donor stem cell transplant in treating patients with high-risk hematologic cancer

Conditions: Leukemia; Lymphoma; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases

Summary: rationale: giving low doses of chemotherapy before a donor stem cell transplant helps stop the growth of cancer cells. it may also stop the patient's immune system from rejecting the donor's stem cells. the donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. giving a monoclonal antibody, such as alemtuzumab, before transplant and tacrolimus and methotrexate after transplant may stop this from happening. purpose: this phase ii trial is studying the side effects of donor stem cell transplant and to see how well it works in treating patients with high-risk hematologic cancer.

objectives: * to evaluate the safety and toxicity of a reduced-intensity conditioning regimen followed by allogeneic bone marrow or peripheral blood stem cell transplantation from an hla-matched unrelated donor in patients with high-risk hematologic malignancies. * to evaluate engraftment by peripheral blood chimerism analysis. * to determine the incidence and severity of acute and chronic graft-versus-host disease following the transplant. * to examine the possibility of controlling hematologic malignancies by induction of a graft-versus-leukemia/tumor effect. * to determine the disease-free survival, relapse, transplant-related mortality, and death from all causes. outline: * reduced-intensity conditioning regimen: patients receive 1 of 2 conditioning regimens according to diagnosis. * regimen 1 (acute leukemia, myelodysplastic syndromes, myeloproliferative syndrome, or chronic myelogenous leukemia): patients receive fludarabine phosphate iv over 30 minutes and busulfan iv over 3 hours on days -6 to -3 or orally 4 times daily on days -7 to -3. * regimen 2 (lymphoproliferative malignancies): patients receive fludarabine phosphate iv over 30 minutes and cyclophosphamide iv over 1 hour on days -5 to -3. patients with cd20+ malignancies also receive rituximab iv over 4-6 hours on days -13, -6, 1, and 8. * transplantation: patients undergo allogeneic bone marrow or peripheral blood stem cell transplantation on day 0. * graft-versus-host disease (gvhd) prophylaxis: patients receive low-dose alemtuzumab subcutaneously on days -11 to -9 and tacrolimus iv over 24 hours beginning on day -3 and then orally twice daily beginning on day 14 and continuing until day 60, followed by a taper until day 180 in the absence of clinically significant gvhd. patients also receive methotrexate on days 1, 3, and 6. patients who exhibit persistent mixed chimerism or disease relapse/progression despite full withdrawal of immunosuppression may receive up to 3 donor lymphocyte infusions. blood samples are taken on days 30, 60, and 100 and then every 4 weeks thereafter for chimerism studies by pcr analysis. after completion of study therapy, patients are followed periodically for up to 60 months.

Eligibility criteria:
* diagnosis of one of the following hematological malignancies: * cml, with 1 of the following: * in first cp and failed imatinib mesylate therapy, defined as failure to obtain a hematologic remission at 3 months or a major cytogenetic response (i.e., ph+ cells \< 35%) at 6 months or demonstrated clonal evolution or disease progression during therapy * in accelerated phase with \< 15% blasts * in blast crisis that has entered into a second cp following induction chemotherapy * aml, with 1 of the following: * in second or subsequent complete remission (cr) (i.e., \< 5% blasts by morphology, no residual leukemia by flow cytometry, and absence of cytogenetic abnormalities) * failed primary induction chemotherapy, but subsequently entered into a cr with ≤ 2 subsequent re-induction chemotherapy treatment(s) * in first cr with intermediate-risk or poor-risk cytogenetics * all with 1 of the following: * in second or subsequent cr * in first cr and presence of t(9;22) * mds, with the following: * high-risk disease, defined by ipss score of ≥ 1.5 at diagnosis and meets 1 of the following criteria: * ≤ 10% blasts at diagnosis * in morphologic cr (\< 5% blasts) following cytoreductive chemotherapy * cmml, with 1 of the following: * ≤ 10% blasts at diagnosis * in morphologic cr (\< 5% blasts) following cytoreductive chemotherapy * cll/pll with the following: * rai stage i-iv disease * failed ≥ 1 prior chemotherapy regimen (including fludarabine phosphate) or asct * documented chemosensitive or stable, non-bulky disease prior to transplant, defined as \< 20% bone marrow involvement and lymph node size \< 3 cm in axial diameter * no bulky tumor masses, elevated lactate dehydrogenase (ldh), b symptoms, or progressive disease prior to transplant * low-grade non-hodgkin lymphoma (nhl) (i.e., small lymphocytic lymphoma, follicular center lymphoma \[grade 1 or 2\], marginal zone lymphoma, or b-cell lymphoma), with the following criteria: * failed ≥ 1 prior chemotherapy regimen or asct * documented chemosensitive or stable, non-bulky disease prior to transplant, defined as \< 20% bone marrow involvement and lymph node size \< 3 cm in axial diameter * received ≤ 3 prior chemotherapy regimens (monoclonal antibody therapy and involved-field radiotherapy are not considered a prior regimen) * no bulky tumor masses, elevated ldh, b symptoms, or progressive disease prior to transplant * mantle cell lymphoma, with the following: * failed to achieve remission or recurred after either conventional chemotherapy or asct * responsive or stable disease to most recent prior therapy * no bulky tumor masses, elevated ldh, b symptoms, or progressive disease prior to transplant * intermediate-grade nhl (i.e., follicular center lymphoma \[grade 3\] or diffuse large cell lymphoma), meeting the following criteria: * failed to achieve remission or recurred after either conventional chemotherapy or asct * documented chemosensitive, non-bulky disease prior to transplant, defined as at least a partial remission to salvage chemotherapy (≥ 50% reduction in diameter of all disease sites) * no bulky tumor masses, elevated ldh, b symptoms, or progressive disease prior to transplant * hodgkin lymphoma, with the following: * relapsed after prior asct or after ≥ 2 combination chemotherapy regimens and ineligible for asct * documented chemosensitive, non-bulky disease prior to transplant, defined as at least a partial remission to salvage chemotherapy (≥ 50% reduction in diameter of all disease sites) * no bulky tumor masses, elevated ldh, b symptoms, or progressive disease prior to transplant * peripheral t-cell nhl, with the following: * failed to achieve remission or recurred after either conventional chemotherapy or asct * documented chemosensitive, non-bulky disease prior to transplant, defined as at least a partial remission to salvage chemotherapy (≥ 50% reduction in diameter of all disease sites) * no bulky tumor masses, elevated ldh, b symptoms, or progressive disease prior to transplant * myeloproliferative syndrome with poor risk features, meeting 1 of the following criteria: * \< 55 years old and lille score of 1 * lille score of 2 * hgb \< 10 g/dl and abnormal karyotype * high-risk disease, with 1 of the following: * age 40-72 years * any age and deemed to be at significantly increased risk of morbidity and death following a standard, myeloablative unrelated donor stem cell transplant (e.g., received extensive prior therapy, including asct) * hla-matched unrelated donor available, with 1 of the following: * 8/8 match at hla-a, b, c, or dr loci by high-resolution genotyping * single allelic mismatch at either the hla-b or hla-c loci donor by high-resolution molecular typing * no single allelic mismatch at hla-a or hla-dr loci * kps 80-100% * adapted weighted charlson comorbidity index \< 3 * serum creatinine ≤ 2.0 mg/dl * ast or alt \< 3 times upper limit of normal (uln) * total bilirubin \< 1.5 times uln * lvef ≥ 45% * dlco \> 50% * no hypoxia at rest with oxygen saturation \< 92% on room air (corrected with bronchodilator therapy) * no other severe pulmonary function abnormalities * no hiv infection * no active hepatitis b or c infection that, in the opinion of a gastroenterologist or the transplant committee, places the patient at moderate to high risk for developing severe hepatic disease * no active opportunistic infection (e.g., fungal pneumonia, tuberculosis, or viral infection)

Keywords: accelerated phase chronic myelogenous leukemia adult acute lymphoblastic leukemia in remission adult acute myeloid leukemia in remission adult aml with 11q23 (mll) abnormalities blastic phase chronic myelogenous leukemia chronic myelomonocytic leukemia chronic phase chronic myelogenous leukemia prolymphocytic leukemia recurrent adult t-cell leukemia/lymphoma refractory chronic lymphocytic leukemia relapsing chronic myelogenous leukemia secondary acute myeloid leukemia stage i adult t-cell leukemia/lymphoma stage i chronic lymphocytic leukemia stage ii adult t-cell leukemia/lymphoma stage ii chronic lymphocytic leukemia stage iii adult t-cell leukemia/lymphoma stage iii chronic lymphocytic leukemia stage iv adult t-cell leukemia/lymphoma stage iv chronic lymphocytic leukemia recurrent adult hodgkin lymphoma anaplastic large cell lymphoma angioimmunoblastic t-cell lymphoma cutaneous b-cell non-hodgkin lymphoma recurrent cutaneous t-cell nhl stage i cutaneous t-cell nhl stage ii cutaneous t-cell nhl stage iii cutaneous t-cell nhl stage iv cutaneous t-cell nhl extranodal marginal zone b-cell lymphoma of mucosal tissue nodal marginal zone b-cell lymphoma splenic marginal zone lymphoma contiguous st ii adult diffuse large cell lymphoma contiguous st ii adult diffuse mixed cell lymphoma contiguous st ii adult diffuse sm cleaved cell lymphoma contiguous st ii grade 1 follicular lymphoma contiguous st ii grade 2 follicular lymphoma contiguous st ii grade 3 follicular lymphoma contiguous st ii mantle cell lymphoma contiguous st ii marginal zone lymphoma contiguous st ii small lymphocytic lymphoma stage i adult diffuse large cell lymphoma stage i adult diffuse mixed cell lymphoma stage i adult diffuse small cleaved cell lymphoma stage i grade 1 follicular lymphoma stage i grade 2 follicular lymphoma stage i grade 3 follicular lymphoma stage i mantle cell lymphoma stage i marginal zone lymphoma stage i small lymphocytic lymphoma noncontiguous st ii adult diffuse large cell lymphoma noncontiguous st ii adult diffuse mixed cell lymphoma noncontiguous st ii adult diffuse sm cleaved cell lymphoma noncontiguous st ii grade 1 follicular lymphoma noncontiguous st ii grade 2 follicular lymphoma noncontiguous st ii grade 3 follicular lymphoma noncontiguous st ii mantle cell lymphoma noncontiguous st ii marginal zone lymphoma noncontiguous st ii small lymphocytic lymphoma stage iii adult diffuse large cell lymphoma stage iii adult diffuse mixed cell lymphoma stage iii adult diffuse small cleaved cell lymphoma stage iii grade 1 follicular lymphoma stage iii grade 2 follicular lymphoma stage iii grade 3 follicular lymphoma stage iii mantle cell lymphoma stage iii marginal zone lymphoma stage iii small lymphocytic lymphoma stage iv adult diffuse large cell lymphoma stage iv adult diffuse mixed cell lymphoma stage iv adult diffuse small cleaved cell lymphoma stage iv grade 1 follicular lymphoma stage iv grade 2 follicular lymphoma stage iv grade 3 follicular lymphoma stage iv mantle cell lymphoma stage iv marginal zone lymphoma stage iv small lymphocytic lymphoma recurrent adult diffuse large cell lymphoma recurrent adult diffuse mixed cell lymphoma recurrent adult diffuse small cleaved cell lymphoma recurrent adult gr iii lymphomatoid granulomatosis recurrent grade 1 follicular lymphoma recurrent grade 2 follicular lymphoma recurrent grade 3 follicular lymphoma recurrent mantle cell lymphoma recurrent marginal zone lymphoma recurrent small lymphocytic lymphoma de novo mds previously treated mds secondary myelodysplastic syndromes waldenstrom macroglobulinemia myelodysplastic/myeloproliferative disease