A Phase 3 Trial Investigating Blinatumomab in Combination with Chemotherapy in Patients with Newly Diagnosed Standard Risk or Down Syndrome B-Lymphoblastic Leukemia (B-ALL) and the Treatment of Patients with Localized B-Lymphoblastic Lymphoma (B-LLy).
1. To determine in a randomized manner if the addition of 2 cycles of blinatumomab to standard therapy improves disease-free survival (DFS) in patients with SR B-ALL and higher risk features(SR-High), and patients with standard-risk average (SR-Avg)B-ALL who are negative for minimal residual disease (MRD)by flow cytometry but have detectable or indeterminate MRD as measured by high-throughput sequencing (HTS)at end of Induction (EOI)
2. To confirm that boys in the standard-risk favorable (SR-Fav)subset of B-ALL, with or without DS, will maintain a 5-year DFS of greater than 93% when treated with a standard chemotherapy regimen with a treatment duration of 2 years from the start of Interim Maintenance I (IM1).
3. To describe the DFS for patients with SR-Avg B-ALL who are negative for MRD measured by flow cytometry and HTS at EOI when treated with standard chemotherapy with a treatment duration of 2 years from the start of IM1, regardless of sex.
4. To determine if patients with DS-High achieve a reduction of treatment-related mortality (TRM) after replacement of intensive elements of standard chemotherapy (omission of anthracyclines in Induction, omission of the second month of DI) with 3 cycles of blinatumomab.
5. To describe the DFS characterized by the replacement of intensive elements of standard chemotherapy with 3 cycles of blinatumomab in patients with DS-HighB-ALL.
6. To describe the DFS for patients with localized (Murphy Stage I and II) B-Lymphoblastic Lymphoma (B-LLy) receiving standard risk B-ALL therapy.
7. To compare the change in neurocognitive functioning, as measured by the CogState Cognitive Composite, from baseline to end-of-therapy among patients with ALL ages 4-<10 years at the time of diagnosis between children from poor families (defined as presence of household material hardship (HMH), including either food, housing or energy insecurity) and non-poor families (absence of HMH).
8. To describe the impact of blinatumomab on caregiver burden and patient/proxy-reported symptoms among a subset of children enrolled in the HMH and neurocognitive outcome study.
9. To define the prevalence of minimal marrow disease (MMD) in B-LLy and to correlate MMD at diagnosis with outcome in patients with B-LLy
Chemotherapy single agent systemic
- Rutgers Cancer Institute of New Jersey
- RWJBarnabas Health
- Newark Beth Israel Medical Center
- Saint Peters University Hospital
Inclusion Criteria
- All B-ALL patients must be enrolled on APEC14B1 and consented to Eligibility Screening
(Part A) prior to treatment and enrollment on AALL1731. APEC 14B1 is not a requirement
for B-LLy patients. B-LLy patients may directly enroll on AALL1731.
- Age at diagnosis:
- Patients must be >= 365 days and < 10 years of age (B-ALL patients without DS).
- Patients must be >= 365 days and =< 31 years of age (B-ALL patients with DS).
- Patients must be >= 365 days and =< 31 years of age (B-LLy patients with or
without DS).
- B-ALL patients without DS must have an initial white blood cell count < 50,000/uL
(performed within 7 days prior to enrollment).
- B-ALL patients with DS are eligible regardless of the presenting white blood cell
count (WBC) (performed within 7 days prior to enrollment).
- Patient has newly diagnosed B-cell ALL, with or without Down syndrome: > 25% blasts on
a bone marrow (BM) aspirate;
- OR if a BM aspirate is not obtained or is not diagnostic of B-ALL, the diagnosis
can be established by a pathologic diagnosis of B-ALL on a BM biopsy;
- OR a complete blood count (CBC) documenting the presence of at least 1,000/uL
circulating leukemic cells;
- OR patient has newly diagnosed B-cell LLy Murphy stages I or II, with or without
Down syndrome.
- Note: For B-LLy patients with tissue available for flow cytometry, the criterion
for diagnosis should be analogous to B-ALL. For tissue processed by other means
(i.e., paraffin blocks), the methodology and criteria for immunophenotypic
analysis to establish the diagnosis of B-LLy defined by the submitting
institution will be accepted (diagnostic biopsy for B-LLy must be performed
within 14 days prior to enrollment).
- 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
- Patient must not have secondary ALL that developed after treatment of a prior
malignancy with cytotoxic chemotherapy. Note: patients with Down syndrome with a prior
history of transient myeloproliferative disease (TMD) are not considered to have had a
prior malignancy. They would therefore be eligible whether or not the TMD was treated
with cytarabine.
- With the exception of steroid pretreatment or the administration of intrathecal
cytarabine, patients must not have received any prior cytotoxic chemotherapy for
either the current diagnosis of B ALL or B LLy or for any cancer diagnosed prior to
initiation of protocol therapy on AALL1731.
- For patients receiving steroid pretreatment, the following additional exclusion
criteria apply:
- Non-DS B-ALL patients must not have received steroids for more than 24 hours in
the 2 weeks prior to diagnosis without a CBC obtained within 3 days prior to
initiation of the steroids.
- DS and non-DS B-LLy patients must not have received > 48 hours of oral or IV
steroids within 4 weeks of diagnosis.
- Patients who have received > 72 hours of hydroxyurea within 1 week (7 days) prior to
the start of systemic protocol therapy.
- B-ALL patients who do not have sufficient diagnostic bone marrow submitted for
APEC14B1 diagnostic testing and who do not have a peripheral blood sample submitted
containing > 1,000/uL circulating leukemia cells.
- Patient must not have acute undifferentiated leukemia (AUL).
- Non-DS B-ALL patients with central nervous system [CNS]3 leukemia (CNS status must be
known prior to enrollment).
- Note: DS patients with CNS3 disease are eligible but will be assigned to the
DS-High B-ALL arm. CNS status must be determined based on a sample obtained prior
to administration of any systemic or intrathecal chemotherapy, except for steroid
pretreatment.
- Non-DS B-ALL patients with testicular leukemia. (Note: DS patients with testicular
disease are eligible but will be assigned to the DS-High B-ALL arm).
- For LLy patients, the following additional exclusion criteria apply:
- T-Lymphoblastic Lymphoma.
- Morphologically unclassifiable lymphoma.
- Absence of both B-cell and T-cell phenotype markers in a case submitted as
lymphoblastic lymphoma.
- CNS positive disease or testicular involvement.
- M2 (5% - 25% blasts) or M3 (> 25% blasts) marrow.
- Patients with known Charcot-Marie-Tooth disease.
- Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL,
regardless of blast immunophenotype.
- Patients requiring radiation at diagnosis.
- Female patients who are pregnant since fetal toxicities and teratogenic effects have
been noted for several of the study drugs. A pregnancy test is required for female
patients of childbearing potential.
- Lactating females who plan to breastfeed their infants.
- Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation.
Please note that we have obtained the inclusion and exclusion criteria information from the National Institutes of Health’s clinical trials web site ClinicalTrials.gov. The listed criteria may not necessarily reflect recent amendments to the protocol and the current criteria.
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