan. N.B. For altered liver and kidney functiontests, eligibility criteria can be reassessed at 24-96 hours, following theinstitution of adequate supportive measures.

5. Presence of serious, active, uncontrolled infections.

6. A history of cancer that is not in a remission phase following surgery and/orradiotherapy and/or chemotherapy, with a life expectancy <2 years.

7. Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug orwho have not recovered from side effects of such therapy.