Lymphoma
Conditions
Brief summary
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.
Interventions
DRUGFludarabine Phosphate
Fludarabine will be administered by IV over approximately 30 minutes for 4 days.
DRUGMesna
Given IV over 24 hours starting prior to cyclophosphamide
DRUGCyclophosphamide
Given IV for 2 days
RADIATIONTotal nodal irradiation
Undergo total lymphoid irradiation
Undergo TCR alpha-beta/DC19-depleted hematopoietic stem cell transplant
PROCEDUREAllogeneic Hematopoietic Stem Cell Transplantation
Undergo TCR alpha-beta/DC19-depleted hematopoietic stem cell transplant
PROCEDUREPeripheral Blood Stem Cell Transplantation
Undergo TCR alpha-beta/CD19-depleted hematopoietic stem cell transplant
DRUGMycophenolate Mofetil
Given PO
DRUGTacrolimus
Given PO or IV ONLY if graft cell content is over 1 x 10\^5 cells/kg ideal BW of the patient
BIOLOGICALRituximab
Given IV ONLY if graft B cell content exceeds 1 x 10\^5 cells/kg ideal BW of the patient
Sponsors
University of Wisconsin, Madison
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | At day 28 after transplantation | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Severe Chronic GVHD | Day +180 | The number of participants with severe chronic GVHD by Day +180 will be reported. |
| Number of Participants With Graft Failure | Up to 2 years after graft | 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. |
| Number of Participants With Grade III-IV Acute GVHD as Determined by International Bone Marrow Transplant Registry (IBMTR) Severity Index Criteria | Day +100 | The number of participants with grade III - IV acute Graft versus host disease (GVHD) by Day +100 is reported. |
| Progression-free Survival | Median follow up of 1689 days | Progression-free survival will be analyzed as time before any progression by either Positron Emission Tomography/Computed Tomography (PET/CT) or bone marrow, |
| Overall Survival (OS) | Median follow up of 1689 days | — |
| Number of Participants With Treatment-related Mortality | Up to 2 years after graft | Treatment-related mortality is defined as death from any cause other than disease progression. |
Countries
United States
Participant flow
Recruitment details
Patients of the University of Wisconsin Carbone Cancer Center were enrolled from March 2016 to June 2018.
Participants by arm
| Arm | Count |
|---|---|
| Peripheral Blood Stem Cell Transplant PREPARATIVE REGIMEN: Participants receive fludarabine phosphate IV over \
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 undergo total nodal irradiation on day -1.
TRANSPLANT: Participants undergo 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 patient BW, Participants may receive a second graft on day 1.
GVHD PROPHYLAXIS: Participants receive mycophenolate mofetil 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 patient). | 11 |
| Total | 11 |
Baseline characteristics
| Characteristic | Peripheral Blood Stem Cell Transplant |
|---|---|
| Age, Customized 20-29 years | 1 Participants |
| Age, Customized 30-39 years | 1 Participants |
| Age, Customized 40-49 years | 1 Participants |
| Age, Customized 50-59 years | 3 Participants |
| Age, Customized 60-69 years | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 11 Participants |
| Region of Enrollment United States | 11 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 11 |
| other Total, other adverse events | 11 / 11 |
| serious Total, serious adverse events | 10 / 11 |
Outcome results
Primary
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.
Time frame: At day 28 after transplantation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Peripheral Blood Stem Cell Transplant | 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 | 11 Participants |
Secondary
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.
Time frame: Day +100
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Peripheral Blood Stem Cell Transplant | Number of Participants With Grade III-IV Acute GVHD as Determined by International Bone Marrow Transplant Registry (IBMTR) Severity Index Criteria | 3 Participants |
Secondary
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.
Time frame: Up to 2 years after graft
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Peripheral Blood Stem Cell Transplant | Number of Participants With Graft Failure | 0 Participants |
Secondary
Number of Participants With Severe Chronic GVHD
The number of participants with severe chronic GVHD by Day +180 will be reported.
Time frame: Day +180
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Peripheral Blood Stem Cell Transplant | Number of Participants With Severe Chronic GVHD | 0 Participants |
Secondary
Number of Participants With Treatment-related Mortality
Treatment-related mortality is defined as death from any cause other than disease progression.
Time frame: Up to 2 years after graft
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Peripheral Blood Stem Cell Transplant | Number of Participants With Treatment-related Mortality | 4 Participants |
Secondary
Overall Survival (OS)
Time frame: Median follow up of 1689 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Blood Stem Cell Transplant | Overall Survival (OS) | 352 days |
Secondary
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,
Time frame: Median follow up of 1689 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Peripheral Blood Stem Cell Transplant | Progression-free Survival | 352 days |