Combination Chemotherapy, Donor Stem Cell Transplant, Tacrolimus, Mycophenolate Mofetil, and Cyclophosphamide in Treating Patients With Hematologic Cancer

Study Overview
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Brief Summary
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RATIONALE: Giving chemotherapy, such as fludarabine, busulfan, and cyclophosphamide, before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving high-dose cyclophosphamide together with tacrolimus and mycophenolate mofetil after transplant may stop this from happening. PURPOSE: This phase II trial is studying how well combination chemotherapy works when given together with a donor stem cell transplant, followed by tacrolimus, mycophenolate mofetil, and high-dose cyclophosphamide, in treating patients with high-risk hematologic cancer.

Detailed Description
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OBJECTIVES: Primary To estimate the incidence of graft rejection and severe graft-versus-host disease after myeloablative HLA-mismatched peripheral blood stem cell transplantation (PBSCT) from first-degree relatives in patients with high-risk hematologic malignancies. Secondary To estimate overall survival, relapse, non-relapse mortality, and event-free survival in these patients. To characterize additional hematologic and non-hematologic toxicities of myeloablative haploidentical PBSCT. To characterize donor hematopoietic chimerism in peripheral blood stem cells after PBSCT. OUTLINE: Preparative regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -2, busulfan IV over 3 hours on days -7 to -4, and cyclophosphamide IV over 1-2 hours on days -3 and -2. Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo infusion of unmanipulated peripheral blood stem cells on day 0. Post-transplant regimen: Patients receive high-dose cyclophosphamide IV over 1-2 hours on days 3 and 4, tacrolimus IV over 24 hours or orally twice daily on days 5-180, and oral mycophenolate mofetil 3 times daily on days 5-34 followed by a taper to day 90. Treatment continues in the absence of disease progression or clinically significant graft-vs-host disease. After completion of PBSCT, patients are followed periodically for 1 year.

Official Title
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A Phase II Trial of Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched Peripheral Blood Stem Cells for Patients With Hematologic Malignancies

Conditions
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Leukemia, Lymphoma, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: busulfan
* Drug: cyclophosphamide
* Drug: fludarabine phosphate
* Drug: mycophenolate mofetil
* Drug: tacrolimus
* Procedure: allogeneic hematopoietic stem cell transplantation
* Procedure: peripheral blood stem cell transplantation


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of one of the following high-risk hematologic malignancies: Chronic myelogenous leukemia meeting one of the following criteria: Disease in chronic phase and resistant to available tyrosine kinase inhibitors Disease in accelerated phase Disease with blast crisis that has entered into a second chronic phase after induction chemotherapy Acute myelogenous leukemia meeting the following criteria: Marrow blasts < 5% but persistence of minimal residual disease by flow cytometry, cytogenetics, or FISH Must meet one of the following criteria: Disease in second or subsequent complete remission Primary induction chemotherapy failure with disease subsequently entering complete remission Disease in first complete remission with poor-risk cytogenetics or arising from preceding hematological disease Myelodysplastic syndrome meeting at least one of the following criteria: Treatment-related Monosomy 7 or complex cytogenetics International prognostic scoring system score ≥ 1.5 Chronic myelomonocytic leukemia Acute lymphocytic leukemia or lymphoblastic lymphoma meeting the following criteria: Marrow blasts < 5% but persistence of minimal residual disease by flow cytometry, cytogenetics, or FISH Must meet one of the following criteria: Disease in second or subsequent complete remission Acute lymphocytic leukemia with poor-risk karyotype [e.g., t(9;22) or bcr-abl fusion, t(4;11), or other MLL translocation] and in first complete remission Chronic lymphocytic leukemia or prolymphocytic leukemia meeting both of the following criteria: Previously treated disease that has either relapsed or failed to respond adequately to conventional-dose therapy including purine analogs In the opinion of the transplant physician, unlikely to benefit from reduced intensity transplantation due to the presence of one or more high-risk features (i.e., bulky tumor masses, B symptoms, and/or inadequate response to salvage chemotherapy) Hodgkin or non-Hodgkin lymphoma (including low-grade, mantle cell, and intermediate-grade/diffuse disease) meeting the following criteria: Previously treated disease that has either relapsed or failed to respond adequately to conventional-dose therapy or autologous transplantation In the opinion of the transplant physician, unlikely to benefit from reduced intensity transplantation due to the presence of one or more high-risk features (i.e., bulky tumor masses, B symptoms, and/or inadequate response to salvage chemotherapy) NOTE: A new classification scheme for adult non-Hodgkin lymphoma has been adopted by PDQ. The terminology of indolent or aggressive lymphoma will replace the former terminology of low, intermediate, or high grade lymphoma. However, this protocol uses the former terminology. No available matched related or unrelated donor OR a matched related or unrelated donor will not be available in the time frame necessary to perform a transplant Availability of a first-degree relative (parent, child, sibling) matched at 3/6-5/6 loci (HLA-A, -B, -DR) Donor must be willing to donate mobilized peripheral blood stem cells No positive HLA crossmatch in the host-vs-graft direction or high titer donor-specific antibodies PATIENT CHARACTERISTICS: Karnofsky performance status 70-100% Bilirubin < 2 mg/dL (unless due to hemolysis, Gilbert syndrome, or primary malignancy) Creatinine < 2 mg/dL OR creatinine clearance ≥ 40 mL/min Not pregnant Fertile patients must use effective contraception LVEF (Left ventriculr ejection fraction) ≥ 45% FEV_1 and forced vital capacity ≥ 50% predicted No HIV positivity No debilitating medical or psychiatric illness that would preclude giving informed consent or receiving optimal treatment and follow-up PRIOR CONCURRENT THERAPY: See Disease Characteristics No immunosuppressive agents ≤ 24 hours after completion of post-transplant cyclophosphamide (including steroids as antiemetics)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Myeloablative Haploidentical Transplant<br>All patients will receive treatment using Fludarabine, Busulfan and Cyclophosphamide prior to receiving a haploidentical transplant followed by post-transplant cyclosphosphamide. | Drug: busulfan<br>* 110 mg/m2 infused over 3 hours once daily on 4 consecutive days (Days -7, -6, -5, -4)<br>Drug: cyclophosphamide<br>* 14.5 mg/kg infused over 1-2 hours once daily on 2 consecutive days (days -3,-2).<br>Drug: fludarabine phosphate<br>* 30mg/m2 infused over 30 minutes once daily on three consecutive days (days -5, -4, -3)<br>Drug: mycophenolate mofetil<br>* 15 mg/kg po three times a daily with a maximum dose of 3gm/day starting D+5. To be discontinued on Day +35 in the absence of clinically significant GVHD.<br>* Other names: CellCept;Drug: tacrolimus<br>* 0.03 mg/kg/day infuse over 24 hours starting on day +5 (adjusted to maintain trough level of 5-15 ng/ml). Switch to oral (twice daily divided dose) on day +21 or when able to tolerate PO. Discontinue on day +180 in the absence of clinically significant GVHD.<br>* Other names: Prograf, FK-506;Procedure: allogeneic hematopoietic stem cell transplantation<br>* Patients to received unmanipulated PBSCs on Day 0<br>* Other names: Allo HSCT;Procedure: peripheral blood stem cell transplantation<br>* patients to receive unmanipulated PBSCs on day 0<br>* Other names: allogeneic hematopoietic stem cell transplant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Graft Rejection for Patients at Day 100 | Number of patients who experienced graft rejection by Day 100 | Day 100 | 
| Number of Patients Who Experienced Severe Graft-versus-host Disease (GVHD)(Grade 3 or 4) | Number of patients who experienced post-transplant complication (GVHD) as seen by clinical evidence | Day 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival at Day 100 | Overall survival is assessed, without regard to disease status, post-transplant, at Day 100. | Day 100 | 
| Non-relapse Mortality at 1 Year After Peripheral Blood Stem Cell Transplantation (PBSCT) | Non-relapse mortality refers to whether a patient dies of causes related to something other than the primary disease. | 1 year | 
| Achievement of >90% (Full) Donor Chimerism in the T-Cell Lineage as Measured by PCR at Day 30 Post-transplantation | Chimerism analysis of peripheral blood mononuclear cells using PCR (polymerase chain reaction) for STR/VNTR (short tandme repeat/variable number tandem repeat) will be performed post transplant. On each occasion, the peripheral blood will be separated into the T-cell component (using e.g. CD3 selection) and the myeloid component (using e.g.CD14/15 selection) before assessment of chimerism. | Day 30 | 
| Non-relapse Mortality at Day 100 After Peripheral Blood Stem Cell Transplantation (PBSCT) |  | Day 100 | 
| Achievement of >90% (Full) Donor Chimerism in the T-Cell Lineage as Measured by PCR at Day 60 Post-transplantation | Chimerism analysis of peripheral blood mononuclear cells using PCR for STR/VNTR will be performed post transplant. On each occasion, the peripheral blood will be separated into the T-cell component (using e.g. CD3 selection) and the myeloid component (using e.g.CD14/15 selection) before assessment of chimerism. | Day 60 | 
| Achievement of >90% (Full) Donor Chimerism in the T-Cell Lineage as Measured by PCR at Day 90 Post-transplantation | Chimerism analysis of peripheral blood mononuclear cells using PCR for STR/VNTR will be performed post transplant. On each occasion, the peripheral blood will be separated into the T-cell component (using e.g. CD3 selection) and the myeloid component (using e.g.CD14/15 selection) before assessment of chimerism. | Day 90 | 
| Overall Survival at 12 Months | Overall survival, defined as a patient being alive after transplant, is without regard to disease status. | 12 months | 
| Disease Free Survival at 12 Months | Disease free survival refers to patients with no evidence of disease after transplant, at the 12 month time point. | 12 months | 
| Disease Free Survival at Day 100 | Disease free survival refers to patients with no evidence of disease after transplant, at the Day 100 time point. | Day 100 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III adult diffuse large cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage III adult Hodgkin lymphoma, stage III adult lymphoblastic 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 IV adult diffuse large cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, stage IV adult Hodgkin lymphoma, stage IV adult lymphoblastic lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage IV mantle cell lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult Hodgkin lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II adult lymphoblastic lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, noncontiguous stage II mantle cell lymphoma, accelerated phase chronic myelogenous leukemia, adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), chronic myelomonocytic leukemia, chronic phase chronic myelogenous leukemia, recurrent adult acute myeloid leukemia, refractory chronic lymphocytic leukemia, relapsing chronic myelogenous leukemia, secondary acute myeloid leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia, de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, prolymphocytic leukemia