Stem cell transplant is an important therapeutic option for pediatric patients with relapsed or refractory leukemia. Although, full myeloablative transplants are widely used for patients with acute leukemia, myeloablative chemo-radiotherapy may not be feasible in some specific settings. These settings include 1) patients with pre-existing health issues and organ toxicities; 2) patients who have relapsed post-ablative transplant and need a second stem cell transplant; and 3) leukemia patients with advanced disease who have been heavily pre-treated. Clofarabine, a new purine nucleoside anti-metabolite, has the advantage of significant antileukemic activity in addition to its possible immuno-suppressive properties. In this study we plan to determine the maximum feasible dose (MFD) of Clofarabine in combination with total body irradiation that can achieve durable donor engraftment without causing excessive toxicity.

Standard non-myeloablative regimens use Fludarabine and low dose total body irradiation (TBI) as pioneered by the Seattle group. Fludarabine is mainly used for its immuno-suppressive properties and has limited anti-leukemic effects. Since, the non-myeloablative and RIC regimens do not include intensive chemotherapy; relapse rates can be higher in RIC regimens compared to full myeloablative regimens. One way to improve overall survival in non-myeloablative / RIC setting is to add more effective anti-leukemia agents to prevent post-transplant relapses, without increasing TRM. Clofarabine, a new purine nucleoside anti-metabolite, has the advantage of significant antileukemic activity in addition to its possible immuno-suppressive properties. Combining Clofarabine with low dose TBI as a non-myeloablative preparative regimen may improve overall outcomes of SCT in advanced hematological malignancies. Therefore, in this study we plan to determine the maximum feasible dose (MFD) of Clofarabine in combination with 2Gy TBI that can achieve durable donor engraftment without causing excessive toxicity. The MFD determined from this pilot will be used in the next phase to study the outcomes after using this combination for SCT in this very high risk population.

Inclusion Criteria

Since this is a Phase 1 study, any patient who is a candidate for a non-myeloablative SCT because he/she cannot tolerate the standard myeloablative preparative therapy is eligible for this trial. Briefly, the following groups of patients will be targeted and are eligible for this trial:

• Patients with presence of organ system dysfunction or severe systemic infections that significantly increase the risk of TRM with standard myeloablative regimens.
• History of previous myeloablative allogeneic or autologous transplantation.
• Heavily pre-treated leukemia patients, eg. Patients in CR after failure of ≥2 prior regimens.(eg. ALL CR ≥ 3).
• Combination of toxicities or co-morbidities that leads the investigator to feel that the child is at high risk (>50%) of TRM with standard ablative regimens.

The eligibility criteria listed below are interpreted literally and cannot be waived.

1. Age: Patients must be >1 and < 21 years of age at the of study entry.

2. Diagnosis

   1. Patients must have a diagnosis of ALL or AML.

      • ALL patients must be in clinical remission defined as BM morphology <5% blasts and CNS 1 status.
      • AML patients must be in M1 (<5% blasts) or M2 (<20% blasts) marrow status with CNS 1 status.

   2. Patient must have an ANC > 750/ul.

3. Donor Selection: Patient must have one of the appropriate donor types as described below:

   1. HLA identical sibling donor.
   2. Complete matched unrelated donor, (matched at A, B, C, DR B1 and DQ, B1 at the allelic level based on high resolution typing for Class I and II antigens, 10/10 match).
   3. 1 allelic mis-matched unrelated donor (antigen mis-matches are not allowed).

4. Stem Cell Source: The stem cell source from the donor must be one of the following:

   1. Bone Marrow or Peripheral blood stem cells (PBSC) from a matched related donor.
   2. PBSC from an unrelated donor. (Bone marrow is not acceptable for unrelated donors)

5. Performance Level: Karnofsky > 50% for patients > 10 years of age and Lansky > 50% for patients < 10 years of age.

6. Reproductive Function

   1. Female patients of childbearing potential must have a negative serum pregnancy test confirmed within 2 weeks prior to enrollment.
   2. Female patients with infants must agree not to breastfeed their infants while on this study.
   3. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study.

7. Renal and Hepatic Function: Patient must have adequate renal and hepatic functions as indicated by the following laboratory values:

   1. Patients must have a calculated creatinine clearance ≥ 70mL/min/m2 as calculated by the Schwartz formula for estimated glomerular filtration rate (GFR) where GFR (ml/min/1.73 m2) = k * Height (cm)/serum creatinine (mg/dl). K is a proportionality constant which varies with age and is a function of urinary creatinine excretion per unit of body size; 0.45 up to 12 months of age; 0.55 children and adolescent girls; and 0.70 adolescent boys.
   2. Total serum bilirubin < 2 mg/dL.
   3. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 5 × ULN.

8. Cardiac Function: Patient must have a shortening fraction (SF) > 25%. If the SF is <25%, patient must have an ejection fraction (EF) by MUGA of >30%. 3.3.9 Pulmonary Function Patient must have pulmonary function as defined below:

   1. DLCO >30%
   2. FVC/TLC >30%
   3. FEV1 > 30% of predicted
   4. Patient is not on continuous oxygen

   If patient is not old enough or unable to comply with pulmonary function tests, they must have a pulse ox >92% in room air and not be on continuous oxygen.

9. Patients with prior exposure to Clofarabine are eligible.

10. Informed Consent: Patients and/or their parents or legal guardians must be capable of understanding the investigational nature, potential risks and benefits of the study. All patients and/or their parents or legal guardians must sign a written informed consent. Age appropriate assent will be obtained per institutional guidelines. To allow non-English speaking patients to participate in this study, bilingual health services will be provided in the appropriate language when feasible.

11. Protocol Approval: All institutional, FDA, and OHRP requirements for human studies must be met.

Exclusion Criteria

Patients will be excluded if they meet any of the following criteria:

1. Infection

   1. Patients will be excluded if they have evidence of an active, progressive invasive infection. All patients with existing infections at the time study entry should be discussed with the study chair.

      • Patients may have stable invasive infections and still be eligible.
      • Patients with infections that are responsive to medical or surgical treatment as shown by radiographic and or microbial assessment may still be eligible.

   2. Patients will be excluded if they have an active, uncontrolled systemic fungal, bacterial, viral or other infection. All patients with existing infections at the time of study entry should be discussed with the study chair.

      • An active uncontrolled infection is defined as exhibiting ongoing signs and symptoms related to the infection (fevers, positive blood cultures, chills, tachycardia, etc) despite appropriate antibiotics or other treatment.

2. Patient has a diagnosis of CML or MDS.

3. Patient has CNS 2 or CNS 3 status.

4. Patient is HIV positive.

5. Current or planned treatment with chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.

6. Use of investigational agents within 30 days or any anticancer therapy within 2 weeks before study entry.

7. Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney (including dialysis patients), liver, or other organ system that may place the patient at undue risk to undergo treatment.

8. Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).

9. Any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, study participation, follow up, or interpretation of study results.