ALL Backbone in AYAs

Treatment of Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in Adolescents and Young Adults (AYAs)

The goal of this research study is to evaluate a chemotherapy regiment for the treatment of newly diagnosed Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYAs).

The names of the study drugs involved in this study are:

• blinatumomab (a type of immunotherapy drug)
• cyclophosphamide (a type of chemotherapy drug)
• cytarabine (a type of antineoplastic agent)
• dexamethasone (a type of synthetic glucocorticoid)
• doxorubicin (a type of antineoplastic agent)
• etoposide (a type of antineoplastic agent)
• mercaptopurine (a type of antineoplastic agent)
• methotrexate (a type of chemotherapy drug)
• pegaspargase (a type of antineoplastic agent)
• vincristine (a type of antineoplastic agent)

Study Overview

• Status: Not yet recruiting
• Conditions: Leukemia; Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia (ALL); Philadelphia Chromosome-Negative Lymphoblastic Leukemia
• Intervention / Treatment: Drug: Blinatumomab; Drug: Oncaspar; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Dexamethasone; Drug: Doxorubicin Hydrochloride; Drug: Etoposide; Drug: Mercaptopurine; Drug: Methotrexate; Drug: Vincristine

Detailed Description

This Phase 2, single-arm research study is to evaluate a chemotherapy regiment the treatment of newly diagnosed Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYAs).

The U.S. Food and Drug Administration (FDA) has approved all of the drugs of treatment being studied but the investigators of this research study want to understand more about the safety and effectiveness of the chemotherapy regimen in adolescents and young adults with newly diagnosed Philadelphia chromosome-negative ALL.

The research study procedures include screening for eligibility, in-clinic visits, blood tests, urine tests, saliva tests, X-rays, electrocardiograms (ECGs), echocardiograms (ECHOs), Dual-Energy X-ray Absorptiometry (DEXA) scans, bone marrow aspirations/biopsies.

Participation in this study is expected to last about 10 years, 2 years of treatment followed by 8 years of follow up.

It is expected that about 67 people will take part in this research study.

• Study Type: Interventional
• Enrollment (Estimated): 67
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Marlise R Luskin, MD, MSCE; Phone Number: 617-632-1906; Email: marlise_luskin@dfci.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

3.1.1Confirmed diagnosis of Philadelphia chromosome-negative acute lymphoblastic leukemia.

• Diagnosis should be made by peripheral blood, bone marrow aspirate, bone marrow biopsy, or tissue biopsy demonstrating ≥25% involvement by lymphoblasts, with flow cytometry or immunohistochemistry confirming B-ALL or T-ALL.

  o Participants with B-cell and T-cell lymphoblastic lymphoma are eligible regardless of bone marrow involvement Participants with mixed phenotype acute leukemia (MPAL) ARE eligible, if an ALL regimen is felt to be most appropriate treatment.

• Participants with CNS leukemia ARE eligible. 3.1.2 Allowed prior therapy:
• Corticosteroids, hydroxyurea, all-trans retinoic acid (ATRA).
• IT chemotherapy.
• Emergent radiation therapy or leukapheresis for life threatening complications.
• One cycle of prior chemotherapy (i.e. an induction cycle given at another institution and participant transfers care for post-induction treatment; OR a participant does not meet eligibility prior to induction but does meet eligibility after remission induction).

3.1.3 Age 18.00 - 50.99 years 3.1.4 Direct bilirubin <1.4 mg/dL (total bilirubin < 1.4 mg/dL is acceptable). 3.1.5 Willingness to use effective means of birth control. The effects of chemotherapy on the developing human fetus are unknown. For this reason and because therapeutic agents used in this trial are known to be teratogenic, 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. 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 of study.

3.1.6 Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

Philadelphia chromosome-positive / BCR::ABL1 fusion 3.2.2 Participants with mature B-cell (Burkitt's) ALL. Mature B-cell ALL is defined by the presence of surface immunoglobulin AND any of the following: t(8;14)(q24;q32), t(8;22), t(2;8), or c-myc-gene rearrangement by FISH, PCR or other testing. [FISH/PCR testing for c-myc rearrangements is not required prior to study entry, but it is suggested for participants with surface immunoglobulin expression or L3 morphology]. 3.2.3 Participants with acute undifferentiated leukemia. 3.2.4 Participants receiving any other investigational agent for this condition.

3.2.5 Uncontrolled intercurrent illness including but not limited to ongoing infection with vital sign instability (hypotension, respiratory insufficiency), life-threatening acute tumor lysis syndrome (e.g., with renal failure), symptomatic congestive heart failure, cardiac arrhythmia, intracranial or other uncontrolled bleeding. Circumstances that may significantly interfere with a participant's ability to safely comply with study procedures, such as attend scheduled study visits, adhere to treatment protocols, or complete study assessments. These include a lack of reliable transportation, unstable housing, or psychiatric illness, but reasonable attempts should be made to overcome these circumstances, including but not limited to identifying sponsor, institutional, or thirdparty financial or social support as well as psychiatric consultation for objective assessment. 3.2.6 Sexually active participants of reproductive potential who have not agreed to use an effective contraceptive method for the duration of study participation are ineligible.

3.2.7 Pregnant women are excluded from this study because many of the agents used on this protocol have potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with these chemotherapy agents, breastfeeding should be discontinued if the mother is enrolled.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ALL Backbone Regimen for B-Cell; Steroid Prophase (3-dy cycle): Dexamethasone & cytarabine; Induction IA (29-dy cycle): Vincristine, dexamethasone, pegaspargase, doxorubicin, IT chemotherapy; Induction IB (42-dy cycle): Cyclophosphamide, cytarabine, mercaptopurine, IT chemotherapy; Blinatumomab Cycle 1, 2 (42-dy cycles): Blinatumomab, dexamethasone, IT chemotherapy; Consolidation I:Phase IA (28-dy cycle), Phase IC (21-dy cycle): Vincristine, mercaptopurine, methotrexate, dexamethasone, cytarabine, etoposide, pegaspargase, IT chemotherapy; Blinatumomab Cycle 3 (42-dy cycle): Dexamethasone, Blinatumomab, IT chemotherapy; Consolidation II (21-dy cycles for 30 wks): Vincristine, dexamethasone, mercaptopurine, doxorubicin, methotrexate, pegaspargase, IT chemotherapy; Blinatumomab Cycle 4 (42-dy cycle): Dexamethasone, Blinatumomab, IT chemotherapy; Continuation (21-dy cycles): Vincristine, dexamethasone, mercaptopurine, methotrexate, IT chemotherapy; End of treatment visit; Follow up	Drug: Blinatumomab; A bispecific T-cell engager (BiTE) antibody, single-use vial via intravenous infusion, per standard of care; Other Names: Blincyto; NSC# 765986; Drug: Oncaspar; A modified enzyme L-asparaginase, single-use vial via intravenous infusion, per standard of care; Other Names: PEGASPARGASE; NSC #624239); Drug: Cyclophosphamide; An alkylating agent, single-use vial via intravenous infusion, per standard of care; Other Names: Cytoxan; NSC #26271; Drug: Cytarabine; An antineoplastic antimetabolite, multi-dose vial via intrathecal injection (through the spinal space), per standard of care; Other Names: Ara-C; Cytosine Arabinoside; Cytostar; NSC#63878; Drug: Dexamethasone; A synthetic glucocorticoid, tablets or single-use vials via orally or intravenous infusion (through the vein), per standard of care; Other Names: Decadron; Dexameth; Dexone; Hexadrol; NSC#34521; Drug: Doxorubicin Hydrochloride; An anthracycline antibiotic, single-use or multi-dose vials via intravenous infusion, per standard of care; Other Names: Adriamycin; NSC#123127; Drug: Etoposide; A derivative of podophyllotoxin, multi-dose vial via intravenous infusion, per standard of care; Other Names: VP-16; Etopophos; VePesid; NSC#141540; Drug: Mercaptopurine; A purine antagonist, tablet via orally, per standard of care; Other Names: 6-MP; Purinethol; 6-Mercaptopurine; Purixan; NSC#000755; Drug: Methotrexate; A folate analogue, multi-dose and single-use vials via intrathecal injection, per standard of care; Other Names: MTX; Amethopterin; Trexall; NSC#000740
Experimental: ALL Backbone Regimen for T-Cell; Steroid Prophase (3-day cycle): Dexamethasone and cytarabine; Induction IA (29-day cycle): Vincristine, dexamethasone, pegaspargase, doxorubicin, IT chemotherapy; Induction IB (42-day cycle): Cyclophosphamide, cytarabine, mercaptopurine, IT chemotherapy; Consolidation I:Phase IA (28-day cycle) and Phase IC (21-day cycle): Vincristine, mercaptopurine, methotrexate, dexamethasone, cytarabine, etoposide, pegaspargase, IT chemotherapy; CNS Phase (21-day cycle): Dexamethasone, vincristine, mercaptopurine, pegaspargase, IT chemotherapy; Consolidation II (21-day cycles for 30 weeks): Vincristine, dexamethasone, mercaptopurine, doxorubicin, methotrexate, pegaspargase, IT chemotherapy; Continuation (21-day cycles): Vincristine, dexamethasone, mercaptopurine, methotrexate, IT chemotherapy; End of treatment visit; Follow up	Drug: Blinatumomab; A bispecific T-cell engager (BiTE) antibody, single-use vial via intravenous infusion, per standard of care; Other Names: Blincyto; NSC# 765986; Drug: Oncaspar; A modified enzyme L-asparaginase, single-use vial via intravenous infusion, per standard of care; Other Names: PEGASPARGASE; NSC #624239); Drug: Cyclophosphamide; An alkylating agent, single-use vial via intravenous infusion, per standard of care; Other Names: Cytoxan; NSC #26271; Drug: Cytarabine; An antineoplastic antimetabolite, multi-dose vial via intrathecal injection (through the spinal space), per standard of care; Other Names: Ara-C; Cytosine Arabinoside; Cytostar; NSC#63878; Drug: Dexamethasone; A synthetic glucocorticoid, tablets or single-use vials via orally or intravenous infusion (through the vein), per standard of care; Other Names: Decadron; Dexameth; Dexone; Hexadrol; NSC#34521; Drug: Doxorubicin Hydrochloride; An anthracycline antibiotic, single-use or multi-dose vials via intravenous infusion, per standard of care; Other Names: Adriamycin; NSC#123127; Drug: Etoposide; A derivative of podophyllotoxin, multi-dose vial via intravenous infusion, per standard of care; Other Names: VP-16; Etopophos; VePesid; NSC#141540; Drug: Mercaptopurine; A purine antagonist, tablet via orally, per standard of care; Other Names: 6-MP; Purinethol; 6-Mercaptopurine; Purixan; NSC#000755; Drug: Methotrexate; A folate analogue, multi-dose and single-use vials via intrathecal injection, per standard of care; Other Names: MTX; Amethopterin; Trexall; NSC#000740; Drug: Vincristine; A vinca alkaloid, single-use vials via intravenous injection, per standard of care; Other Names: VCR; Oncovin; LCR; NSC#67574

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Completion Rate Through Time Point 3 (TP3)	Treatment completion rate through TP3 is defined as the proportion of Adolescents and Young Adults (AYAs) participants who receive all protocol-specified therapy through TP3, without early discontinuation.	Timeframe for TP3 depends on disease immunophenotype. Participants with CD19-positive B-ALL, TP3 occurs at the end of Blinatumomab Cycle 2 on Day 28 (130 days from study start). For participants with T-cell ALL or those who do not receive blinatum

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Treatment-Related Mortality (TRM)	Rate of TRM is defined as the proportion of participants who die due to treatment-related causes.	Up to 115 weeks
Rate of Treatment Discontinuation due to Toxicity or Disease	Rate of treatment discontinuation during Induction, Consolidation, and Continuation phases, defined as the proportion of participants who stop protocol-specified therapy due to regimen-related toxicity and/or treatment failure.	Up to 115 weeks
Rate of Asparaginase Non-Completion	Rate of asparaginase non-completion is defined as the proportion of participants who did not complete all planned doses of asparaginase per protocol.	This endpoint is assessed during Consolidation II, which occurs approximately from Day 270 to Day 480 of study treatment.
Reason of Asparaginase Non-Completion	This outcome summarizes the reasons participants discontinue asparaginase treatment earlier than planned.	Up to 115 weeks
Grade 3 Infections Toxicity Rate	Grade 3 infection toxicity rate is defined as the proportion of participants who experience grade 3 bacterial or fungal infections that are assessed as possibly, probably, or definitely related to the study treatment during the induction, consolidation, and continuation phases. Toxicity grades are determined according to the Common Terminology Criteria for Adverse Events (CTCAE) version 6.0.	Adverse events will be followed for 30 days after completion of protocol treatment, with the overall treatment period up to 115 weeks.
Grade 3 Asparaginase-associated Toxicities Rate	Grade 3 asparaginase-associated toxicity rate is defined as the proportion of participants who experience grade 3 asparaginase-associated toxicities (including thromboembolic events, pancreatitis, hypertriglyceridemia, hyperbilirubinemia, hypersensitivity, and hyperglycemia) that are assessed as possibly, probably, or definitely related to the study treatment during the induction, consolidation, or continuation phases. Toxicity grades are determined according to the Common Terminology Criteria for Adverse Events (CTCAE) version 6.0.	Adverse events will be followed for 30 days after completion of protocol treatment, with the overall treatment period up to 115 weeks.
Grade 3 Orthopedic Toxicity Rate	Grade 3 orthopedic toxicity rate is defined as the proportion of participants who experience grade 3 osteopenia or osteoporosis that are assessed as possibly, probably, or definitely related to the study treatment at the end of treatment, or osteonecrosis (ON) or fractures during or after treatment. Toxicity grades are assigned according to the Common Terminology Criteria for Adverse Events (CTCAE) version 6.0.	Adverse events will be followed for 30 days after completion of protocol treatment, with the overall treatment period up to 115 weeks. Ostenonecrosis and fractures will be followed up to 10 years.
Complete remission Rate (CRR)	CRR is defined as proportion of participants who achieve CR. Complete response (CR) is defined as an interpretable bone marrow with less than 5% malignant lymphoblasts, no lymphoblasts in peripheral blood, an absolute phagocyte count greater than 1000/µL and platelets above 100,000/µL (for participants with M2 marrow at Day 32 who achieve CR at TP2, APC above 500/µL and platelets above 50,000/µL are acceptable), no evidence of extramedullary leukemia or blasts in spinal fluid, at least a 70% reduction in the anterior mediastinal mass if present at diagnosis as measured by the sum of the products of the two greatest diameters on CT or chest X-ray, and for any other large radiographic masses at diagnosis, a 70% reduction in SPD if restaging imaging is obtained.	CR can be documented either at the end of Induction IA (32 days) or Induction IB (74 days).
Measurable Residual Disease (MRD) Negativity Rate at the end of Induction IA (Time Point 1)	The proportion of who achieve measurable residual disease (MRD) negativity at the end of Induction IA (Time Point 1). MRD negativity is assessed by multiparameter flow cytometry (MPFC), next-generation sequencing (NGS), and/or KMT2A::AFF4 RT-PCR.	At the end of Induction IA (32 days from study start)
Measurable Residual Disease (MRD) Negativity Rate at the end of Induction IB (Time Point 2)	The proportion of who achieve measurable residual disease (MRD) negativity at the end of Induction IB (Time Point 2). MRD negativity is assessed by multiparameter flow cytometry (MPFC), next-generation sequencing (NGS), and/or KMT2A::AFF4 RT-PCR.	At the end of Induction IB (74 days from study start)
Measurable Residual Disease (MRD) Negativity Rate at Time Point 3 (TP3)	The proportion of who achieve measurable residual disease (MRD) negativity at TP3. MRD negativity is assessed by multiparameter flow cytometry (MPFC), next-generation sequencing (NGS), and/or KMT2A::AFF4 RT-PCR.	For CD19-positive B-ALL, TP3 is reached at the end of Blinatumomab Cycle 2 on Day 28 (Day 130 from study start). For T-cell ALL or participants not receiving blinatumomab, TP3 occurs on Day 28 of Consolidation IC (Day 102 from study start).
Median Event-Free Survival (EFS)	EFS based on Kaplan-Meier method is defined as the time from registration to induction failure, relapse, second malignancy, or death due to any cause. Relapse is defined as the presence of more than 5% lymphoblasts in bone marrow confirmed by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests; the development of biopsy-proven extramedullary disease (e.g., CSF, testicle, lymph node, skin); or CNS relapse, defined as a CSF sample with more than 5 WBCs per high-power field with lymphoblasts on cytospin, or two consecutive CSF specimens meeting the CNS-2 criteria (<5 WBC/µL with lymphoblasts) obtained at least three weeks apart. Participants alive without disease relapse are censored at date of last disease evaluation (which can include clinical evaluation and blood counts, does not require a bone marrow examination).	Up to 10 years
Median Disease-Free Survival (DFS)	DFS based on Kaplan-Meier method is defined as the time from confirmed complete remission (CR) to the earlier of relapse or death due to any cause. Relapse is defined as the presence of more than 5% lymphoblasts in bone marrow confirmed by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests; the development of biopsy-proven extramedullary disease (e.g., CSF, testicle, lymph node, skin); or CNS relapse, defined as a CSF sample with more than 5 WBCs per high-power field with lymphoblasts on cytospin, or two consecutive CSF specimens meeting the CNS-2 criteria (<5 WBC/µL with lymphoblasts) obtained at least three weeks apart. Participants who are alive without disease relapse are censored at the date of last disease evaluation.	Up to 10 years
Median Overall Survival (OS)	Overall Survival (OS) based on Kaplan-Meier method is defined as the time from registration to death due to any cause or censored at date last known alive.	Up to 10 years
Rate of Allogeneic Transplantation	Rate of allogeneic transplantation is defined as the proportion of participants who undergo allogeneic transplantation while in their first complete remission (CR).	CR can be documented either at the end of Induction IA (32 days) or Induction IB (74 days).
Reason of Allogeneic Transplantation	This outcome measures the number of participants who undergo allogeneic transplantation in their first complete remission (CR) and the reasons for transplantation.	CR can be documented either at the end of Induction IA (32 days) or Induction IB (74 days).

Collaborators and Investigators

• Sponsor: Dana-Farber Cancer Institute
• Investigators: Principal Investigator: Marlise R Luskin, MD, MSCE, Dana-Farber Cancer Institute

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): July 31, 2030
• Study Completion (Estimated): July 31, 2035

Study Registration Dates

• First Submitted: November 10, 2025
• First Submitted That Met QC Criteria: November 10, 2025
• First Posted (Actual): November 12, 2025

Study Record Updates

• Last Update Posted (Actual): November 12, 2025
• Last Update Submitted That Met QC Criteria: November 10, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Leukemia; Acute Lymphoblastic Leukemia; Acute Lymphoblastic Leukemia (ALL); Philadelphia Chromosome-Negative lymphoblastic leukemia
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, Lymphoid; Hemic and Lymphatic Diseases; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Alkaloids; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glucosides; Glycosides; Indoles; Purines; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated; Benzene Derivatives; Sulfonic Acids; Sulfur Acids; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Nucleosides; Pterins; Pteridines; Pregnadienetriols; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indolizidines; Indolizines; Arabinonucleosides; Aminopterin; Anthracyclines; Naphthacenes; Aminoglycosides; Daunorubicin; Benzenesulfonates; Arylsulfonates; Arylsulfonic Acids; Sulfhydryl Compounds; Dexamethasone; Methotrexate; Cyclophosphamide; Cytarabine; Etoposide; Doxorubicin; Vincristine; Mercaptopurine; Calcium Dobesilate; blinatumomab; pegaspargase; etoposide phosphate
• Other Study ID Numbers: 25-533

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: 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: [contact information for Sponsor Investigator or designee]. 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.
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication
• IPD Sharing Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes