Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Rare Diseases

Syndrome

Leukemia

Preleukemia

Myelodysplastic Syndromes

Bone Marrow Diseases

Hematologic Diseases

Precancerous Conditions

Antineoplastic Agents

All Drugs and Chemicals

Azacitidine

Antimetabolites

Enzyme Inhibitors

5-azacitidine therapy followed Allogeneic Hematopoietic Cell Transplantation (HCT).

Once enrolled, the patients will receive pre-transplant 5-azacitidine (Vidaza) 75 mg/M\^2/day subcutaneously for 5-7 days every 28 days). Adjustments in dose and timing may occur based on clinical and hematological parameters.

5-azacitidine

Patients will receive transplantation if there is either a suitable sibling or an unrelated donor.

* Response will be evaluated by bone marrow biopsy after 4 cycles of 5-azacitidine or prior to HCT whichever comes first. Due to the very high risk of progression to AML or death in this patient population, the HCT will be done as soon as possible.
* The patients may have additional cycles of 5-azacitidine per standard hematology practice until scheduled for transplant or until progression of disease.
* All patients will be followed until time to progression of MDS, AML or death or a maximum of 1 year. For patients that are transplanted, follow up will be to one year post-transplant.

Allogeneic Hematopoietic Cell Transplantation (HCT)

Teresa Field, M.D., Ph.D.

Janelle Perkins, Pharm.D.

The purpose of this study is to find out if treating people who have high-risk myelodysplastic syndrome (MDS) with 5-Azacitidine (Vidaza) prior to their allogeneic hematopoietic cell transplant (HCT) is helpful in preventing their myelodysplastic syndrome from coming back.

In previous research, 5-Azacitidine appeared to help the bone marrow of a patient with MDS begin to function more normally. This means bone marrow cells can grow and do their work the way they were meant to. 5-Azacitidine is approved by the Food and Drug Administration (FDA) for the treatment of MDS. The effect of 5-Azacitidine in patients receiving hematopoietic cell transplants have not been studied.

RESEARCH PLAN

* This will be a single-center prospective trial
* Patients with high risk MDS that are potentially eligible for HCT will be enrolled.
* A donor search will be initiated, and 5-Azacitidine will be given per standard practice.
* 5-Azacitidine dose is 75 mg/M\^2/day subcutaneously by standard practice (generally this is 7 days per monthly cycle, but alterations occur depending on clinical and laboratory parameters).
* Patients where a suitable donor is not found can continue with 5-Azacitidine per standard treatment. These patients will be followed until progression of MDS to acute myelogenous leukemia (AML) or death, for up to one year.
* If a suitable donor is obtained, the patient will proceed to HCT. The HCT conditioning regimen will be dictated by the Blood and Marrow Transplant (BMT) physician. While waiting HCT, additional cycles 5-Azacitidine may be given. Pre-HCT conditioning regimen therapy will begin no more than 8 weeks and no less than 4 weeks after the last administration of 5-Azacitidine.
* As the number of cycles of 5-Azacitidine is not standardized and the retrospective review of our patients noted above indicated a benefit to ANY exposure to 5-Azacitidine, the actual number of cycles of 5-Azacitidine delivered will not be specified. In addition, as high risk MDS patients have an average time to death of 0.4 years, any delay to HCT once it is available is to be avoided.
* A bone marrow biopsy will be performed to reassess disease response to therapy after the last cycle of 5-Azacitidine before transplant, or after the fourth cycle of 5-Azacitidine, whichever comes first. Note that both the biopsy and the timing of the biopsy is a standard evaluation procedure.
* Donor progenitor cell collection will be prescribed by the BMT Attending Physician.

HCT

* The patient will undergo HCT designated per attending BMT physician.
* Supportive care will be based on institutional guidelines, Stem cell collections, processing and laboratory studies

Stem cell collections, processing and laboratory studies

* Graft assessment, processing, and characterization will be done as per institutional guidelines
* Chimerism testing will be obtained to document post-transplant engraftment, per standard practice.

Pre-Transplant 5-Azacitidine In Patients With High-Risk Myelodysplastic Syndrome Who Are Candidates For Allogeneic Hematopoietic Cell Transplant

A Pilot Study Of Pre-Transplant 5-Azacitidine (Vidaza) In Patients With High-Risk Myelodysplastic Syndrome (MDS) Who Are Candidates For Allogeneic Hematopoietic Cell Transplantation

Relapse-free survival one year after allogeneic HCT in MDS patients receiving at least one complete cycle of 5-azacitidine (Vidaza) in the pre-transplantation setting. Relapsed disease: if with complete remission (CR) - greater than 5% blasts in bone marrow; if with partial response (PR) - greater than 30% increase in blasts in the marrow; if with stable disease (SD) - return to pretreatment peripheral blood levels and transfusion requirements due to disease.

Pre-allogeneic HCT responses to 5-azacitidine (Vidaza), based on the International Working Group criteria: Complete Remission (CR); Partial Response (PR); Stable Disease (SD). Point estimates and 95% confidence intervals were calculated for the response rate to 5-azacitidine, evaluated at marrow evaluation after 4 cycles of 5-azacitidine or prior to HCT whichever came first. CR: Bone marrow with 5% myeloblasts and normal maturation of all cell lines. PR: All CR criteria if abnormal before treatment except bone marrow blasts decreased by 50% over pretreatment but still \> 5%. SD: Failure to attain CR, PR, relapsed (or progressive) disease.

Proportion of patients enrolled who subsequently proceeded to allogeneic HCT.

Overall survival for all participants at one year after first dose of 5-azacitidine (Vidaza). Overall survival was calculated by the method of Kaplan-Meier with standard errors computed using Greenwood's formula.

Celgene Corporation

H. Lee Moffitt Cancer Center and Research Institute

This was a standard of care study for Myelodysplastic Syndrome patients, with 5-Azacitidine prior to standard transplant.

Combined Therapy

Age, Continuous

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

21 of 25 participants proceeded to allogeneic HCT and were evaluated for most measures.

Limitation: Small single center pilot study to show the use of pre-treatment 5-Azacitidine and successfully proceeding to transplant.

Participants who proceeded to allogeneic HCT

Percentage of Participants With Relapse-free Survival (RFS)

Partial Response

Complete Remission

Stable Disease

Progressive Disease

Overall Response Rate (ORR)

Percentage of Participants Who Proceed to Hematopoietic Cell Transplantation (HCT)

Percentage of Participants With Overall Survival (OS)

Overall Study

Leukemia, Myeloid

Hematologic Neoplasms

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Myeloproliferative Disorders

Neoplasms by Histologic Type

Chronic Disease

Disease Attributes

Myeloid Leukemia

Chronic Graft Versus Host Disease

Chronic Myeloid Leukemia

Acute Graft Versus Host Disease

Chronic Myeloproliferative Disorders

Antirheumatic Agents

Anti-Infective Agents

Tacrolimus

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Melphalan

Plerixafor

Lenograstim

Mycophenolic Acid

Thiotepa

Alkylating Agents

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Antiviral Agents

Adjuvants, Immunologic

Calcineurin Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antitubercular Agents

Anti-HIV Agents

Anti-Retroviral Agents

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:.

* Fludarabine (160 mg/m2)
* Melphalan (50 mg/m2)
* TBI (4Gy)

All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.

Subjects without an identified matched related or matched unrelated donor will receive a haploidentical transplantation with reduced intensity preparative conditioning:

-. Fludarabine (160 mg/m2)

* Melphalan (100 mg/m2
* TBI (4Gy)

Patients will receive GVHD prophylaxis with post-transplant cyclophosphamide and tacrolimus.

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:

* Fludarabine (160 mg/m2)
* Thiotepa (10 mg/kg)
* TBI (4Gy)

All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:

* Fludarabine (160 mg/m2)
* Thiotepa (5 mg/kg)
* TBI (2-3 Gy).

All enrolled subjects will receive GVHD prophylaxis with single-agent tacrolimus.

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:

* Fludarabine (160 mg/m2)
* Thiotepa (10 mg/kg)
* TBI (4 Gy) All enrolled subjects will receive GVHD prophylaxis with tacrolimus and mycophenolate mofetil (MMF).

Subjects will receive reduced intensity preparative chemotherapy conditioning for a matched related/ unrelated donor transplant:

* Fludarabine (160 mg/m2)
* Thiotepa (5 mg/kg)
* TBI (2-3 Gy)

All enrolled subjects will receive GVHD prophylaxis with tacrolimus and ruxolitinib.

Purified regulatory T-cells (Treg) plus CD34+ hematopoietic progenitor cells ("CD34+ HSPC"), followed by conventional T-cells (Tcon) Manufactured at SCTT Laboratory, dose 1x10\^6 cells/ kg to 3x10\^6 cells/kg

Purified regulatory T-cells (Treg) plus CD34+ HSPC

The CliniMACS® CD34 Reagent System is a medical device that is used in vitro to select and enrich specific cell populations is manufactured by Miltenyi Biotec

CliniMACS CD34 Reagent System

Single-use vials contain either 300 mcg or 480 mcg filgrastim at a fill volume of 1.0 mL or 1.6 mL

Filgrastim granulocyte colony-stimulating factor (G-CSF) or equivalent

Mycophenolate Mofetil (MMF)

Ruxolitinib

Lindsay Danley

Everett Meyer, MD, PhD

Everett Meyer, MD,PhD

Reduced intensity conditioning (RIC) has emerged and been increasingly adopted as a modality to allow preparative conditioning pre transplant to be tolerated by older adults or those patients that are otherwise unfit for myeloablative conditioning. In this study, we aim to use RIC followed by matched related/unrelated donor, 7/8 matched related/unrelated donor, or haploidentical donor peripheral blood stem cell transplantation. Standard strategies to control the alloreactivity following HCT utilize immunosuppressive or cytotoxic medications. In this study, we explore donor graft engineering to enrich for immmunoregulatory populations to facilitate post transplantation immune reconstitution while minimizing graft versus host disease (GVHD) with post-transplant immunosuppressive agents.

The objectives for the study are listed below:

Primary Objectives

\*Determine the safety, and feasibility of administration of several dose combinations of conventional T-cells (Tcon) and regulatory T-cells (Treg) in subjects undergoing allogeneic hematopoietic cell transplantation (HCT) with related/unrelated HLA-matched or mismatched donors, or haploidentical donors with reduced intensity conditioning preparative regimen.

Secondary Objectives

* To determine the GVHD-free relapse-free survival (GRFS) post-HCT
* To determine the overall survival (OS) post-HCT
* To measure the incidence and severity of acute and chronic GVHD

Exploratory Objectives

* To measure the incidence of serious infections
* To measure the incidence and timing of engraftment
* To measure T cell immunity reconstitution parameters

Reduced Intensity Allogeneic HCT in Advanced Hematologic Malignancies w/T-Cell Depleted Graft

Phase 1 Trial for Patients With Advanced Hematologic Malignancies Undergoing Reduced Intensity Allogeneic HCT With a T-cell Depleted Graft With Infusion of Conventional T-cells and Regulatory T-cells

Neutrophil engraftment is defined as having an ANC ≥ 500 cells/µL for three consecutive days. The first of three days will be designated as the day of engraftment.

Platelet engraftment is defined as achieving a platelet count \> 20,000 cells/µL for three consecutive days without platelet transfusion in the preceding 7 days. The first of three days will be designated as the day of engraftment.

Incidence of serious infections will be measured as event of infections that led to hospitalization or death or required antibiotic treatment. Infections will be graded according to the CTCAE version 5.0

Clinical effect will be assessed as graft vs host disease (GVHD)-free relapse free survival (GRFS), GVHD-free is defined as no GVHD symptoms, and relapse free survival is defined as survival at 12 months without relapse. The outcome will be measured in Arm A only.

Overall survival is measured as number of participants alive. Alive at the time of last observation will be censored.

Acute GVHD will be staged and graded per Mount Sinai Acute GvHD International Consortium (MAGIC) Standardization criteria.

Primary graft failure is defined as being alive with donor CD3 chimerism \<5% at day +30 after transplant without recovery of neutrophils (i.e. without achieving an absolute neutrophil count \[ANC\] ≥ 500/mm3 for 3 consecutive days) at Day+28

Defined as a percentage on donor CD3 cells chimerism at day +60 after transplantation.

Clinical effect will be assessed as graft vs host disease (GVHD)-free relapse free survival (GRFS), GVHD-free is defined as no GVHD grade 3 and 4, and relapse free survival is defined as survival at 12 months without relapse.

Secondary graft failure (defined by donor CD3 chimerism \<5% at day +30 after transplant) and neutrophil engraftment followed by subsequent decline in ANC \< 500/mm3 unresponsive to growth factor therapy, by Day +100

TEAEs will be categorized by the System Organ Class and preferred term and will be graded according to the CTCAE version 5.0

Steroid refractory acute GVHD will be defined as per the EBMT-NIH-CIBMTR Task Force position statement

Non-relapse mortality is measured as number of participants died without relapse/ recurrent disease. Subjects without evidence of relapse/progression at last follow-up date or date of death will be censored.

Overall survival is measured as number of participants alive and in remission. Alive in remission at the time of last observation will be censored.

Chronic GVHD will be diagnosed per 2014 International NIH Chronic GVHD Diagnosis and Staging Consensus Working Group criteria (Jagasia 2015). Chronic GVHD scored according to the first day of chronic GVHD onset will be used to calculate cumulative incidence curves. Subjects will be followed for 2 years from the Day 0 (day of CD34+ peripheral blood stem cell infusion) for estimation of cGVHD incidence.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Pre-Transplant 5-Azacitidine In Patients With High-Risk Myelodysplastic Syndrome Who Are Candidates For Allogeneic Hematopoietic Cell Transplant	NCT00660400	Leukemia	5-azacitidine Allogeneic Hema...	18 Years - 68 Years	H. Lee Moffitt Cancer Center and Research Institute
Reduced Intensity Allogeneic HCT in Advanced Hematologic Malignancies w/T-Cell Depleted Graft	NCT05088356	Allogeneic Hema... Advanced Hemato... Acute Leukemia Chronic Myeloge... Myelodysplastic... Myeloproliferat...	Purified regula... Fludarabine Melphalan CliniMACS CD34 ... Tacrolimus Cyclophosphamid... Plerixafor Filgrastim gran... Thiotepa Mycophenolate M... Ruxolitinib	18 Years - 75 Years	Stanford University

Spots Global Cancer Trial Database for allogeneic hematopoietic cell transplantation (hct)