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For Part 1, participants will receive:

* Patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 14-20 people will participate in Part 2 (Dose Expansion) of this cohort Treatment cycle is approximately 28 days for up to 4 cycles

  * Venetoclax-once daily on predetermined days per protocol
* Azacitidine-once daily on predetermined days per protocol

  * Cytarabine, Methotrexate, Hydrocortisone and Leucovorin will be given only if MDS/leukemia cells are detected in spinal fluid per determination of treating physician

Patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) with an underlying genetic condition that increases their risk for developing treatment-related toxicities. It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 6 people will participate in Part 2 (Dose Expansion) of this cohort.

* Venetoclax-once daily on predetermined days per protocol
* Azacitidine-once daily on predetermined days per protocol
* Cytarabine, Methotrexate, Hydrocortisone and Leucovorin will be given only if MDS/leukemia cells are detected in spinal fluid per determination of treating physician

Patients with relapsed/refractory acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LBL) or acute leuekmai of ambiguous lineage. It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 12 people will participate in Part 2 (Dose Expansion) of this cohort.

Cohort C: Treatment cycle is approximately 32 days for one cycle and will be a single treatment cycle:

Dosage, duration and timings as outlined in protocol.

* Venetoclax
* Dexamethasone
* Vincristine
* Doxorubicin
* Dexrazoxane
* Calaspargase pegol

  ---Short acting Erwinia preparations (recombinant or native Erwinia asparaginase) may be used for participants with known pegaspargase or calaspargase pegol allergy
* Cytarabine
* Methotrexate
* Hydrocortisone
* Leucovorin- \*Cytarabine, Methotrexate, Hydrocortisone and Leucovorin may be given more frequently if leukemia/lymphoma cells are detected in spinal fluid),

Calaspargase Pegol

Erwinia asparaginase

Andrew E Place, MD, PhD

Jessica A Pollard, MD, PhD

Elliot Stieglitz, MD

This trial is evaluating the safety and tolerability of venetoclax with chemotherapy in pediatric and young adult patients with hematologic malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia derived from myelodysplastic syndrome (MDS/AML), and acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL).

The names of the study drugs involved in this study are below. Please note this is a list for the study as a whole, participants will receive drugs according to disease cohort.

* Venetoclax
* Azacitidine
* Cytarabine
* Methotrexate
* Hydrocortisone
* Leucovorin
* Dexamethasone
* Vincristine
* Doxorubicin
* Dexrazoxane
* Calaspargase pegol
* Hydrocortisone

This is an investigator-initiated open-label multi-institutional phase I study of venetoclax combination therapy in both myeloid and lymphoid hematologic malignancies. This study is designed as a basket trial with three separate cohorts. All cohorts include a dose finding portion (Part I) followed by a dose expansion at the Recommended Phase II dose (RP2D, Part II).

This research study is looking to learn more about how Venetoclax works and aims to determine the safest, highest possible dose that can be combined with standard of care chemotherapies. Because of this, not everyone who participates in this research study may receive the same dose of the study drug. The dose participants receive will depend on the number of participants who have been enrolled in the study previously and how well the doses have been tolerated.

Study procedures include screening for eligibility as well as study treatment visits including evaluations and follow up visits.

* Cohort A: Patients with myelodysplastic syndrome (MDS), acute myelogenous leukemia arising from MDS (MDS/AML) or treatment-related myeloid neoplasms (tMDS/AML). It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 14-20 people will participate in Part 2 (Dose Expansion) of this cohort.
* Cohort B: Patients with myelodysplastic syndrome (MDS), acute myelogenous leukemia arising from MDS (MDS/AML) or treatment-related myeloid neoplasms (tMDS/AML) with an underlying genetic condition that increases their risk of experiencing toxic side effects of chemotherapy. It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 6 people will participate in Part 2 (Dose Expansion) of this cohort.
* Cohort C: Patients with relapsed/refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL). It is expected that up to 18 people will participate in Part 1 (Dose Determination) and an additional 12 people will participate in Part 2 (Dose Expansion) of this cohort.

This research study is a Phase I clinical trial, which tests the safety of an investigational drug and also tries to define the appropriate dose of the investigational drug to use for further studies. "Investigational" means that the drug is being studied. The U.S. Food and Drug Administration (FDA) has not approved Venetoclax for use in children. However, Venetoclax is FDA-approved as a treatment for certain types of leukemia in adults. It is actively being studied in children and adults with other types of cancer. Information from these research studies has suggested that venetoclax may also be effective in treating participants with MDS or leukemia, including MDS or leukemia that did not respond to standard treatment or that has come back after standard treatment. The survival of cancer cells is controlled by proteins within the cancer cell. One of these proteins is called BCL-2. The study drug, venetoclax, blocks this protein and is thought to reduce cell survival in some cancer cells.

Venetoclax Basket Trial for High Risk Hematologic Malignancies

A Phase I Study of Venetoclax in Combination With Cytotoxic Chemotherapy, Including Calaspargase Pegol, for Children, Adolescents and Young Adults With High-Risk Hematologic Malignancies

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Andrew E. Place (Sponsor-Investigator). The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Estimate the proportion of patients who are able to receive all doses of venetoclax in cycle 1 for each cohort.

Define the percentage of patients in cohorts A\&B who successfully proceed to HSCT after treatment with venetoclax combination therapy

To determine the maximum tolerated dose (MTD of venetoclax given in combination with regimen-prescribed chemotherapy. The MTD is defined as the dose level associated with observed DLTs in \<33% of enrolled subjects

To determine the Recommended Phase 2 Dose (RP2D) of venetoclax given in combination with regimen-prescribed chemotherapy.

The RP2D is defined either as the MTD or maximum dose tested should MTD not be reached.

All grade 2 or higher adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAE v5 criteria. Incidence is the number of patients experiencing at least one treatment-related grade 2 or higher AE of any type during the time of observation.

Describe the incidence and severity of calaspargase pegol-related toxicities in subjects with relapsed/refractory ALL/LBL per collected Adverse Events using CTCAE v5 criteria.

ORR will be defined as the number of patient experiencing complete remission (CR), complete remission with incomplete platelet recovery (CRp), complete remission with incomplete count recovery (CRi) and partial response.

CR Rate is defined as the percentage of participants that reach Complete Remission (CR):

Cohorts A and B:

* Bone marrow \< 5% myeloblasts by flow cytometry.
* No evidence of circulating blasts or extramedullary disease AND
* Platelet count ≥50k/uL (or to pre-treatment baseline) and transfusion independent for 7 days AND
* Neutrophil count ≥500 cells/uL without G-CSF support.

Cohort C (Leukemia):

* Absolute phagocyte count (APC) ≥1000/μL and platelets ≥75,000/μL without transfusions and/or exogenous growth factor support AND
* Bone marrow with evidence of trilineage hematopoiesis and with \<5% blasts AND
* No evidence of extramedullary disease

Cohort C only:

* APC \<1000/μL and/or platelets \<75,000/μL AND
* Bone marrow with \<5% blasts AND
* No evidence of extramedullary disease

CRp Rate is defined as the percentage of participant that reach to CRp:

Cohorts A \&B:

* A bone marrow with \<5% blasts AND
* No evidence of circulating blasts or extramedullary disease AND
* Recovery of absolute neutrophil counts (ANC \> 500/μL), but with insufficient recovery of platelets (PLT counts \<50,000 ul), and platelet transfusion independence (defined as no platelet transfusion x 1 week)

Cohort C:

* Absolute neutrophil count (APC ≥1000/μL) AND
* Platelets \< 75,000/μL AND
* Bone marrow with evidence of trilineage hematopoiesis and with \<5% blasts AND
* No evidence of extramedullary disease

Based on the Kaplan-Meier method defined as the time from study entry to death or censored at date last known alive

EFS is defined as the time from first dose of study treatment until evidence of progression to leukemia, relapse of MDS or leukemia after HSCT, or death from any cause.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Venetoclax Basket Trial for High Risk Hematologic Malignancies	NCT05292664	Myelodysplastic... Myelodysplastic... Myelodysplastic... Treatment-Relat... Therapy-Related... Acute Lymphobla... Acute Lymphobla... Lymphoblastic L... Lymphoblastic L... Acute Leukemia ... Acute Leukemia ...	Venetoclax Azacitidine Cytarabine Methotrexate Hydrocortisone Leucovorin Dexamethasone Vincristine Doxorubicin Dexrazoxane Calaspargase Pe... Erwinia asparag...	1 Year - 40 Years	Dana-Farber Cancer Institute
Venetoclax Basket Trial for High Risk Hematologic Malignancies	NCT05292664	Myelodysplastic... Myelodysplastic... Myelodysplastic... Treatment-Relat... Therapy-Related... Acute Lymphobla... Acute Lymphobla... Lymphoblastic L... Lymphoblastic L... Acute Leukemia ... Acute Leukemia ...	Venetoclax Azacitidine Cytarabine Methotrexate Hydrocortisone Leucovorin Dexamethasone Vincristine Doxorubicin Dexrazoxane Calaspargase Pe... Erwinia asparag...	1 Year - 40 Years	Dana-Farber Cancer Institute

Spots Global Cancer Trial Database for relapsed or refractory acute lymphoblastic lymphoma