PREREGISTRATION (STEP 0):

Patient must be able to undergo diagnostic bone marrow aspirate following preregistration if not performed previously
* NOTE: Bone marrow aspirate must be submitted to Dr. Brent Wood’s laboratory at Children’s Hospital Los Angeles for central assessment of the establishment of MRD status to confirm patient’s eligibility for registration to Step 1

Bone marrow must be from the first pull (initial or redirect needle) and specimens must contain sufficient blast cells. In cases where the bone marrow aspiration is not adequate or the bone marrow examination has already been performed prior to study consent and enrollment on Step 0, peripheral blood can be submitted regardless of peripheral blast percentage

Dr. Brent Wood’s laboratory at Children’s Hospital Los Angeles will forward results within 48 hours (two business days) of receipt of the specimen to the submitting institution

* NOTE: If MRD status testing was performed previously as part of standard of care at Dr. Brent Wood’s laboratory, eligible patients can proceed from Step 0 preregistration directly to Step 1 registration after forwarding MRD report to Dr. Brent Wood for verification and uploading report via Medidata Rave. MRD testing will not be accepted from other laboratories. Step 0 preregistration cannot be bypassed. MRD must be quantified within 14 days prior to starting daratumumab treatment on study

Patient must be >= 18 years of age

Patient must have documented T cell ALL and must be in first or later hematologic complete remission (CR) or complete remission incomplete (CRi) after a minimum of 2 blocks of intensive chemotherapy
* Patients >= 65 years of age that the physician judges to be unfit for 2 blocks of intensive chemotherapy may enroll after one cycle of chemotherapy as long as they are in CR or CRi at least 28 days after initiation of Leukemia directed therapy. These patient must have received at least 4 weekly doses of vincristine and steroids

REGISTRATION (STEP 1):

Patients in hematologic CR or CRi must have persistent or recurrent MRD >= 10^-4

Institution must have received central MRD status test results confirming persistent or recurrent MRD >= 10^-4 by flow cytometry

Patient may have undergone a prior allogeneic stem cell transplant, but patient may not have grafts versus host disease (GVHD) that requires ongoing immunosuppressive therapy. Patient may receive prednisone if the dose is =< 10 mg per day

Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used

* All patients of childbearing potential must have a blood test or urine study within 14 days prior to Step 1 registration to rule out pregnancy

* A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

Patients must not expect to conceive or father children by using an accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and continue to 3 months after the last dose of protocol treatment. Patients must also agree to abstain from donating sperm, even if they have had a successful vasectomy, or donating eggs while on study treatment and for 3 months after the last dose of protocol treatment

Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible

Absolute neutrophil count (ANC) >= 750/mL (must be obtained =< 7 days prior to Step 1 registration)

Platelets >= 75,000/mL (must be obtained =< 7 days prior to Step 1 registration)

Total or direct bilirubin =< 2 mg/dL (must be obtained =< 7 days prior to Step 1 registration)

Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate-pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal (ULN) (must be obtained =< 7 days prior to Step 1 registration)

Creatinine =< 1.5 x institutional ULN or Creatinine Clearance > 30 ml/min (must be obtained =< 7 days prior to Step 1 registration)

Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial

For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated

Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

Patients with prior central nervous system (CNS) involvement are eligible as long as they do not have active CNS involvement at time of Step 1 registration

Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better

PRIMARY OBJECTIVE:
I. To evaluate the rate of complete minimal residual disease (MRD) response by flow cytometry after 4 weekly doses of daratumumab-hyaluronidase (Day 29) among patients with MRD positive T-cell acute lymphoblastic leukemia (T-ALL) in hematologic morphologic complete remission or complete remission with incomplete hematologic recovery.

SECONDARY OBJECTIVES:
I. To evaluate morphologic relapse free survival (RFS).
II. To evaluate overall survival (OS).
III. To assess the survival outcomes in patients that undergo allogeneic stem cell transplant after complete MRD response with daratumumab-hyaluronidase.
IV. To assess adverse effects and tolerability of daratumumab-hyaluronidase in T-ALL.
IVa. To assess adverse effects of daratumumab-hyaluronidase during Course 1 among all treated patients.
IVb. To assess adverse effects of combined daratumumab-hyaluronidase and chemotherapy during Course 1A.
IVc. To assess adverse effects of daratumumab-hyaluronidase received during Course 2.
V. To assess flow cytometry based MRD status on Day 64 of treatment or upon count recovery for patients that receive chemotherapy in addition to daratumumab-hyaluronidase during Course 1A.
VI. To assess MRD response in patients receiving daratumumab-hyaluronidase after first line chemotherapy compared to patients receiving daratumumab-hyaluronidase after second or later lines of chemotherapy.

EXPLORATORY OBJECTIVES:
I. To determine MRD relapse free survival (RFS) in patients that achieve MRD negative response with daratumumab-hyaluronidase. 
II. To compare the outcomes of patients with MRD relapse ranging 0.01% to < 0.1% to patients with MRD relapse >= 0.1%.
III. To determine the rate of complete molecular MRD response on Day 29 based on Clonal Ig/T-cell receptor (TCR) gene rearrangements using Adaptive clonoSEQ next generation sequencing.
IV. To identify molecular abnormalities that are associated with MRD relapse or morphologic relapse.

OUTLINE:
COURSE 1: Patients receive daratumumab and hyaluronidase-fihj subcutaneously (SC) on days 1, 8, 15, and 22.

COURSE 1A: Patients who are MRD positive after Course 1 receive daratumumab and hyaluronidase-fihj SC on days 36, 43, 50, and 57. Patients also receive 1 of 2 methotrexate-based chemotherapy regimens: 1) cytarabine intravenously (IV) on days 37 and 38 and methotrexate IV on day 36; OR 2) methotrexate IV on days 36, 46, and 56, vincristine IV on days 36, 46, and 56, pegaspargase IV on days 37 and 58, and methotrexate intrathecally (IT) on days 36 and 56.

COURSE 1B: Patients who are MRD negative after Course 1 may proceed to allogeneic stem cell transplant OR may receive daratumumab and hyaluronidase-fihj SC on days 36, 43, 50, and 57.

COURSE 2: Patients who are MRD negative after Course 1A or 1B may proceed to allogeneic stem cell transplant OR may receive daratumumab and hyaluronidase-fihj SC on days 1, 15, 29, 43, 57, 71, 85, and 99. Patients who are MRD positive after Course 1A or 1B discontinue study treatment.

After completion of study treatment, patients are followed every 2 months for up to 18 months from start of treatment.