A Two-Step Approach to Bone Marrow Transplant Using Cells From Two Partially-Matched Relatives

A Two Step Approach to Allogeneic Hematopoietic Stem Cell Transplantation for High-Risk Hematologic Malignancies Using Two Related Donors

This phase II clinical trial studies how well two donors stem cell transplant work in treating patients with high-risk hematologic malignancies. After receiving radiation to help further treat the disease, patients receive a dose of donors' T cells. T cells can fight infection and react against cancer cells. Two days after donors' T cells are given, patients receive cyclophosphamide (CY) to help destroy the most active T cells that may cause tissue damage (called graft versus host disease or GVHD). Some of the less reactive T cells are not destroyed by CY and they remain in the patient to help fight infection. A few days after the CY is given, patients receive donors' stem cells to help their blood counts recover. Using two donors' stem cell transplant instead of one donor may be more effective in treating patients with high-risk disease and may prevent the disease from coming back.

Study Overview

• Status: Terminated
• Conditions: Lymphoma; Leukemia; Hodgkin's Lymphoma; Acute Lymphoblastic Leukemia; Chronic Lymphocytic Leukemia; AML; Acute Myelogenous Leukemia; Hematologic Malignancy; Myeloma; Non-hodgkin's Lymphoma; CLL; ALL
• Intervention / Treatment: Radiation: Total Body Irradiation (TBI); Biological: Donor Lymphocyte Infusion (DLI); Drug: Cyclophosphamide (CY); Drug: Tacrolimus; Drug: Mycophenolate Mofetil (MMF); Biological: Hematopoietic Stem Cell Transplant (HSCT)

Detailed Description

PRIMARY OBJECTIVES:

I. To assess 1 year relapse free survival in patients undergoing hematopoietic stem cell transplant (HSCT) using the Thomas Jefferson University (TJU) 2 step approach using 2 donors.

SECONDARY OBJECTIVES:

I. To assess the consistency and pace of engraftment. II. To assess the pace of T cell and B cell immune recovery in patients in each arm.

III. To assess regimen related toxicity, graft-versus-host disease (GVHD) incidence and severity, and overall survival.

IV. To assess the tolerance of the period of fever, diarrhea, and rash after the introduction of second donor and qualitatively compare it to prior patient groups or concurrent patient groups.

V. To assess chimerism to ascertain whether one donor is emerging as dominant at regular intervals beginning at the time of engraftment.

VI. If dominance is observed, to compare the donors with regard to degree of human leukocyte antigen (HLA) mismatch, killer Ig-like receptor (KIR) types, cluster of differentiation (CD)34+ cell doses, infusion order, donor age, and donor alloreactivity points in an effort to identify potential biologic factors that predict for dominance. To determine if trends toward dominance occur in T cell, natural killer (NK) cell, or other cellular subsets prior to emerging in the graft as a whole.

VII. To assess if establishment of a dominant donor versus persistent chimerism of both donors is associated with a lower relapse rate.

VIII. To collect leukemia samples prior to transplant and after relapse whenever possible. To assess the overall degree of HLA-class I and class II expression on these paired samples. To test for loss of one or both HLA haplotypes in the relapsed tumor specimens. When observed, to correlate loss of one HLA haplotype with: a) receipt of a transplant capable of targeting only that haplotype; b) establishment of dominance in a 2 haplotype transplant such that the lost haplotype would be the primary target of the dominant donor; c) being the target of the donor predicted to be more alloreactive in a 2 haplotype transplant.

OUTLINE:

CONDITIONING: Patients undergo total-body irradiation (TBI) twice daily (BID) on days -9 to -6, undergo donor lymphocyte infusion (DLI) on day -6, and receive cyclophosphamide intravenously (IV) over 2 hours on days -3 and -2.

TRANSPLANTATION: Patients undergo CD34+ selected allogeneic HSCT on day 0.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV or orally (PO) beginning on day -1 with taper beginning on day 42 and mycophenolate mofetil IV or PO BID on days -1 to 28.

After completion of study treatment, patients are followed up for 1 year, and then periodically thereafter.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Any patient with a hematologic malignancy with residual disease (morphological, cytogenetic, molecular, or radiographic) after treatment with 1 or more chemotherapy regimens in whom achievement of remission with additional chemoradiotherapy is felt to be unlikely or who is in 3rd or greater CR. Patients with marrow based diseases in which the marrow biopsy does not meet criteria for active disease (i.e. <5% blasts in acute leukemia) but who does not have full count recovery will be eligible for treatment on this high risk trial.
2. Patients must have two related donors that meet an acceptable scenario as described above.

3. Patients must adequate organ function:

   • LVEF of >= 50%
   • DLCO (adjusted for hemoglobin) >= 50% of predicted
   • Adequate liver function as defined by a serum bilirubin =< 1.8, AST or ALT < 2.5X upper limit of normal
   • Creatinine clearance of >= 60 ml/min
4. Karnofsky Performance Status of > 80 % on the modified KPS tool (see Appendix A).
5. Patients must be willing to use contraception if they have childbearing potential.
6. Able to give informed consent

Exclusion Criteria:

1. Modified KPS of < 80%
2. >= 5 Comorbidity Points on the HCT-CI Index (See Appendix B)
3. Class I or II antibodies against donor HLA antigens
4. HIV positive
5. Active involvement of the central nervous system with malignancy
6. Psychiatric disorder that would preclude patients from signing an informed consent
7. Pregnancy, or unwillingness to use contraception if they have child bearing potential
8. Patients with life expectancy of =< 6 months for reasons other than their underlying hematologic/oncologic disorder
9. Alemtuzumab treatment within 8 weeks of HSCT admission.
10. ATG level of >= 2 ugm/ml
11. Patients with active inflammatory processes (such as flair of an autoimmune disease) including T max > 101, or active tissue inflammation are excluded.
12. Inability to tolerate cyclophosphamide or undergo total body irradiation at the doses specified in the treatment plan.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Allogeneic HSCT Using Two Related Donors; CONDITIONING: Patients undergo TBI BID on days -9 to -6, undergo DLI on day -6, and receive cyclophosphamide IV over 2 hours on days -3 and -2. TRANSPLANTATION: Patients undergo CD34+ selected allogeneic HSCT on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV or PO beginning on day -1 with taper beginning on day 42 and mycophenolate mofetil IV or PO BID on days -1 to 28.

Radiation: Total Body Irradiation (TBI); TBI twice daily for 4 days and occurs 6 to 9 days prior to the transplant. Total radiation dose is 12 Gy.; Other Names: TBI; radiotherapy; Biological: Donor Lymphocyte Infusion (DLI); DLI given 6 days prior to transplant (HSCT).; Other Names: DLI; T cell infusion; Drug: Cyclophosphamide (CY); Cyclophosphamide given once daily at 60 mg/kg on days 2 and 3 prior to transplant (HSCT).; Other Names: Cytoxan; Endoxan; Neosar; Revimmune; Procytox; CY; cytophosphane; Drug: Tacrolimus; Tacrolimus is started the day before the transplant and stops a few months after transplant.; Other Names: Prograf; Protopic; FK-506; Advagraf; fujimycin; Drug: Mycophenolate Mofetil (MMF); MMF is started the day before transplant and stops a few weeks after transplant.; Other Names: CellCept; Myfortic; MMF; Biological: Hematopoietic Stem Cell Transplant (HSCT); CD34+ selected Hematopoietic Stem Cell Transplant (HSCT) is performed using donor cells from two related donors. The CliniMACS® Plus Instrument will be used for the selection of human CD34+ hematopoietic stem cells.; Other Names: HSCT; CliniMACS; stem cell transplant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
One Year Relapse-Free Survival	To assess one year relapse-free survival (RFS) in patients undergoing HSCT (hematopoietic stem cell transplantation) using the TJU 2 step-approach with two donors. Survival will be estimated by the Kaplan-Meier method. All estimates of rates will be presented with corresponding confidence intervals. For 1 year RFS rates, the method of Atkinson and Brown will be used to allow for the two-stage design; otherwise the method of Conover.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Chimerism Assessment	To assess chimerism to ascertain whether one donor is emerging as dominant at regular intervals beginning at the time of engraftment.	1 year
Assessment of Dominance	If dominance is observed, to compare the 2 donors with regard to degree of HLA mismatch, KIR types, CD 34+ cell doses, infusion order, donor age, and donor alloreactivity points in an effort to identify potential biologic factors that predict for dominance. To determine if trends toward dominance occur in T cell, NK cell, or other cellular subsets prior to emerging in the graft as a whole.	1 year
Relapse Rates	To assess if establishment of a dominant donor versus persistent chimerism of both donors is associated with a lower relapse rate.	1 year
Engraftment	To assess the consistency and pace of engraftment of both donors.	1 year
Immune Reconstitution	Assess T and B cell Reconstitution	1 year
Non-relapse Morbidity and Mortality	Assessment of regimen related toxicity, GVHD incidence and severity, and overall survival.	1 year
Tolerance of DLI	Assessment of the tolerance of the period of fever, diarrhea, and rash after the introduction of second donor and qualitatively compare it to prior patient groups or concurrent patient groups	2-6 days prior to transplant
Assessment for Tumor Escape Mechanisms	To test for loss of one or both HLA haplotypes in patients who relapse post-transplant and examine the relapse in the context of the characteristics of the 2 donors	1 year post transplant

Collaborators and Investigators

• Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University
• Investigators: Principal Investigator: Dolores Grosso, DNP, CRNP, Thomas Jefferson University; Principal Investigator: Neal Flomenberg, MD, Thomas Jefferson University

Publications and helpful links

Helpful Links

• Kimmel Cancer Center at Thomas Jefferson University, an NCI-Designated Cancer Center
• Thomas Jefferson University Hospitals

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: February 6, 2012
• First Submitted That Met QC Criteria: February 9, 2012
• First Posted (Estimated): February 14, 2012

Study Record Updates

• Last Update Posted (Actual): May 4, 2025
• Last Update Submitted That Met QC Criteria: May 1, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: lymphoma; AML; ALL; hematologic malignancy; Cyclophosphamide; MMF; Mycophenolate Mofetil; CLL; Acute myelogenous leukemia; HSCT; Hematopoietic stem cell transplant; Chronic lymphocytic leukemia; leukemia; Acute lymphoblastic leukemia; bone marrow transplant; myeloma; non-hodgkin's lymphoma; allogeneic stem cell transplant; hodgkin's lymphoma; TJU 2-step
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, B-Cell; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Hematologic Neoplasms; Lymphoma; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Lymphoma, Non-Hodgkin; Hodgkin Disease; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antibiotics, Antitubercular; Antitubercular Agents; Calcineurin Inhibitors; Cyclophosphamide; Mycophenolic Acid; Tacrolimus
• Other Study ID Numbers: 11D.570; 2011-101 (Other Identifier: CCRRC); JT 1832 (Other Identifier: JeffTrial Number)