Haploidentical Hematopoietic Stem Cell Transplantation Using A Novel Clofarabine Containing Conditioning Regimen For Patients With Refractory Hematologic Malignancies

The primary objective of this trial is to determine the maximum tolerated dose of
clofarabine in combination with thiotepa and melphalan as a conditioning regimen for a
haploidentical stem cell transplant with an engineered graft depleted of CD3+ cells. Study
participants will children and young adults with refractory hematologic malignancies.

Secondary objectives include the following:

- To describe the one-year overall survival (OS) and event-free survival (EFS) rates in
these study participants.

- To determine the time to hematopoietic recovery and donor cell engraftment following
this study treatment.

- To estimate the cumulative incidence of relapse in study participants.

- To estimate the incidence of overall grade II-IV and grade III-IV acute GVHD and the
rate of chronic GVHD.

- To estimate the incidence and describe the causes of non-hematologic regimen-related
toxicity and regimen-related mortality in the first 100 days post HSCT.

- To explore the biologic significance of soluble interleukin-2 (IL-2) receptor, tumor
necrosis factor (TNF), and lymphocyte reconstitution (qualitative and quantitative, V
beta spectratyping, TREC

Inclusion Criteria:

- Age less than or equal to 21 years old; may be greater than 21 years old if a
previously treated St. Jude patient and within 3 years of completion of most recent
prior disease specific therapy.

- One of the following refractory hematologic malignancies (chemoresistant relapse or
primary induction failure) or diagnoses:

- ALL

- AML (>25% blasts in the bone marrow)

- secondary AML/MDS

- CML in accelerated phase or blast crisis

- juvenile myelomonocytic leukemia (JMML)

- myelodysplastic syndrome (MDS)

- Hodgkin or non-Hodgkin lymphoma (NHL) with residual or recurrent disease following
autologous HSCT, who are unable to undergo autologous HSCT due to chemo-resistant
disease or inability to have an acceptable quantity of tumor-free stem cells
collected (> 1 x 108 TNC/kg marrow or > 1 x 106 CD34+/kg PBS

- patients with a hematologic malignancy who have undergone prior allogeneic HSCT or
who have a co-morbid condition that in the medical opinion of medical faculty
(Division of Bone Marrow Transplantation and Cellular Therapy) makes standard
myeloablation prohibitive

- Does not have any other active malignancy other than the one for which this
transplant is indicated

- Cardiac shortening fraction greater than or equal to 25%

- For pediatric patients, creatinine clearance greater than or equal to 90 ml/min/1.73
m2 according to the Schwartz formula for estimated GFR (ml/min/1.73m2) = k*height
(cm)/serum creatinine (mg/dL). k is a proportionality constant that varies with age
and is a function of urinary creatinine clearance per unit of body size; 0.45 up to
12 months of age; 0.55 children and adolescent girls; and 0.70 for adolescent boys

- For adolescent or adult patients, serum creatinine 1.0 mg/dL; if serum creatinine 1.0
mg/dL, then the estimated glomerular filtration rate (GFR) must be 60 mL/min/1.73 m2
as calculated by the Modification of Diet in Renal Disease equation where predicted
GFR (ml/min/1.73 m2) = 186 x (serum creatinine)-1.154 x (age in years)-0.023 x (0.742
if patient is female) x (1.212 if patient is black)

- Forced vital capacity (FVC) greater than or equal to 40% of predicted value or pulse
oximetry greater than or equal to 92% on room air.

- Karnofsky or Lansky (age-dependent) performance score of greater than or equal to 50
(See APPENDIX A)

- Does not have active acute or active chronic GVHD defined as requiring medical
therapy.

- Does not have active acute bronchiolitis obliterans (BO) or bronchiolitis obliterans
organizing pneumonia (BOOP).

- Has a suitable HLA partially matched family member donor available for stem cell
donation

- Bilirubin less than or equal to 1.5 times the upper limit of normal for age.

- Alanine aminotransferase (ALT) less than or equal to 1.5 times the upper limit of
normal for age.

- Aspartate aminotransferase (AST) less than or equal to 1.5 times the upper limit of
normal for age.

- Not pregnant (confirmed by negative serum or urine pregnancy test within 14 days
prior to enrollment).

- Not lactating

Inclusion criteria (stem cell donor):

- Partially HLA-matched family member.

- At least 18 years of age.

- HIV negative

- Not pregnant (confirmed by negative serum or urine pregnancy test within 14 days
prior to enrollment).

- Not lactating