Donor T Cells After Donor Stem Cell Transplant in Treating Patients With Hematologic Malignancies

PRIMARY OBJECTIVES:

I. To determine the feasibility of escalating dose regimen (EDR) donor lymphocyte infusion (DLI) as measured by the proportion of patients who receive at least one DLI.

SECONDARY OBJECTIVES:

I. To assess progression free survival (PFS) at 2 years after stem cell transplant (SCT) for high-risk hematologic malignancies receiving T-cell depleted grafts followed by escalating dose regimen (EDR) prophylactic DLI compared to historical controls not receiving DLI.

II. To assess the safety of EDR DLI for high-risk hematologic malignancies as measured by cumulative incidence of severe grade III-IV acute graft-versus-host disease (GVHD).

III. To measure outcomes of grade II-IV acute GVHD, non-relapse mortality, overall survival and chronic GVHD of EDR DLI.

IV. To assess the full donor chimerism rate in the CD3 compartment and immune reconstitution after EDR DLI.

OUTLINE:

Patients receive DLI intravenously (IV). Treatment repeats every 4-8 weeks for 5 doses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for 2 years.

• therapeutic allogeneic lymphocytes (Biological), also known as ALLOLYMPH: Given IV
• laboratory biomarker analysis (Other): Correlative studies

Primary outcomes

• Percentage of Patients Who Are Able to Receive at Least One DLI Treatment [Up to 2 years]

Secondary outcomes

• Progression Free Survival (PFS) [2 years]: Time to relapse or death as a result of any cause was evaluated at 2 years and the progression free survival rate was reported.
• Overall Survival (OS) [At 2 years]: Computed using the Kaplan-Meier product-limit estimate and expressed as probabilities with a 95% CI.
• Rate of Acute GVHD (aGVHD) With Any Grade [At 1 year and 2 year]: Estimated by cumulative incidence method.
• Rate of Chronic GVHD (cGVHD) [At 1 year and 2 year]: Estimated by cumulative incidence method.
• Treatment-related Mortality [At 2 year]: Estimated by cumulative incidence method. Cumulative incidence of treatment-related mortality with relapse of the original disease as the competing risk will be calculated.

Sex: All, ages: 14 Years to 75 Years

Inclusion Criteria:

* INCLUSION CRITERIA PRIOR TO TRANSPLANT:
* The clinical trial will be offered to all high risk (defined 3 below) patients with hematologic malignancies who require stem cell transplants as part of their standard of care using matched related or unrelated donors
* Patients with high risk myeloid or lymphoid malignancies at stem cell transplant following American Society for Blood and Marrow Transplantation (ASBMT) criteria, including but not limited to conditions listed; these criteria apply BEFORE cyto-reductive therapy given within 28 days of planned conditioning:

  * Refractory acute myelogenous or lymphoid leukemia
  * Relapsed acute myelogenous or lymphoid leukemia
  * Myelodysplastic syndromes with 5% or more blasts
  * Chronic myelogenous leukemia in chronic phase 3 or more, blast phase presently, or second accelerated phase
  * Recurrent or refractory malignant lymphoma or Hodgkin's disease with less than a partial response at transplant
* High risk chronic lymphocytic leukemia defined as no response or stable disease to the most recent treatment regimen
* DONORS: Matched related or unrelated donor stem cell transplant (SCT) matched at human leukocyte antigen (HLA) A- B, C, and DRB1 by molecular methods; 7 of 8 matched donor acceptable for related donors
* T-cell depletion with anti-thymocyte globulin (ATG) (rabbit or horse) or at least 30 mg of alemtuzumab total in the conditioning regimen
* Immune suppression; planned post-transplant immune suppression should include tacrolimus or cyclosporin monotherapy (i.e., calcineurin inhibitor or CN) for alemtuzumab regimens and a second immune suppressant for ATG treated patients; other agents may be used if CN intolerance or toxicity occurs post-transplant
* Zubrod performance status (PS) 0-2 or equivalent Karnofsky PS
* Eligible for allogeneic transplant in the treating physicians' judgment and by institutional standards
* ELIGIBILITY TO RECEIVE DLI POST-TRANSPLANT:
* Donor lymphocytes available or able to be collected
* No evidence of disease by standard morphology; minimal residual disease or molecular evidence of disease will not exclude
* Absolute neutrophil count >= 500/μl
* Platelet count >= 20,000/μl without transfusion for 7 days
* Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) =< 5 x upper limit of normal (ULN)
* Bilirubin =< 3 x ULN
* No evidence of grade II or higher acute GVHD or chronic GVHD at initiation of first DLI
* No systemic corticosteroids or immunosuppressive drugs (topical acceptable); replacement steroids for adrenal insufficiency are not excluded

Exclusion Criteria:

* EXCLUSION CRITERIA PRIOR TO TRANSPLANT:
* Pregnant or lactating females
* Hepatitis B with positive viral load prior to transplant conditioning or hepatitis C virus
* Human immune deficiency virus
* Psychiatric illness that may make compliance to the clinical protocol unmanageable or may compromise the ability of the patient to give informed consent
* Creatinine >= 2.0 mg/dL
* SGOT and SGPT >= 5 x ULN; liver biopsy preferred for such patients
* Bilirubin >= 3 x ULN (unless Gilbert's syndrome)
* Diffusing capacity of the lung for carbon monoxide (DLCO) < 50% corrected for hemoglobin
* Left ventricular ejection fraction or shortening fraction < 40%
* Unlikely to be able to procure additional donor lymphocytes

Participant flow

Outcome results

• Percentage of Patients Who Are Able to Receive at Least One DLI Treatment (Primary), Count of participants, Participants: Treatment (DLI) 36
• Progression Free Survival (PFS) (Secondary), Number, percentage of patients: Treatment (DLI) 43 (29 to 63.9)
• Overall Survival (OS) (Secondary), Number, percentage of patients: Treatment (DLI) 59.7 (44.8 to 79.4)
• Rate of Acute GVHD (aGVHD) With Any Grade (Secondary), Number, percentage of patients: Treatment (DLI) 41.8 (24.6 to 58.1)
• Rate of Chronic GVHD (cGVHD) (Secondary), Number, percentage of patients: Treatment (DLI) 26.6 (12.2 to 43.4)
• Treatment-related Mortality (Secondary), Number, percentage of patients: Treatment (DLI) 12.1 (3.7 to 25.9)

Adverse events

Time frame: 2 year

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2019-06-12)

• Hongtao Liu, Principal investigator, University of Chicago Comprehensive Cancer Center