Trial Information

A Study of Therapy for Pediatric Relapsed or Refractory Acute Lymphoblastic Leukemia

In this study, subjects will be divided into high-risk and standard-risk subgroups according
to the length of their first remission, the type of early cancer cell (T or B-cell) and the
site or sites of disease relapse. The remission induction phase (the beginning phase of
therapy) will consist of three blocks of therapy. Block A features daily IV low-dose
etoposide in combination with cytarabine given by continuous IV, weekly vincristine, and
daily dexamethasone. In block B, a combination of weekly PEG-asparaginase, vincristine, and
daily dexamethasone will be given. Block C will be a combination of high-dose methotrexate,
high-dose cytarabine, and teniposide.

There will be two phases of consolidation (treatment phase after induction therapy).
Additional therapy will be given between the two consolidation phases. Continuation will
consist of eight weekly cycles of chemotherapy. Periodic intrathecal therapy (medicine given
into the spinal fluid) will be given throughout the treatment. Participants who do not
achieve remission (absence of leukemia) after consolidation will be offered enrollment on
St. Jude NKEHM protocol (NK cell transplant). Hematopoietic stem cell transplant (HSCT) is
planned for participants with high risk disease. HSCT will be done according to current
institutional practice. The duration of chemotherapy will be one year for patients with
extramedullary (outside the bone marrow) relapse and two years for all others.

Exploratory objectives include:

- To determine the prevalence of MRD in children undergoing treatment for relapsed ALL
and to compare the results to those obtained in children with newly diagnosed ALL.

- To compare the level of MRD in bone marrow and peripheral blood concomitantly in
children undergoing treatment for relapsed ALL.

- To characterize the gene expression profile of leukemia cells at the time of diagnosis
and relapse to improve our understanding of mechanisms of relapse and of the
development of drug resistance.

- To study whether pre-existing or emerging development of serum antibodies to
asparaginase is related to hypersensitivity reaction to asparaginase in patient with
relapsed ALL.

Detailed Description of Treatment Plan:

All patients will receive the same remission induction. All high-risk patients will be
offered HSCT which will be performed after a suitable donor is identified and preferably
after MRD becomes negative. If they do not have a donor or they refuse HSCT, they will
continue to receive chemotherapy. Standard-risk patients continue chemotherapy if MRD is
negative after induction, but will be offered HSCT if MRD is >0.01% after Block C of
Induction. Those who do not achieve morphological CR after induction will be treated
according to the contingency plan.

Block A (14 days)

Dexamethasone 5 mg/m2/day, days 1-14

Vincristine 1.5 mg/m2 (max 2 mg), days 1 and 8

Etoposide 25 mg/m2, days 1-14

Cytarabine 25 mg/m2, days 1-14

All patients will proceed to Block B if the clinical condition permits.

CNS prophylaxis (IT MHA)

CNS-1: At the time of relapse and day 14.

CNS-2 and 3: At the time of relapse, day 8 and 14.

Leucovorin: 5 mg/m2 (5 mg max dose) PO, 24 and 30 hours after each IT MHA.

Block B (15 days)

All patients will proceed to Block B immediately after Block A if they are clinically well.

Dexamethasone 6 mg/m2, Days 1-14

Vincristine 1.5 mg/m2, days 1 and 8

PEG-Asparaginase 2500 units/m2, days 1, 8 and 15

CNS prophylaxis (IT MHA): CNS-2 or 3 only, if necessary.

- CNS-1: no IT MHA

- CNS-2 and 3: day 8 (minimum 4 doses and maximum 8 doses during induction)

Leucovorin: 5 mg/m2 (5 mg max) PO 24 and 30 hours after each IT MHA

Block C (1 day)

All patients who received Block B will proceed to Block C when WBC >1,000/microL, ANC
>300/microL and platelets >50,000 microL after recovery from Block B.

Methotrexate 8 gm/m2, day 1

Cytarabine 1 g/m2 at least 24 h after ITHMA, day 1

Teniposide 165 mg/m2, day 1

CNS prophylaxis (IT MHA):

- CNS-1: at the time of BMA after Block C

- CNS-2 and 3: day 1 and 8 (These two doses of IT MHA may be omitted if the patient had
negative CSF for blasts in the 3 preceding CSF exam) and at the time of BMA after Block
C (regardless of the previous CSF status).

Leucovorin: 5 mg/m2 (5 mg maximum dose) PO 24 and 30 hours after each IT MHA

Consolidation I

This is a 4-week phase. It will be started if WBC >1000/microL, ANC >500/microL and
platelets >50,000 /microL

Week 1: Dex day 1, 2, 3, PEG, VCR, Mito day 4

Week 2: Dex day 1, 2, 3, PEG, VCR, day 4

Week 3: Dex day 1, 2, 3, PEG, VCR, Mito day 4

Week 4: Dex day 1, 2, 3, PEG, VCR, day 4

Dexamethasone 8 mg/m2/day, day 1-3

PEG-Asparaginase 2500 units/m2 IM, day 4 each week

Vincristine 2 mg/m2 (max 2 mg), day 4 each week

Mitoxantrone 12 mg/m2, day 4 week 1 and 3

Interim Continuation

Week 1*†:

etoposide 300 mg/m2 IV, 1 dose on day 1

Cyclophosphamide 300 mg/m2 IV, 1 dose on day 1

Week 2*:

Methotrexate 40 mg/m2 IV, 1 dose on day 1

6-mercaptopurine# 75 mg/m2 PO, Days 1 to 7

Week 3*:

teniposide 150 mg/m2 IV, 1 dose on day 1

Cytarabine 300 mg/m2 IV, 1 dose on day 1

Week 4*:

Dexamethasone§ 12 mg/m2/day PO, TID Days 1 to 5

Vinblastine 6 mg/m2 IV (max 10 mg), 1 dose on day 1

Consolidation II

Week 1*†:

etoposide 300 mg/m2 IV, 1 dose on day 1

Cyclophosphamide 300 mg/m2 IV, 1 dose on day 1

Week 2*:

Methotrexate 40 mg/m2 IV, 1 dose on day 1

6-mercaptopurine# 75 mg/m2 PO, Days 1 to 7

Week 3*:

teniposide 150 mg/m2 IV, 1 dose on day 1

Cytarabine 300 mg/m2 IV, 1 dose on day 1

Week 4*:

Dexamethasone§ 12 mg/m2/day PO, TID, Days 1 to 5

Vinblastine 6 mg/m2 IV (max 10 mg), 1 dose on day 1

Continuation

Week 1*†¶:

etoposide 300 mg/m2 IV, 1 dose on day 1

Cyclophosphamide 300 mg/m2 IV, 1 dose on day 1

Week 2*:

Methotrexate 40 mg/m2 IV, 1 dose on day 1

6-mercaptopurine# 75 mg/m2 PO, QHS, Days 1 to 7

Week 3*:

teniposide 150 mg/m2 IV, 1 dose on day 1

Cytarabine 300 mg/m2 IV, 1 dose on day 1

Week 4:

Dexamethasone§ 12 mg/m2/day PO, TID, Days 1 to 5

Vincristine§ 2 mg/m2 IV(maximum 2mg), 1 dose on day 1

Week 5*‡:

etoposide 300 mg/m2 IV, 1 dose on day 1

Cyclophosphamide 300 mg/m2 IV, 1 dose on day 1

Week 6*:

Methotrexate 40 mg/m2 IV, 1 dose on day 1

6-mercaptopurine# 75 mg/m2 PO, QHS, Days 1 to 7

Week 7*:

teniposide 150 mg/m2 IV, 1 dose on day 1

Cytarabine 300 mg/m2 IV, 1 dose on day 1

Week 8*:

Dexamethasone§ 12 mg/m2/day PO, TID, Days 1 to 5

Vinblastine 6 mg/m2 IV(max 10 mg), 1 dose on day 1

Plan for Stem Cell Transplant

Patients who have positive MRD (high-risk or standard-risk) at the end of induction or all
high-risk patients regardless of MRD are eligible for HSCT

- All high-risk patients are eligible for HSCT. HSCT will be performed as soon as MRD
becomes negative after induction. If MRD becomes negative (<0.01%) and a donor has not
been found, the patient will continue chemotherapy phases (Consolidation I, Interim
Continuation, etc) until a suitable donor is found.

- Those who have persistent positive MRD (>0.01%) after Block C are also eligible for
HSCT

All standard-risk patients will continue chemotherapy if MRD is negative (<0.01%) after
induction.

- If MRD is positive (>0.01%) after Block C of induction, they become eligible for HSCT.

- Standard-risk patients who have no response or progressive disease after Block A and
who have positive MRD (>0.01%) after Block B will be candidates for HSCT. They will be
re-evaluated after Block C. If MRD after Block C is positive, follow the plan above.
If MRD is negative after Block C, the management will be discussed with Transplant
Service

Contingency Plan

Patients who do not achieve morphological CR (M1 marrow) after Induction

If CR (M1 marrow) is not achieved after Induction, patients will proceed to Consolidation I.
If they do not achieve CR after Consolidation I, they will be offered enrollment on the St.
Jude NKHEM protocol or offered alternative therapy. If they do not achieve CR after NKHEM,
they will come off treatment.

Patients who achieve CR but have positive MRD (>0.01%) after Block C of induction: Become
eligible for HSCT. Up to two more courses of chemotherapy (course 1 and 2) will be given to
attempt reducing MRD. They will receive HSCT as soon as MRD becomes negative (MRD may be
repeated every 2-4 weeks as indicated).

Standard-risk patients who have positive MRD (>0.01%) after Block B will proceed to Block C.
Patients in this category will become candidates for HSCT, but if MRD becomes negative
after Block C, the management will be discussed with Transplant Service. Chemotherapy may
be administered to reduce MRD prior to HSCT. Patients will be transplanted as soon as the
MRD becomes negative.

Patients (high-risk or standard-risk) who achieved CR, but have positive MRD (>0.01%) after
Block C of Induction will become eligible for HSCT. Up to two more courses of chemotherapy
(course 1 and 2) will be given to attempt reducing MRD. They will receive HSCT as soon as
MRD becomes negative. If MRD remains positive after course 2, then, they will proceed to
HSCT after discussion with Transplant Service.

Course 1

Give chemotherapy according to the plan for Consolidation I. Start it immediately
regardless of CBC. BMA will be performed when WBC >1000/microL, ANC >300/microL and
platelets >50,000/microL. If MRD is negative, they will receive HSCT.

Course 2

This course will be given if MRD is positive after Course 1. Patients will be offered
enrollment on St. Jude NKHEM protocol.

If they are still MRD positive after Course 2, patients may receive Interim Continuation,
Consolidation II, and then Continuation until MRD becomes negative or while awaiting HSCT.