thiotepa, busulfan and fludarabin for pt with refractory/early relapsed aggressive b-cell non hodgkin lymphomas

Conditions: B-cell Lymphoma Refractory

Summary: the purpose of this study is to evaluate progression free survival, transplant-related morbidity (trm) at day +100 and at +365, overall survival and incidence of acute and chronic gvhd in refractory/early relapsed aggressive b-cell non hodgkin lymphomas patients treated with allogeneic transplantation after a conditioning with thiotepa, busulfan and fludarabin.

in the present study, it is hypothesised that patients with aggressive b cell lymphomas refractory to or relapsed early (within 12 months) after the completion of standard first-line immunoprotocol tbf2012 version 1, 20 nov 2012 9 chemotherapy can benefit from de-bulking salvage therapy (i.e. r-dhap + bortezomib) followed by an allograft to improve progression-free survival. patient inclusion criteria * patients with refractory/relapsed aggressive b-cell non hodgkin lymphomas after frontline therapy. * patients with stable disease or partial or complete remission (pet-negative) after salvage therapy * patients younger than 65 years old * a fully hla-identical sibling or matched unrelated donor is available. patients with one antigen mismatched donors can be considered * patient must be competent to give consent patient exclusion criteria * patients treated with an autologous transplant as salvage therapy * patients with progressive lymphomas despite conventional therapies * patients with progressive lymphomas despite conventional therapies * uncontrolled cns involvement with disease * fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment * females who are pregnant or breastfeeding * organ dysfunction defined as follows: * cardiac function: ejection fraction \<30% or uncontrolled cardiac failure * pulmonary: dlco \<40% predicted * liver function abnormalities: elevation of bilirubin to \> 3 mg/dl and/or transaminases \>4 the upper limit of normal * renal: creatinine clearance \<50 cc/min (24 hour urine protocol tbf2012 version 1, 20 nov 2012 6 collection) * karnofsky performance score \< 60% * patients with poorly controlled hypertension despite multiple antihypertensives * documented fungal disease that is progressive despite treatment * viral infections: hiv positive patients. * positive serology for hepatitis b (hb) defined as a positive test for hbsag. in addition, if negative for hbsag but hbcab positive (regardless of hbsab status), a hbv dna test will be performed and if positive the subject will be excluded. * positive serology for hepatitis c (hc) defined as a positive test for hcab, in which case reflexively perform a hc riba immunoblot assay on the same sample to confirm the result * psychiatric disorders or psychosocial problems which in the opinion of the primary physician or principal investigator would place the patient at unacceptable risk from this regimen. * patients with active non-hematologic malignancies (except nonmelanoma skin cancers). * patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a \>20% risk of disease recurrence. donor inclusion criteria: * related or unrelated hla identical donors who are in good health and have no contra-indication to donation. one antigen hlamismatched (9/10 match) donors will also be considered. * no contra-indication for the donor to collection by apheresis of mononuclear cells mobilized by g-csf at a dose of 10-12 μg/kg of body weight. * donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian). donor exclusion criteria: * age \< 18 years. * identical twin. * pregnancy. * infection with hiv. * inability to achieve adequate venous access. * known allergy to filgrastin (g-csf). * current serious systemic illness. donor inclusion criteria: * related or unrelated hla identical donors who are in good health and have no contra-indication to donation. one antigen hlamismatched (9/10 match) donors will also be considered. * no contra-indication for the donor to collection by apheresis of mononuclear cells mobilized by g-csf at a dose of 10-12 μg/kg of body weight. * donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian). donor exclusion criteria: * age \< 18 years. * identical twin. * pregnancy. * infection with hiv. * inability to achieve adequate venous access. * known allergy to filgrastin (g-csf). * current serious systemic illness. donor inclusion criteria: * related or unrelated hla identical donors who are in good health and have no contra-indication to donation. one antigen hlamismatched (9/10 match) donors will also be considered. * no contra-indication for the donor to collection by apheresis of mononuclear cells mobilized by g-csf at a dose of 10-12 μg/kg of body weight. * donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian). donor exclusion criteria: * age \< 18 years. * identical twin. * pregnancy. * infection with hiv. * inability to achieve adequate venous access. * known allergy to filgrastin (g-csf). * current serious systemic illness.

Eligibility criteria:
patient inclusion criteria: * patients with refractory/relapsed aggressive b-cell non hodgkin lymphomas after frontline therapy. * patients with stable disease or partial or complete remission (pet-negative) after salvage therapy * patients younger than 65 years old * a fully hla-identical sibling or matched unrelated donor is available. patients with one antigen mismatched donors can be considered * patient must be competent to give consent. patient exclusion criteria: * patients treated with an autologous transplant as salvage therapy * patients with progressive lymphomas despite conventional therapies * patients with progressive lymphomas despite conventional therapies * uncontrolled cns involvement with disease * fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment * females who are pregnant or breastfeeding * organ dysfunction defined as follows: * cardiac function: ejection fraction \<30% or uncontrolled cardiac failure * pulmonary: dlco \<40% predicted * liver function abnormalities: elevation of bilirubin to \> 3 mg/dl and/or transaminases \>4x the upper limit of normal * renal: creatinine clearance \<50 cc/min (24 hour urine collection) * karnofsky performance score \< 60% * patients with poorly controlled hypertension despite multiple antihypertensives * documented fungal disease that is progressive despite treatment * viral infections: hiv positive patients. * positive serology for hepatitis b (hb) defined as a positive test for hbsag. in addition, if negative for hbsag but hbcab positive (regardless of hbsab status), a hbv dna test will be performed and if positive the subject will be excluded. * positive serology for hepatitis c (hc) defined as a positive test for hcab, in which case reflexively perform a hc riba immunoblot assay on the same sample to confirm the result * psychiatric disorders or psychosocial problems which in the opinion of the primary physician or principal investigator would place the patient at unacceptable risk from this regimen. * patients with active non-hematologic malignancies (except non-melanoma skin cancers). * patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a \>20% risk of disease recurrence. donor inclusion criteria: * related or unrelated hla identical donors who are in good health and have no contra-indication to donation. one antigen hla-mismatched (9/10 match) donors will also be considered. * no contra-indication for the donor to collection by apheresis of mononuclear cells mobilized by g-csf at a dose of 10-12 mg/kg of body weight. * donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian). donor exclusion criteria: * age \< 18 years. * identical twin. * pregnancy. * infection with hiv. * inability to achieve adequate venous access. * known allergy to filgrastin (g-csf). * current serious systemic illness.

Keywords: non hodgkin lymphomas allogeneic transplantation thiotepa busulfan fludarabin