A Pediatric Blood and Marrow Transplant Consortium (PBMTC) multi-center Phase II Pilot Trial of Myeloablative Conditioning and Transplantation of Partially HLA-mismatched T cell replete Bone Marrow with post-transplantation cyclophosphamide for Children and Young Adults with Hematologic Malignancies
Johns Hopkins Kimmel Cancer Center in Baltimore
We propose a multi-institutional phase II study in children with high-risk leukemias in 1st CR, acute leukemias in 2nd CR, MDS, and JMML. The myeloablative conditioning regimen prescribed will be TBI-based for lymphoid leukemias and busulfan-based for myeloid leukemias, or for lymphoid leukemias in which a TBI-based regimen was used for the first transplant. Our goal is to establish an easily exportable, inexpensive platform for haplotransplantation that has a safety profile equivalent to matched related and unrelated BMTs. The primary objective will be to estimate the incidence of 6-month non-relapse mortality, hypothesizing that NRM is less than 18%.
Patient age 0.5-25years Patients must have a first-degree related donor or half-sibling who is at minimum HLA haploidentical. The donor and recipient must be identical at at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. A minimum match of 5/10 is therefore required, and will be considered sufficient evidence that the donor and recipient share one HLA haplotype. An unrelated donor search is not required for a patient to be eligible for this protocol, or a donor search and donor mobilization may be abandoned if the clinical situation dictates an urgent transplant. Clinical urgency is defined as 6-8 weeks from referral to transplant or a low-likelihood of finding a matched, unrelated donor. Patients must have at least one of the following high-risk conditions listed below (criteria are meant to complement existing criteria within COG protocols): a)Acute lymphocytic leukemia (ALL) in CR1* as defined by at least one of the following: i. hypodiploidy ii. induction failure iii. MRD after consolidation b)Acute myeloid leukemia (AML) in CR1* with high risk features defined as: i. High allelic ratio FLT3/ITD+ ii. Monosomy 7 iii. Del (5q) iv. Standard risk cytogenetics with positive minimal residual disease at the end of Induction I chemotherapy (for patients being treated on or according to COG AAML1031 who have had MRD studies sent to Seattle or performed at their local institution where the flow assay is sensitive enough to detect greater than 0.1% blasts) c) Acute Leukemias in 2nd or subsequent CR (CR greater than 2) d) Mixed phenotype/Undifferentiated Leukemias in 1st or subsequent CR* e) Secondary or therapy related leukemias f) NK cell lymphoblastic leukemia CR greater than 1 g) Myelodysplastic syndrome (MDS) h) JMML (patients are eligible if they are not eligible for COG1221) i) Prior transplant eligible if greater than 6 months has elapsed since BMT, and patient is off immunosuppression for greater than 3 months with no GVHD j) No known active CNS involvement or extramedullary involvement by malignancy. Such disease treated into remission is permitted. *Acute Leukemia - Remission is defined as morphology with less than 5% blasts with no morphological characteristics of acute leukemia (e.g., Auer Rods) in a bone marrow with greater than 20% cellularity. Criteria for recipient ineligibility Patients will not be excluded on the basis of sex, racial or ethnic background. Poor cardiac function: left ventricular ejection fraction less than 45% as determined by MUGA or ECHO. For pediatric patients LVEF less than 45% or a shortening fraction below normal limits for age. Symptomatic pulmonary disease. Poor pulmonary function: FEV1, FVC, and DLCO less than 50% predicted (corrected for hemoglobin) for patients who have not received thoracic or mantle irradiation. For patients who have received thoracic or mantle irradiation, FEV1 and FVC less than 70% predicted or DLCO less than 50 of predicted. For children unable to perform PFTs because of developmental stage pulse oximetry less than 92% on RA. Poor liver function: bilirubin greater than 2 mg/dl (not due to hemolysis, Gilbertï¿½s or primary malignancy). ALT or AST greater than 3 x laboratory upper normal limits. Poor renal function: Creatinine greater than 2.0mg/dl or creatinine clearance (calculated creatinine clearance is permitted) less than 60 mL/min based on Traditional Cockcroft-Gault formula: 140 - age (yrs) x Smaller of Actual Weight vs. Ideal Body Weight (kg) / 72 x Serum creatinine (mg/dl) ï¿½ Multiply by another factor of 0.85 if female ï¿½ Intended for ages 18-110, serum creatinine 0.6-7 mg/dl For patients less than 18 years: CrCl will be estimated by the Schwartz formula. A measured CrCl or a GFR may be substituted to determine the subjectï¿½s CrCL Schwartz equation: CrCl (ml/min/1.73m2) equal to [length (cm) x k] /serum creatinine K equal to 0.45 for infants 1 to 52 weeks old k equal to 0.55 for children 1 to 13 years old k equal to 0.55 for adolescent females 13-18 years old k equal to 0.7 for adolescent males 13-18 years old HIV-positive Positive leukocytotoxic crossmatch Specifically, complement dependent cytotoxicity and flow cytometric crossmatch assays must be negative, and the mean fluorescence intensity (MFI) of any anti-donor HLA antibody by solid phase immunoassay should be less than 3000. Consult with PI for the clinical significance of any anti-donor antibody. Women of childbearing potential who currently are pregnant (-HCG+) or who are not practicing adequate contraception or who are breastfeeding Uncontrolled viral, bacterial, or fungal infections (currently taking medication and have progression of clinical symptoms) Patients with symptoms consistent with RSV, influenza A, B, or parainfluenza at the time of enrollment will be assayed for the above viruses and if positive are not eligible for the trial until they are no longer symptomatic (patients may have continued assay positivity for a period of time post resolution of symptoms secondary to the nature of the assay. Criteria for donor eligibility Age greater than 0.5 years Donors must meet the selection criteria as defined by the Foundation for the Accreditation of Hematopoietic Cell Therapy (FACT). The patient must lack antibodies against donor HLA molecules (see section 6.1.3j) In the event that two or more eligible donors are identified, the following order of priority will be used to determine the preferred donor (in decreasing order of priority): 1. Medically and psychologically fit and willing to donate 2. ABO compatibility (see Appendix 6) a. Compatible or minor ABO incompatibility b. Major ABO incompatibility 4. CMV status a. For a CMV seronegative recipients, use a CMV seronegative donor b. For a CMV seropositive recipient, use a CMV seropositive donor If more than one preferred donor is identified and there is no medical reason to prefer one of them, then the following guidelines are recommended (in no particular order): 1. Male donors may be preferred over nulliparous female donors who may be preferred over multiparous female donors 2. Younger (18 years of age or older), then consider minors 3. If the patient and family express a strong preference for a particular donor, use that one
Hematopoietic stem cell transplantation (HSCT) is a curative treatment for a variety of malignant and non-malignant hematologic disorders1-3. Of the potential sources of allografts, HSCT from a human leukocyte antigen (HLA)-matched sibling has produced the best outcomes as measured by overall and progression-free survival4. Unfortunately, only about a third of candidates for HSCT have HLA-matched siblings, with increased disparity for minority racial groups5;6. For patients who lack HLA-matched siblings, there are two alternative sources of unrelated HLA-matched stem cells for HSCT: 1) volunteer matched unrelated donors; 2) umbilical cord blood7. Worldwide, one million HSCT had been performed by the end of 2012, as treatment for over 70 different diseases8. Despite this success, over 1,000 patients are estimated to die each year in the U.S. because a suitable matched donor cannot be identified. Thus, alternative mismatched donors represent an important source of stem cells for this proven therapy. Cost is also a consideration for alternative donor strategies, as overall transplant costs, duration of hospitalization, and donor acquisition fees vary by graft source and are greatly increased in unrelated transplants. A recently published singleinstitution report of pediatric allogeneic HSCT demonstrated the increased costs of unrelated donor and umbilical cord blood transplants compared to matched related donor transplants. For 2004-2006, the mean costs per day survived were $3,446 for matched related donors (median duration of hospitalization 36 days), $4,050 for matched unrelated donors (median duration of hospitalization 47 days), and $4,522 for umbilical cord blood recipients (median duration of hospitalization 57 days). Additionally, costs of graft acquisition varied by donor source. The mean costs of graft acquisition were $8,891 for matched related donors, $57,134 for matched unrelated donors, and $58,910 for umbilical cord blood9. Thus, an unrelated donor source adds approximately $100,000 to the cost of the first 3 months of HSCT medical care
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