Autologous and Allogeneic Transplant for Relapsed Lymphoma

Phase 1

Completed

Conditions: Hodgkins Disease
Non-Hodgkin's Lymphoma

Interventions: Drug: Fludarabine
Drug: Busulfan
Drug: Anti-Thymocyte Globulin

Registration Number: NCT00802113

Lead Sponsor: Columbia University

Brief Summary: The sequential combination of myeloablative therapy and autologous stem cell transplantation (APBSCT) followed by a reduced intensity allogeneic stem cell transplant (Allo SCT) and post SCT adoptive cellular immunotherapy will be well tolerated in patients with refractory or recurrent non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD).

Detailed Description: Lymphomas are the third most common group of cancers in children and adolescents in the United States. While Hodgkin's Disease (HD) has been described for many years, some subtypes of the non-Hodgkin's Lymphomas (NHL) have only recently been described. Non-Hodgkin's lymphomas traditionally have been classified as low, intermediate or high grade based on their clinical aggressiveness. More recently they have been divided into two major subgroups indolent and aggressive lymphomas by the current National Cancer Institute (NCI/PDQ) reference. Among children, aggressive histologies are prevalent including small non-cleaved cell lymphoma, lymphoblastic lymphoma, and diffuse large cell lymphoma. The most common histologic classifications of childhood non-Hodgkin's lymphoma over the past 30 years has included the morphological schema developed by Rappaport, the morphologically and immunologically based schema of Lukes and Collins, the Kiel classifications, the prognostic sub-groupings of the National Cancer Institute's Working Formulation, and the most recently developed classification that utilizes morphological, immunophenotypic and genetic information in the Revised European-American Lymphoma (REAL) classification.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 30

Inclusion Criteria

Patient must have adequate organ function as below

Adequate renal function defined as:
1. Serum creatinine less than or equal to 2.0 x normal, or
2. Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 40 ml/min/m2 or >60 ml/min/1.73 m2 or an equivalent GFR as determined by the institutional normal range
Adequate liver function defined as:
1. Total bilirubin <2.0 x normal; or
2. Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase (AST)) or serum glutamic-pyruvic transaminase (SPGT) (alanine aminotransferase (ALT)) <5.0 x normal
Adequate cardiac function defined as:
1. Shortening fraction of >27% by echocardiogram, or
2. Ejection fraction of >47% by radionuclide angiogram or echocardiogram
Adequate pulmonary function defined as:
1. Diffusing capacity of the lungs for carbon monoxide (DLCO) >50% by pulmonary function test for autologous transplant
2. DLCO > 40% by pulmonary function test for reduced intensity allogeneic transplant
3. For children who are uncooperative, no evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry >94% in room air.

Disease Status (Eligibility)

Patients with Non-Hodgkin's Lymphoma with either of the following:
1. Primary induction failure (failure to achieve initial CR) who have a partial response (PR) or stable disease (SD) with reinduction chemotherapy. *All patients are required to have a biopsy regardless of positron emission tomography (PET)/Gallium results.
2. Patients with 1st PR, 2nd CR, 2nd PR, or 2nd SD following reinduction chemotherapy
3. Patients with 3rd CR, 3rd PR, 3rd SD following reinduction chemotherapy
Patients with Hodgkin's Disease with either of the following:
1. Primary induction failure (failure to achieve initial CR) and/or primary refractory disease.
2. First relapse
  1. Early relapse (within 12 months off therapy) (excluding those who received no therapy or radiation therapy only for initial therapy)
  2. Late relapse (greater than 12 months off therapy). Only patients with recurrent Stage III or IV disease and/or those with B symptoms at relapse (all other late relapses are excluded).
  3. Second relapse.
  4. Third relapse.
Patients must achieve a CR, PR or SD after reinduction chemotherapy.

Exclusion Criteria

Patients with NHL or HD with 4th or greater CR, PR, and/or SD
Patients with progressive disease (PD) unresponsive to reinduction chemo, radio, or immunotherapy
Hodgkin's Disease in late relapse (other than those discussed above).
Patients with post-transplant lymphoproliferative disease following a solid organ transplantation or AIDS associated NHL
Patients who don't have an eligible donor
Women who are pregnant

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm B - Unrelated Cord Blood or Adult	Anti-Thymocyte Globulin	Fludarabine, Busulfan and ATG: For patients who don't have a matched family donor, a cord blood search and unrelated adult search will be done at all of the cord blood banks and adult donor registries in the world. If a closely matched cord blood donor or unrelated adult donor is found, non-ablative chemotherapy with busulfan, ﬂudarabine and antithymocyte globulin (ATG) followed by the infusion of matched unrelated cord blood cells or adult donor stem cells or bone marrow to restore the bone marrow will be given.
Arm A - Family Donor	Busulfan	Fludarabine and Busulfan: Patients who have a matched family (allogeneic) donor will go on to receive non-ablative therapy, followed by an infusion of donor stem cells; this is called an allogeneic peripheral blood stem cell transplant. The non-ablative therapy will be busulfan and ﬂudarabine, Usually large (myeloablative) doses of these drugs are used for an allogeneic transplant. However, in this study lower doses (non-ablative) of chemotherapy will be given. In patients who still have evidence of disease after allogeneic transplant, additional donor immune cells (donor lymphocyte infusion) (DLI) will be given twice to further treat the lymphoma.
Arm B - Unrelated Cord Blood or Adult	Fludarabine	Fludarabine, Busulfan and ATG: For patients who don't have a matched family donor, a cord blood search and unrelated adult search will be done at all of the cord blood banks and adult donor registries in the world. If a closely matched cord blood donor or unrelated adult donor is found, non-ablative chemotherapy with busulfan, ﬂudarabine and antithymocyte globulin (ATG) followed by the infusion of matched unrelated cord blood cells or adult donor stem cells or bone marrow to restore the bone marrow will be given.
Arm A - Family Donor	Fludarabine	Fludarabine and Busulfan: Patients who have a matched family (allogeneic) donor will go on to receive non-ablative therapy, followed by an infusion of donor stem cells; this is called an allogeneic peripheral blood stem cell transplant. The non-ablative therapy will be busulfan and ﬂudarabine, Usually large (myeloablative) doses of these drugs are used for an allogeneic transplant. However, in this study lower doses (non-ablative) of chemotherapy will be given. In patients who still have evidence of disease after allogeneic transplant, additional donor immune cells (donor lymphocyte infusion) (DLI) will be given twice to further treat the lymphoma.
Arm B - Unrelated Cord Blood or Adult	Busulfan	Fludarabine, Busulfan and ATG: For patients who don't have a matched family donor, a cord blood search and unrelated adult search will be done at all of the cord blood banks and adult donor registries in the world. If a closely matched cord blood donor or unrelated adult donor is found, non-ablative chemotherapy with busulfan, ﬂudarabine and antithymocyte globulin (ATG) followed by the infusion of matched unrelated cord blood cells or adult donor stem cells or bone marrow to restore the bone marrow will be given.

Primary Outcome Measures

Name	Time	Method
Total Number of Subjects With a Disease Relapse or Progression Following MAC AutoSCT	Up to 1 year post-transplantation	Includes subjects with any measurable growth of disease in a previously affected site or detection of disease in a new site confirmed by biopsy.
Total Number of Subjects With a Complete Response (CR) Following Myeloablative Conditioning (MAC) and Autologous Stem Cell Transplantation (AutoSCT)	Up to 1 year post-transplantation	Complete Response is defined as the complete resolution of B symptoms (i.e., weight loss, night sweats and fever) and normalization of all sites of disease on the basis of physical exam, bone marrow biopsy, and imaging studies.
Total Number of Subjects With Partial Response or Stable Disease Following MAC AutoSCT	Up to 1 year post-transplantation	Total includes subjects with partial response and patients with stable disease, defined as \<50% reduction in measurable disease or the uninterrupted persistence of B symptoms.

Secondary Outcome Measures

Name	Time	Method
Time to Neutrophil Engraftment	Up to 1 year post-transplantation	Following MAC AutoSCT, the median time to neutrophil (PMN) recovery will be measured.
Total Number of Subjects That Experienced Transplant-related Mortality (TRM)	Up to 1 year post-transplantation	Status as subjects died post-AlloHCT
Time to Platelet Engraftment	Up to 1 year post-transplantation	Following MAC AutoSCT, the median time to platelet recovery will be measured.
Total Number of Subjects With Grade II-IV Acute Graft-versus-Host-Disease (GVHD)	Up to 1 year post-transplantation	The criteria for grading is based on extent of organ involvement (i.e., Skin, Liver and Gut - rash on \>50% of skin, bilirubin 2-3 mg/dl, diarrhea \> 500 ml/day) with Grade II being better outcome and Grade IV being worse outcome.

Trial Locations

Locations (6): Children's Memorial Hospital in Chicago
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Chicago, Illinois, United States
Columbia University Medical Center
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New York, New York, United States
Hackensack University Medical Center
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Hackensack, New Jersey, United States
New York Medical College
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Valhalla, New York, United States
Duke University
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Durham, North Carolina, United States
Medical College of Wisconsin
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Milwaukee, Wisconsin, United States