Autologous and Allogeneic Transplant for Relapsed Lymphoma

Sequential Myeloablative Stem Cell Transplantation and Reduced Intensity Allogeneic Stem Cell Transplantation in Patients With Refractory or Recurrent Non-Hodgkin's Lymphoma and Hodgkin's Disease

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).

Study Overview

• Status: Completed
• Conditions: Non-Hodgkin's Lymphoma; Hodgkins Disease
• Intervention / Treatment: Drug: Fludarabine; Drug: Busulfan; Drug: Anti-Thymocyte Globulin

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Children's Memorial Hospital in Chicago
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Durham, North Carolina, United States, 27708
      • Duke University
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 55 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A - Family Donor; 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.	Drug: Fludarabine; Fludarabine 30 mg/m2 x 5 days; Other Names: Fludara; Drug: Busulfan; Busulfan 3.2 mg/kg/day x 2 days; Other Names: Busulfex
Experimental: Arm B - Unrelated Cord Blood or Adult; 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.	Drug: Fludarabine; Fludarabine 30 mg/m2 x 5 days; Other Names: Fludara; Drug: Busulfan; Busulfan 3.2 mg/kg/day x 2 days; Other Names: Busulfex; Drug: Anti-Thymocyte Globulin; Anti-Thymocyte Globulin 2.0 mg/kg/day x 4 days; Other Names: ATG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Number of Subjects With a Complete Response (CR) Following Myeloablative Conditioning (MAC) and Autologous Stem Cell Transplantation (AutoSCT)	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.	Up to 1 year post-transplantation
Total Number of Subjects With a Disease Relapse or Progression Following MAC AutoSCT	Includes subjects with any measurable growth of disease in a previously affected site or detection of disease in a new site confirmed by biopsy.	Up to 1 year post-transplantation
Total Number of Subjects With Partial Response or Stable Disease Following MAC AutoSCT	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.	Up to 1 year post-transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Neutrophil Engraftment	Following MAC AutoSCT, the median time to neutrophil (PMN) recovery will be measured.	Up to 1 year post-transplantation
Time to Platelet Engraftment	Following MAC AutoSCT, the median time to platelet recovery will be measured.	Up to 1 year post-transplantation
Total Number of Subjects With Grade II-IV Acute Graft-versus-Host-Disease (GVHD)	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.	Up to 1 year post-transplantation
Total Number of Subjects That Experienced Transplant-related Mortality (TRM)	Status as subjects died post-AlloHCT	Up to 1 year post-transplantation

Collaborators and Investigators

• Sponsor: Columbia University

Study record dates

Study Major Dates

• Study Start: June 1, 2003
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): October 22, 2014

Study Registration Dates

• First Submitted: May 5, 2008
• First Submitted That Met QC Criteria: December 3, 2008
• First Posted (Estimate): December 4, 2008

Study Record Updates

• Last Update Posted (Actual): March 27, 2019
• Last Update Submitted That Met QC Criteria: March 4, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Allogeneic Stem Cell Transplant; Autologous Stem Cell Transplant; Cord Blood Transplant; Relapsed Lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Hodgkin Disease; Lymphoma, Non-Hodgkin; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Fludarabine; Busulfan; Antilymphocyte Serum
• Other Study ID Numbers: AAAA5185; CHNY-01-501 (Other Identifier: CUMC)