Use of a New Medicine "Daratumumab" to Treat Left-over Cancer in a Blood Cancer Called "T Acute Lymphoblastic Leukemia"

Hypothesis - Daratumumab will increase the MRD negative CR rate in newly diagnosed T-ALL who are MRD positive after two-cycles of induction chemotherapy.

Rationale of dosing Daratumumab being a monoclonal antibody primarily depends on its target mediated clearance. In myeloma, dose finding studies of daratumumab showed that the drug at a dose of 16mg per kg was able to saturate all the receptors due to which a lower clearance and higher trough concentrations were observed. On the other hand, a lower dose of 8 mg/kg demonstrated higher clearance due to lack of complete target engagement / saturation. Hence, 16 mg/kg was the approved dose. In accordance with the above concept, daratumumab has been used in multiple indications apart from myeloma viz. PRCA post-transplant, Extranodal NK/T lymphoma, Blastic Plasmacytoid Dendritic Cell Neoplasm, at the myeloma approved dose of 16 mg/kg. Moreover, from its phenomenon of indirect coombs test positivity, it is evident that daratumumab binds CD38 antigen on RBCs, even though the expression of CD38 on RBCs is low. Its ability to bind to CD38 antigen across cell lineages, further supports that the same dose will be valid for T-ALL.

Method - T-ALL adult patients (on modified BFM-90 induction chemotherapy or any other pediatric inspired protocol) who are MRD positive by flow cytometry (≥0.01%) at end of phase 1a induction, will undergo a bone marrow-minimal residual disease (BM-MRD) testing at the end of phase 1b induction (or after 2 phases of induction of any pediatric inspired protocol), at count recovery (ANC>1000/cumm, Platelet >75,000/cumm).

Multicolor flow-cytometry for MRD will be performed using a 13-color T-MRD panel in Dx FLEX flow-cytometer (Beckman Coulter). The analysis will be performed with Kaluza version 2.0 software.

T-ALL patients in CR-1 who are MRD positive i.e., ≥0.01% on flow-cytometry at the end of phase 1b induction (two phases of chemotherapy) and CD38 positive (expression on >=20% blasts) will be eligible for the study

Study schema MRD positive patients of T-ALL who fulfil criteria as mentioned above will be enrolled in the study. Before starting daratumumab, investigations will be performed as mentioned below. First dose of daratumumab will be administered as an in-patient for 24 hours, as per protocol mentioned below. Those who tolerate daratumumab well i.e., not more than grade 1 infusion related reaction (IRR) will be given subsequent doses on out-patient basis in day-care. BM aspirate for MRD analysis will be done 7days (± 2days) after second dose of daratumumab. Those who become MRD negative (<0.01% by flow-cytometry), will be off-study and continued on conventional treatment regimen as per institution policy. Those who are still MRD positive (≥0.01% by flow-cytometry) after two doses, will be given two additional weekly doses of daratumumab. In patients who receive two additional doses, BM aspirate for MRD analysis will be done 7days (± 2days) after fourth dose of daratumumab. Irrespective of MRD result after fourth dose, patients will be continued on conventional treatment regimen as per institution policy. Last follow-up time point for SAE related to intervention will be four weeks after last dose of daratumumab.

Inclusion criteria

• Adults ≥18 - ≤65 years of age
• Baseline diagnosis of T-ALL, including ETP-ALL
• MRD positive (≥0.01%) disease (by flow-cytometry) assessed on BM after two phases of induction chemotherapy in CR-1
• CD38 positive
• Eastern cooperative oncology group (ECOG) performance status ≤2
• Acceptable liver functions, as specified below:

Total bilirubin <2 times upper limit of normal (ULN); Aspartate transaminase (AST;SGOT), alanine transaminase (ALT;SGPT) <3 ULN

• Subject ready to sign an informed consent form
• Patients with baseline CSF cytology positive, but who have cleared CSF by either modality (cytology or flow cytometry)

Exclusion criteria

• T-LBL (T-lymphoblastic lymphoma) without BM involvement
• Patients with persistently positive CSF cytology after two phases of induction or baseline testicular involvement
• Patients with symptomatic obstructive airway disease, as per assessing clinician
• Presence of an active systemic infection, as per assessing clinician
• New York Heart Association (NYHA) Class III or IV cardiac disease, or left ventricular ejection fraction <40%
• Human immunodeficiency virus (HIV) positive.
• Pregnant or breastfeeding female
• HBsAg positive or HBV-DNA positivity