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Blinatumomab and Nivolumab With or Without Ipilimumab in Treating Patients With Poor-Risk Relapsed or Refractory CD19+ Precursor B-Lymphoblastic Leukemia

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ClinicalTrials.gov Identifier: NCT02879695
Recruitment Status : Recruiting
First Posted : August 26, 2016
Last Update Posted : January 20, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase I trial studies the side effects and best dose of blinatumomab when given with nivolumab alone or nivolumab and ipilimumab in treating patients with poor-risk CD19+ precursor B-lymphoblastic leukemia that has come back after a period of improvement (relapsed) or has not responded to treatment (refractory). Immunotherapy with monoclonal antibodies, such as blinatumomab, nivolumab, and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Condition or disease Intervention/treatment Phase
Recurrent B Acute Lymphoblastic Leukemia Recurrent Mixed Phenotype Acute Leukemia Refractory B Acute Lymphoblastic Leukemia Refractory Mixed Phenotype Acute Leukemia Biological: Blinatumomab Biological: Ipilimumab Biological: Nivolumab Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of the blinatumomab given in combination with nivolumab alone, or in combination with both nivolumab and ipilimumab in subjects with poor-risk, relapsed or refractory CD19+ pre-B cell acute lymphoblastic leukemia (ALL) or CD19+ mixed phenotype acute leukemia (MPAL).

II. To determine the maximum tolerated dose (MTD) of the combination of blinatumomab plus nivolumab, and blinatumomab plus both nivolumab and ipilimumab and to further confirm the safety of the combination therapy in subjects with poor-risk, relapsed or refractory CD19+ pre-B cell ALL or CD19+ mixed phenotype acute leukemia (MPAL).

SECONDARY OBJECTIVES:

I. To observe and record anti-leukemia activity of blinatumomab and nivolumab, and blinatumomab plus both nivolumab and ipilimumab, including the effects on minimal residual disease (MRD).

II. To assess preliminary anti-leukemia activity in expansion cohorts of patients with poor-risk, relapsed or refractory CD19+ precursor B-lymphoblastic leukemia, or CD19+ mixed phenotype acute leukemia (MPAL).

EXPLORATORY OBJECTIVES:

I. To examine changes in absolute lymphocyte count and distribution of T cell subsets (CD4+, CD8+, regulatory T cells [Tregs], effector T cells [Teffs]) and their differentiation status, natural killer (NK) cells, and B cells before and post-blinatumomab, and immune checkpoint inhibitor(s) therapy in both peripheral blood and the bone marrow microenvironment.

II. To explore changes in T cell co-signaling receptors expression in defined T cell subpopulations and their canonic transcription factor expression in both peripheral blood and bone marrow before and post-blinatumomab, and immune checkpoint inhibitor(s) therapy.

III. To examine changes in expression of co-signaling molecules on leukemia blasts (CD10+/CD19+/CD34+) before and after treatment with blinatumomab and checkpoint inhibitors.

IV. To examine the serum levels of cytokines before and after treatment with blinatumomab and checkpoint inhibitors, including the levels of sCTLA-4.

V. To perform immune profiling of T cell repertoire and characterize T cell transcriptional signature before and after treatment.

OUTLINE: This is a dose-escalation study of blinatumomab.

Patients receive blinatumomab intravenously (IV) continuously on days 1-28. Treatment repeats every 42 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab IV over 30 minutes on day 11 and then every 2 weeks for up to year. Some patients also receive ipilimumab IV over 90 minutes on day 11 and then every 6 weeks for up to 1 year.

After completion of study treatment, patients are followed up every 3 months for up to 2 years.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of Blinatumomab in Combination With Checkpoint Inhibitor(s) of PD-1 (Nivolumab) or Both PD-1 (Nivolumab) and CTLA-4 (Ipilimumab) in Patients With Poor-Risk, Relapsed or Refractory CD19+ Precursor B-Lymphoblastic Leukemia
Actual Study Start Date : May 5, 2017
Estimated Primary Completion Date : November 5, 2021
Estimated Study Completion Date : November 5, 2021


Arm Intervention/treatment
Experimental: Treatment (blinatumomab, nivolumab, ipilimumab)
Patients receive blinatumomab IV continuously on days 1-28. Treatment repeats every 42 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab IV over 30 minutes on day 11 and then every 2 weeks for up to year. Some patients also receive ipilimumab IV over 90 minutes on day 11 and then every 6 weeks for up to 1 year.
Biological: Blinatumomab
Given IV
Other Names:
  • Anti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody
  • Anti-CD19/Anti-CD3 Recombinant Bispecific Monoclonal Antibody MT103
  • Blincyto
  • MEDI-538
  • MT-103

Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • Ipilimumab Biosimilar CS1002
  • MDX-010
  • MDX-CTLA4
  • Yervoy

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo




Primary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Up to 2 years ]
    Incidence of adverse events will be graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. All adverse events and toxicities will be tabulated and reported by type and grade for all dose levels of all treatment combinations and the proportions reported with exact 95% binomial confidence intervals.

  2. Maximum tolerated dose [ Time Frame: Up to 2 years ]
    Maximum tolerated dose will be defined as the maximum dose level in the absence of dose limiting toxicity in each patient assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The maximum tolerated dose of the combination of blinatumomab plus nivolumab, and blinatumomab plus both nivolumab and ipilimumab will be determined in subjects with poor-risk, relapsed or refractory CD19+ Pre-B cell acute lymphoblastic leukemia or CD19+ mixed phenotype acute leukemia.


Secondary Outcome Measures :
  1. Minimal residual disease [ Time Frame: Up to 2 years ]
    Will be assessed by flow cytometry. For patients who have a clinical response, the frequency of minimal residual disease positive versus minimal residual disease negative responses will be reported by treatment arm and dose level for all patients on study.

  2. Anti-leukemia activity [ Time Frame: Up to 2 years ]
  3. Complete remission [ Time Frame: Up to 2 years ]
    The frequency distribution of responses, including complete remission, complete remission with incomplete blood count recovery or progressive disease will be reported by treatment arm and dose level for all patients on study and reported with exact 95% confidence intervals.

  4. Complete remission with incomplete blood count recovery [ Time Frame: Up to 2 years ]
    The frequency distribution of responses, including complete remission, complete remission with incomplete blood count recovery or progressive disease will be reported by treatment arm and dose level for all patients on study and reported with exact 95% confidence intervals.

  5. Progressive disease [ Time Frame: Up to 2 years ]
    The frequency distribution of responses, including complete remission, complete remission with incomplete blood count recovery or progressive disease will be reported by treatment arm and dose level for all patients on study and reported with exact 95% confidence intervals.

  6. Duration of response [ Time Frame: Time from measured response to progressive disease, death, or study end, assessed up to 2 years ]
    Will be analyzed using the Kaplan Meier method. A sensitivity analysis may be performed to evaluate duration of response while excluding patients who go on to have an allogeneic-hematopoietic stem cell transplantation.

  7. Overall survival [ Time Frame: From the first day of treatment on the study until death or last known follow up, assessed up to 2 years ]
    Will be measured using the Kaplan Meier method.


Other Outcome Measures:
  1. Changes in absolute lymphocyte count [ Time Frame: Baseline up to 2 years ]
  2. Changes in distribution of T cell subsets and differentiation status, natural killer (NK) cells, and B cells [ Time Frame: Baseline up to 2 years ]
    Will be assessed by flow cytometry. The analyses of pre- and post-treatment peripheral blood and bone marrow specimens for immune parameters will be descriptive and graphical in nature. Data will be summarized for each patient group separately. Flow values at each time point will be summarized using geometric means and standard deviation. Differences in baseline values between patient subgroups will be explored using linear regression models.

  3. Changes in T cell co-signaling receptors expression [ Time Frame: Baseline up to 2 years ]
  4. Changes in expression of co-signaling molecules on leukemia blasts [ Time Frame: Up to 2 years ]
    Will be summarized using descriptive statistics and either Wilcoxon rank sum tests or paired t tests, as appropriate for a single time point, or using the mixed effects linear regression models for simultaneously modelling data from multiple time points as previously described for analyzing the T cell population data. The changes in blasts in terms of expression of co-signaling molecules over time will be explored and summarize any correlation in the pattern of blast changes over time using the regression models and interaction tests.

  5. Changes in cytokines levels in serum [ Time Frame: Baseline up to 2 years ]
    Will be summarized using descriptive statistics and either Wilcoxon rank sum tests or paired t tests, as appropriate for a single time point, or using the mixed effects linear regression models previously described for simultaneously modelling data from multiple time points for the T cell population data.

  6. Characterization of T cell transcriptional signature [ Time Frame: Up to 2 years ]
    Expression levels will be summarized at pre-treatment and post-treatment using standard descriptive statistics. Differentially-expressed genes and corresponding fold-changes will be analyzed using standard statistics and through the use of Ingenuity pathway analysis.



Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • PRE-REGISTRATION ELIGIBILITY CRITERIA
  • Patients must have suspected refractory or relapsed pre-B cell ALL or mixed phenotype acute leukemia (MPAL), or if newly diagnosed, the patient must be 60 years of age or older
  • Bone marrow and/or peripheral blood specimens will be submitted for correlative studies; patients who have a dry tap will still be eligible
  • REGISTRATION ELIGIBILITY CRITERIA
  • Patients must have histologically or cytologically confirmed by the local institution CD19+ precursor B-acute lymphoblastic leukemia (pre-B cell ALL) OR CD19+ mixed phenotype acute leukemia (MPAL): a) with relapse following or refractory to at least one prior line of therapy if older than 21 years; b) in second or higher relapse or refractory to at least two prior lines of therapy if 21 years old and younger (16-21); c) or they must have a new diagnosis of pre-B cell ALL or CD19+ MPAL but are >= 60 years old and are either not a candidate for or do not wish to receive traditional induction chemotherapy
  • The evidence of CD19+ expression on leukemia cells must be confirmed by pathology review of the bone marrow and/or peripheral blood specimens (flow cytometry and/or immunohistochemistry) collected at the time of current relapse and prior to the initiation of therapy
  • Patients with Philadelphia chromosome (Ph) positive (+) pre-B cell ALL OR Ph+ MPAL will be eligible if they have been refractory to or intolerant of treatment with at least 1 second-generation or third-generation tyrosine kinase inhibitor (TKI)
  • Patients who were treated with blinatumomab in the past will be allowed on the study as long as they have persistent CD19 expression on leukemia cells and did not experience unacceptable toxicities with prior blinatumomab administration; patients who were treated with chimeric antigen receptor (CAR)-modified T cells targeting CD19 in the past will be allowed on the study as long as they have persistent CD19 expression on leukemia cells
  • Patients with a history of allogeneic hematopoietic stem cell transplantation (HSCT) will be eligible if they are more than 90 days removed from the date of stem cell infusion, have no evidence of acute graft-versus-host disease (GVHD) or active chronic (grade 2-4) GVHD, and are off of all transplant-related immunosuppression for at least 2 weeks
  • Eastern Cooperative Oncology Group (ECOG)/Karnofsky performance status of 0-2 (Karnofsky >= 60%)
  • Life expectancy of greater than 12 weeks
  • Total bilirubin =< 2.0 mg/dL (except patients with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x upper limit of normal (ULN)
  • Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula)
  • The effects of nivolumab, ipilimumab, and blinatumomab on the developing human fetus are unknown; for this reason, women of child-bearing potential (WOCBP) 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; WOCBP should use an adequate method to avoid pregnancy for 23 weeks after the last dose of investigational drug; women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of treatment on the study; women must not be breastfeeding; men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year; men receiving nivolumab +/- ipilimumab and blinatumomab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product; women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception

    • Note: Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal; menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes; in addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL
    • Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she (or the participating partner) should inform the treating physician immediately
  • Adequate pulmonary function as assessed by oxygen saturation >= 90% when ambulating and not requiring supplemental oxygen
  • Patients with a known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) will be eligible if:

    • They are generally healthy from an HIV perspective and on a stable anti-retroviral regimen for > 6 months
    • They have had no AIDS-defining conditions in the past 12 months other than historically low CD4+ cell counts
    • They have an undetectable viral load on standard assays
  • Patients with a known history of hepatitis C (HCV) will be eligible if they have an undetectable viral load; if the patient received treatment for HCV, then that treatment must have been completed at least three weeks prior to enrollment
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had chemotherapy or other systemic therapy or radiotherapy, or those who have not recovered from adverse events due to prior administered agents as follows: chemotherapy, radiotherapy or surgery =< 3 weeks prior to entering the study, targeted therapy (e.g., TKI) =< 1 week prior to entering the study; autologous HSCT =< 6 weeks prior to entering the study; investigational drug or immunotherapy (e.g. rituximab) =< 4 weeks prior to entering the study; prophylactic intrathecal chemotherapy within one week of enrollment allowed; patients will be allowed to receive cytoreduction with hydroxyurea, 6-mercaptopurine, corticosteroids (dexamethasone, prednisone or similar) or cyclophosphamide provided that it is discontinued at least 24 hours prior to the initiation of study treatment; pre-phase treatment with dexamethasone 10 mg/m^2 (maximum total 24 mg per day) for up to 5 days is required for patients with bone marrow blasts more than 50%, peripheral blood blasts of 15,000/uL or higher, or elevated lactate dehydrogenase suggesting rapidly progressing disease as per investigator's assessment; pre-phase treatment must be stopped at least 24 hours prior to the initiation of blinatumomab
  • Patients who are receiving any other investigational agents
  • Patients should be excluded if they have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
  • Patients with active central nervous system leukemia are excluded from this clinical trial because they may develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with a history of central nervous system (CNS) leukemia but no active disease at the time of enrollment are eligible; the absence of CNS disease must be confirmed by flow cytometric and cytologic examination of the cerebrospinal fluid (CSF) within 7 days of study enrollment
  • Active leukemia in the testes or isolated extramedullary relapse; patients with a history of treated leukemia in testes but no active disease at the time of enrollment are eligible
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab, ipilimumab, or blinatumomab
  • History of severe hypersensitivity reaction to any monoclonal antibody
  • Uncontrolled intercurrent illness including, but not limited to, active, uncontrolled infection; symptomatic congestive heart failure; unstable angina pectoris; cardiac arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements; patients with infection under treatment and controlled with antibiotics are eligible
  • Pregnant women are excluded from this study because nivolumab and ipilimumab have the 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 nivolumab and ipilimumab, breastfeeding should be discontinued if the mother is treated with nivolumab and ipilimumab; these potential risks may also apply to blinatumomab
  • History of any chronic hepatitis including alcoholic, non-alcoholic steatohepatitis (NASH), drug related, autoimmune, chronic viral positive tests for hepatitis B virus surface antigen (HBsAg), hepatitis B core antibody (anti-HBc) in the absence of hepatitis B surface antibody (anti-HBs), or a positive hepatitis C (HCV) viral load; these patients are excluded due to the risk for autoimmune hepatitis with immune checkpoint inhibitors exacerbating their known liver disease as well as the unknown risk for hepatitis B and/or C reactivation with blinatumomab and immune checkpoint inhibitors
  • Subjects with active autoimmune disease, a history of known or suspected autoimmune disease or a history of a syndrome requiring systemic corticosteroids (> 10 mg daily of prednisone equivalent) except for the treatment of malignancy with the exception of:

    • Isolated vitiligo
    • Resolved childhood atopy
    • History of a positive antinuclear antibody (ANA) titer without associated symptoms or history of symptoms of an autoimmune disorder
    • Controlled thyroid disorders
    • Type I diabetes mellitus
    • Psoriasis, Sjogren's syndrome, and arthropathies not requiring systemic treatment
    • Autoimmune diseases: these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, autoimmune vasculitis, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease
  • Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses =< 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen), or as pre-phase treatment for cytoreduction; patients will receive steroids with blinatumomab to reduce cytokine release syndrome (CRS) as specified in the protocol
  • Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study
  • Patients who have a history of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, psychosis, or other significant CNS abnormalities; a history of treated CNS leukemia will be allowed if recent CNS studies confirm the absence of active CNS disease at the time of study entry (screening)
  • Patients with a known concurrent malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or carcinoma in situ of the cervix
  • Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02879695


Locations
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United States, Connecticut
Yale University Recruiting
New Haven, Connecticut, United States, 06520
Contact: Site Public Contact    203-785-5702    canceranswers@yale.edu   
Principal Investigator: Amer M. Zeidan         
United States, Kentucky
University of Kentucky/Markey Cancer Center Recruiting
Lexington, Kentucky, United States, 40536
Contact: Site Public Contact    859-257-3379      
Principal Investigator: Gerhard C. Hildebrandt         
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Site Public Contact    410-955-8804    jhcccro@jhmi.edu   
Principal Investigator: Ivana Gojo         
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Site Public Contact    877-442-3324      
Principal Investigator: Marlise R. Luskin         
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Site Public Contact    800-293-5066    Jamesline@osumc.edu   
Principal Investigator: Meixiao Long         
United States, Pennsylvania
University of Pittsburgh Cancer Institute (UPCI) Active, not recruiting
Pittsburgh, Pennsylvania, United States, 15232
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Ivana Gojo JHU Sidney Kimmel Comprehensive Cancer Center LAO
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02879695    
Other Study ID Numbers: NCI-2016-01300
NCI-2016-01300 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ETCTN10030
10030 ( Other Identifier: JHU Sidney Kimmel Comprehensive Cancer Center LAO )
10030 ( Other Identifier: CTEP )
UM1CA186691 ( U.S. NIH Grant/Contract )
First Posted: August 26, 2016    Key Record Dates
Last Update Posted: January 20, 2021
Last Verified: December 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Acute Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease Attributes
Pathologic Processes
Antineoplastic Agents, Immunological
Nivolumab
Ipilimumab
Blinatumomab
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Muromonab-CD3
Antibodies, Bispecific
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Immunosuppressive Agents