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