umbilical cord blood (ucb) transplantation in pediatric patients with high risk leukemia and myelodysplasia

Conditions: Leukemia; Myelodysplasia; Acute Lymphocytic Leukemia; Acute Myelogenous Leukemia

Summary: unrelated cord blood (ucb) transplant in children is a viable stem cell transplant modality for patients with leukemia and myelodysplasia. ucb is now considered "standard of care" in cases where a suitable living bone marrow donor is not available. the survival of ucb is similar to matched unrelated marrow transplant. this study is considered "research" since ucb is not a licensed product and requires investigational new drug (ind). there are no specific research questions in this protocol. this protocol merely provides ucb as a stem cell treatment modality to pediatric patients who may require it after a conditioning regimen that excludes total body irradiation.

the preparative regimen will consist of: * fludarabine: 25 mg/m2/day iv x 5 doses on days -13, to -9 * busulfan 1mg/kg iv every 6 hrs x 16 doses on days -8 to -5 * melphalan 45 mg/m2/day iv x 3 doses on days -4 to -2 * atgam 30mg/kg/day x 3 doses on days -3 to -1 * day 0 will be the day of the ucb transplant * the graft-versus-host-disease (gvhd) prophylaxis will be cyclosporin a to maintain level 200-400 beginning on day -3, through 200-400. solumedrol at 1mg/kg/day on day 1 until d+4, then solumedrol 2mg/kg/day until day +19 or till absolute neutrophil count (anc) reaches 500/mm2, then taper by 0.2 mg/kg/week.

Eligibility criteria:
inclusion criteria: * patients must be up to 21 years of age * patients cannot receive total body irradiation (tbi) because of: * young age - \< 2 years at diagnosis of leukemia resulting in an age \< 4 years at transplantation (due to risk of severe growth retardation and brain damage). * inability to tolerate tbi because of prior radiation or organ toxicity. * refractory/multiply relapsed leukemia, for which a traditional tbi/cyclophosphamide regimen would unlikely lead to a successful outcome. * patients must have a partially human leukocyte antigen (hla)-matched ucb unit. unit must be hla-matched minimally at 4 of 6 hla-a and b (at intermediate resolution by molecular typing) and drb1 (at high resolution by molecular typing) loci with the patient. the unit must deliver a pre-cryopreserved nucleated cell dose of at least 2.5 x 10\^7 per kilogram. * acute myelogenous leukemia (aml) at the following stages: * high risk first complete remission (cr1), defined as: * having preceding myelodysplasia (mds) * high risk cytogenetics (high-risk cytogenetics: del (5q) -5, -7, abn (3q), t (6;9) complex karyotype (\>= 5 abnormalities) * requiring \> 2 cycles chemotherapy to obtain cr; * second or greater cr. * first relapse with \< 25% blasts in bone marrow. * patients with therapy-related aml whose prior malignancy has been in remission for at least 12 months. * acute lymphocytic leukemia (all) at the following stages: * high risk first remission, defined as: 1. ph+ all; or, 2. myeloid/lymphoid leukemia (mll) rearrangement with slow early response \[defined as having m2 (5-25% blasts) or m3 (\>25% blasts on bone marrow examination on day 14 of induction therapy)\]; or, 3. hypodiploidy (\< 44 chromosomes or dna index \< 0.81); or, 4. end of induction m3 bone marrow; or, 5. end of induction m2 with m2-3 at day 42. * high risk second remission, defined as: 1. bone marrow relapse \< 36 months from induction; or, 2. t-lineage relapse at any time; or, 3. very early isolated central nervous system (cns) relapse (6 months from diagnosis); or, 4. slow reinduction (m2-3 at day 28) after relapse at any time. * any third or subsequent cr. * biphenotypic or undifferentiated leukemia in any cr or if in 1st relapse must have \< 25% blasts in bone marrow (bm). * mds at any stage. * chronic myelogenous leukemia (cml) in chronic or accelerated phase. * all patients with evidence of cns leukemia must be treated and be in cns cr to be eligible for study. * patients ≥ 16 years old must have a karnofsky score ≥ 70% and patients \< 16 years old must have a lansky score ≥ 70%. * signed informed consent. * patients with adequate physical function as measured by: 1. cardiac: left ventricular ejection fraction at rest must be \> 40%, or shortening fraction \> 26% 2. hepatic: bilirubin ≤ 2.5 mg/dl; and alanine transaminase (alt), aspartate transaminase (ast) and alkaline phosphatase ≤ 5 x upper limit of normal (uln) 3. renal: serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then renal function (creatinine clearance or gfr) \> 70 ml/min/1.73 m2. 4. pulmonary: diffusing capacity of the lungs for carbon monoxide (dlco), forced expiratory volume in 1 second (fev1), forced vital capacity (fvc) (diffusion capacity) \> 50% of predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then o2 saturation \> 92% of room air. exclusion criteria: * pregnant (b-positive hcg) or breastfeeding. * evidence of hiv infection or hiv positive serology. * current uncontrolled bacterial, viral or fungal infection (currently taking medication and progression of clinical symptoms). * autologous transplant \< 6 months prior to enrollment. * prior autologous transplant for the disease for which the ucb transplant will be performed. * allogeneic hematopoietic stem cell transplant \< 6 months prior to enrollment. * active malignancy other than the one for which the ucb transplant is being performed within 12 months of enrollment * active cns leukemia. * requirement of supplemental oxygen. * hla-matched related donor able to donate.

Keywords: leukemia myelodysplasia acute lymphocytic leukemia all acute myelogenous leukemia aml pediatric