TLI & ATG for Non-Myeloablative Allogeneic Transplantation for MDS and MPD

Total Lymphoid Irradiation and Anti-Thymocyte Globulin as Conditioning for Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation for the Treatment of Myelodysplastic Syndromes and Myeloproliferative Disorders (Except CML)

To evaluate the feasibility and safety of TLI/ATG conditioning for allogeneic HCT for elderly patients with advanced stage MDS and MPD.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes; Myeloproliferative Disorders; Blood Cancer
• Intervention / Treatment: Procedure: Total Lymphoid Irradiation (TLI); Procedure: Anti-Thymocyte Globulin as Conditioning (ATG)

Detailed Description

Total Lymphoid Irradiation and Anti-Thymocyte Globulin as Conditioning for Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation for the Treatment of Myelodysplastic Syndromes and Myeloproliferative Disorders (except CML). To evaluate the feasibility and safety of TLI/ATG conditioning for allogeneic HCT for elderly patients or those with co-morbid conditions that preclude myeloablative transplantation for advanced stage MDS and MPD.

• Study Type: Interventional
• Enrollment (Actual): 77
• 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: 49 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

GENERAL INCLUSION CRITERIA

• General inclusion criteria must include at least one of the following:

  • Patients aged > 49 and < 75 years with MDS or MPD
  • Patients aged < 49 years at high risk for regimen related toxicity using standard high dose regimens. Factors considered high risk include pre-existing conditions such as a chronic disease affecting kidneys, liver, lungs, or heart.
  • Patients with secondary MDS following a prior autologous transplant.
• An HLA-identical related or an HLA-matched unrelated donor is available. ABO incompatibility is acceptable.
• A signed informed consent form.

MYELODYSPLASTIC SYNDROME CRITERIA

• Diagnosis of MDS classifiable by the FAB system as refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), chronic myelomonocytic leukemia (CMML), refractory anemia with excess blasts (RAEB), and MDS transformed to acute leukemia.
• Patients with advanced MDS must be cytoreduced to < 10% marrow blasts prior to receiving conditioning with TLI/ATG. Less than 10% marrow blasts must be documented by marrow examination within 1 month of starting conditioning. The cytoreductive regimen will be determined by referring centers.
• Patients with evolution to AML are required to be in a complete remission as defined by a blast count of less than 5% in a marrow aspirate with adequate cellularity. Presence of residual dysplastic features following cytoreductive therapy is acceptable.
• All patients with high risk disease, for example "intermediate-2" or "high risk" disease by the IPSS score. Other selected patients with a lower IPSS score may be considered but only after discussion with the BMT attending physicians, as a group, and the PI of the study.

MYELOPROLIFERATIVE DISORDERS

• Myeloproliferative disorders to be included:

  • Philadelphia chromosome-negative CML.
  • Patients with polycythemia vera with persistent thrombotic or hemorrhagic complications despite conventional therapy, or who have progressed to post-polycythemic marrow fibrosis.
  • Patients with essential thrombocythemia with persistent thrombotic or hemorrhagic complications despite conventional therapy, or who have progressed to myelofibrosis.
  • Patients with agnogenic myeloid metaplasia with high risk disease, for example "intermediate" or "high risk" according to the Lille Scoring System.
• Patients must be cytoreduced to < 10% marrow blasts. Less than 10% marrow blasts must be documented by marrow examination within 1 month of initiation of TLI/ATG. The cytoreductive regimen will be determined by referring centers.
• Patients with evolution to AML are required to be in a complete remission as defined by a blast count of less than 5% in a marrow aspirate with adequate cellularity. Presence of residual dysplastic features following cytoreductive therapy is acceptable.

INCLUSION CRITERIA - RELATED DONORS

• Related to the patient and is genotypically or phenotypically HLA-identical.
• Donor age < 75 unless cleared by P.I
• Capable of giving written, informed consent.
• Donor must consent to PBSC mobilization with G-CSF and apheresis

INCLUSION CRITERIA - UNRELATED DONORS

• Donors must be HLA-matched as defined by the following criteria:

  • Matched for HLA-DRB1 and DQB1 by high resolution typing.
  • Serologic match for all recognized HLA-A, HLA-B, and HLA-C antigens, and molecular match for at least 5 of 6 HLA-A, HLA-B, or HLA-C antigens by high resolution typing.
• Donor must consent to PBSC mobilization with G-CSF and apheresis. Bone marrow unrelated donors are not eligible for this protocol.

Exclusion Criteria:GENERAL EXCLUSION CRITERIA

• Organ dysfunction as defined by the following:

  • Renal: Patients with a normal creatinine are eligible for study without the need for a 24 hr urine collection for creatinine clearance. Patients with an elevated creatinine require a 24 hr urine collection. If the creatinine clearance is < 50 ml/min patients will be determined for inclusion on a case by case basis.
  • Cardiac: Ejection fraction < 40%, symptomatic congestive heart failure requiring therapy, poorly controlled cardiac arrythmias, or poorly controlled hypertension with inability to maintain a steady-state blood pressure of 150/90.
  • Pulmonary: Requirement for supplemental oxygen administration, or pulmonary function testing showing (1) DLCO < 50% of predicted, (2) TLC < 30%, or (3) FEV1 < 30%.
  • Hepatic: Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function and degree of portal hypertension. Patients will be excluded if they are found to have fulminant liver failure, cirrhosis if the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess. Biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dl, and symptomatic biliary disease.
• Bone marrow documenting blast count >=10%.
• Presence of active of non-hematologic malignancy (except localized non-melanoma skin malignancies) or hematologic malignancy other than MDS or MPD as listed in inclusion criteria.
• Active CNS involvement of disease.
• Karnofsky performance score <= 60% or Lansky-Play Performance score <50 for pediatric patients.
• Life expectancy severely limited by diseases other than malignancy.
• Fungal infections with radiological progression despite with an amphotericin product or active triazole for > 1 month.
• Active bacterial infection.
• Patients of fertile age who refuse contraception for a twelve month period post-transplant.
• Pregnant or lactating females.
• HIV seropositivity.
• Severe psychological illness.

EXCLUSION CRITERIA - RELATED DONORS

• Identical twin
• Any contra-indication to the administration of subcutaneous G-CSF at a dose of 16mg/kg/d for five consecutive days
• Serious medical or psychological illness
• Pregnant or lactating females
• Prior malignancy within the preceding five years, with the exception of non-melanoma skin cancers.
• HIV seropositivity

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

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: TLI/ATG conditioning; Lymphoid irradiation and anti-thymocyte globulin (TLI/ATG).

Procedure: Total Lymphoid Irradiation (TLI); TLI is administered ten times in 120cGy fractions on day -11 through day -7 and day -4 through day -1; Procedure: Anti-Thymocyte Globulin as Conditioning (ATG); Thymoglobulin will be administered five times intravenously at 1.5 mg/kg/day from day -11 through day -7 for a total dose of 7.5 mg/kg. Thymoglobulin doses will be based on the adjusted ideal body weight if the patient is greater than or equal to 15 kg over ideal body weight.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To improve survival outcome for selected patients with advanced stages of MDS and MPD with non-myeloablative allogeneic HCT from related and unrelated donors.	7/15/2017
To evaluate the feasibility and safety of TLI/ATG conditioning for allogeneic HCT for elderly patients or those with co-morbid conditions that preclude myeloablative transplantation for advanced stage MDS and MPD.	7/15/2017

Secondary Outcome Measures

Outcome Measure	Time Frame
To evaluate myeloid and platelet engraftment.	7/15/2017
To evaluate the incidence of acute and chronic GVHD.	7/15/2017
To evaluate the rate of primary and secondary graft failure.	7/15/2017
To evaluate the rate of relapse, survival and event-free survival.	7/15/2017
To evaluate if DLI can be used safely in patients with mixed chimerism.	7/15/2017

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: National Institutes of Health (NIH)

Study record dates

Study Major Dates

• Study Start: July 1, 2004
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): February 1, 2015

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 (Estimate): March 18, 2015
• Last Update Submitted That Met QC Criteria: March 16, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplasms by Site; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Hematologic Neoplasms; Preleukemia; Myeloproliferative Disorders; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Antilymphocyte Serum
• Other Study ID Numbers: BMT168; 13680 (Stanford IRB); 95130; NCT00185796