haploidentical hematopoietic stem cell transplantation using a novel clofarabine containing conditioning regimen for patients with refractory hematologic malignancies

Conditions: Hematologic Malignancies

Summary: 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

Eligibility criteria:
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

Keywords: stem cell transplantation, hematopoietic peripheral blood stem cell transplantation maximal tolerated dose clofarabine hematological malignancies apheresis