Patients with refractory hematologic malignancies including those who develop recurrent disease after allogeneic hematopoietic stem cell transplantation (HSCT) have a dismal prognosis. Historically, both regimen-related mortality and disease recurrence have been significant causes of treatment failure in this heavily pre-treated patient population. The investigators institution has utilized mismatched family member donors for these patients for several reasons: (1) Only 30% of patients have matched related donors available; (2) transplantation can be performed more rapidly since the time to unrelated donor trans-plantation averages 3 to 4 months; (3) the alloimmune reactivity of natural killer (NK) cells following haploidentical HSCT has been shown to reduce relapse rates in certain patient groups; and, (4) no other curative treatment options are available.

In the present trial, the investigators propose a novel conditioning regimen using clofarabine in an effort to enhance cytotoxicity while simultaneously reducing regimen related toxicity. In this phase I trial, the goal is to determine the maximum tolerated dose (MTD) of clofarabine when used in combination with melphalan and thiotepa pre-transplant.

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