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

• ClinicalTrials.gov Identifier: NCT00185640
• Recruitment Status: Completed
• First Posted: September 16, 2005
• Results First Posted: October 3, 2017
• Last Update Posted: June 29, 2021
• Sponsor: Stanford University
• Information provided by (Responsible Party): Robert Lowsky, Stanford University

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Blood Cancer; Leukemia	Drug: Cyclosporine; Drug: Anti-thymocyte globulin (ATG); Drug: Mycophenolate mofetil (MMF); Drug: Filgrastim; Radiation: Total Lymphoid Irradiation (TLI)	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 303 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Allogeneic Hematopoietic Cell Transplantation Using a Non-Myeloablative Preparative Regimen of Total Lymphoid Irradiation and Anti-Thymocyte Globulin for Older Patients With Hematologic Malignancies
• Study Start Date: March 2003
• Actual Primary Completion Date: April 2014
• Actual Study Completion Date: January 2016

Arms and Interventions

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 Name: 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 Name: 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.

Outcome Measures

Primary Outcome Measures :

1. Acute Graft vs Host Disease (GvHD) [ Time Frame: 100 days post-transplant ]

   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

Secondary Outcome Measures :

1. Acute Graft vs Host Disease (GvHD), All Evaluable [ Time Frame: 100 days post-transplant ]

   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
2. Incidence of Relapse [ Time Frame: 3 years ]
   Reports the overall rate of disease relapse, occurring any time within 3 years after transplant
3. Overall Survival (OS) [ Time Frame: 3 and 5 years ]
4. Event-free Survival (EFS) [ Time Frame: 3 and 5 years ]
   Reports the number and proportion of participants who neither died due to any cause nor experienced relapse.
5. Transplant-related Mortality [ Time Frame: 1 year ]
   Reports the proportion of participants who expired within 1 year due to any complication or failure of the transplant.

Eligibility Criteria

• Ages Eligible for Study: 50 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, California

Stanford University School of Medicine

Stanford, California, United States, 94305

Sponsors and Collaborators

Stanford University

Investigators

• Principal Investigator: Robert Lowsky; Stanford University

More Information

Publications of Results:

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.

• Responsible Party: Robert Lowsky, Professor of Medicine, Stanford University
• ClinicalTrials.gov Identifier: NCT00185640
• Obsolete Identifiers: NCT00186615
• Other Study ID Numbers: IRB-11960; 78998 ( Other Identifier: Stanford University Alternate IRB Approval Number ); BMT153 ( Other Identifier: OnCore )
• First Posted: September 16, 2005
• Results First Posted: October 3, 2017
• Last Update Posted: June 29, 2021
• Last Verified: June 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Hematologic Neoplasms; Neoplasms; Neoplasms by Site; Hematologic Diseases; Cyclosporine; Mycophenolic Acid; Lenograstim; Cyclosporins; Thymoglobulin; Antilymphocyte Serum; Adjuvants, Immunologic; Immunologic Factors; Physiological Effects of Drugs; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Antifungal Agents; Anti-Infective Agents; Dermatologic Agents; Antirheumatic Agents; Calcineurin Inhibitors; Antibiotics, Antineoplastic; Antineoplastic Agents; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents