Donor Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies

Study Overview
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Brief Summary
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The purpose of this research study is to examine the survival of patients undergoing partially matched hematopoietic stem cell transplant (HSCT) on a new type of treatment approach, which has been developed specifically for patients who have evidence of their disease at the time of transplant. In this research study, a way of strengthening the response of the donor cells against the disease has been developed. Patients will undergo one additional day between the two steps of the transplant which may allow their donor's cells to fight the disease more effectively.

Detailed Description
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This is a phase II study in which patients receive a haploidentical HSCT from a single donor. The period between the donor lymphocyte infusion (DLI) and tolerizing doses of CY has been extended to allow for an increased period of allogeneic response against tumor targets. The outcomes of patients undergoing this extra time period will be compared to historical data to assess efficacy. Primary Objective: 1) To assess 1 year relapse free survival in patients undergoing hematopoietic stem cell transplant (HSCT) using the Thomas Jefferson University (TJU) 2 step approach with an extra day inserted between the DLI and administration of cyclophosphamide (CY). Secondary Objectives: To assess the consistency and pace of engraftment. To assess the pace of T cell and B cell immune recovery. To assess regimen related toxicity, (GVHD) graft-versus-host disease incidence and severity, and overall survival in patients undergoing treatment on this protocol. . To assess the tolerance of the period of fever, diarrhea, and rash in each arm in an effort to determine whether a longer interval prior to cytoxan changes this side effect qualitatively compared to prior patient groups or concurrent patient groups. N.B. Patients with hematologic malignancies in remission will continue to be transplanted without modification to the original 2-step approach and will serve as a concurrent comparison group. To collect leukemia samples prior to transplant and after relapse whenever possible. To assess the overall degree of HLA-class I and class II expression on these paired samples. To test for loss of one or both HLA haplotypes in the relapsed tumor specimens. To determine the number of cluster of differentiation 4 (CD4+) cluster of differentiation 25 (CD25+) FOXP3+ regulatory cells post HSCT and to assess whether this is correlated with the development of GVHD after transplant.

Official Title
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A Two Step Approach to Allogeneic Hematopoietic Stem Cell Transplantation for High-Risk Hematologic Malignancies Using One Human Leukocyte Antigen Partially-Matched Related Donor

Conditions
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Hematologic Malignancy

Intervention / Treatment
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* Radiation: Total Body Irradiation
* Biological: Donor Lymphocyte Infusion (DLI)
* Drug: Cyclophosphamide
* Drug: Tacrolimus
* Drug: Mycophenolate mofetil
* Procedure: Allogeneic hematopoietic stem cell transplantation
* Other: Laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any patient with a hematologic malignancy with residual disease after treatment with 1 or more chemotherapy regimens in whom achievement of remission with additional chemoradiotherapy is felt to be unlikely or who is in 3rd or greater complete remission (CR). Patients with marrow based diseases in which the marrow biopsy does not meet criteria for active disease (ie <5% blasts in acute leukemia) but who does not have full count recovery will be eligible for treatment on this high risk trial. Patients must have at least one related donor who is HLA mismatched in the GVHD direction at two or more HLA loci. Patients must adequate organ function: Left ventricular ejection fraction (LVEF) of >50 % Diffusion capacity of the lung for carbon monoxide (DLCO) (adjusted for hemoglobin) >50 % of predicted Adequate liver function as defined by a serum bilirubin <1.8, Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 times upper limit of normal Creatinine clearance of > 60 ml/min Karnofsky Performance Status of > 80% on the modified KPS tool Patients must be willing to use contraception if they have childbearing potential. Able to give informed consent Exclusion Criteria: Modified Karnofsky performance status (KPS) of <80% > 5 Comorbidity Points on the hematopoietic cell transplantation comorbidity index (HCT-CI) Index Untreated class I or II antibodies against donor HLA antigens HIV positive Active involvement of the central nervous system with malignancy Psychiatric disorder that would preclude patients from signing an informed consent Pregnancy, or unwillingness to use contraception if they have child bearing potential Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder Alemtuzumab treatment within 8 weeks of HSCT admission. Anti-thymocyte globulin (ATG) level of > 2 ugm/ml Patients with active inflammatory processes including Tmax >101 or active tissue inflammation are excluded Inability to tolerate cyclophosphamide or undergo total body irradiation at the doses specified in the treatment plan

Ages Eligible for Study
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Minimum Age: 18 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: Allogeneic HSCT<br>CONDITIONING: Patients undergo Total Body Irradiation (TBI) twice daily (BID) on days -10 to -7. Patients also receive cyclophosphamide IV over 2 hours on days -3 and -2. TRANSPLANTATION: Patients receive DLI on day -6 and undergo cluster of differentiation 34 (CD34+) selected allogeneic HSCT on day 0 GVHD PROPHYLAXIS: Beginning on day -1, patients receive tacrolimus IV or PO on days -1 with taper beginning on day 42. Patients also receive mycophenolate mofetil IV BID or PO on days -1 to 28. | Radiation: Total Body Irradiation<br>* Undergo TBI<br>* Other names: TBI;Biological: Donor Lymphocyte Infusion (DLI)<br>* Undergo DLI<br>* Other names: DLI;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: Enduxan;Drug: Tacrolimus<br>* Given IV or PO<br>* Other names: Protopic;Drug: Mycophenolate mofetil<br>* Given IV or PO<br>* Other names: Cellcept;Procedure: Allogeneic hematopoietic stem cell transplantation<br>* Undergo allogeneic HSCT<br>Other: Laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants That Experience One Year Relapse Free Survival After Undergoing Hematopoietic Stem Cell Transplant (HSCT) | To assess relapse free survival in participants undergoing Hematopoietic Stem Cell Transplant (HSCT) using the Thomas Jefferson University 2 step approach with an extra day inserted between the donor lymphocyte infusion (DLI) and administration of cyclophosphamide. | 1 year after undergoing hematopoietic stem cell transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pace of T-cell and B-cell Immune Recovery | Reported descriptively | Assessed up to 1 year | 
| Regimen Related Toxicities Graded According to the National Cancer Institute (NCI) Common Toxicity Criteria, Version 3.0 | Reported descriptively | Assessed up to 1 year | 
| Incidence and Severity of GVHD, Graded According to Standard Criteria | Reported descriptively | Assessed up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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allogeneic stem cell transplant, TJU 2 Step, HSCT, Hematopoietic stem cell transplantation