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Title:
Reduced intensity, partially HLA mismatched allogeneic BMT for hematologic malignancies using donors other than first-degree relatives
Protocol Number:
J1055
Phase:
Phase I/II
Physician:
Yvette Kasamon
Purpose:
Primary objective 1.In reduced-intensity, partially HLA mismatched allogeneic BMT from unrelated or non-first-degree related donors, identify a transplant regimen associated with acceptable rates of severe acute GVHD (less than or equal to 25%) and transplant-related NRM (less than or equal to 20%) by Day 100. Secondary objectives 1.Estimate the event-free survival, overall survival, cumulative incidence of progression or relapse, and cumulative incidence of NRM. 2.Estimate the cumulative incidence of acute grade II-IV GVHD, acute grade III-IV GVHD, and chronic GVHD. 3.Determine the need for systemic immunosuppressive treatment for GVHD beyond the originally planned prophylaxis regimen. 4.Describe graft failure frequency, kinetics of T-cell donor chimerism and total leukocyte donor chimerism in peripheral blood, and kinetics of neutrophil and platelet recovery. 5.Characterize immune reconstitution and the immunobiology of sirolimus and post-transplantation Cy by analyzing peripheral blood mononuclear cells collected prospectively at defined time points.
Eligibility:
Patient eligibility 1.Patient age 0.5-70 years old. 2.Absence of a suitable related or unrelated bone marrow donor who is molecularly matched at HLA-A, B, Cw, DRB1, and DQB1. 3.Absence of a suitable partially HLA-mismatched (haploidentical), first-degree related donor. Note: Determination of matching is based on allele or allele group level typing. To be considered haploidentical, the donor and recipient must be identical at at least one allele of each of the following genetic loci: HLA-A, -B, -Cw, -DRB1, and -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. 4.Eligible diagnoses: a.Relapsed or refractory acute leukemia (acute myeloid leukemia or acute lymphoblastic leukemia or lymphoma) in second or subsequent remission, with remission defined as less than 5% bone marrow blasts morphologically b.Poor-risk acute leukemia in first remission, with remission defined as less than 5% bone marrow blasts morphologically: �AML with at least one of the following: �AML arising from MDS or a myeloproliferative disorder, or secondary AML �Presence of Flt3 internal tandem duplications �Poor-risk cytogenetics: Complex karyotype [ greater than 3 abnormalities], inv(3), t(3;3), t(6;9), MLL rearrangement with the exception of t(9;11), or abnormalities of chromosome 5 or 7 �Primary refractory disease �ALL (leukemia and/or lymphoma) with at least one of the following: �Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), or MLL rearrangement �Clear evidence of hypodiploidy �Primary refractory disease �Biphenotypic leukemia c.MDS with at least one of the following poor-risk features: �Poor-risk cytogenetics (7/7q minus or complex cytogenetics) �IPSS score of INT-2 or greater �Treatment-related MDS �MDS diagnosed before age 21 years �Progression on or lack of response to standard DNA-methyltransferase inhibitor therapy �Life-threatening cytopenias, including those generally requiring greater than weekly transfusions d.Interferon- or imatinib-refractory CML in first chronic phase, or non-blast crisis CML beyond first chronic phase. e.Philadelphia chromosome negative myeloproliferative disease. f.Chronic myelomonocytic leukemia. g.Juvenile myelomonocytic leukemia. h.Low-grade non-Hodgkin lymphoma (including SLL and CLL) or plasma cell neoplasm that has progressed after at least two prior therapies (excluding single agent rituximab and single agent steroids), or in the case of lymphoma undergone histologic conversion i.Poor-risk CLL or SLL as follows: 11q deletion disease that has progressed after a combination chemotherapy regimen, 17p deletion disease, or histologic conversion. j.Aggressive non-Hodgkin lymphoma as follows, provided there is stable disease or better to last therapy: �NK or NK-T cell lymphoma, hepatosplenic T-cell lymphoma, or subcutaneous panniculitic T-cell lymphoma �Hodgkin or aggressive non Hodgkin lymphoma that has failed at least one multiagent regimen, and the patient is either ineligible for autologous BMT or autologous BMT is not recommended. Eligible subtypes of aggressive non-Hodgkin lymphoma include: �mantle cell lymphoma �follicular grade 3 lymphoma �diffuse large B-cell lymphoma or its subtypes, excluding primary CNS lymphoma �primary mediastinal large B-cell lymphoma �large B-cell lymphoma, unspecified �anaplastic large cell lymphoma, excluding skin-only disease �peripheral T-cell lymphoma, including angioimmunoblastic T-cell lymphoma �Burkitt�s lymphoma or atypical Burkitt�s lymphoma (high-grade B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt�s), in complete remission 5.Patients with CLL, SLL, or prolymphocytic leukemia must have less than 20% bone marrow involvement by malignancy (to lower risk of graft rejection). 6.Any previous BMT must have occurred at least 3 months prior to start of conditioning. 7.No previous allogeneic BMT. 8.No active extramedullary leukemia or known active CNS involvement by malignancy. Such disease treated into remission is permitted. 9.Adequate end-organ function as measured by: a.Left ventricular ejection fraction � 35%, or shortening fraction greater than 25% b.Bilirubin � 3.0 mg/dL (unless due to Gilbert�s syndrome or hemolysis), and ALT and AST less than 5 x ULN c.FEV1 and FVC greater than 40% of predicted; or in pediatric patients, if unable to perform pulmonary function tests due to young age, oxygen saturation greater than 92% on room air 10.ECOG performance status less than 2 or Karnofsky or Lansky score greater than 60 11.Not pregnant or breast-feeding. 12.HIV negative. 13.No uncontrolled bacterial, viral, or fungal infection (infection is permitted if there is evidence of response to medication). Donor eligibility 1.Potential donors consist of: b.Unrelated donors c.Second-degree relatives d.First cousins 2.Donor must not be HLA identical to the recipient and must be HLA-haploidentical, i.e. 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. 3.Meets institutional selection criteria and medically fit to donate. 4.Lack of recipient anti-donor HLA antibody. Note: In some instances, low level, non-cytotoxic HLA specific antibodies may be permissible if they are found to be at a level well below that detectable by flow cytometry. This will be decided on a case-by-case basis by the PI and one of the immunogenetics directors. 5.Has not donated blood products to recipient.
Treatment:
REGIMEN B Days â??6 through â??2, Fludarabine 30 mg/m2 IV QD, adjusted for CrCl and Days â??5 through â??2, Busulfan 1 mg/kg PO (0.8 mg/kg IV) BID (pts greater than 6 y) b, with PK adjustments and seizure prophylaxis, Day -1Day of rest (additional day permissible), Day 0, Infuse T-cell replete bone marrow, Begin antibiotic prophylaxis (no voriconazole) Days 3, 4, Cyclophosphamide 50 mg/kg IV QD, Mesna 40 mg/kg IV QD in divided doses Day 5, Sirolimus loading dose: 6 mg PO once (pts greater than 18 y) c Begin MMF 15 mg/kg PO TID (maximum daily dose 3 g/day) (Immunosuppression must begin at least 24 hours after Cy completion). Begin GCSF 5 ï?­g/kg SC or IV QD, until ANC greater than 1000/mm3 over 3 days Day 6-Begin sirolimus 2 mg PO QD (pts greater than 18 y) c, target trough 3 â?? 12 ng/mL Day 30 (+/- 3 d)-Assess chimerism in peripheral blood Day 35, Discontinue MMF (optional if GVHD is active) Day 60 (+/- 5 d)-Assess chimerism in peripheral blood Evaluate disease Day 100 (+/- 5 d)-GVHD evaluation Day 180Discontinue sirolimus (optional if GVHD is active); Day 180 (+/- 21 d)Assess chimerism in peripheral blood Evaluate disease 1 yr (+/- 30 d)Assess chimerism in peripheral blood Evaluate disease
Population:
Both
Last Update
10/02/2014 04:03 AM
 

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