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

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

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

Study Overview

• Status: Completed
• Conditions: Leukemia; Blood Cancer
• Intervention / Treatment: Drug: Cyclosporine; Drug: Anti-thymocyte globulin (ATG); Drug: Mycophenolate mofetil (MMF); Drug: Filgrastim; Radiation: Total Lymphoid Irradiation (TLI)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 303
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Non-myeloablative transplantation; 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; Starting day -3 at a dose of 5 mg/kg orally twice daily with a target trough level of 350 to 450 ng/mL; Other Names: Cyclosporin; Cyclosporin A; Drug: Anti-thymocyte globulin (ATG); 1.5 mg/kg for total dose of 7.5mg/kg, IV starting on day -11 to day -7 before HCT; Other Names: Thymoglobulin; Drug: Mycophenolate mofetil (MMF); 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.; Other Names: CellCept; Drug: Filgrastim; Donors mobilized with 16 µg/kg/day filgrastim.; As needed, myelosuppression in transplant recipients will be managed with subcutaneous filgrastim 5 µg/kg/day; Other Names: Neupogen; Granulocyte-colony stimulating factor (G-CSF; GCSF); colony-stimulating factor 3 (CSF-3); Radiation: Total Lymphoid Irradiation (TLI); 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Stanford University

Publications and helpful links

General Publications

• Lowsky R, Takahashi T, Liu YP, Dejbakhsh-Jones S, Grumet FC, Shizuru JA, Laport GG, Stockerl-Goldstein KE, Johnston LJ, Hoppe RT, Bloch DA, Blume KG, Negrin RS, Strober S. Protective conditioning for acute graft-versus-host disease. N Engl J Med. 2005 Sep 29;353(13):1321-31. doi: 10.1056/NEJMoa050642. Erratum In: N Engl J Med. 2006 Feb 23;354(8):884.
• Jones CD, Arai S, Lowsky R, Tyan DB, Zehnder JL, Miklos DB. Complete donor T-cell engraftment 30 days after allogeneic transplantation predicts molecular remission in high-risk chronic lymphocytic leukaemia. Br J Haematol. 2010 Sep;150(5):637-9. doi: 10.1111/j.1365-2141.2010.08252.x. Epub 2010 Jun 7. No abstract available.
• Rezvani AR, Kanate AS, Efron B, Chhabra S, Kohrt HE, Shizuru JA, Laport GG, Miklos DB, Benjamin JE, Johnston LJ, Arai S, Weng WK, Negrin RS, Strober S, Lowsky R. Allogeneic hematopoietic cell transplantation after failed autologous transplant for lymphoma using TLI and anti-thymocyte globulin conditioning. Bone Marrow Transplant. 2015 Oct;50(10):1286-92. doi: 10.1038/bmt.2015.149. Epub 2015 Jul 6.
• Kohrt HE, Turnbull BB, Heydari K, Shizuru JA, Laport GG, Miklos DB, Johnston LJ, Arai S, Weng WK, Hoppe RT, Lavori PW, Blume KG, Negrin RS, Strober S, Lowsky R. TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors. Blood. 2009 Jul 30;114(5):1099-109. doi: 10.1182/blood-2009-03-211441. Epub 2009 May 7.
• Benjamin J, Chhabra S, Kohrt HE, Lavori P, Laport GG, Arai S, Johnston L, Miklos DB, Shizuru JA, Weng WK, Negrin RS, Lowsky R. Total lymphoid irradiation-antithymocyte globulin conditioning and allogeneic transplantation for patients with myelodysplastic syndromes and myeloproliferative neoplasms. Biol Blood Marrow Transplant. 2014 Jun;20(6):837-43. doi: 10.1016/j.bbmt.2014.02.023. Epub 2014 Mar 7.

Study record dates

Study Major Dates

• Study Start: March 1, 2003
• Primary Completion (ACTUAL): April 1, 2014
• Study Completion (ACTUAL): January 1, 2016

Study Registration Dates

• First Submitted: September 12, 2005
• First Submitted That Met QC Criteria: September 12, 2005
• First Posted (ESTIMATE): September 16, 2005

Study Record Updates

• Last Update Posted (ACTUAL): June 29, 2021
• Last Update Submitted That Met QC Criteria: June 24, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Hematologic Diseases; Hematologic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Lenograstim; Mycophenolic Acid; Thymoglobulin; Antilymphocyte Serum; Cyclosporine; Cyclosporins
• Other Study ID Numbers: IRB-11960; 78998 (OTHER: Stanford University Alternate IRB Approval Number); BMT153 (OTHER: OnCore)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No