A combination therapy for teens and young adults with relapsed or refractory T-ALL/T-LBL

Inclusion Criteria:

* Weight must be \> or = to 40 kg
* Patients must have histologically or cytologically confirmed relapsed or refractory T-ALL or TLBL.
* Age ≥ 12 year to ≤ 30 years.
* Lansky ≥60 for patients \<16, Karnofsky ≥60 for patients ≥ 16 years of age. (See Appendix I)
* Baseline ejection fraction must be \> 40% OR Shortening fraction \>20%. Either can be used at the investigator's discretion.
* Adequate hepatic function (direct bilirubin \< 1.5x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement, and AST and/or ALT \< 5x ULN unless considered due to leukemic involvement, in which case direct bilirubin \< 3x ULN or AST and/or ALT \< 10x ULN will be considered eligible.
* Adequate renal function (calculated creatinine clearance ≥ 30 mL/min) unless related to disease as determined by PI.
* In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 14 days for cytotoxic or non-cytotoxic (immunotherapy agent(s), or an interval of 5 half-lives of the prior therapy (whichever is shorter). Hydroxyurea and/or cytarabine (up to 2 g/m2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the PI.
* Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted.
* Patients may have received any of the study agents prior to enrollment in study if not previously provided in study combination.
* For patients with history or 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 treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of active progression.
* 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 as determined by PI.
* Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114). This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:

  * Postmenopausal (no menses in greater than or equal to 12 consecutive months).
  * History of hysterectomy or bilateral salpingo-oophorectomy.
  * Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).
  * History of bilateral tubal ligation or another surgical sterilization procedure.
* Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, Implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
* Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion.

Exclusion Criteria:

* Patients with any concurrent uncontrolled medical condition, laboratory abnormality, or psychiatric illness which could place the patient at unacceptable risk of study treatment.
* No investigational or commercial anti-cancer agents or therapies other than those described below may be administered with the intent to treat the patient's malignancy.
* The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during study with the following exceptions:

  i. intrathecal chemotherapy for prophylactic use or for controlled CNS leukemia.

Previous CNS evaluation and intrathecal (IT) chemotherapy administered prior to consent can be considered as the Cycle 1 Day 1 IT chemotherapy, provided it was completed within 7 days of C1D1. ii. use of hydroxyurea or cytarabine for patients with rapidly proliferative disease.

iii. use of steroids for treatment of rapidly proliferative disease. iv. Investigational or commercial agent for supportive care may be used in consultation with the treating physician.

* Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications.
* Patients with severe uncontrolled peripheral neuropathy significantly impairing motor or sensory function.
* Patients with a concurrent second active malignancy under treatment.
* Known active hepatitis B (HBV) or Hepatitis C (HCV) infection or known HIV infection.

Testing is not required for patients without a known or suspected history.

* Female subjects who are pregnant or breast-feeding.
* Patient has an infection that is both active and uncontrolled.
* History of or any concurrent condition, therapy, or laboratory abnormality that in the Investigator's opinion might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition venetoclax, dexamethasone, bortezomib, daratumumab.