PRIMARY OBJECTIVES:
I. 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 standard risk (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).
II. To confirm that boys in the standard-risk favorable (SR-Fav) subset of B-ALL, with or
without Down syndrome (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).
SECONDARY OBJECTIVES:
I. 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.
II. To describe the DFS for patients with standard-risk favorable (SR-Fav) B-ALL when treated
with a standard chemotherapy regimen.
III. 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 delayed intensification [DI])
with 3 cycles of blinatumomab.
IV. To describe the DFS characterized by the replacement of intensive elements of standard
chemotherapy with 3 cycles of blinatumomab in patients with DS-High B ALL.
V. To describe the DFS for patients with localized (Murphy stage I and II) B lymphoblastic
lymphoma (B-LLy) receiving standard risk B-ALL therapy.
VI. 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).
VII. 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.
EXPLORATORY OBJECTIVES:
I. To explore adaptive and innate immune functions and host genetic factors associated with
severe infectious complications in children with DS B-ALL.
II. To explore the impact of acute lymphoblastic leukemia (ALL) and its therapy on
neurocognitive, functional, and quality of life outcomes in patients with DS and ALL, as
measured by caregiver (parent/legal guardian) questionnaires.
III. 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.
OUTLINE: All patients are assigned to, and complete an INDUCTION treatment regimen. Patients
are then assigned to a CONSOLIDATION treatment regimen. Finally, following CONSOLIDATION,
patients are either assigned or randomized to 1 of 7 arms.
NON-DS SR B-ALL INDUCTION: Patients receive cytarabine intrathecally (IT) on day 1,
vincristine intravenous (IV) push over 1 minute on days 1, 8, 15, and 22, dexamethasone
orally (PO) or IV twice daily (BID) on days 1-28, pegaspargase IV over 1-2 hours or
intramuscularly (IM) on day 4, and methotrexate IT on days 8 and 29. CNS2 patients also
receive cytarabine IT twice weekly except during weeks when days 8 and 29 methotrexate is
administered. Treatment continues for 35 days in the absence of disease progression or
unacceptable toxicity.
* After Non-DS SR B-ALL INDUCTION, SR-Fav and SR-Avg patients complete SR CONSOLIDATION,
while patients with SR-High complete high-risk (HR) CONSOLIDATION.
DS B-ALL INDUCTION: Patients receive cytarabine IT on day 1, vincristine IV push over 1
minute on days 1, 8, 15, and 22, pegaspargase IV over 1-2 hours or IM on day 4, methotrexate
IT on days 8 and 29, and leucovorin PO or IV every 6 hours for 2 doses on days 9 and 30.
Additionally, patients under 10 years of age receive dexamethasone PO or IV BID on days 1-28,
and patients 10 years of age or older receive prednisone or prednisolone PO or IV BID on days
1-28. CNS2 patients also receive cytarabine IT twice weekly except during weeks when days 8
and 29 IT methotrexate is administered. CNS3 patients also receive methotrexate IT on days 15
and 22, and leucovorin PO or IV every 6 hours for 2 doses on days 16 and 23. Treatment
continues for 35 days in the absence of disease progression or unacceptable toxicity.
* After DS B-ALL INDUCTION, patients without high risk features and MRD < 0.01 % complete SR
CONSOLIDATION. Patients without high risk features and MRD >= 0.01%, OR with high risk
features and any MRD complete HR CONSOLIDATION.
NON-DS B-LLy INDUCTION: Patients receive cytarabine IT on day 1 and twice weekly if CNS2,
vincristine IV push over 1 minute on days 1, 8, 15, and 22, dexamethasone PO or IV BID on
days 1-28, pegaspargase IV over 1-2 hours or IM on day 4, and methotrexate IT on days 8 and
29. Treatment continues for 35 days in the absence of disease progression or unacceptable
toxicity.
* After NON-DS B-LLy INDUCTION, all B-LLy patients then complete SR CONSOLIDATION.
DS B-LLY INDUCTION: Patients receive cytarabine IT on day 1, vincristine IV push over 1
minute on days 1, 8, 15, and 22, pegaspargase IV over 1-2 hours or IM on day 4, methotrexate
IT on days 8 and 29, and leucovorin PO or IV every 6 hours for 2 doses on days 9 and 30.
Additionally, patients under 10 years of age receive dexamethasone PO or IV BID on days 1-28,
and patients 10 years of age or older receive PO or IV prednisone or methylprednisolone on
days 1-28. Treatment continues for 35 days in the absence of disease progression or
unacceptable toxicity.
* After DS B-LLy INDUCTION, patients then complete SR CONSOLIDATION.
SR CONSOLIDATION: Patients receive vincristine IV push over 1 minute on day 1, mercaptopurine
PO on days 1-28, and methotrexate IT on days 1, 8, and 15. DS patients also receive
leucovorin PO or IV every 6 hours for 2 doses on days 2, 9, and 16. Treatment continues for
28 days in the absence of disease progression or unacceptable toxicity.
* After SR CONSOLIDATION, patients with MRD undetectable are assigned to ARM A, and patients
with MRD detectable/indeterminate/unavailable are randomized to ARM A or B. Patients with
SR-Fav and all B-LLy patients are assigned to treatments identical to that in ARM A.
HR CONSOLIDATION: Patients receive cyclophosphamide IV over 30-60 minutes on days 1 and 29,
cytarabine IV over 1-30 minutes or SC on days 1-4, 8-11, 29-32, and 36-39, vincristine IV
push over 1 minute on days 15, 22, 43, and 50, mercaptopurine PO on days 1-14 and 29-42,
methotrexate IT on days 1, 8, 15, and 22 , and pegaspargase IV over 1-2 hours or IM on days
15 and 43. DS patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2,
9, 16, and 23 (on days 2 and 9 only for DS CNS3 patients). Treatment continues for 56 days in
the absence of disease progression or unacceptable toxicity. Patients with continued clinical
evidence of DS or testicular leukemia (from diagnosis through the end of Induction) undergo
testicular radiation therapy over 12 fractions once daily (QD).
* After HR CONSOLIDATION, patients are randomized to ARM C or D. DS B-ALL patients with MRD <
1% are assigned to an arm including three blocks of blinatumomab.
ARM A:
- INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 11,
21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted)
on days 1, 11, 21, 31, and 41, and methotrexate IT on day 31. DS patients also receive
leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days
in the absence of disease progression or unacceptable toxicity.
- DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1 and 29, dexamethasone
PO BID or IV on days 1-7 and 15-21, vincristine IV push over 1 minute on days 1, 8, and
15, doxorubicin IV push/infusion over 1-15 minutes on days 1, 8, and 15, pegaspargase IV
over 1-2 hours or IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29,
thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or subcutaneously (SC)
on days 29-32 and 36-39. DS patients receive leucovorin PO or IV every 6 hours for 2
doses on days 2 and 30. Treatment continues for 56 days in the absence of disease
progression or unacceptable toxicity.
- INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on days 1,
11, 21, 31, and 41, methotrexate IV over 2-5 minutes undiluted or 10-15 minutes diluted
on days 1, 11, 21, 31, and 41, and methotrexate IT on days 1 and 31. DS patients receive
leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32. Treatment continues for
56 days in the absence of disease progression or unacceptable toxicity.
- MAINTENANCE: Non-DS patients receive methotrexate IT on day 1, vincristine IV push over
1 minute on day 1, dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and
methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. DS patients
receive vincristine IV push over 1 minute on day 1, methotrexate IT on day 1,
dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84, and methotrexate PO on
days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78, and leucovorin IV or PO on day 2 if
DS. Treatment repeats every 84 days until a total duration of therapy of 2 years from
start of INTERIM MAINTENANCE I is reached in the absence of disease progression or
unacceptable toxicity.
ARM B:
- BLINATUMOMAB BLOCK I: Patients receive dexamethasone IV or PO on day 1, methotrexate IT
on day 1, and blinatumomab IV continuously on days 1-28. DS patients also receive
leucovorin IV or PO every 6 hours for 2 doses on day 2. Treatment continues for 35 days
in the absence of disease progression or unacceptable toxicity.
- INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 11,
21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes (diluted)
on days 1, 11, 21, 31, and 41, and methotrexate IT on day 31. DS patients also receive
leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days
in the absence of disease progression or unacceptable toxicity.
- BLINATUMOMAB BLOCK II: Patients receive methotrexate IT on day 1, and blinatumomab IV
continuously on days 1-28. DS patients also receive leucovorin PO or IV every 6 hours
for 2 doses on day 2. Treatment continues for 35 days in the absence of disease
progression or unacceptable toxicity.
- DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1 and 29, dexamethasone
PO or IV on days 1-7 and 15-21, vincristine IV push over 1 minute on days 1, 8, and 15,
doxorubicin IV push/infusion over 1-15 minutes on days 1, 8, and 15, pegaspargase IV
over 1-2 hours or IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29,
thioguanine PO on days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32
and 36-39. DS patients receive leucovorin PO or IV every 6 hours for 2 doses on days 2
and 30. Treatment continues for 56 days in the absence of disease progression or
unacceptable toxicity.
- INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on days 1,
11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes
(diluted) on days 1, 11, 21, 31, and 41, and methotrexate IT on days 1 and 31. DS
patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32.
Treatment continues for 56 days in the absence of disease progression or unacceptable
toxicity.
- MAINTENANCE: Non-DS patients receive methotrexate IT on day 1 (omit on final 2 cycles),
vincristine IV push over 1 minute on day 1, dexamethasone PO on days 1-5, mercaptopurine
PO on days 1-84, and methotrexate PO on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71,
and 78 (omit day 1 on final 2 cycles). DS patients receive methotrexate IT on day 1
(omit on final 2 cycles), dexamethasone PO on days 1-5, mercaptopurine PO on days 1-84,
and methotrexate PO on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (omit day 1
except for final 2 cycles), for DS patients and leucovorin IV or PO every 6 hours for 2
doses on day 2 (omit on final 2 cycles). Treatment repeats every 84 days until a total
duration of therapy of 2 years from start of INTERIM MAINTENANCE I is reached in the
absence of disease progression or unacceptable toxicity.
ARM C:
- INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 15,
29, and 43, high dose methotrexate IV on days 1, 15, 29, and 43, mercaptopurine PO on
days 1-14, 15-28, 29-42, and 43-56, methotrexate IT on day 1 and 29, and leucovorin PO
or IV on days 3-4, 17-18, 31-32, and 45-46. Treatment continues for 56 days in the
absence of disease progression or unacceptable toxicity.
- DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1, dexamethasone PO BID
or IV on days 1-7 and 15-21, vincristine IV over 1 minute on days 1, 8, 15, 43, and 50,
doxorubicin IV over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or
IM on days 4 and 43, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on
days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. Treatment
continues for 56 days in the absence of disease progression or unacceptable toxicity.
- INTERIM MAINTENANCE II: Patients receive vincristine IV over 1 minute on days 1, 11, 21,
31, and 41, Capizzi style methotrexate IV over 2-5 minutes (undiluted) or over 10-15
minutes (diluted) on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and
pegaspargase IV over 1-2 hours or IM on days 2 and 22. Treatment continues for 56 days
in the absence of disease progression or unacceptable toxicity.
- MAINTENANCE: Patients receive vincristine IV over 1 minute on day 1, prednisone or
prednisolone or methylprednisolone PO or IV on days 1-5, mercaptopurine PO on days 1-84,
methotrexate IT on days 1 and 29 of cycles 1-2 and on day 1 of subsequent cycles,
methotrexate PO on days 8, 15, 22, 29 (for cycle 3 and later only), 36, 43, 50, 57, 64,
71, and 78. Treatment repeats every 84 days until a total duration of therapy of 2 years
from start of interim maintenance I is reached in the absence of disease progression or
unacceptable toxicity.
ARM D:
- BLINATUMOMAB BLOCK I: Patients receive dexamethasone PO or IV on day 1, methotrexate IT
on day 1, and blinatumomab IV continuously on days 1-28. Treatment continues for 35 days
in the absence of disease progression or unacceptable toxicity.
- INTERIM MAINTENANCE I: Patients receive vincristine IV over 1 minute on days 1, 15, 29,
and 43, high dose methotrexate IV on days 1, 15, 29, and 43, mercaptopurine PO on days
1-14, 15-28, 29-42, and 43-56, methotrexate IT on days 1 and 29, and leucovorin PO or IV
on days 3-4, 17-18, 31-32, and 45-46. Treatment continues for 56 days in the absence of
disease progression or unacceptable toxicity.
- BLINATUMOMAB BLOCK II: Patients receive blinatumomab IV on days 1-28 and methotrexate IT
on day 1. Treatment continues for 35 days in the absence of disease progression or
unacceptable toxicity.
- DELAYED INTENSIFICATION: Patients receive methotrexate IT on day 1, dexamethasone PO or
IV on days 1-7 and 15-21, vincristine IV over 1 minute on days 1, 8, 15, 43, and 50,
doxorubicin IV over 1-15 minutes on days 1, 8, and 15, pegaspargase IV over 1-2 hours or
IM on days 4 and 43, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on
days 29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. Treatment
continues for 56 days in the absence of disease progression or unacceptable toxicity.
- INTERIM MAINTENANCE II: Patients receive vincristine IV over 1 minute on days 1, 11, 21,
31, and 41, Capizzi style methotrexate IV over 2-5 minutes (undiluted) or over 10-15
minutes (diluted) on days 1, 11, 21, 31, and 41, methotrexate IT on days 1 and 31, and
pegaspargase IV over 1-2 hours or IM on days 2 and 22. Treatment continues for 56 days
in the absence of disease progression or unacceptable toxicity.
- MAINTENANCE: Patients receive methotrexate IT on day 1, vincristine IV over 1 minute on
day 1, prednisone, prednisolone or methylprednisolone PO or IV on days 1-5,
mercaptopurine PO on days 1-84, and methotrexate PO on days 8, 15, 22, 29, 36, 43, 50,
57, 64, 71, and 78. Treatment repeats every 84 days until a total duration of therapy of
2 years from start of interim maintenance I is reached in the absence of disease
progression or unacceptable toxicity.
DS-HIGH B-ALL:
- BLINATUMOMAB BLOCK I: Patients receive dexamethasone PO or IV on day 1, blinatumomab IV
continuously on days 1-28, methotrexate IT on day 1 (or on day 56 of Consolidation), and
leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment continues for 35 days
in the absence of disease progression or unacceptable toxicity.
- INTERIM MAINTENANCE: Patients receive vincristine IV push over 1 minute on days 1, 15,
29, and 43, intermediate dose methotrexate IV over 24 hours on days 1, 15, 29, and 43,
mercaptopurine PO on days 1-14, 15-28, 29-42, and 43-46, methotrexate IT on days 1 and
29, and leucovorin PO or IV every 6 hours for 2 doses on days 2-4, 16-18, 30-32, and
44-46. Treatment continues for 63 days in the absence of disease progression or
unacceptable toxicity.
- BLINATUMOMAB BLOCK II: Patients receive blinatumomab IV on days 1-28, methotrexate IT on
day 1, and leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment continues
for 35 days in the absence of disease progression or unacceptable toxicity.
- DELAYED INTENSIFICATION: Patients receive vincristine IV over 1 minute on days 1, 8, and
15, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, dexamethasone PO or IV on
days 1-7 and 15-21, methotrexate IT on day 1, leucovorin PO or IV every 6 hours for 2
doses on day 2, and pegaspargase IV over 1-2 hours or IM on day 4. Treatment continues
for 28 days in the absence of disease progression or unacceptable toxicity.
- BLINATUMOMAB BLOCK III: Patients receive blinatumomab IV on days 1-28, methotrexate IT
on day 1, and leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment
continues for 35 days in the absence of disease progression or unacceptable toxicity.
- MAINTENANCE: Patients receive vincristine IV push over 1 minute on day 1, prednisone,
prednisolone or methylprednisolone PO or IV BID on days 1-5, mercaptopurine PO on days
1-84, methotrexate IT on day 1, methotrexate PO on days 8, 15, 22, 29 (omit day 29 for
first 3 cycles for patients who do not receive cranial radiotherapy), 36, 43, 50, 57,
64, 71, and 78, and leucovorin PO on days 2 and 30 (day 30 dose is for cycles 1-3 and
for patients who do not receive cranial radiotherapy). CNS3 patients receive cranial
radiotherapy during first 4 weeks of cycle 1. Treatment repeats every 84 days until a
total duration of therapy of 2 years from start of interim maintenance I is reached in
the absence of disease progression or unacceptable toxicity.
All B-LLy patients:
- INTERIM MAINTENANCE I: Patients receive vincristine IV push over 1 minute on days 1, 11,
21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 (diluted) on days
1, 11, 21, 31, and 41, and methotrexate IT on day 31. DS patients also receive
leucovorin PO or IV every 6 hours for 2 doses on day 32. Treatment continues for 56 days
in the absence of disease progression or unacceptable toxicity.
- DELAYED INTENSIFICATION: Patients receive vincristine IV push over 1 minute on days 1, 8
and 15, doxorubicin IV over 1-15 minutes on days 1, 8, and 15, dexamethasone PO or IV on
days 1-7 and 15-21, methotrexate IT on days 1 and 29, pegaspargase IV over 1-2 hours or
IM on day 4, cyclophosphamide IV over 30-60 minutes on day 29, thioguanine PO on days
29-42, and cytarabine IV over 1-30 minutes or SC on days 29-32 and 36-39. DS patients
additionally receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 30.
Treatment continues for 56 days in the absence of disease progression or unacceptable
toxicity.
- INTERIM MAINTENANCE II: Patients receive vincristine IV push over 1 minute on days 1,
11, 21, 31, and 41, methotrexate IV over 2-5 minutes (undiluted) or 10-15 minutes
(diluted) on days 1, 11, 21, 31, and 41, and methotrexate IT on days 1 and 31. DS
patients also receive leucovorin PO or IV every 6 hours for 2 doses on days 2 and 32.
Treatment continues for 56 days in the absence of disease progression or unacceptable
toxicity.
- MAINTENANCE: Patients receive vincristine IV push over 1 minute on day 1, dexamethasone
PO on days 1-5, mercaptopurine PO on days 1-84, methotrexate IT on day 1, and
methotrexate PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. DS patients also
receive leucovorin PO or IV every 6 hours for 2 doses on day 2. Treatment repeats every
84 days until a total duration of therapy of 2 years from start of interim maintenance I
is reached in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 4 weeks until complete
blood count(CBC)/differential/platelet count recovery, then every 3 months for the first 2
years, then every 4-6 months for the 3rd year, and every 6-12 months for the 4th and 5th
years.
