Study of Nonmyeloablative Peripheral Blood Stem Cell Transplant With High-dose Posttransplantation Cyclophosphamide in Hematopoietic Malignancies Including Those That Are Challenging to Engraft

Study Overview
=================
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: Estimate the cumulative incidences of severe acute grade III or higher GVHD, chronic GVHD (overall and by extent) Estimate the cumulative incidence of systemic steroid initiation, Summarize the graft failure frequency, Summarize the kinetics of neutrophil and platelet recovery, and kinetics of donor chimerism in unsorted and CD3+ sorted peripheral blood. 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).

Official Title
-----------------
Phase II Study of Nonmyeloablative Peripheral Blood Stem Cell Transplant With High-dose Posttransplantation Cyclophosphamide in Hematopoietic Malignancies Including Those That Are Challenging to Engraft

Conditions
-----------------
Hematopoietic Malignancies

Intervention / Treatment
-----------------
* Drug: Cyclophosphamide


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cyclophosphamide<br> | Drug: Cyclophosphamide<br>* Shortened duration immunosuppression following nonmyeloablative peripheral blood stem cell transplant with high dose post transplantation cyclophosphamide in malignancies to engraft.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | One Year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 1 year | 
| Number of Major Toxicities and Complications Associated With Transplantation Procedure | Summarize major toxicities and complications associated with the transplantation procedure | 1 year | 
| 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. | 1 year | 
| 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. | 1 year | 
| 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. | 1 year | 
| 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. | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hematopoietic Malignancies, Nonmyeloablative Peripheral Blood Stem Cell Transplant, Posttransplantation