Reduced-Intensity Conditioning for the Prevention of Treatment-Related Mortality in Patients Who Undergo a Hematopoietic Stem Cell Transplant

Sponsor

Thomas Jefferson University (Other)

Overall Status

Recruiting

CT.gov ID

NCT05031897

Collaborator

(none)

Enrollment

Location

Arms

35.2

Anticipated Duration (Months)

1.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase II clinical trial evaluates whether a modified modality of conditioning reduces treatment-related mortality (TRM) in patients who undergo a hematopoietic stem cell transplant (HSCT) for a hematological malignancy. HSCT is a curative therapy for many hematopoietic malignancies, however this regimen results in higher rates of TRM than other forms of treatment. In recent years, less intense conditioning regimens with radiation and chemotherapy prior to HSCT have been developed. Radiation therapy uses high energy sources to kill cancer cells and shrink tumors while chemotherapy drugs like fludarabine and cyclophosphamide work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This study evaluates whether a two-step approach with lower-intensity regimens of these treatments prior to HSCT reduces the rate of TRM.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Aplastic Anemia Chronic Lymphocytic Leukemia Chronic Myelomonocytic Leukemia Essential Thrombocythemia Hematopoietic and Lymphoid Cell Neoplasm Hodgkin Lymphoma Myelodysplastic Syndromes Myelofibrosis Myeloid Leukemia Myeloid Neoplasm Non-Hodgkin Lymphoma Plasma Cell Myeloma Polycythemia Vera Small Lymphocytic Lymphoma	Procedure: Hematopoietic Cell Transplantation Drug: Mycophenolate Mofetil Drug: Tacrolimus Drug: Cyclophosphamide Radiation: Total-Body Irradiation Procedure: Donor Lymphocyte Infusion Drug: Fludarabine Drug: Melphalan	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

To assess the 2 year cumulative incidence of TRM in patients undergoing reduced intensity conditioning (RIC) haploidentical (HI) HSCT in this protocol.

SECONDARY OBJECTIVES:

To assess the 2 year cumulative incidence of relapse in patients undergoing RIC HI HSCT in this protocol.
To assess the consistency and pace of engraftment. III. To assess the pace of T cell and B cell immune recovery. IV. To assess the incidence and severity of graft versus host disease (GVHD).

OUTLINE: Patients are assigned to 1 of 2 cohorts.

RADIATION-BASED COHORT: Patients receive fludarabine intravenously (IV) on days -11, -10, -9, and -8, undergo total-body irradiation (TBI) twice a day (BID) on days -10 and -9, undergo donor lymphocyte infusion (DLI) on day -6, and receive cyclophosphamide IV on days -3 and -2. Patients begin tacrolimus and mycophenolate mofetil IV on day -1. Patients then undergo HSCT on day 0. Treatment continues in the absence of disease progression or unacceptable toxicity.

CHEMOTHERAPY-BASED COHORT: Patients receive fludarabine IV on days -11, -10, -9, and -8 and melphalan IV on days -10 and -9. Patients undergo TBI and DLI once on day -6. Patients receive cyclophosphamide IV on days -3 and -2 and begin tacrolimus and mycophenolate mofetil on day -1. Patients undergo HSCT on day 0. Treatment continues in the absence of disease progression or unacceptable toxicity.

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

67 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A 2 Step Approach to Haploidentical Transplant Using Radiation-Based Reduced Intensity Conditioning

Actual Study Start Date :

Oct 25, 2021

Anticipated Primary Completion Date :

Oct 1, 2024

Anticipated Study Completion Date :

Oct 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Radiation-Based Cohort (fludarabine, TBI, infusion) Patients receive fludarabine IV on days -11, -10, -9, and -8, undergo TBI BID on days -10 and -9, undergo DLI on day -6, and receive cyclophosphamide IV on days -3 and -2. Patients begin tacrolimus and mycophenolate mofetil IV on day -1. Patients then undergo HSCT on day 0. Treatment continues in the absence of disease progression or unacceptable toxicity.	Procedure: Hematopoietic Cell Transplantation Undergo HSCT Other Names: HCT Hematopoietic Stem Cell Infusion Hematopoietic Stem Cell Transplantation HSCT Stem Cell Transplant Drug: Mycophenolate Mofetil Given IV Drug: Tacrolimus Given IV Drug: Cyclophosphamide Given IV Radiation: Total-Body Irradiation Undergo TBI Procedure: Donor Lymphocyte Infusion Undergo DLI Drug: Fludarabine Given IV
Experimental: Chemotherapy-Based Cohort (fludarabine, melphalan, TBI) Patients receive fludarabine IV on days -11, -10, -9, and -8 and melphalan IV on days -10 and -9. Patients undergo TBI and DLI once on day -6. Patients receive cyclophosphamide IV on days -3 and -2 and begin tacrolimus and mycophenolate mofetil on day -1. Patients undergo hematopoietic stem cell transplant on day 0.	Procedure: Hematopoietic Cell Transplantation Undergo HSCT Other Names: HCT Hematopoietic Stem Cell Infusion Hematopoietic Stem Cell Transplantation HSCT Stem Cell Transplant Drug: Mycophenolate Mofetil Given IV Drug: Tacrolimus Given IV Drug: Cyclophosphamide Given IV Radiation: Total-Body Irradiation Undergo TBI Procedure: Donor Lymphocyte Infusion Undergo DLI Drug: Fludarabine Given IV Drug: Melphalan Given IV

Arm

Intervention/Treatment

Experimental: Radiation-Based Cohort (fludarabine, TBI, infusion)

Patients receive fludarabine IV on days -11, -10, -9, and -8, undergo TBI BID on days -10 and -9, undergo DLI on day -6, and receive cyclophosphamide IV on days -3 and -2. Patients begin tacrolimus and mycophenolate mofetil IV on day -1. Patients then undergo HSCT on day 0. Treatment continues in the absence of disease progression or unacceptable toxicity.

Procedure: Hematopoietic Cell Transplantation

Undergo HSCT

Other Names:

HCT

Hematopoietic Stem Cell Infusion

Hematopoietic Stem Cell Transplantation

HSCT

Stem Cell Transplant

Drug: Mycophenolate Mofetil

Given IV

Drug: Tacrolimus

Given IV

Drug: Cyclophosphamide

Given IV

Radiation: Total-Body Irradiation

Undergo TBI

Procedure: Donor Lymphocyte Infusion

Undergo DLI

Drug: Fludarabine

Given IV

Experimental: Chemotherapy-Based Cohort (fludarabine, melphalan, TBI)

Patients receive fludarabine IV on days -11, -10, -9, and -8 and melphalan IV on days -10 and -9. Patients undergo TBI and DLI once on day -6. Patients receive cyclophosphamide IV on days -3 and -2 and begin tacrolimus and mycophenolate mofetil on day -1. Patients undergo hematopoietic stem cell transplant on day 0.

Procedure: Hematopoietic Cell Transplantation

Undergo HSCT

Other Names:

HCT

Hematopoietic Stem Cell Infusion

Hematopoietic Stem Cell Transplantation

HSCT

Stem Cell Transplant

Drug: Mycophenolate Mofetil

Given IV

Drug: Tacrolimus

Given IV

Drug: Cyclophosphamide

Given IV

Radiation: Total-Body Irradiation

Undergo TBI

Procedure: Donor Lymphocyte Infusion

Undergo DLI

Drug: Fludarabine

Given IV

Drug: Melphalan

Given IV

Outcome Measures

Primary Outcome Measures

Incidence of treatment-related mortality (TRM) [At 2 years post hematopoietic stem cell transplant (HSCT)]
TRM is defined as death without evidence of recurrent disease in the 2 year period post HSCT. Summarized using Kaplan-Meier curves and the respective Kaplan-Meier estimates of the 2-year event rate are reported as well as their 95% confidence intervals.

Secondary Outcome Measures

Development of relapsed disease [Up to 2 years]
Relapse is measured by evidence of recurrent disease in the blood, marrow, or lymph nodes. Summarized using Kaplan-Meier curves and the respective Kaplan-Meier estimates of the 2-year event rate are reported as well as their 95% confidence intervals.
Engraftment [Up to 2 years]
Measure by chimerism studies of the blood and marrow at multiple time points after the HSCT. Chimerism refers to the percentage of donor cells in the hematopoietic system of the patient post HSCT. Reported using mean and standard deviations.
Immune reconstitution [Up to 2 years]
Evaluated by T-cell recovery and B-cell recovery. Assessed by the quantitative measurement of CD3/4 and CD3/8 cells and immunoglobulin levels in the blood at multiple time points post HSCT. CD3/4 and CD3/8 counts are measured by an immune reconstitution panel and immunoglobulin levels are measured by a quantitative immunoglobulin assay. Reported using mean and standard deviations
Incidence and degree of graft versus host disease (GVHD) after HSCT [Up to 2 years]
Assessment includes presence and degree of skin rash, presence and amount of diarrhea, and/or abnormal liver function test. Summarized using Kaplan-Meier curves and the respective Kaplan-Meier estimates of the 2-year event rate are reported as well as their 95% confidence intervals.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Radiation-based cohort diagnoses:
Acute myeloid leukemia
Acute lymphoid leukemia in remission
Myelodysplasia (MDS)
Chronic lymphocytic leukemia (CLL) with no or minimal lymph node involvement
Multiple myeloma
Chronic myeloid leukemia
Myelofibrosis
Myeloid malignancy not otherwise specified
Chronic myelomonocytic leukemia
Essential thrombocytopenia or polycythemia vera
T cell leukemia
T cell lymphoma without significant lymph node disease burden
Any hematological malignancy or dyscrasia not cited above in which HSCT is potentially curable * Any patient who has a hematological disease that would normally be treated on a myeloablative study, but is prevented from doing so by factors in their past medical history. Examples are patients with previous treatment with radiation therapy precluding total-body irradiation (TBI), or a past history of myeloablative therapy, precluding a 2nd myeloablative regimen.
Patients must have a donor who is one-haplotype mismatched (number of mismatches in either direction not considered)
Chemotherapy-based cohort diagnoses:
Hodgkin or non-Hodgkin lymphoma
Small lymphocytic lymphoma/CLL
Any other diagnosis in which chemotherapy is thought to be superior to radiotherapy for treatment of the disease
Hematological malignancy in patients who cannot receive > 2 Gy radiation * Aplastic anemia and other non-malignant hematologic dyscrasias
Patients must have a donor who is one-haplotype mismatched (number of mismatches in either direction not considered)
HLA identical cohort diagnoses:

Patients in this group will be treated in parallel to the radiation-based cohort or the chemotherapy-based group based on what category their diagnosis falls into. However, these patients will have HLA identical related donors (one-antigen cross-over event included).

Left ventricular ejection fraction of >= 50%
Diffusion lung capacity of oxygen >= 50% and forced expiratory volume at 1 second >= 50% of predicted corrected for hemoglobin
Adequate liver function as defined by a serum bilirubin =< 1.8, aspartate aminotransferase or alanine aminotransferase =< 2.5 x upper limit of normal
Creatinine clearance of >= 60 mL/min
Patients must have adequate Karnofsky performance status (KPS) and hematopoietic cell transplantation-comorbidity index (HCT-CI) scores:
Patients < age 60 years must have a KPS of >= 80% and an HCT-CI score of 5 or less
Patients aged 60 to 65 years must have a KPS of >= 80% and an HCT-CI score of 4 or less
Patients aged 66 to 69 years must have a KPS of 90% and an HCT-CI score of 3 or less * Patients aged 70 years or more must have a KPS of 90% and an HCT-CI score of 2 or less
(Patients with greater than the allowable HCT-CI points for age can be enrolled for trial with approval of the principal investigator and at least 1 co-investigator not on the primary care team of the patient). This is an adjustment to account for healthy patients who meet the spirit of this protocol but have histories that result in higher than guideline HCT-CI points. An example is a patient with a solid tumor malignancy in their remote history (adds 3 points to HCT-CI total) where the treatment for the malignancy occurred years to decades before and there has been complete recovery of toxicities
Patients must be willing to use contraception if they have childbearing potential
Patient or patient's guardian is able to give informed consent
Patients should have a life expectancy of >= 6 months for reasons other than their underlying hematologic/oncologic disorder

Exclusion Criteria:

Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled on this protocol
Patients should not be:
Human immunodeficiency virus positive
Have active involvement of the central nervous system with malignancy. This can be documented by a normal neurological exam, magnetic resonance imaging (MRI) of the head, and/or a negative cerebral spinal fluid analysis
Pregnant or breastfeeding