Chemotherapy and Unrelated Donor Stem Cell Transplantation for Patients With Cancers of the Blood and Immune System

Study Overview
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Brief Summary
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Background: Major problems with stem cell transplantation (SCT) for cancer treatment are a lack of suitable donors for patients without a human leukocyte-antigen (HLA) tissue-matched sibling and graft-versus-host disease (GVHD), a serious side effects of immune-suppressing chemotherapy that is given to bring the cancer under control before SCT. In GVHD, the patients immune system attacks the transplanted donor cells. This study will try to improve the results of SCT from unrelated HLA-matched donors using targeted immune-depleting chemotherapy to bring the cancer under control before transplantation and to lower the chance of graft rejection, followed by reduced-intensity transplant chemotherapy to make the procedure less toxic. Objectives: To evaluate the safety and effectiveness of targeted immune-depleting chemotherapy followed by reduced-intensity transplant chemotherapy in patients with advanced cancers of the blood and immune system. To evaluate the safety and effectiveness of two different drug combinations to prevent GVHD. Both regimens have been successful in preventing GVHD, but they work by different mechanisms and affect the rebuilding of the immune system after the transplant. Eligibility: People 18 to 74 years of age with advanced or high-risk cancers of the blood and immune system who do not have a suitable HLA-matched sibling. Design: All patients receive chemotherapy before transplant to treat the cancer and suppress immune function. All patients receive a conditioning regimen of cyclophosphamide for 4 days and fludarabine for 4 days before SCT to prepare for the transplant. Patients are randomly assigned to one of two combination drug treatments to prevent GHVD as follows: Group 1: Tacrolimus starting 3 days before SCT and continuing for 6 months, plus methotrexate on days 1, 3, 6, and 11 post-SCT, plus sirolimus starting 3 days before the SCT and continues for 6 months following SCT. Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine starting 1 day before SCT and continuing for 6 months. Patients receive the donors stem cells and immune cells 2 days after completing the conditioning regimen. Patients are followed at the clinic regularly for the first 6 months after SCT, and then less often for at least 5 years. Some visits may include bone marrow aspirates and biopsies, blood draws, and other tests to monitor disease status. A skin biopsy, oral mucosa biopsy, and saliva collection are done to study chronic GVHD. ...

Detailed Description
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Background: The major limitations to the broader applicability of allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignancies are lack of suitable donors and therapy-related toxicities which include delayed and incomplete immune reconstitution and graft-versus-host disease (GVHD). Based on the theory that the rapid establishment of donor chimerism was essential for an optimal graft-versus-tumor effect, we have employed a strategy of targeted immune depleting chemotherapy prior to reduced-intensity allogeneic HSCT. It is our intent to investigate this approach in the setting of human leukocyte-antigen (HLA)-matched unrelated donors in a pilot manner. A clearly superior GVHD prophylaxis regimen has not been established in the unrelated donor transplant setting. The best results that have been reported are with the combination of alemtuzumab plus cyclosporine [AC] and the combination of tacrolimus, methotrexate, and sirolimus [TMS]. These two regimens work by mechanisms which are biologically distinct and potentially have markedly different effects upon immune reconstitution that have not been well studied. In addition, neither of these regimens has been assessed for their effects on chronic GVHD using the National Institutes of Health (NIH) Consensus Conference Criteria. It is our intent to study the effects that these two regimens have on immune reconstitution and chronic GVHD in the setting sequential targeted immune-depleting chemotherapy and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors. Objectives: Primary objectives: to assess the effects of two biologically distinct GVHD prophylaxis regimens, TMS and AC, on immune reconstitution in patients receiving targeted-immune depletion and reduced-intensity allogeneic HSCT from HLA-matched unrelated donors. As part of a comprehensive assessment of immune reconstitution, the primary immunologic endpoint will be the determination of cluster of differentiation 4 (CD4)+ T cell receptor V BETA repertoire by complementarity determining region 3 (CDR3) spectratyping at 3 months post-transplant. to assess overall safety of these two regimens in this setting, as determined by engraftment, acute GVHD, early and late treatment-related mortality, and overall survival. to determine and monitor incidence, organ severity and overall severity of chronic GVHD prospectively using the newly developed NIH Consensus Conference diagnosis and staging criteria and preliminarily validate those tools for use in clinical practice and trials. Secondary objectives include further assessment of immune reconstitution, study of engraftment kinetics, and assessment of those patients who receive higher doses of anthracyclines for long and short term toxicities Eligibility: Adults (18-74 years) with advanced or high risk hematologic malignancies including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL), non-hodgkin lymphoma (NHL), hodgkin lymphoma (HL), chronic myelogenous leukemia (CML), multiple myeloma, and myeloproliferative disorder (MPD) who lack a suitable HLA matched sibling. An unrelated donor matched at a minimum of 7 of 8 alleles (HLA-A,-B,-C, and DRB1) by high resolution typing, identified through the National Marrow Donor Program. Life expectancy of at least 3 months, Eastern Cooperative Oncology Group (ECOG) less than or equal to 2 and relatively normal major organ functions. Design: Patients will receive disease-specific induction chemotherapy (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (EPOCH-fludarabine (F)/rituximab (R) or fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG)) prior to transplant for disease control and immune depletion. If disease is controlled (greater than partial response (PR)) and immune depletion objectives have been met, patients may forgo induction chemotherapy and move forward to the transplant conditioning regimen. All patients will receive an identical conditioning regimen consisting of cyclophosphamide 1200 mg/m(2)/day intravenous (IV) for 4 days and fludarabine 30 mg/m(2)/day for 4 days. Patients will be stratified according to degree of HLA-match and randomized at the time of enrollment to one of two GHVD prophylaxis regimens: Group 1: Tacrolimus starting 3 days before stem cell transplant (SCT), and continuing for 6 months, plus methotrexate on days 1, 3, 6, and 11 post-SCT, plus sirolimus starting 3 days before the SCT and continues for 6 months following SCT. Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine starting 1 day before SCT and continuing for 6 months. A maximum of 105 patients will be enrolled and randomly assigned to the two arms in order to yield 44 patients per arm (88 total patients) who are able to be evaluated for development of severe chronic GVHD.

Official Title
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Phase II Trial of Targeted Immune-Depleting Chemotherapy and Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation Using 8/8 and 7/8 HLA-matched Unrelated Donors and Utilizing Two Graft-versus-Host Disease Prophylaxis Regimens for the Treatment of Leukemias, Lymphomas, and Pre-malignant Blood Disorders

Conditions
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Myelodysplastic Syndrome, Hodgkin's Lymphoma, Non-Hodgkin's Disease, Acute Leukemia, Multiple Myeloma

Intervention / Treatment
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* Biological: Rituximab
* Drug: Cyclosporine
* Drug: Allogenic stem cell transplant (ASCT)
* Drug: Conditioning Chemotherapy
* Drug: TMS
* Drug: FLAG
* Drug: EPOCH-F
* Biological: Alemtuzumab


Participation Criteria
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Eligibility Criteria
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ELIGIBILITY CRITERIA RECIPIENT ON STANDARD CARE THERAPY: The patient is 18-74 years of age. The patient has a potentially suitable 8/8 donor if they are between the ages of 69-74 years of age or a potentially suitable 8/8 or 7/8 unrelated donor(s) in the National Marrow Registry or Other Available Registry if they are between the ages of 18-74. The patient currently does not meet the protocol s eligibility/enrollment criteria for any reason. There is a high likelihood that the patient, in the opinion of the principal investigator (PI) or lead associate investigator (LAI), will meet the protocols eligibility/enrollment criteria to proceed to transplant after standard therapy is completed. The patient or legal guardian is able to give informed consent. EXCLUSION CRITERIA RECIPIENT ON STANDARD CARE THERAPY: Human immunodeficiency virus (HIV) infection. There is theoretical concern that the degree of immune suppression associated with the treatment may result in progression of HIV infection. Pregnant or lactating. Patients of childbearing potential must use an effective method of contraception. The effects of the chemotherapy, the subsequent transplant and the medications used after the transplant are highly likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to the infant.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 74 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A - Tacrolimus, methotrexate, sirolimus (TMS) Arm<br>TMS Arm | Biological: Rituximab<br>* Rituximab: 375 mg/m(2) intravenous (IV), day 1 for patients with cluster of differentiation 20 (CD20)-positive disease.<br>* Other names: Rituxan;Drug: Allogenic stem cell transplant (ASCT)<br>* Allogenic stem cell transplant<br>Drug: Conditioning Chemotherapy<br>* Fludarabine:30 mg/m(2) per day IV infusion over 30 minutes, daily. On days -6, -5, -4, and -3. Cyclophosphamide:1200 mg/m(2) per day IV infusion over 2 hours on Days 6, -5, -4, -3 Mesna: 1200 mg/m(2) per day IV infusion, Daily on days 6, -5,-4, and -3<br>Drug: TMS<br>* Tacrolimus: starting day -3 before transplant, given initially at 0.02 mg/kg/day CIV. Continue IV and then switch to an equivalent oral dose (when patient taking po) titrated for a goal level of 5 to 10 ng/ml; Sirolimus: given as an initial loading dose of 12 mg p.o. on day -3 pre-transplant, 4 mg starting day -2 pre-transplant and titrated for levels 3-12 ng/ml; Methotrexate 5 mg/m2 IV on days +1, +3, +6, and +11 post-transplant. Tacrolimus and sirolimus will be tapered at day +63, day +119 and day +180 post-transplant as tolerated.<br>* Other names: Prograf;Drug: FLAG<br>* Fludarabine:25 mg/m(2) per day IV over 30 minutes, Daily on days 1-5 Cytarabine: 2,000 mg/m(2) IV over 4 hours,on Days 1, 2, 3, 4, 5 Filgrastim: 5 mcg/kg per day subcutaneous (SC) beginning 24 hours PRIOR to initiation of chemotherapy<br>* Other names: Fludarabine+high-dose cytarabine+G-CSF (Filgrastim));Drug: EPOCH-F<br>* Fludarabine:25 mg/m(2) per day IV infusion over 30 minutes, daily on days 1-4 Etoposide :50 mg/m(2) per day continuous IV infusion over 24 hours on days 1-4 Doxorubicin:10 mg/m(2)/day CIV, days 1-4 Vincristine:0.4 mg/m(2) per day continuous IV infusion over 24 hours daily on days 1-4 Cyclophosphamide:750 mg/m(2) IV infusion over 30 minutes on day 5<br>|
| Experimental: B - Cyclosporine (AC) Arm<br>AC Arm | Biological: Rituximab<br>* Rituximab: 375 mg/m(2) intravenous (IV), day 1 for patients with cluster of differentiation 20 (CD20)-positive disease.<br>* Other names: Rituxan;Drug: Cyclosporine<br>* Cyclosporine: IV over 2 hours or orally every 12 hours on days -1 to 100, followed by a taper if graft versus host disease (GVHD) does not develop.<br>* Other names: Neoral;Drug: Allogenic stem cell transplant (ASCT)<br>* Allogenic stem cell transplant<br>Drug: Conditioning Chemotherapy<br>* Fludarabine:30 mg/m(2) per day IV infusion over 30 minutes, daily. On days -6, -5, -4, and -3. Cyclophosphamide:1200 mg/m(2) per day IV infusion over 2 hours on Days 6, -5, -4, -3 Mesna: 1200 mg/m(2) per day IV infusion, Daily on days 6, -5,-4, and -3<br>Drug: FLAG<br>* Fludarabine:25 mg/m(2) per day IV over 30 minutes, Daily on days 1-5 Cytarabine: 2,000 mg/m(2) IV over 4 hours,on Days 1, 2, 3, 4, 5 Filgrastim: 5 mcg/kg per day subcutaneous (SC) beginning 24 hours PRIOR to initiation of chemotherapy<br>* Other names: Fludarabine+high-dose cytarabine+G-CSF (Filgrastim));Drug: EPOCH-F<br>* Fludarabine:25 mg/m(2) per day IV infusion over 30 minutes, daily on days 1-4 Etoposide :50 mg/m(2) per day continuous IV infusion over 24 hours on days 1-4 Doxorubicin:10 mg/m(2)/day CIV, days 1-4 Vincristine:0.4 mg/m(2) per day continuous IV infusion over 24 hours daily on days 1-4 Cyclophosphamide:750 mg/m(2) IV infusion over 30 minutes on day 5<br>Biological: Alemtuzumab<br>* Alemtuzumab:20 mg/day IV over 8 h on days 8 to 4 pre-transplant.<br>* Other names: Campath;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Grade II-IV Acute Graft Versus Host Disease (GVHD) | Acute GVHD is assessed by the 1994 Consensus Conference on Acute GVHD Grading criteria. See Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995; 15:825-8., for grading criteria. | 6 months | 
| Percentage of Participants With Chronic Graft Versus Host Disease (cGVHD) | Chronic GVHD is assessed by the 2005 Chronic GVHD Consensus Project. First the individual organ scoring is done, and then based on that the Global score is determined (mild-moderate-severe). See Citation: Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005; 11:945-56., for grading criteria. | 2 years post transplant | 
| Recovery of Naïve Cluster of Differentiation 4 (CD4) T Cells | The percentage of C-C motif chemokine receptor 7 (CCR7)+CD45RA+ naïve T cells within the CD4 T cell populations was determined by flow cytometry. | Recipient recovery at 6, 12 and 24 months post transplant | 
| Recovery of Naïve Cluster of Differentiation 8 (CD8) T Cells | The percentage of CCR7+CD45RA+ naïve T cells within the CD4 and CD8 T cell populations was determined by flow cytometry. | Recipient recovery at 6, 12 and 24 months post transplant | 
| Changes in Cluster of Differentiation 4 (CD4) T Cell Receptor Vbeta Repertoire | Ribonucleic acid (RNA) was extracted from sorted CD4 and cluster of differentiation 8 (CD8) T cells and analyzed for Vbeta repertoire by nested polymerase chain reaction (PCR) analysis using Vbeta family specific primers and a labeled constant region primer (spectratyping). The receptor repertoire diversity was calculated from spectratyping data by creating a normal standard for repertoire diversity from healthy normal controls and assessing the divergence of individual patient's T cell receptor repertoire from these standard normal donor values. In this Vbeta repertoire divergence index, lower numbers are consistent with a more normal highly diverse repertoire, and high numbers represent a highly skewed, oligoclonal repertoire. The assay is described in Memon SA et al, J Immunol Methods, 2012, 375: 84-92. The repertoire diversity of the CD4 and CD8 T cells of the donor infusion is shown for comparison. | Donor at time of collection and recipient at 1, 3, 6 and 12 months post transplant | 
| Changes in CD8 T Cell Receptor Vbeta Repertoire | Ribonucleic acid (RNA) was extracted from sorted CD4 and cluster of differentiation 8 (CD8) T cells and analyzed for Vbeta repertoire by nested polymerase chain reaction (PCR) analysis using Vbeta family specific primers and a labeled constant region primer (spectratyping). The receptor repertoire diversity was calculated from spectratyping data by creating a normal standard for repertoire diversity from healthy normal controls and assessing the divergence of individual patient's T cell receptor repertoire from these standard normal donor values. In this Vbeta repertoire divergence index, lower numbers are consistent with a more normal highly diverse repertoire, and high numbers represent a highly skewed, oligoclonal repertoire. The assay is described in Memon SA et al, J Immunol Methods, 2012, 375: 84-92. The repertoire diversity of the CD4 and CD8 T cells of the donor infusion is shown for comparison. | Donor at time of collection and recipient at 1, 3, 6 and 12 months post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Grade III-IV Acute Graft Versus Host Disease (GVHD) | Acute GVHD is assessed by the 1994 Consensus Conference on acute GVHD Grading criteria. See Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995; 15:825-8., for grading criteria. | 6 months | 
| Toxicities | Here are the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module. | 103 months and 22 days | 
| Days to Engraftment of Neutrophils | Days to engraftment is defined as neutrophil recovery: designated by the first of 3 consecutive days with an absolute neutrophil count (ANC) above 500/mm(3). | 2 years | 
| Days to Engraftment of Platelets | Platelet recovery: designated by the first of 7 days where the platelet count remains above 20,000/mm(3) without transfusion support | 2 years | 
| Days to Engraftment of Lymphocytes | Lymphocyte recovery: designated by the first of 3 consecutive days with absolute lymphocyte count (ALC) above 500/mm(3). | 2 years | 
| Overall Survival | Time between the first day of transplant to the day of death. | Patients were followed for an average of up to 5 years. | 
| Early Treatment Related Mortality | Any death occurring within 28 days after transplantation in a patient in continuous remission. | Less than or equal to 28 days after transplantation | 
| Percentage of Participants With Late Treatment Related Mortality | Any death occurring 28 days or more after transplantation in a patient in continuous remission. | Greater than 28 days after transplantation | 
| Decline in Homeostatic Cytokine Interleukin 7 (IL-7) Post-Transplant | During depletion of lymphocytes during transplant conditioning, levels of homeostatic cytokines increase in the blood. These then decline with the expansion of new donor-derived cells. The rapidity of decline may predict acute graft versus host disease (AGVHD). Decline in cytokine IL-7 will be assessed by the enzyme-linked immunosorbent assay (ELISA). | Day 0, 1 week and 2 weeks | 
| Immune Reconstitution of Normal Killer (NK) Cells | Cluster of differentiation 3 (CD3) - cluster of differentiation 56 (CD56) + Natural Killer (NK) cells within the lymphocyte population were determined by flow cytometry. The absolute numbers of cells/µl were calculated from the absolute lymphocyte count. | 2 weeks, and 1, 3, 6, 12, and 24 months post transplant | 
| Immune Reconstitution of Cluster of Differentiation 4 (CD4) T Cell Populations | Cluster of Differentiation 3 (CD3)+CD4+ and CD3+Cluster of Differentiation 8 (CD8)+ T cells within the lymphocyte population were determined by flow cytometry. The absolute numbers of cells/µl were calculated from the absolute lymphocyte count. | 2 weeks, and 1, 3, 6, 12 and 24 months post transplant | 
| Immune Reconstitution of Cluster of Differentiation 8 (CD8) T Cell Populations | Cluster of differentiation 3 (CD3)+cluster of differentiation 4 (CD4)+ and CD3+CD8+ T cells within the lymphocyte population were determined by flow cytometry. The absolute numbers of cells/µl were calculated from the absolute lymphocyte count. | 2 weeks, 1, 3, 6, 12 and 24 months post transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Unrelated Donors, Reduced Intensity Stem Cell Transplant, Leukemia, Lymphoma, Allogeneic Stem Cell Transplant, Myelodysplastic Syndrome, Multiple Myeloma