reduced intensity, partially hla mismatched bmt to treat hematologic malignancies

Conditions: Hematologic Malignancies

Summary: if transplantation using mismatched unrelated donors or non-first-degree relatives could be performed with an acceptable toxicity profile, an important unmet need would be served. towards this goal, the current study extends our platform of nonmyeloablative, partially hla-mismatched bone marrow transplant (bmt) and peripheral blood stem cell transplant (pbsct) to the use of such donors, investigating up to several postgrafting immunosuppression regimens that incorporate high-dose cy. of central interest is the incorporation of sirolimus into this postgrafting immunosuppression regimen. the primary goal for phase 1 is to identify a transplant regimen associated with acceptable rates of severe acute gvhd and nrm by day 100 and for phase 2 estimate the 6-month probability of survival without having had acute grade iii- iv gvhd or graft failure.


Eligibility criteria:
patient inclusion criteria: 1. patient age 0.5-75 years 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. donors who are homozygous for the ccr5delta32 polymorphism are given preference. 4. eligible diagnoses: 1. relapsed or refractory acute leukemia in second or subsequent remission, with remission defined as \<5% bone marrow blasts morphologically 2. poor-risk acute leukemia in first remission, with remission defined as \<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 \[\> 3 abnormalities\], 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 3. 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 4. interferon- or imatinib-refractory cml in first chronic phase, or non-blast crisis cml beyond first chronic phase. 5. philadelphia chromosome negative myeloproliferative disease. 6. chronic myelomonocytic leukemia. 7. juvenile myelomonocytic leukemia. 8. 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; * patients with transformed lymphomas must have stable disease or better. 9. poor-risk cll or sll as follows: * 11q deletion disease that has progressed after a combination chemotherapy regimen, * 17p deletion disease, * or histologic conversion; * patients with transformed lymphomas must have stable disease or better. 10. 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, blastic/ blastoid variant of mantle 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 * 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 \< 20% bone marrow involvement by malignancy (to lower risk of graft rejection). 6. one of the following, in order to lower risk of graft rejection: * cytotoxic chemotherapy, an adequate course of 5-azacitidine or decitabine, or alemtuzumab within 3 months prior to start of conditioning; or * previous bmt within 6 months prior to start of conditioning. note: patients who have received treatment outside of these windows may be eligible if it is deemed sufficient to reduce graft rejection risk; this will be decided on a case-by-case basis by the pi or co-pi. 7. any previous bmt must have occurred at least 3 months prior to start of conditioning. 8. adequate end-organ function as measured by: 1. left ventricular ejection fraction greater than or equal to 35%, or shortening fraction \> 25%, unless cleared by a cardiologist 2. bilirubin ≤ 3.0 mg/dl (unless due to gilbert's syndrome or hemolysis), and alt and ast \< 5 x uln 3. fev1 and fvc \> 40% of predicted; or in pediatric patients, if unable to perform pulmonary function tests due to young age, oxygen saturation \>92% on room air 9. ecog performance status \ 60 patient exclusion criteria: * not pregnant or breast-feeding. * no uncontrolled bacterial, viral, or fungal infection. * note: hiv-infected patients are potentially eligible. eligibility of hiv-infected patients will be determined on a case-by-case basis. * no previous allogeneic bmt (syngeneic bmt permissible). * active extramedullary leukemia or known active cns involvement by malignancy. such disease treated into remission is permitted. donor inclusion criteria: 1. potential donors consist of: * unrelated donors * second-degree relatives * first cousins 2. the donor and recipient must be identical at at least 5 hla alleles based on high resolution typing of hla-a, -b, -cw, -drb1, and -dqb1, with at least one allele matched for a hla class i gene (hla-a, -b, or -cw) and at least one allele matched for a class ii gene (hla-drb1 or -dqb1). 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. pheresis to reduce anti-hla antibodies is permissible; however eligibility to proceed with the transplant regimen would be contingent upon the result. donor exclusion criteria: * donor must not be hla identical to the recipient. * has not donated blood products to recipient.

Keywords: reduced intensity partially hla mismatched allogeneic bmt acute leukemias chronic leukemias myelodysplasia lymphomas unrelated or non-first-degree related donors peripheral blood stem cell transplant