TCR-α/β and CD19 Depleted Stem Cell Grafts From Haplo Donors for HSCT in Relapsed Lymphoma

A Pilot Study to Assess Engraftment Using CliniMACS TCR-α/β and CD19 Depleted Stem Cell Grafts From Haploidentical Donors for Hematopoietic Progenitor Cell Transplantation (HSCT) in Patients With Relapsed Lymphoma

To determine engraftment of neutrophils and platelets at 28 days following alpha/beta T-cell and CD19 cell depletion using Human Leukocyte Antigen (HLA) haploidentical donors for peripheral blood stem cell transplant in relapsed lymphoma.

Assess incidence of acute Graft Versus Host Disease (GVHD), chronic GVHD, graft failure rate, treatment related mortality rate, progression free survival and overall survival of patients.

The stem cell product will be processed using an investigational Miltenyi cell selection device/system that removes the alpha/beta T-cells and CD19+ cells, immune system cells that are more likely to cause GVHD.

Study Overview

• Status: Completed
• Conditions: Lymphoma
• Intervention / Treatment: Drug: Mycophenolate Mofetil; Drug: Fludarabine Phosphate; Drug: Mesna; Drug: Cyclophosphamide; Radiation: Total nodal irradiation; Biological: T Cell-Depleted Hematopoietic Stem Cell Transplantation; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Drug: Tacrolimus; Biological: Rituximab

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin Carbone Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participants must meet one of the following disease criteria within 24 months of registration. Salvage therapy is allowed between the participant meeting one of the below criterion and registration. Participant will be considered eligible regardless of their current disease status (i.e. complete remission, partial remission, stable disease, progressive disease) unless otherwise noted below as long as one of the below criterion has been met within the previous 24 months:

  • Relapsed/refractory Hodgkin lymphoma after autologous stem cell transplantation
  • Relapsed/refractory Hodgkin lymphoma, deemed ineligible for autologous stem cell transplantation due to refractory disease
  • Relapsed/refractory diffuse large B cell lymphoma after autologous stem cell transplantation (history of transformed lymphoma is acceptable). Disease must be in at least complete remission or partial remission with the use of salvage therapy before study treatment commences.
  • Relapsed/refractory diffuse large B cell lymphoma, deemed ineligible for autologous stem cell transplantation due to refractory disease (history of transformed lymphoma is acceptable). Disease must be in at least complete remission or partial remission with the use of salvage therapy before study treatment commences.
  • Relapsed/refractory T cell lymphoma relapsed after at least 1 prior line of therapy
  • Relapsed/refractory follicular lymphoma relapsed after at least 1 prior line of therapy
  • Relapsed/refractory mantle cell lymphoma relapsed after at least 1 prior line of therapy
  • Relapsed/refractory small lymphocytic lymphoma/chronic lymphocytic leukemia relapsed after at least 1 prior line of therapy
  • Relapsed/refractory non-Hodgkin Lymphoma, if not specified above, relapsed after at least 1 prior line of therapy
• Karnofsky score of 60% or better ("Requires occasional assistance, but is able to care for most of his/her needs").
• Pulmonary: Carbon Monoxide Diffusion Capacity (DLCO) (corrected for hemoglobin) > 40%; and Forced Expiratory Volume (FEV1) > 50%
• Cardiac: ejection fraction (EF) ≥ 50%. No uncontrolled angina or active cardiac symptoms consistent with congestive heart failure (class III or IV), by the New York Heart Association criteria. No symptomatic ventricular arrhythmias or ECG evidence of active ischemia. No evidence by echocardiography of severe valvular stenosis or regurgitation.
• Renal: estimated glomerular filtration rate (GFR) by Modification of Diet in Renal Disease (MDRD) formula > 40 mL/min/1.73m2
• Women of child bearing potential must have a negative serum or urine pregnancy test within 14 days prior to study registration and agree to use adequate birth control during study treatment. A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
• Voluntary written consent

Exclusion Criteria:

• Active Central nervous system (CNS) lymphoma within two weeks of registration. Patients with a history of CNS involvement must have adequate treatment as defined by at least two negative spinal fluid assessments separated by at least one week. (Otherwise Lumbar Puncture (LP) is not required if no clinical suspicion or evidence of CNS involvement.) Patients who have received cranial radiation therapy must still be eligible to receive total lymphoid irradiation to 7 Gy.
• New or active infection as determined by fever, unexplained pulmonary infiltrate or sinusitis on radiographic assessment. Infections diagnosed within 4 weeks of registration must be determined to be controlled or resolving prior to treatment.
• Presence of HIV, or active hepatitis A, B, or C infection
• Allergy or hypersensitivity to agents used within the treatment protocol.
• For an indolent lymphoma histology (follicular lymphoma, Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia (SLL/CLL)) or mantle cell lymphoma, the patient should not have an HLA-matched sibling, who would be an eligible donor, available.
• History of prior mediastinal radiation
• Reported illicit drug use
• Vulnerable population groups, i.e., prisoners, those lacking consent capacity, non-English speaking, illiterate, pregnant females.

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: Peripheral Blood Stem Cell Transplant; PREPARATIVE REGIMEN: Participants receive fludarabine phosphate IV over approximately 30 minutes on days -5 to -2, and mesna IV over 24 hours and cyclophosphamide IV over approximately 2 hours on days -5 and -4. Participants also undergo total nodal irradiation on day -1. TRANSPLANT: Participants undergo T-Cell Receptor (TCR) alpha-beta/CD19 depleted hematopoietic stem cell transplant on day 0. If the graft contains less than 4 x 10^6 CD34+ cells/kg participant body weight (BW), patients may receive a second graft on day 1. GVHD PROPHYLAXIS: Participants receive mycophenolate mofetil orally twice a day (PO BID) on days -1 to 30, tacrolimus PO or IV on days 2-180 with a taper beginning on day 90 (given only if graft TCR alpha-beta+ cell content is over 1 x 10^5 cells/kg ideal BW of the patient), and rituximab IV on day 2 (given only if graft B cell content exceeds 1 x 10^5 cells/kg ideal BW of the participant).

Drug: Mycophenolate Mofetil; Given PO; Other Names: MMF; Drug: Fludarabine Phosphate; Fludarabine will be administered by IV over approximately 30 minutes for 4 days.; Drug: Mesna; Given IV over 24 hours starting prior to cyclophosphamide; Drug: Cyclophosphamide; Given IV for 2 days; Radiation: Total nodal irradiation; Undergo total lymphoid irradiation; Biological: T Cell-Depleted Hematopoietic Stem Cell Transplantation; Undergo TCR alpha-beta/DC19-depleted hematopoietic stem cell transplant; Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo TCR alpha-beta/DC19-depleted hematopoietic stem cell transplant; Other Names: HSC; HSCT; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo TCR alpha-beta/CD19-depleted hematopoietic stem cell transplant; Drug: Tacrolimus; Given PO or IV ONLY if graft cell content is over 1 x 10^5 cells/kg ideal BW of the patient; Biological: Rituximab; Given IV ONLY if graft B cell content exceeds 1 x 10^5 cells/kg ideal BW of the patient

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Absolute Neutrophil Count >= 500/Mcl for 3 Consecutive Measurements on Different Days and Platelet Count > 20,000/mm^3 With no Platelet Transfusions in the Preceding 7 Days	To determine engraftment of neutrophils and platelets at 28 days following alpha/beta T-cell depletion using Human Leukocyte Antigen (HLA) haploidentical donors for stem cell transplant in relapsed lymphoma.	At day 28 after transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Grade III-IV Acute GVHD as Determined by International Bone Marrow Transplant Registry (IBMTR) Severity Index Criteria	The number of participants with grade III - IV acute Graft versus host disease (GVHD) by Day +100 is reported.	Day +100
Number of Participants With Severe Chronic GVHD	The number of participants with severe chronic GVHD by Day +180 will be reported.	Day +180
Number of Participants With Graft Failure	Graft failure - defined as < 5% donor chimerism in the CD3 and/or CD33 selected cell populations at any time during the study follow up period once initial engraftment has been achieved.	Up to 2 years after graft
Number of Participants With Treatment-related Mortality	Treatment-related mortality is defined as death from any cause other than disease progression.	Up to 2 years after graft
Progression-free Survival	Progression-free survival will be analyzed as time before any progression by either Positron Emission Tomography/Computed Tomography (PET/CT) or bone marrow,	Median follow up of 1689 days
Overall Survival (OS)		Median follow up of 1689 days

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Investigators: Principal Investigator: Vaishalee P Kenkre, Principal Investigator

Publications and helpful links

Helpful Links

• UW Carbone Cancer Center Home Page

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2016
• Primary Completion (Actual): September 1, 2018
• Study Completion (Actual): September 17, 2021

Study Registration Dates

• First Submitted: January 5, 2016
• First Submitted That Met QC Criteria: January 7, 2016
• First Posted (Estimate): January 11, 2016

Study Record Updates

• Last Update Posted (Actual): January 5, 2022
• Last Update Submitted That Met QC Criteria: December 7, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Rituximab; Fludarabine; Fludarabine phosphate; Tacrolimus; Mycophenolic Acid
• Other Study ID Numbers: UW14113; A534260 (Other Identifier: UW Madison); SMPH\MEDICINE\HEM-ONC (Other Identifier: UW Madison); 2015-0996 (Other Identifier: IRB); NCI-2015-02269 (Registry Identifier: NCI Trial ID); Protocol Version 4/24/2020 (Other Identifier: UW Madison)

Drug and device information, study documents

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