A Study to Compare Blinatumomab Alone to Blinatumomab With Nivolumab in Patients Diagnosed With First Relapse B-Cell Acute Lymphoblastic Leukemia (B-ALL)
A Study to Compare Blinatumomab Alone to Blinatumomab With Nivolumab in Patients Diagnosed With First Relapse B-Cell Acute Lymphoblastic Leukemia (B-ALL)
This phase II trial studies the effect of nivolumab in combination with blinatumomab compared
 to blinatumomab alone in treating patients with B-cell acute lymphoblastic leukemia (B-ALL)
 that has come back (relapsed). Down syndrome patients with relapsed B-ALL are included in
 this study. Blinatumomab is an antibody, which is a protein that identifies and targets
 specific molecules in the body. Blinatumomab searches for and attaches itself to the cancer
 cell. Once attached, an immune response occurs which may kill the cancer cell. Nivolumab is a
 medicine that may boost a patient's immune system. Giving nivolumab in combination with
 blinatumomab may cause the cancer to stop growing for a period of time, and for some
 patients, it may lessen the symptoms, such as pain, that are caused by the cancer.
PRIMARY OBJECTIVES:

 I. To compare rate of minimal residual disease (MRD) negative second remission (Rem-2) after
 up to two cycles of reinduction with blinatumomab versus (vs.) blinatumomab/nivolumab in
 Group 1 patients aged >= 1 to < 31 years old with first relapse of CD19+ B-ALL.

 II. To compare event-free survival (EFS) PI (EFS post-induction) between consolidation with
 blinatumomab vs. blinatumomab/nivolumab in Group 3 patients aged >= 1 to <31 years old with
 first relapse of CD19+ B ALL.

 SECONDARY OBJECTIVES:

 I. To evaluate the safety and tolerability of blinatumomab/nivolumab in patients aged >= 1 to
 < 31 years old with first relapse of CD19+ B ALL.

 II. To compare EFS post-induction between blinatumomab vs. blinatumomab/nivolumab in Group 2
 patients aged >= 1 to < 31 years old with first relapse of CD19+ B ALL.

 EXPLORATORY OBJECTIVES:

 I. In Group 1 patients, compare EFS between blinatumomab monotherapy and
 blinatumomab/nivolumab arms as compared to similar patients treated on the predecessor trial
 AALL1331.

 II. In Group 1 patients, compare toxicity as defined by grade 3 or greater adverse events
 during the first cycle of blinatumomab or blinatumomab/nivolumab to similar patients treated
 with block 1 of cytotoxic chemotherapy on the predecessor trial AALL1331.

 III. In Group 2 patients with MRD >= 0.1% after vincristine sulfate, dexamethasone, pegylated
 asparaginase, and doxorubicin hydrochloride (VXLD), compare MRD negative second remission
 (Rem-2) rate after the first cycle of immunotherapy between blinatumomab monotherapy and
 blinatumomab/nivolumab arms.

 IV. In patients with Down syndrome (DS) with first relapse of B-ALL, describe the safety,
 tolerability and efficacy (as defined by MRD negative second remission, Rem-2) after up to
 two cycles of blinatumomab/nivolumab.

 OUTLINE: Patients >= 18 years old with marrow +/- extramedullary (EM) relapse of any duration
 after initial diagnosis, or patients < 18 years old with marrow +/- EM relapse < 24 months
 after initial diagnosis are assigned to Group 1. Patients < 18 years old with marrow +/- EM
 relapse >= 24 months from initial diagnosis, or all isolated extramedullary (IEM) relapses >=
 1 to < 31 years old are assigned to Groups 2-3 re-induction. Patients with DS are assigned to
 Arm G. NOTE: Patients in Group 1 and DS patients with white blood cells (WBC) >= 30,000/uL,
 CNS 2/3 disease, or testicular disease must first receive 1 of 3 pre-immunotherapy
 treatments.

 PRE-IMMUNOTHERAPY TREATMENT FOR PATIENTS WITH WBC >= 30,000/uL: Patients receive methotrexate
 (MTX) intrathecally (IT) or cytarabine IT or intrathecal triple therapy (ITT) consisting of
 MTX, hydrocortisone sodium succinate, and cytarabine IT at the time of diagnostic lumbar
 puncture (LP) or on day 1 (if intrathecal therapy is given with relapse diagnostic LP < 7
 days prior to the start of protocol therapy). Patients also receive dexamethasone
 intravenously (IV) or orally (PO) twice daily (BID) on days 1-5, vincristine sulfate IV push
 over 1 minute or via infusion on day 1. Patients with DS also receive leucovorin calcium PO
 or IV every 6 hours (q6h) for 2 doses on day 2 or at 24 and 30 hours after each MTX or ITT
 dose. Patients should proceed to the next cycle when CNS 1 and no testicular disease is
 present, no sooner than Day 8 and no later than Day 15.

 PRE-IMMUNOTHERAPY TREATMENT FOR CNS 2/3 DISEASE: Patients receive MTX IT or cytarabine IT
 twice weekly (Q2W) for 5-7 doses or Intrathecal Triple Therapy (ITT) IT Q2W for 3-4 doses
 until patient is CNS 1. Patients with DS also receive leucovorin calcium PO or IV q6h for 2
 doses at 24 and 30 hours after each MTX or ITT dose. Patients should proceed to the next
 cycle when CNS 1 and no testicular disease is present, no sooner than Day 15 and no later
 than Day 24.

 PRE-IMMUNOTHERAPY TREATMENT FOR TESTICULAR DISEASE: Patients receive MTX IT, cytarabine IT,
 or ITT IT on days 1 and 15 (day 1 may be omitted if intrathecal therapy is given with relapse
 diagnostic LP < 7 days prior to the start of protocol therapy). Patients with DS also receive
 leucovorin calcium PO or IV q6h for 2 doses on days 2 and 16 or at 24 and 30 hours after each
 IT MTX or ITT dose. Males with testicular disease at relapse undergo radiation once daily
 (QD) for a total of 12 fractions over 12 days. Patients should proceed to the next cycle when
 CNS 1 and no testicular disease is present, no sooner than Day 15 and no later than Day 22.

 GROUP 1: Patients are randomized to Arm A or Arm B.

 ARM A: Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1, blinatumomab via
 continuous IV infusion on days 1-28 of cycles 1-2, MTX IT, cytarabine IT, or ITT IT on days 1
 and 15 of cycle 1 (MTX on day 1 may be omitted if intrathecal therapy is given with relapse
 diagnostic LP < 7 days prior to the start of protocol therapy), and MTX IT on days 1 and 15
 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease
 progression or unacceptable toxicity. NOTE: Patients with MRD < 0.01% after cycle 1 may stop
 study treatment or may choose to continue to cycle 2. Patients with MRD >= 0.01% after cycle
 1 proceed to cycle 2.

 ARM B: Patients receive dexamethasone, blinatumomab, and MTX, cytarabine, or ITT as in Arm A.
 Patients also receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1
 and 15 of cycle 2. Treatment repeats every 36 days for 2 cycles in the absence of disease
 progression or unacceptable toxicity. NOTE: Patients with MRD < 0.01% after cycle 1 may stop
 study treatment or may choose to continue to cycle 2. Patients with MRD >= 0.01% after cycle
 1 proceed to cycle 2.

 GROUPS 2-3 REINDUCTION: Patients receive vincristine sulfate IV push over 1 minute or via
 infusion on days 1, 8, 15, and 22, dexamethasone PO or IV on days 1-14, doxorubicin
 hydrochloride IV over 1-15 minutes on day 1, MTX IT on days 1, 8, and 29 (day 1 may be
 omitted if intrathecal therapy is given with relapse diagnostic LP < 7 days prior to the
 start of protocol therapy) (days 8 and 29 for CNS 1/2 patients at relapse only), pegaspargase
 intramuscularly (IM) or IV over 1-2 hours on days 2 and 16, cytarabine IT on days 4 and 11
 (CNS 2 patients at relapse only), then Q2W until 3 consecutive samples are clear of blasts,
 and ITT IT on days 8, 15, 22, and 29 (CNS 3 patients at relapse only). Treatment continues in
 the absence of disease progression or unacceptable toxicity.

 GROUP 2: The following patients are randomized to Arm C or Arm D: 1) >= 1 to < 31 years old,
 IEM relapse < 18 months from diagnosis, regardless of MRD after Re-Induction. 2) < 18 years
 old with marrow relapse >= 24 to < 36 months from diagnosis regardless of MRD after
 Re-Induction, 3) >= 1 to < 31 years old, IEM relapse >= 18 months, and MRD >= 0.1% after
 Re-Induction, 4) < 18 years old with marrow relapse >= 36 months, and MRD >= 0.1% after
 Re-Induction.

 ARM C: Patients receive dexamethasone PO or IV on day 1 of cycle 1, blinatumomab via
 continuous IV infusion on days 1-28 of cycles 1 and 2, and MTX IT on days 1 and 15 of cycles
 1 and 2 (day 1 may be omitted from cycle 1 if intrathecal MTX is given < 7 days prior to the
 start of cycle 1 ). Treatment repeats every 36 days for 2 cycles in the absence of disease
 progression or unacceptable toxicity. NOTE: Patients with MRD < 0.01% after cycle 1 may stop
 study treatment or may choose to continue to cycle 2. Patients with MRD >= 0.01% after cycle
 1 proceed to cycle 2.

 ARM D: Patients receive dexamethasone, blinatumomab, and MTX as in Arm C. Patients also
 receive nivolumab IV over 30 minutes on days 11 and 25 of cycle 1 and days 1 and 15 of cycle
 2. Treatment repeats every 36 days for 2 cycles in the absence of disease progression or
 unacceptable toxicity. NOTE: Patients with MRD < 0.01% after cycle 1 may stop study treatment
 or may choose to continue to cycle 2. Patients with MRD >= 0.01% after cycle 1 proceed to
 cycle 2.

 GROUP 3: The following patients are randomized to Arm E or Arm F: 1) >= 1 to < 31 years old
 with IEM relapse >= 18 months from diagnosis and MRD < 0.1% after Re-Induction, 2) < 18 years
 old with marrow relapse >= 36 months from diagnosis and MRD < 0.1% after Re-Induction.

 ARM E:

 IMMUNOTHERAPY CYCLES 1-2: Patients receive dexamethasone PO or IV on day 1 of cycle 1 only,
 blinatumomab IV via continuous infusion on days 1-28, and MTX IT on days 1 and 15 (day 1 may
 be omitted from cycle 1 if intrathecal therapy is given < 7 days prior to the start of this
 cycle).Immunotherapy Cycles 1-2 alternate with Continuation Cycles 1-2.

 CONTINUATION CYCLES 1-2: Patients receive dexamethasone PO on days 1-5, vincristine sulfate
 IV push over 1 minute or via infusion on day 1, mercaptopurine PO on days 1-42, MTX PO on
 days 8, 15, 29, and 36, cyclophosphamide IV over 15-30 minutes on days 43 and 50, etoposide
 IV over 90-120 minutes on days 43 and 50, thioguanine PO once daily (QD) on days 43-49, and
 cytarabine IV over 1-30 minutes or subcutaneously (SC) on days 44-47 and 51-54. CNS 1/2
 patients at relapse also receive MTX IT on days 1 and 43 and PO q6h for 4 doses on day 22,
 and leucovorin calcium PO q6h for 2 doses on day 24. CNS 3 patients at relapse also receive
 ITT IT on days 1 and 43, intermediate dose MTX IV over 36 hours on day 22, and leucovorin
 calcium IV or PO q6h on days 24 and 25. Treatment repeats every 8 weeks for 2 cycles in the
 absence of disease progression or unacceptable toxicity.

 IMMUNOTHERAPY CYCLE 3: Patients receive blinatumomab IV via continuous infusion on days 1-28,
 and MTX IT on days 1 and 15.

 MAINTENANCE: Patients receive dexamethasone PO BID on days 1-5, 29-33, and 57-61, vincristine
 sulfate IV push over 1 minute or via infusion on days 1, 29, and 57, mercaptopurine PO on
 days 1-84, MTX IT on day 1 (CNS 1/2 patients at relapse only), ITT IT on day 1 (CNS 3
 patients at relapse only), and MTX PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.
 Treatment repeats every 12 weeks for 2 years from the start of Re-Induction therapy in the
 absence of disease progression or unacceptable toxicity.

 MAINTENANCE CHEMORADIATION (FOR CNS 3 PATIENTS ONLY): Beginning between the first and second
 cycles of maintenance therapy, patients receive dexamethasone PO BID on days 1-7 and 15-21,
 vincristine sulfate IV push over 1 minute or via infusion on days 1, 8, and 15, and
 pegaspargase IM or IV over 1-2 hours on day 1. Patients with CNS 3 and isolated CNS relapse
 undergo cranial radiation in the form of 3-dimensional (D)-conformal radiation therapy (CRT)
 over 5 days per week for a total of 10 treatments.

 ARM F:

 IMMUNOTHERAPY CYCLES 1-2: Patients receive dexamethasone PO or IV on day 1 of cycle 1 only,
 blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days
 11-25 of cycle 1 and on days 1 and 15 of cycles 2 and 3, and MTX IT on days 1 and 15 (day 1
 may be omitted from cycle 1 if intrathecal therapy is given with < 7 days prior to the start
 of this cycle). Immunotherapy Cycles 1-2 alternate with Continuation Cycles 1-2.

 CONTINUATION CYCLES 1-2: Patients receive dexamethasone PO on days 1-5, vincristine sulfate
 IV push over 1 minute or via infusion on day 1, mercaptopurine PO on days 1-42, MTX PO on
 days 8, 15, 29, and 36, cyclophosphamide IV over 15-30 minutes on days 43 and 50, etoposide
 IV over 90-120 minutes on days 43 and 50, thioguanine PO QD on days 43-49, and cytarabine IV
 over 1-30 minutes or SC on days 44-47 and 51-54. CNS 1/2 patients at relapse also receive MTX
 IT on days 1 and 43 and PO q6h for 4 doses on day 22, and leucovorin calcium PO q6h for 2
 doses on day 24. CNS 3 patients at relapse also receive ITT IT on days 1 and 43, intermediate
 dose MTX IV over 36 hours on day 22, and leucovorin calcium IV or PO q6h on days 24 and 25.

 IMMUNOTHERAPY CYCLE 3: Patients receive blinatumomab IV via continuous infusion on days 1-28,
 nivolumab IV over 30 minutes on days 1 and 15 and MTX IT on days 1 and 15.

 MAINTENANCE: Patients receive dexamethasone PO BID on days 1-5, 29-33, and 57-61, vincristine
 sulfate IV push over 1 minute or via infusion on days 1, 29, and 57, mercaptopurine PO on
 days 1-84, MTX IT on day 1 (CNS 1/2 patients at relapse only), ITT IT on day 1 (CNS 3
 patients at relapse only), and MTX PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78.
 Treatment repeats every 12 weeks for 2 years from the start of Re-Induction therapy in the
 absence of disease progression or unacceptable toxicity.

 MAINTENANCE CHEMORADIATION (FOR CNS 3 PATIENTS): Beginning between the first and second
 cycles of maintenance therapy, patients receive dexamethasone PO BID on days 1-7 and 15-21,
 vincristine sulfate IV push over 1 minute or via infusion on days 1, 8, and 15, and
 pegaspargase IM or IV over 1-2 hours on day 1. Patients with CNS 3 and isolated CNS relapse
 undergo cranial radiation in the form of 3D-CRT over 5 days per week for a total of 10
 treatments in the absence of disease progression or unacceptable toxicity.

 ARM G (DS PATIENTS): Patients receive dexamethasone PO or IV on days 1 and 8 of cycle 1 only,
 blinatumomab IV via continuous infusion on days 1-28, nivolumab IV over 30 minutes on days 11
 and 25 of cycle 1 and days 1 and 15 of cycle 2, and MTX IT, cytarabine IT, or ITT IT on days
 1 and 15 of cycle 1 (MTX on day 1 may be omitted if intrathecal therapy is given with relapse
 diagnostic LP < 7 days prior to the start of protocol therapy), MTX IT on days 1 and 15 of
 cycle 2, and leucovorin calcium IV or PO q6h for 2 doses on days 2 and 16.

 Patients with MRD < 0.01% are eligible to come off protocol therapy to receive Consolidation
 therapy at the end of Cycle 1, or may choose to proceed to Arm G, Cycle 2.

 After completion of study treatment, patients are followed up every 3 months for 1 year.
Inclusion Criteria:

 -  Patients must be >= 1 and < 31 years at time of enrollment

 -  Patients must have first relapse of CD19+ B-ALL (relapse blasts must express CD19) in
 one of the following categories:

 -  Isolated bone marrow relapse

 -  Isolated central nervous system (CNS) (excluding known optic nerve/retinal and
 CNS chloromas) and/or testicular relapse

 -  Combined bone marrow with extramedullary relapse in the CNS (excluding known
 optic nerve/retinal and CNS chloromas) and/or testes

 -  Patients with Down syndrome (DS) are eligible in the following categories:

 -  Isolated bone marrow relapse

 -  Combined bone marrow with CNS (excluding known optic nerve/retinal and CNS
 chloromas) and/or testicular relapse

 -  Patients must have a performance status corresponding to Eastern Cooperative Oncology
 Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and
 Lansky for patients =< 16 years of age

 -  Patients must have fully recovered from the acute toxic effects of all prior
 chemotherapy, immunotherapy, or radiotherapy prior to entering this study

 -  Patients with prior blinatumomab or CD19+ chimeric antigen receptor therapy in
 the upfront setting will be eligible, provided relapsed lymphoblasts retain CD19
 expression

 -  Radiation therapy (RT): >= 3 months must have elapsed if prior RT. This includes
 any patient requiring urgent radiation to any sites of extramedullary disease
 prior to enrollment (e.g. retinal/optic nerve involvement)

 -  Hematopoietic stem cell transplant (HSCT): Patients must not have had a prior
 hematopoietic stem cell transplant

 -  A single intrathecal chemotherapy at the time of relapse will be allowed. If < 7
 days have elapsed between this intrathecal therapy (IT) and the start of protocol
 therapy, then the day 1 intrathecal chemotherapy (i.e. methotrexate, cytarabine,
 or triple intrathecal) may be omitted

 -  In the 28 days prior to enrollment, up to five days of post-relapse,
 pre-enrollment therapy (steroid and/or hydroxyurea only) is permissible

 -  Group 1 and Down syndrome patients who received pre-enrollment therapy and
 have a white blood count (WBC) >= 30,000/ul at the time of enrollment must
 receive protocol specified cytoreductive therapy with vincristine and
 dexamethasone, and no "washout" is required

 -  Group 1 and Down syndrome patients who received pre-enrollment therapy and
 have a WBC < 30,000/ul at the time of enrollment must be given a 24 hour
 "washout" before starting immunotherapy

 -  Note: There is no waiting period or "washout" for patients who relapse while
 receiving upfront therapy

 -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
 mL/min/1.73 m^2 OR a serum creatinine based on age/gender as follows (within 5
 calendar days prior to enrollment):

 -  Age: Maximum serum creatinine (mg/dL)

 -  1 to < 2 years: 0.6 (male), 0.6 (female)

 -  2 to < 6 years: 0.8 (male), 0.8 (female)

 -  6 to < 10 years: 1 (male), 1 (female)

 -  10 to < 13 years: 1.2 (male), 1.2 (female)

 -  13 to < 16 years: 1.5 (male), 1.4 (female)

 -  >= 16 years: 1.7 (male), 1.4 (female)

 -  Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by
 echocardiogram, cardiac magnetic resonance imaging (MRI) or radionuclide angiogram

 -  No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if
 there is clinical indication for determination.

 -  All patients and/or their parents or legal guardians must sign a written informed
 consent

 -  All institutional, Food and Drug Administration (FDA), and National Cancer Institute
 (NCI) requirements for human studies must be met

 Exclusion Criteria:

 -  Patients with B-lymphoblastic lymphoma (B-LLy)

 -  Patients with Burkitt leukemia/lymphoma or mature B-cell leukemia

 -  Patients with Philadelphia chromosome positive (Ph+) B-ALL

 -  Patients with mixed phenotype acute leukemia (MPAL)

 -  Patients with known Charcot-Marie-Tooth disease

 -  Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL,
 regardless of blast immunophenotype

 -  Patients with active, uncontrolled infection defined as:

 -  Positive bacterial blood culture within 48 hours of study enrollment

 -  Receiving IV or PO antibiotics for an infection with continued signs or symptoms.
 Note: Patients may be receiving IV or oral antibiotics to complete a course of
 therapy for a prior documented infection as long as cultures have been negative
 for at least 48 hours and signs or symptoms of active infection have resolved.
 For patients with clostridium (C.) difficile diarrhea, at least 72 hours of
 antibacterial therapy must have elapsed and stools must have normalized to
 baseline.

 -  Fever above 38.2 degrees Celsius (C) within 48 hours of study enrollment with
 clinical signs of infection. Fever without clinical signs of infection that is
 attributed to tumor burden is allowed as long as blood cultures are negative for
 > 48 hours

 -  A positive fungal culture within 30 days of study enrollment or active therapy
 for presumed invasive fungal infection

 -  Active viral or protozoal infection requiring IV treatment

 -  Patients known to have one of the following concomitant genetic syndromes: Bloom
 syndrome, ataxia-telangiectasia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome
 or any other known bone marrow failure syndrome are not eligible. Of note, patients
 with known human immunodeficiency virus (HIV) infection on effective anti-retroviral
 therapy with undetectable viral load for at least the last 6 months prior to
 enrollment are eligible. Similarly, hepatitis B and hepatitis C positive patients who
 have been treated and have no viral detectable burden are also eligible

 -  Patients with significant central nervous system pathology that would preclude
 treatment with blinatumomab, including history of severe neurologic disorder or
 autoimmune disease with CNS involvement

 -  Note: Patients with a history of seizures that are well controlled on stable
 doses of anti-epileptic drugs are eligible Patients with a history of
 cerebrovascular ischemia/hemorrhage with residual deficits are not eligible.
 Patients with a history of cerebrovascular ischemia/hemorrhage remain eligible
 provided all neurologic deficits have resolved

 -  Patients with an active known/suspected autoimmune disease are not eligible. However,
 patients with type I diabetes mellitus, hypothyroidism only requiring hormone
 replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring
 systemic treatment, or conditions not expected to recur in the absence of an external
 trigger are permitted to enroll

 -  Group 1 and DS patients with known non-hematopoietic, non-CNS/testicular
 extramedullary disease (i.e., chloromatous disease) are not eligible

 -  Note: Group 2 and 3 patients with known non-hematopoietic, non-CNS/testicular
 extramedullary disease (i.e., chloromatous disease) are eligible provided that
 this is NOT the only site of relapsed disease

 -  Female patients of childbearing potential are not eligible unless a negative pregnancy
 test result has been obtained within 7 days prior to enrollment. Patients who are
 sexually active and of reproductive potential are not eligible unless they agree to
 use an effective contraceptive method for the duration of this study. Men with female
 partners of childbearing potential should use effective contraception during the
 duration of their treatment. The effect of blinatumomab on fertility has not been
 evaluated. Blinatumomab is not recommended for pregnant women or women of childbearing
 potential (WOCBP) not using contraception. Females of reproductive potential must use
 effective contraception during treatment and for at least 48 hours after the last dose
 of blinatumomab. Studies in animal models have shown that nivolumab can adversely
 impair pregnancy. Thus, nivolumab is expected to cause fetal harm during pregnancy.
 WOCBP receiving nivolumab must continue contraception for a period of at least 5
 months after the last dose of nivolumab. It is unknown whether nivolumab is present in
 breast milk, thus breastfeeding should be discontinued while a patient is receiving
 nivolumab. Men receiving nivolumab and who are sexually active with WOCBP must
 continue contraception for 7 months after the last dose of nivolumab

 -  Lactating females are not eligible unless they agree not to breastfeed their infants.
 It is unknown whether blinatumomab or its metabolites are excreted in human breast
 milk. Women are not permitted to breastfeed while receiving blinatumomab and for the
 last 48 hours after the last blinatumomab dose. Due to the potential for serious
 adverse reactions in the breastfed infant, women are not permitted to breastfeed
 during treatment and for 5 months after the last nivolumab dose