Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma

Primary objective

- To estimate the 3-year survival rate of participants with first relapse or primary
refractory precursor B-cell ALL and lymphoblastic lymphoma treated with risk-directed
therapy.

Secondary objectives

- To determine minimal residual disease (MRD) levels at the end of remission induction
therapy for participants with relapsed precursor B-cell ALL and compare the results with
those in protocol ALLR17

- To estimate levels of CD20 expression at baseline, during treatment with
dexamethasone-containing chemotherapy and following rituximab treatment in Block 1 of
remission induction therapy for relapsed precursor B-cell ALL.

STUDY DESCRIPTION:

The general treatment plan will consist of chemotherapy for standard-risk participants and
chemotherapy followed by HSCT for high risk participants in first relapse of B-precursor ALL
or lymphoblastic lymphoma. Remission induction for all participants consists of three blocks
of therapy, wherein the first block is a novel immunotherapy regimen that includes cytotoxic
chemotherapy, rituximab and infusion of haploidentical natural killer (NK) cells.
Standard-risk patients will continue to receive chemotherapy for a total duration of
approximately 2 years. High-risk patients will be candidates for HSCT and will proceed to
transplant once a suitable donor is found and the patient achieves negative MRD.

Participants will be assigned to the standard arm if they experience late relapse (> or = 6
months after completion of frontline therapy) AND maximum residual disease (MRD) is <0.01% at
the end of Block II or remission induction therapy. Provisional standard risk participants
(i.e., late relapse) will be re-assigned to high risk if MRD is > or = 0.01% at the end of
Block II. participants with lymphoma must be in complete remission at the end of Block III.

High risk participants will meet one of the following criteria:

- Early relapse (on therapy or <6 months after completion of frontline therapy), OR

- Any relapse after hematopoietic stem cell transplant, OR

- MRD > or = 0.01% at the end of Block II of remission induction therapy, OR

- Re-emergence of MRD at any time after attaining negative MRD on this clinical trial.

Natural killer (NK) cell collection: Donors who meet eligibility criteria will undergo
apheresis once. The cells obtained will be purified for CD56+ cells utilizing the CliniMACS
selection system. The NK cell product will undergo quality control testing following standard
operating procedures of the St. Jude Human Applications Laboratory.

OUTLINE (STANDARD RISK):

REMISSION INDUCTION:

BLOCK I: Patients receive dexamethasone orally (PO) or intravenously (IV) thrice daily (TID)
on days 1-8 and 21-28; vincristine sulfate IV on days 1, 21, 28, and 35; rituximab IV on days
4, 13, 20, and 27; clofarabine, cyclophosphamide, and etoposide IV on days 6-10; aldesleukin
subcutaneously (SC) once every other day (QOD) on days 11-19; and pegaspargase IV on days 21,
28, and 35. Patients also undergo natural killer (NK) cell infusion on day 12. Patients may
receive triple intrathecal therapy comprising methotrexate, therapeutic hydrocortisone, and
cytarabine on days 1, 5, 8, 11, 21, and 28. Patients continue on to Block II after count
recovery.

BLOCK II: Patients receive methotrexate IV over 24 hours on days 1 and 8 and mercaptopurine
PO on days 1-21. Patients also receive triple intrathecal therapy on day 1. High-risk
patients with negative MRD continue on to transplantation. All patients with positive MRD
continue on to Block III after count recovery.

BLOCK III: Patients receive cytarabine IV over 2 hours twice daily (BID) on days 1-4 and
mitoxantrone hydrochloride IV over 1 hour on days 3-5. Patients also receive triple
intrathecal therapy on day 7.

INTERIM CONTINUATION (for patients unable to tolerate dose intensive chemotherapy): Patients
receive etoposide and cyclophosphamide IV on day 1, methotrexate IV on day 8, mercaptopurine
PO on days 8-14, teniposide and cytarabine IV on day 15, dexamethasone PO TID on days 22-26,
and vinblastine IV on day 22.

RE-INDUCTION THERAPY: Patients receive clofarabine, cyclophosphamide, and etoposide IV on
days 1-5; dexamethasone PO on days 1-6; and pegaspargase and vincristine sulfate IV on days
6, 13, and 20.Patients may also receive triple intrathecal therapy on days 1 and 15. Patients
continue on to continuation treatment after count recovery.

CONTINUATION TREATMENT: Patients receive methotrexate IV over 2 hours on day 1 and
mercaptopurine PO on days 1-7 of weeks 1, 2, 5, and 6; teniposide and cytarabine IV on day 1
of weeks 3 and 7; vincristine sulfate IV on day 1 of week 4; dexamethasone PO TID on days 1-5
of weeks 4 and 8; and vinblastine IV on day 1 of week 8. Treatment repeats every 8 weeks for
up to 10 courses in the absence of disease progression or unacceptable toxicity. Patients may
also receive triple intrathecal therapy on day 1 of week 1 of all courses and day 1 of week 5
of courses 6-10.

OUTLINE: GROUP 2 (high risk defined as participants not meeting the standard risk criteria
noted above):

Patients receive Remission Induction (Blocks I, II, and III) treatment as described above for
Group 1. Patients then undergo allogeneic hematopoietic stem cell transplantation (HSCT) as
soon as they have negative MRD. Patients with negative MRD may continue chemotherapy until a
suitable donor is found.

After completion of study treatment, patients are followed up every 4 months for 1 year,
every 6 months for 1 year, and then yearly for up to 10 years.

INCLUSION CRITERIA:

- Must have relapsed or refractory precursor B-cell acute lymphoblastic leukemia or
acute lymphoblastic lymphoma.

- Participants with leukemia must meet one of the following:

1. In first hematologic relapse, defined as the reappearance (in a patient who has
previously achieved remission) of leukemia blasts in the bone marrow or
peripheral blood, OR

2. Refractory to one or two courses of frontline induction therapy (≥ 5% blasts in
the bone marrow or peripheral blood confirmed by flow cytometric analysis).

- Participant with lymphoma must meet one of the following:

1. In first relapse, OR

2. Refractory to one or two courses of frontline induction therapy with measurable
disease

- Should flow cytometric analyses suggest relapse (by the reappearance of a
similar immunophenotype to the original leukemia) in the presence of <5%
blasts morphologically, a repeat bone marrow test is recommended to confirm
relapse.

- Molecular or genetic relapse is characterized by the reappearance of a
cytogenetic or molecular abnormality.

- Early relapse is defined as relapse on therapy or < 6 months after
completion of frontline therapy. Late relapse is defined as relapse
occurring ≥ 6 months after completion of frontline therapy.

- Participant's age is < 22 years at time of enrollment (e.g. participant is eligible
until 22nd birthday).

- Prior therapy:

1. There is no waiting period for participants who relapse while receiving frontline
therapy and are free from side effects attributable to such therapy.

2. Emergent radiation therapy, one dose of intrathecal chemotherapy, and up to 7
days of steroids for treatment of relapse are permitted before start of treatment
in participants who relapse after completion of frontline therapy.

3. At least 90 days have elapsed since bone marrow transplant and participant is off
immune suppression for a minimum of 2 weeks, if applicable. Participants with ALL
or NHL who were transplanted in first remission are eligible for this study.

Organ function requirements

- Hepatic: Total bilirubin ≤ upper limit of normal (ULN) for age, or if total bilirubin
is > ULN, direct bilirubin < 1.4 mg/dl

- Cardiac: Shortening fraction > 28%

- Renal: Glomerular filtration rate >50cc/min/1.73 m^2, OR maximum serum creatinine (SC)
based on age as follows:

- If age is 1 to 2 years, then maximum SC is 0.6 mg/dL

- If age is 2 to 6 years, then maximum SC is 0.8 mg/dL

- If age is 6 to 10 years, then maximum SC is 1 mg/dL

- If age is 10 to <13 years, then maximum SC is 1 mg/dL

- If age is 13 to 16 years, then maximum SC is 1.5 mg/dL for males and 1.4 mg/dL
for females

- If age is >16 years, then maximum SC is 1.7 mg/dL for males and 1.4 mg/dL for
females

EXCLUSION CRITERIA:

- Leukemia participants ages 1 to 5 years with induction failure AND favorable
cytogenetics (i.e., hyperdiploidy defined as DNA index ≥1.16 or modal chromosome
number ≥51, or ETV6-RUNXI).

- Hepatitis B or HIV infection.

- Pregnant or breast-feeding

- Inability or unwillingness or research participant or legal guardian/representative to
give written informed consent.

INCLUSION CRITERIA FOR NK CELL DONORS:

- Donor is at least 18 years of age.

- Donor is a family member.