Hematopoietic Malignancies
Conditions
Keywords
Hematopoietic Malignancies, Nonmyeloablative Peripheral Blood Stem Cell Transplant, Posttransplantation
Brief summary
This is an open label phase II single arm study of peripheral blood stem cell transplantation and posttransplantation cyclophosphamide, using HLA full match or haploidentical related donors, in hematological malignancies including those difficult to engraft. The objective of this study is to evaluate the safety and feasibility in nonmyeloablative, partially HLA-mismatched or HLA-matched PBSC transplant from haploidentical donors or fully matched donors with post-grafting immunosuppression that includes high-dose cyclophosphamide, tacrolimus, and Mycophenolate mofetil (MMF).
Detailed description
Primary Objective Estimate event free survival (EFS) (relapse, progression, or death) rate one year after transplant. Secondary Objectives: 1. Estimate the cumulative incidences of severe acute grade III or higher GVHD, chronic GVHD (overall and by extent) 2. Estimate the cumulative incidence of systemic steroid initiation, 3. Summarize the graft failure frequency, 4. Summarize the kinetics of neutrophil and platelet recovery, and kinetics of donor chimerism in unsorted and CD3+ sorted peripheral blood. 5. Summarize major toxicities and complications associated with the transplantation procedure selected toxicities. Exploratory Objectives: Explore the association between the amount of donor T cell chimerism at \ Day 28 and patient/graft characteristics (e.g., prior therapies, graft cell dose) and transplantation outcomes (sustained engraftment, relapse or progression, GVHD).
Interventions
DRUGCyclophosphamide
Shortened duration immunosuppression following nonmyeloablative peripheral blood stem cell transplant with high dose post transplantation cyclophosphamide in malignancies to engraft.
Sponsors
NYU Langone Health
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
The following are eligibility for study entry and transplantation. * Presence of a suitable related, HLA-haploidentical or HLA-matched stem cell donor * The donor and recipient must be identical at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. A minimum match of 5/10 is therefore required for related donors, and will be considered sufficient evidence that the donor and recipient share one HLA haplotype. * Eligible diagnoses: * Myelodysplastic syndrome (MDS) including chronic myelomonocytic leukemia \[CMML\] with at least one poor risk factor * No active extramedullary leukemia or known active CNS involvement by malignancy. Such disease treated into remission is permitted. * Any previous autologous HSCT must have occurred at least 3 months prior to start of conditioning * No previous allogeneic HSCT * Adequate end-organ function Note: Infection is permitted if there is evidence of response to medication. Eligibility of HIV infected patients will be determined on a case-by-case basis. * ECOG performance status \< 2 or Karnofsky or Lansky score \> 60. * Age \> 18 years and older. * Not pregnant or breast-feeding. * No uncontrolled infection. Eligible diagnoses: * Myelodysplastic syndrome (MDS) including chronic myelomonocytic leukemia \[CMML\] with at least one of the following poor-risk features * SLL or CLL with 17p deletion, or with progression \< 6 months after second or greater treatment regimen. Must have the following to be an acceptable candidate as well: * \< 20% of bone marrow cellularity involved by SLL/CLL (to lower risk of graft rejection) * No lymph nodes \> 5 cm in any dimension * No massive splenomegaly, defined as \> 6 cm below the left costal margin * T-cell PLL in PR or better prior to transplantation. Must also have \< 20% of bone marrow cellularity involved by PLL (to lower risk of graft rejection). * Interferon- or tyrosine kinase-refractory CML in first chronic phase, TKI-intolerant CML in first chronic phase, or CML in second or subsequent chronic phase * Philadelphia chromosome negative myeloproliferative disease (including myelofibrosis) o Intermediate-2 or High risk score by DIPSS Plus is required for a diagnosis of myelofibrosis * Multiple myeloma or plasma cell leukemia with a PR or better to the last treatment regimen, based on the International Myeloma Working Group (IMWG) criteria.49 * Hematologic malignancy in complete remission with minimal residual disease (MRD) non detectable OR detectable by conventional cytogenetics, FISH, flow cytometry, or molecular testing or hematologic malignancies in partial remission Donor eligibility * Donors must be either: * HLA-haploidentical or HLA-identical relatives of the patient based on allele or allele group level typing as defined in Section 4.1. * Medically fit to and willing to donate * Lack of recipient anti-donor HLA antibody * Has not donated blood products to patient
Exclusion criteria
* Any individual that does not meet the eligibility criteria for transplantation or donor eligibility will not be a part of this trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event Free Survival (EFS) | One Year | Estimate the one year after transplantation event free survival (EFS) rate using a Kaplan-Meier curve with a 90% confidence interval. An event for EFS is defined as the first of any of the following failures: relapse or disease progression or death from any cause |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Major Toxicities and Complications Associated With Transplantation Procedure | 1 year | Summarize major toxicities and complications associated with the transplantation procedure |
| Cumulative Incidences of Systemic Steroid Initiation | 1 year | Estimate the cumulative incidence of systemic steroid initiation, by 1 year after HSCT. This is will be reported as number of participants who started steroids over the course of the study. |
| Number of Participants With Chronic GVHD and Grades I-IV GVHD | 1 year | Acute GVHD is graded by standard criteria, and all suspected cases of acute GVHD will be confirmed histologically by biopsy of an affected organ. The severity of acute GVHD is determined by an assessment of the degree of involvement of the skin, liver, and gastrointestinal tract. Grade I is characterized as mild disease (skin involvement alone), Grade II as moderate, Grade III as severe (involvement of any organ system), and Grade IV as life-threatening. The diagnosis of a chronic GVHD per NIH criteria requires a) at least 1 diagnostic manifestation or b) 1 distinctive manifestation confirmed by biopsy or testing of the same or other involved organ. |
| Time to Neutrophil Recovery | 1 year | Neutrophil recovery is defined as post-nadir ANC greater than or equal to 500/mm3 for three consecutive measurements on different days. The first of the three days will be designated as the day of neutrophil recovery. |
| Time to Platelet Recovery | 1 year | Platelet recovery is defined as sustained platelet count greater than or equal to 20,000/mm3 or greater than or equal to 50,000/mm3 with no platelet transfusions in the preceding seven days. The first of three consecutive measurements on different days will be designated as the day of initial platelet recovery. |
| Graft Failure Frequency | 1 year | Graft failure and death, or graft failure, death and treatment of relapse/progressions. This will be reported as the number of participants with graft failures. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cyclophosphamide Cy 50 mg/kg IV, over approximately 1-2 hours (depending on volume), is given on Day 3 posttransplantation (ideally between 60 and 72 hours after marrow infusion) and on Day 4 (approximately 24 hours after Day 3 Cy). | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Termination of study | 4 |
Baseline characteristics
| Characteristic | Cyclophosphamide |
|---|---|
| Age, Continuous | 51 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 1 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 4 / 6 |
| serious Total, serious adverse events | 6 / 6 |
Outcome results
Primary
Event Free Survival (EFS)
Estimate the one year after transplantation event free survival (EFS) rate using a Kaplan-Meier curve with a 90% confidence interval. An event for EFS is defined as the first of any of the following failures: relapse or disease progression or death from any cause
Time frame: One Year
Population: 2 participants reached the 1 year time point but disease assessment was completed for only 1 subject (complete remission).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cyclophosphamide | Event Free Survival (EFS) | 1 Participants |
Secondary
Cumulative Incidences of Systemic Steroid Initiation
Estimate the cumulative incidence of systemic steroid initiation, by 1 year after HSCT. This is will be reported as number of participants who started steroids over the course of the study.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cyclophosphamide | Cumulative Incidences of Systemic Steroid Initiation | 6 Participants |
Secondary
Graft Failure Frequency
Graft failure and death, or graft failure, death and treatment of relapse/progressions. This will be reported as the number of participants with graft failures.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cyclophosphamide | Graft Failure Frequency | 0 Participants |
Secondary
Number of Major Toxicities and Complications Associated With Transplantation Procedure
Summarize major toxicities and complications associated with the transplantation procedure
Time frame: 1 year
Population: While AE data was reported (see AE / SAE section), due to termination of the study, relationship of major AEs to transplant procedures was unable to be assessed. Therefore, this information cannot be reported.
Secondary
Number of Participants With Chronic GVHD and Grades I-IV GVHD
Acute GVHD is graded by standard criteria, and all suspected cases of acute GVHD will be confirmed histologically by biopsy of an affected organ. The severity of acute GVHD is determined by an assessment of the degree of involvement of the skin, liver, and gastrointestinal tract. Grade I is characterized as mild disease (skin involvement alone), Grade II as moderate, Grade III as severe (involvement of any organ system), and Grade IV as life-threatening. The diagnosis of a chronic GVHD per NIH criteria requires a) at least 1 diagnostic manifestation or b) 1 distinctive manifestation confirmed by biopsy or testing of the same or other involved organ.
Time frame: 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cyclophosphamide | Number of Participants With Chronic GVHD and Grades I-IV GVHD | chronic GVHD | 0 Participants |
| Cyclophosphamide | Number of Participants With Chronic GVHD and Grades I-IV GVHD | acute grade IV GVHD | 0 Participants |
| Cyclophosphamide | Number of Participants With Chronic GVHD and Grades I-IV GVHD | acute grade III GVHD | 0 Participants |
| Cyclophosphamide | Number of Participants With Chronic GVHD and Grades I-IV GVHD | acute grade II GVHD | 0 Participants |
| Cyclophosphamide | Number of Participants With Chronic GVHD and Grades I-IV GVHD | acute grade I GVHD | 2 Participants |
Secondary
Time to Neutrophil Recovery
Neutrophil recovery is defined as post-nadir ANC greater than or equal to 500/mm3 for three consecutive measurements on different days. The first of the three days will be designated as the day of neutrophil recovery.
Time frame: 1 year
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cyclophosphamide | Time to Neutrophil Recovery | 24.17 days |
Secondary
Time to Platelet Recovery
Platelet recovery is defined as sustained platelet count greater than or equal to 20,000/mm3 or greater than or equal to 50,000/mm3 with no platelet transfusions in the preceding seven days. The first of three consecutive measurements on different days will be designated as the day of initial platelet recovery.
Time frame: 1 year
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cyclophosphamide | Time to Platelet Recovery | 9.4 days |