Combination Chemotherapy With or Without Blinatumomab in Treating Patients With Newly Diagnosed BCR-ABL-Negative B Lineage Acute Lymphoblastic Leukemia

PRIMARY OBJECTIVES:

I. To compare the overall survival (OS) of blinatumomab in conjunction with chemotherapy to
chemotherapy alone in patients with BCR-ABL-negative B cell precursor acute lymphoblastic
leukemia (ALL) who are minimal residual disease (MRD) positive after induction and
intensification chemotherapy, based on multiparameter flow cytometric (MFC) assessment of
residual blasts.

SECONDARY OBJECTIVES:

I. To compare the relapse-free survival (RFS) of blinatumomab in conjunction with
chemotherapy to chemotherapy alone in MRD positive patients, MRD negative patients and
overall population after induction and intensification chemotherapy.

II. To compare the OS and RFS of those patients who are MRD+ at step 3 randomization/
registration and then convert to MRD- after 2 cycles of blinatumomab to those patients who
are MRD- at randomization and remain MRD- after 2 cycles of blinatumomab or consolidation
chemotherapy.

III. To assess the toxicities of blinatumomab in this patient population. IV. To assess the
toxicities of the modified E2993 chemotherapy regimen in this patient population.

V. To describe the outcome of patients who proceed to allogeneic blood or marrow transplant
after treatment with or without blinatumomab.

LABORATORY OBJECTIVES:

I. To determine differences in MRD kinetics among patients with the BCR/ABL1-like B-lineage
ALL, and assess the efficacy of blinatumomab in each molecular subgroup.

II. To evaluate the incidence of anti-blinatumomab antibody formation.

OUTLINE:

INDUCTION CHEMOTHERAPY: Patients receive cytarabine intrathecally (IT) on day 1; daunorubicin
hydrochloride intravenously (IV) over 10-15 minutes on days 1, 8, 15, and 22; vincristine
sulfate IV on days 1, 8, 15, and 22; dexamethasone orally (PO) daily on days 1-7 (and 15-21
for patients age < 55 years only); methotrexate IT on day 14; pegaspargase intramuscularly
(IM) or IV on day 18 (patients age =< 55 years); and CD20 positive patients may optionally
receive rituximab IV on day 8 and 15. Beginning on day 29, patients with absolute neutrophil
count (ANC) >= 0.75 x 10^9/L and platelets > 75 x 10^9/L (patients with delayed hematologic
recovery) (patients with residual disease that is delaying count begin treatment immediately)
receive cyclophosphamide IV over 30 minutes on days 1 and 29, cytarabine IV over 30 minutes
or subcutaneously (SC) on days 1-4, 8-11, 29-32, and 36-39, mercaptopurine PO on days 1-14,
29-42, pegaspargase IM or IV on day 15 (patients age < 55 years), patients receiving
treatment for central nervous system (CNS) 2 or 3 leukemia in course 1 receive methotrexate
IT on days 1, 8, 15, and 22, and CD20 positive patients may optionally receive rituximab IV
on days 8 and 15.

INTENSIFICATION THERAPY: Beginning 4 weeks after the completion of course 2 of induction
therapy, patients receive intensification therapy comprising high-dose methotrexate IV over 2
hours on days 1 and 8, and pegaspargase IM or IV on day 9.

Patients are then randomized to 1 of 2 treatment arms.

Patients randomized to the blinatumomab group receive blinatumomab IV continuously on days
1-28. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or
unacceptable toxicity. Patients may then undergo allogeneic stem cell transplant (SCT) or
proceed to consolidation therapy per investigator discretion.

CONSOLIDATION THERAPY: Beginning after the second course of blinatumomab (patients randomized
to the blinatumomab group) or after intensification therapy (patients not randomized to
blinatumomab), patients receive cytarabine IV over 30 minutes or SC on days 1-5, etoposide IV
over 1 hour on days 1-5, methotrexate IT on day 1, and pegaspargase IM or IV on day 5, and
CD20 positive patients may optionally receive rituximab IV on day 5. Beginning 4 weeks from
day 1 of course 1, patients receive cytarabine, etoposide, methotrexate, and CD20 positive
patients may receive rituximab as in course 1. Beginning 4 weeks from day 1 of course 2,
patients receive daunorubicin hydrochloride IV over 10-15 minutes on day 1, 8, 15, and 22;
vincristine sulfate IV on days 1, 8, 15, and 22; dexamethasone PO daily on days 1-7 (and
15-21 for patients age < 55 years); methotrexate IT on day 2; cyclophosphamide PO or IV over
30 minutes on day 29; cytarabine IV over 30 minutes or SC on days 30-33 and 37-40;
mercaptopurine PO on days 29-42 and CD20 positive patients may receive rituximab on day 8.
Beginning 8 weeks from day 1 of course 3, patients receive cytarabine, etoposide,
methotrexate, and CD20 positive patients may optionally receive rituximab as in course 1.
Patients randomized to blinatumomab repeat course 4 and then receive blinatumomab IV
continuously on days 1-28.

MAINTENANCE THERAPY: Within 12 weeks after beginning last course of consolidation therapy,
patients receive mercaptopurine PO daily, methotrexate PO or IV over 6 hours once weekly for
2.5 years, vincristine sulfate IV on day 1 every 3 months, prednisone PO on days 1-5 every 3
months, and methotrexate IT on day 1 every 3 months. Treatment continues for up to 2.5 years
in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 3 years, and then every 12 months for 5 years.

Inclusion Criteria:

- PRE-REGISTRATION

- Diagnostic bone marrow and peripheral blood specimens must be submitted for
immunophenotyping and selected molecular testing, and the establishment of BCR/ABL
status; testing will be performed by the Eastern Cooperative Oncology Group
(ECOG)-American College of Radiation Imaging Network (ACRIN) Leukemia Translational
Research Laboratory (LTRL) and reported to the institution

- NOTE: IT IS ESSENTIAL THAT A SAMPLE CONTAINING SUFFICIENT BLAST CELLS BE
SUBMITTED TO THE ECOG-ACRIN LTRL AT BASELINE SO THAT SUBSEQUENT BONE MARROW
ASSESSMENTS OF MRD CAN BE DONE; IN ADDITION TO ALLOWING THE LTRL TO CONFIRM
ELIGIBILITY BASED ON BLAST CELL IMMUNOPHENOTYPE AND BCR/ABL STATUS, IT IS ALSO
IMPERATIVE THAT AN ADEQUATE NUMBER OF BLASTS BE BANKED FOR ANALYSIS BY DRS
MULLIGHAN/WILLMAN. WITHOUT ADEQUATE BASELINE SAMPLES, PATIENTS WILL NOT BE ABLE
TO BE TREATED AND RANDOMIZED ON THIS PROTOCOL; IF A BONE MARROW ASPIRATE IS NOT
AVAILABLE FOR LTRL SUBMISSION AT BASELINE, IT IS IMPERATIVE THAT DR PAIETTA FROM
THE LTRL IS CALLED TO DISCUSS THE PERIPHERAL BLOOD WBC AND BLAST COUNT BEFORE
BLOOD ONLY IS SUBMITTED

- NOTE: Hydroxyurea can be given for up to 5 days prior to initiation of protocol
therapy for control of leukocyte count and/or other symptoms or signs;
corticosteroids can be given after pre-registration to the protocol and
submission of baseline marrow and blood samples for control of leukocyte count
and/or other symptoms or signs prior to initiation of protocol therapy if needed;
if corticosteroids are given prior to pre-registration, contact the study chair
as the patient may still be eligible to participate

- INDUCTION ELIGIBILITY CRITERIA-STEP 1

- New diagnosis of B lineage ALL must be made upon bone marrow or peripheral blood
immunophenotyping; cases with myeloid antigen expression, but unequivocal lymphoid
immunophenotype, are eligible

- Mature B ALL (Burkitt's-like leukemia) is excluded from enrollment in this trial;
pre-study bone marrow biopsy and aspirate must be completed =< 1 week prior to
registration

- Negativity for the Philadelphia chromosome must be established by conventional
cytogenetics, fluorescence in situ hybridization (FISH) and/or polymerase chain
reaction (PCR); patients who are negative for the Philadelphia chromosome by
conventional cytogenetics must have FISH or PCR performed for BCR/ABL to exclude
occult translocations

- Cytogenetic analysis must be performed from diagnostic bone marrow (preferred) or if
adequate number of circulating blasts from peripheral blood; FISH testing for common
B-lineage ALL abnormalities including t(9;22) (BCR/ABL1), t(12;21) (ETS-variant gene 6
[ETV6]/runt-related transcription factor 1 [RUNX1]), t(1;19) (pre-B-cell leukemia
homeobox 1 [PBX1]/transcription factor 3 [TCF3]), +4,+10,+17, (centromeric
[Cen]4/Cen10/Cen17), t(11q23;var), (myeloid/lymphoid or mixed lineage leukemia [MLL]),
deletion (del)(9p) (cyclin-dependent kinase inhibitor 2A [CDKN2A]/Cen9), and t(14;var)
(immunoglobulin heavy chain [IGH] is encouraged); if there are few or no circulating
blasts and an adequate marrow sample cannot be obtained for cytogenetic analysis, the
patient may still enroll on the trial

- Patient must not have a concurrent active malignancy for which they are receiving
treatment

- Serum direct bilirubin < 2 mg/dl or serum total bilirubin =< 3 (obtained =< 48 hours
prior to registration); NOTE: the above stipulation for normal hepatic function does
not apply if liver dysfunction is due to leukemia infiltration

- Serum creatinine < 2 mg/dl (obtained =< 48 hours prior to registration); NOTE: the
above stipulation for normal hepatic function does not apply if liver dysfunction is
due to leukemia infiltration

- Patient should be human leukocyte antigen (HLA) typed (A, B, C, DR and DQ) during
induction therapy phase or a written explanation for not undergoing HLA typing on the
flow sheet

- Patient must not have intercurrent organ damage or medical problems that will
jeopardize the outcome of therapy (i.e., psychiatric disorder, drug abuse, pregnancy)

- Patients with known human immunodeficiency virus (HIV) infection are eligible if they
meet all of the following criteria:

- No history of acquired immune deficiency syndrome (AIDS)-related complications
other than a history of low CD4+ T-cell count (< 200/mm^3) prior to initiation of
combination antiretroviral therapy; on study CD4+ T-cell count may not be
informative due to leukemia and should not be used as an exclusion criterion if
low

- Patient must be healthy on the basis of HIV disease with high likelihood of near
normal life span were it not for the leukemia

- Patient must have serum HIV viral load of < 200 copies/mm^3

- Patient must be on combination antiretroviral therapy with minimal
pharmacokinetic interactions with study therapy and minimal overlapping clinical
toxicity with protocol therapy

- Patient must not be receiving protease inhibitors or once daily formulations
containing cobicistat, stavudine, or on regimens containing stavudine or
zidovudine

- It is recommended to utilize a regimen of the integrase inhibitor, dolutegravir,
combined with either disoproxil fumarate/emtricitabine or dolutegravir combined
with tenofovir alafenamide/emtricitabine

- Patient must not have an antecedent hematologic disorder

- Patient must have no history of recent myocardial infarction (within three months),
uncontrolled congestive heart failure, or uncontrolled cardiac arrhythmia

- Patient must not have a history or presence of clinically relevant central nervous
system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe
brain injuries, dementia; Parkinson's disease, cerebellar disease, organic brain
syndrome, psychosis, or other significant CNS abnormalities

- Patient must have a normal cardiac ejection fraction by pretreatment multigated
acquisition scan (MUGA) or echocardiogram within 4 weeks prior to registration
(resting ejection fraction >= 40% or >= 5% increase with exercise), shortening
fraction by echocardiogram >= 24%, or to within the normal range of values for the
institution

- Patient must not have an active uncontrolled infection

- Women must not be pregnant or breast-feeding and must not become pregnant or
breastfeed during protocol therapy and for at least 3 months after protocol therapy;
woman of childbearing potential must abstain from sexual activity or be willing to use
2 highly effective forms of contraception throughout protocol therapy and for at least
an additional 3 months after the last dose of protocol-specified therapy; all females
of childbearing potential must have a blood test or urine study within 2 weeks prior
to registration to rule out pregnancy; a female of childbearing potential is any
woman, regardless of sexual orientation or whether they have undergone tubal ligation,
who meets the following criteria: has not undergone a hysterectomy or bilateral
oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive
months (i.e., has had menses at any time in the preceding 24 consecutive months)

- Men who have a female partner of childbearing potential must be willing to use 2
highly effective forms of contraception throughout protocol therapy and for at least
an additional 3 months after the last dose of protocol-specified therapy; men who have
a pregnant partner must be willing to use a condom during sexual activity throughout
protocol therapy and for 3 months after the last dose of protocol-specified therapy

- ECOG performance score 0-3

- Patient must have given written informed consent

- POST-INDUCTION THERAPY ELIGIBILITY CRITERIA (PRIOR TO INTENSIFICATION-STEP 2)

- ECOG performance status 0-2

- Patients must have achieved a CR or CRi

- Patients who have achieved a CR or CRi must have maintained peripheral blood evidence
of a CR or CRi

- Patient must be CNS (cerebrospinal fluid [CSF]) negative for leukemia

- Patients must have resolved any serious infectious complications related to induction

- Any significant medical complications related to induction must have resolved

- Serum creatinine =< 2.0 mg/dl (obtained =< 48 hours prior to registration)

- Serum direct bilirubin < 2 mg/dL or serum total bilirubin =< 3 (obtained =< 48 hours
prior to registration)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit
of normal (ULN) (obtained =< 48 hours prior to registration)

- RANDOMIZATION TO BLINATUMOMAB OR NO BLINATUMOMAB-STEP 3

- Patients must have an ECOG performance status of 0-2

- Patients must have maintained peripheral blood evidence of a remission and must have a
CR or CRi, confirmed on restaging bone marrow (BM) aspirate and biopsy

- Patients must have resolved any serious infectious complications related to therapy

- Any significant medical complications related to therapy must have resolved

- Direct or total bilirubin < 1.5 x ULN (unless related to Gilbert's or Meulengracht's
syndrome); the values must be obtained within 48 hours prior to randomization

- Serum creatinine < 1.5 x ULN; the values must be obtained within 48 hours prior to
randomization

- Bone marrow aspirates must be submitted for centralized minimal residual disease (MRD)
assessment performed by the ECOG-ACRIN Leukemia Translational Research Laboratory

- MRD results will be reported to the submitting institution

- NOTE: FOR MRD ASSESSMENTS, AN ASPIRATE FROM A SEPARATE BONE MARROW ASPIRATION
SITE MUST BE SUBMITTED (THE NEEDLE CAN BE RE-DIRECTED THROUGH THE SAME SKIN
PUNCTURE SITE); ONLY SUBMIT ASPIRATES FROM THE FIRST PULL OF AN ASPIRATION SITE
FOR MRD TESTING; DO NOT SUBMIT SAMPLES FROM THE SECOND OR THIRD PULL OF THE SAME
ASPIRATION SITE

- In B-lineage ALL, MRD levels in peripheral blood or from a dilute marrow
aspiration can be 300% lower, on average, than those in bone marrow at a given
time point; submitting a first pull from a separate aspiration site will ensure
that MRD determinations used in randomization and trial interpretation are
accurate

- NOTE: failure to submit bone marrow aspirates will result in a major
violation at the time of an audit

- CRITERIA FOR ALLOGENEIC TRANSPLANTATION

- A suitable donor must be identified; there are no restrictions on donor type and can
include a matched sibling, a matched or mismatched unrelated donor, a family haplotype
matched donor or a cord blood donor (single or double)

- Patients should meet the eligibility criteria for RANDOMIZATION TO BLINATUMOMAB OR NO
BLINATUMOMAB-STEP 3

- Patients must be considered reliable enough to comply with the medication regimen and
follow-up, and have social support necessary to allow this compliance

- CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Patients must have an ECOG performance status
of 0-3

- CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Patients must have maintained peripheral
blood evidence of a remission and must have a CR or CRi, confirmed on restaging BM
aspirate and biopsy

- CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Patients must have resolved any serious
infectious complications related to therapy

- CRITERIA FOR MAINTENANCE THERAPY-STEP 4: Any significant medical complications related
to therapy must have resolved