Allogeneic Transplantation Using Total Lymphoid Irradiation (TLI) and Anti-Thymocyte Globulin (ATG) for Older Patients With Hematologic Malignancies

Study Overview
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Brief Summary
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To measure how frequently and to what degree a complication of transplant cell acute graft versus host disease (GvHD) occurs.

Detailed Description
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This study evaluated whether TLI-ATG conditioning followed by allogeneic hematpoietic cell transplant (HCT), which has provided excellent overall survival for patients with relapsed lymphoma after failed autologous HCT, provides a similar benefit in the setting of elderly patients with hematologic malignancies.

Official Title
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Allogeneic Hematopoietic Cell Transplantation Using a Non-Myeloablative Preparative Regimen of Total Lymphoid Irradiation and Anti-Thymocyte Globulin for Older Patients With Hematologic Malignancies

Conditions
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Blood Cancer, Leukemia

Intervention / Treatment
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* Drug: Cyclosporine
* Drug: Anti-thymocyte globulin (ATG)
* Drug: Mycophenolate mofetil (MMF)
* Drug: Filgrastim
* Radiation: Total Lymphoid Irradiation (TLI)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Any patient with one of the following hematolymphoid malignancies or syndromes in whom allogeneic hematopoietic stem cell transplant (HST) is warranted. Specific disease categories include: Indolent advanced stage non-Hodgkin lymphomas Mantle cell lymphoma Chronic lymphocytic leukemia Hodgkin disease (Hodgkin's lymphoma) Acute leukemias in complete remission Aplastic anemia Paroxysmal nocturnal hemoglobinuria Myelodysplastic or myeloproliferative syndromes. Other selected malignancies/disorders may also be considered but must be approved by the transplant team and the Principal Investigator. Age > 50 years, or if < 50 years of age, considered to be at high risk for regimen-related toxicity associated with conventional myeloablative transplants due to pre-existing medical conditions or prior therapy. A fully human leukocyte antigen (HLA)-identical sibling or matched unrelated donor is available. Potential participants with one antigen mismatched donors can be considered but only after discussion with the transplant team and the Principal Investigator. Participant must be competent to give consent. EXCLUSION CRITERIA: Progressive hematolymphoid malignancies despite conventional therapies, or acute leukemias not in complete remission. Uncontrolled central nervous system (CNS) involvement with disease Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment Pregnant Cardiac ejection fraction < 30% Uncontrolled cardiac failure Pulmonary diffusing capacity (DLCO) < 40% predicted Elevation of bilirubin to > 3 mg/dL Transaminases > 4 x the upper limit of normal Creatinine clearance < 50 cc/min (24-hour urine collection) Karnofsky performance score < 60% Poorly controlled hypertension on multiple antihypertensives Documented fungal disease that is progressive despite treatment HIV-positive. Other viral infections, ie, Hepatitis B- and C- positive, evaluated on a case-by-case basis 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.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 70 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: Non-myeloablative transplantation<br>Pre-transplant total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) infusion with Day 0 allogeneic hematopoietic cell transplant (HCT), followed by post-transplant immunosuppression by cyclosporine and mycophenolate mofetil. | Drug: Cyclosporine<br>* Starting day -3 at a dose of 5 mg/kg orally twice daily with a target trough level of 350 to 450 ng/mL<br>* Other names: Cyclosporin A;Drug: Anti-thymocyte globulin (ATG)<br>* 1.5 mg/kg for total dose of 7.5mg/kg, IV starting on day -11 to day -7 before HCT<br>* Other names: Thymoglobulin;Drug: Mycophenolate mofetil (MMF)<br>* Begins on day 0 after HCT at a dose of 15 mg/kg. Transplant recipients who received related donor grafts received MMF twice daily and those who received unrelated donor grafts received MMF 3 times daily.<br>* Other names: CellCept;Drug: Filgrastim<br>* Donors mobilized with 16 µg/kg/day filgrastim. As needed, myelosuppression in transplant recipients will be managed with subcutaneous filgrastim 5 µg/kg/day<br>* Other names: colony-stimulating factor 3 (CSF-3);Radiation: Total Lymphoid Irradiation (TLI)<br>* 0.8 Gy/day from day -11 to day -7 (inclusive) from day -4 to day -2 (inclusive) with 2 additional fractions of 0.8 Gy delivered on day -1 for total dose of 8 Gy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Graft vs Host Disease (GvHD) | The incidence of acute GvHD after transplantation was assessed per Glucksberg GvHD grade, a compound scale based on the following combinations of disease stages. Skin Stages 0: No rash 1: Maculopapular (MP) rash <25% of body surface area 2: MP rash on 25-50% of body surface area 3: Generalized erythroderma (ED) 4: Generalized ED with bullous formation and desquamation Liver Stages (Bilirubin in mg/dL) 0: <2 1: 2-3 2: 3.01-6 3: 6.01-15.0 4: >15 Gastrointestinal (GI) Stages (diarrhea) 0: None or < 500 mL/day 1: 500-999 mL/day 2: 1000-1499 mL/day 3: >1500 mL/day 4: Severe abdominal pain, with or without ileus Glucksberg Overall grade Grade 1: Skin 1/2; GI 0; Liver 0; Karnofsky performance scale (KPS) 90-100% Grade 2: Skin 1-3; GI 1; Liver 1; KPS 70-80 Grade 2: Skin 2/3; GI 2/3; Liver 2-4; KPS 50-60 Grade 4: Skin 2-4; GI 2-4; Liver 2-4; KPS 30-40 | 100 days post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Graft vs Host Disease (GvHD), All Evaluable | The incidence of acute GvHD after transplantation was assessed per Glucksberg GvHD grade, a compound scale based on the following combinations of disease stages. Skin Stages 0: No rash 1: Maculopapular (MP) rash <25% of body surface area 2: MP rash on 25-50% of body surface area 3: Generalized erythroderma (ED) 4: Generalized ED with bullous formation and desquamation Liver Stages (Bilirubin in mg/dL) 0: <2 1: 2-3 2: 3.01-6 3: 6.01-15.0 4: >15 Gastrointestinal (GI) Stages (diarrhea) 0: None or < 500 mL/day 1: 500-999 mL/day 2: 1000-1499 mL/day 3: >1500 mL/day 4: Severe abdominal pain, with or without ileus Glucksberg Overall grade Grade 1: Skin 1/2; GI 0; Liver 0; Karnofsky performance scale (KPS) 90-100% Grade 2: Skin 1-3; GI 1; Liver 1; KPS 70-80 Grade 2: Skin 2/3; GI 2/3; Liver 2-4; KPS 50-60 Grade 4: Skin 2-4; GI 2-4; Liver 2-4; KPS 30-40 | 100 days post-transplant | 
| Incidence of Relapse | Reports the overall rate of disease relapse, occurring any time within 3 years after transplant | 3 years | 
| Overall Survival (OS) |  | 3 and 5 years | 
| Event-free Survival (EFS) | Reports the number and proportion of participants who neither died due to any cause nor experienced relapse. | 3 and 5 years | 
| Transplant-related Mortality | Reports the proportion of participants who expired within 1 year due to any complication or failure of the transplant. | 1 year |