Clinical trial NCT01247701: Umbilical Cord Blood Transplant for Children With Myeloid Hematological Malignancies
Official title: Umbilical Cord Blood Transplant for Children With Myeloid Hematological Malignancies (UCAML)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Myeloid Hematological Malignancies
Keywords: UCB
Umbilical Cord Blood
Transplant
Umbilical Cord Blood Transplant
Cord Blood Stem Cell Transplantation
Pediatric
Myeloid Hematological Malignancies
Busulfan
Cytoxan
Cyclophosphamide
Fludarabine
Lead sponsor: Baylor College of Medicine
Sponsor class: OTHER
Collaborators: name: Center for Cell and Gene Therapy, Baylor College of Medicine
First posted: 2010-11-24
Enrollment: 16
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: In this study, the investigators will use busulfan and cyclophosphamide (BuCy) backbone with the addition of fludarabine as the preparative Stem Cell Transplant (SCT) regimen. As an attempt to improve engraftment rate and reduce infections, the investigators are going to incorporate fludarabine in the conditioning regimen. The use of a BuCy backbone has been widely used and comparable to total body irradiation and cyclophosphamide (Cy/TBI) regimen.

Encouraging data on adding fludarabine to the SCT regimen have been reported. A fludarabine-based, conditioning regimen, with adequate immunosuppressive activity could conceivably allow engraftment of stem cells from alternative donors in hematologic malignancies patients with acceptable engraftment rates and low transplant-related mortality. Regimen-related toxicity is believed to be a major contributing factor to GVHD. Therefore this approach may also lead to reduced GVHD, as some investigators have suggested.

In an attempt to decrease the rate of viral infection and reactivation, the investigators will avoid ATG (Thymoglobulin) / Campath (anti-CD52), and instead administer Mycophenolate Mofetil (MMF). The addition of fludarabine should compensate any increase risk of graft failure with the removal of the ATG/Campath. The investigators anticipate that the removal of ATG/Campath will facilitate immune reconstitution more efficiently after receiving a UCBT.

Detailed description: The following will be given as the conditioning regimen for the transplant:

BUSULFAN: Busulfan (intravenous BUSULFEX) dosing will be as follows: patients \<12 kg: 1.1 mg/kg/dose IV every 6 hours for 16 doses total; patients \>12 kg: 0.8 mg/kg/dose IV every 6 hours for 16 doses. Administration and pharmacokinetic monitoring will be performed as per standard practice. Anticonvulsants will be given in accordance with standard Blood and Marrow Transplant Program recommendations.

CYCLOPHOSPHAMIDE: Cyclophosphamide (50 mg/kg/dose) will be given IV on Days -5, - 4, -3, and -2 over 1 hour. The total dose to be given over 4 days is 200 mg/kg. Mesna will be given in accordance with standard Blood and Marrow Transplant.

FLUDARABINE: Fludarabine will be given IV daily over 1 hour for 3 days. Dosing will be as follows: for patients ≤ 10 kg: 1.3 mg/kg; for patients \> 10 kg: 40 mg/m2. Preparation, administration and monitoring will be according to standard practice procedure

POST-TRANSPLANT IMMUNOSUPPRESSION:

* CSA will begin on Day -3. For children \< 40 kg, the initial dose will be 2.5 mg/kg IV over 2 hours every 12 hours. Dose adjustments will be made to maintain levels above 200 ng/mL. Levels will be done on Day 0 and then as clinical indicated. CSA will be tapered per institutional SOP. Once the patient can tolerate oral medications and has a normal gastrointestinal transit time, CSA will be converted to an oral form.
* MMF will begin on Day 0 at a dose of 15 mg/Kg IV or orally TID, and will be discontinued on Day +45 unless GVHD is present.

CNS Disease: Patients with CNS relapse or primary CNS disease that is symptomatic or associated to radiological changes will receive additional irradiation to the craniospinal axis.

SUPPORTIVE CARE:

* Supportive care will be provided as per standard practice of the Blood and Marrow Stem Cell Transplant program at the Texas Children's Hospital, including all prophylactic and therapeutic clinical care issues. These practices may be modified if necessary for any individual patient in order to provide optimum care for that particular patient.
* IVIG: Intravenous immunoglobulin (500 mg/kg per dose) will be given monthly until discontinuation of GVHD therapy and documentation of antibody production.
* CB-CTLs: Patients enrolled in this protocol may also be eligible for infusion of CB-derived multivirus-specific CTL to provide virus-specific immune reconstitution and treatment of viral infections after CBT.

EVALUATIONS DURING THE STUDY:

Screening Procedures; Pre-HCT:

* Physical examination
* Pregnancy test
* Complete blood count and chemistries
* Electrocardiogram
* Echocardiograph
* PT/PTT/Fibrinogen/Anti-Thrombin III/von Willebrand Factor
* Viral tests
* Bone marrow aspirate and biopsy/Lumbar puncture
* Renal Function (GFR)
* Lumbar puncture will be performed
* Pulmonary Function test

EVALUATIONS BETWEEN DAY 0 AND DAY 100:

* Physical examination
* Complete blood count and chemistries
* Lytes/BUN/Cr
* Peripheral blood for STRs or FISH analysis for molecular diagnostics
* Lymphocyte phenotype testing and lymphoproliferative responses
* Bone marrow aspirate and biopsy for assessment of leukemia status and UCB engraftment
* Lumbar puncture
* Immunoglobulins

EVALUATIONS AFTER DAY 100:

* Physical examination
* Complete blood count and chemistries
* Lytes/BUN/Cr
* Serum chemistries
* Peripheral blood with assessment of engraftment by STRs or FISH analysis and enzyme levels
* Echocardiograph with LVEF
* Bone marrow aspirate and biopsy assessment of leukemia status and UCB engraftment
* Lymphocyte phenotype testing (CD3, CD4, CD8, CD19 and CD56) and lymphoproliferative responses
* Immunoglobulins

FOLLOW-UP INTERVAL:

Patients will be seen in the hospital everyday until discharge. After discharge from the hospital, the patient will be following on the BMT clinics on a regular basis as recommended by the primary physician.

Eligibility criteria: Inclusion Criteria:

* Patients with a myeloid hematologic malignancy (acute myelogenous leukemia, secondary myelogenous leukemia or myelodysplastic syndrome) unlikely to be cure by standard chemotherapy. This includes patients who have relapsed after standard chemotherapy treatments and patients in first remission with unfavorable prognostics features.
* Related or Unrelated Umbilical Cord Blood Unit with 0-1 antigen mismatch at HLA-A and B (at low resolution) and DRB1 (at high resolution), with a total nucleated cell dose of ≥ 4 x 10\^7/kg.
* Lansky/Karnofsky scores at least 60.
* Written informed consent and/or signed assent line from patient, parent or guardian.
* Negative pregnancy test, if applicable.

Exclusion Criteria:

* Patients with uncontrolled infections. For bacterial infections, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to enrollment. For fungal infections, patients must be receiving definitive systemic antifungal therapy and have no signs of progressing infection for 1 week prior to enrollment. Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
* Severe renal disease (Creatinine \> 3X normal for age).
* Severe hepatic disease (direct bilirubin \> 3 mg/dL or SGOT \> 500).
* Patient has DLCO \< 50% predicted or FEV1 \< 50% of predicted, if applicable.
* Patients with symptomatic cardiac failure unrelieved by medical therapy or evidence of significant cardiac dysfunction by echocardiogram (shortening fraction \< 20%).
* HIV positive.

Primary outcomes:
measure: Overall Survival at 100 Days, 1 Year, and 3 Years After Umbilical Cord Blood Transplant in Pediatric Patients.
timeFrame: 100 days, 1 year, and 3 years
Secondary outcomes:
measure: Number of Participants With Severe Acute GVHD Grade III-IV
timeFrame: Day 100
measure: Number of Participants With Chronic GvHD
timeFrame: 1 year
measure: Number of Participants With Relapse Rate After Transplant
timeFrame: 1 and 3 years
measure: Number of Participants With Donor Engraftment After Transplant.
timeFrame: 100 days, 6, 9, 12, 24 and 36 months
measure: Number of Participants With Platelet Engraftment
timeFrame: Day 180
measure: Number of Participants With Neutrophil Engraftment
timeFrame: Day 42
Other outcomes:
Locations:
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
Study officials:
affiliation: Baylor College of Medicine
name: Caridad A Martinez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Baylor College of Medicine
name: Robert A Krance, MD
role: PRINCIPAL_INVESTIGATOR
References: