Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Rare Diseases

Syndrome

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Neoplasms by Histologic Type

Hematologic Diseases

Bone Marrow Diseases

Precancerous Conditions

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Fludarabine

Fludarabine phosphate

Melphalan

Busulfan

Vidarabine

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Antiviral Agents

Antineoplastic Agents, Alkylating

Alkylating Agents

fludarabine (30 mg/m\^2/day, days -6 to days -2, the total dase is 150 mg/m\^2) and busulfan (3.2 mg/kg/day, days -3 to days -2, the total dose is 6.4 mg/kg)

fludarabine (30 mg/m\^2/day, days -6 to days -2, the total dose is 150 mg/m\^2) and melphalan (70 mg/m\^2/day, days -3 to days -2, the total dose is 140 mg/m\^2)

Fludarabine with total dose of 150 mg/m\^2 in combination with Busulfan with total dose of 6.4 mg/kg

Fludarabine and Busulfan

Fludarabine with total dose of 150 mg/m\^2 in combination with Melphalan with total dose of 140 mg/m\^2

Fludarabine and Melphalan

Linghui Xia, Professor

Wei Shi, Professor

Miaomiao Zhao, Doctor

The goal of this clinical trial is to compare outcomes of two reduced intensity conditioning (RIC) regimens (fludarabine plus busulfan and fludarabine plus melphalan) in allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) patients. The main questions it aims to answer are:

* The safety of two reduced intensity conditioning (RIC) regimens (fludarabine plus busulfan and fludarabine plus melphalan) in allogeneic hematopoietic stem cell transplantation for adult AML/MDS patients with HCT-CI≥3 or aged ≥55 years.
* The efficacy of two reduced intensity conditioning (RIC) regimens (fludarabine plus busulfan and fludarabine plus melphalan) in allogeneic hematopoietic stem cell transplantation for adult AML/MDS patients with HCT-CI≥3 or aged ≥55 years.

Participants will be randomized to one of two reduced intensity conditioning (RIC) regimens (fludarabine plus busulfan and fludarabine plus melphalan)

Patients are randomized to one of two reduced intensity conditioning (RIC) regimens: the combination of fludarabine (30 mg/m\^2/day, days -6 to days -2, the total dase is 150 mg/m\^2) and busulfan (3.2 mg/kg/day, days -3 to days -2, the total dose is 6.4 mg/kg) (Flu/Bu) or fludarabine (30 mg/m\^2/day, days -6 to days -2, the total dose is 150 mg/m\^2) and melphalan (70 mg/m\^2/day, days -3 to days -2, the total dose is 140 mg/m\^2) (Flu/Mel). A total of 200 patients (100 to each arm) will be recruited in this study over a period of two years. Patients will be followed for up to 18 months from allogeneic hematopoietic stem cell transplantation.

Participants will be randomized to one of two reduced intensity conditioning (RIC) regimens (fludarabine plus busulfan and fludarabine plus melphalan)

Reduced Intensity Conditioning Regimens for Acute Myeloid Leukemia and Myelodysplastic Syndrome

Reduced Intensity Conditioning With Fludarabine and Busulfan Versus Fludarabine and Melphalan Before Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Randomised, Single-Center, Phase III Study

Neutrophil engraftment is defined as achieving an absolute neutrophil count greater than 500x10\^6/liter for 3 continuous measurements on different days. The first of the 3 days will be labeled as the day of neutrophil engraftment. Platelet engraftment is defined as achieving platelet counts greater than 20,000/microliter for continuous measurements over 7 days without requiring platelet transfusions. The first day of the 7 days will be marked as the day of platelet engraftment.

List the type, number, and severity of infection events

The severity of oral ulcer or diarrhea in the early stage after transplantation, clinically significant abnormal laboratory findings.

Number of Lymphocyte Subsets of Participants

Survival without relapse or progression of the primary disease. Kaplan-Meier (KM) method was used to estimate median PFS.

Overall survival is defined as survival duration from the date of randomization to the date of death from any cause. Kaplan-Meier (KM) method was used to estimate median OS

Death not due to recurrence or progression of the primary disease. Recurrence was considered as a competing risk event, and the Gray test was used for statistical analysis.

Relapse of the primary disease. Non-relapse mortality (TRM) was considered as a competing risk event, and Gray's test was used for statistical analysis.

Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995:

Skin stage:

0: No rash

Rash \<25% of body surface area Rash on 25-50% of body surface area Rash on \> 50% of body surface area Generalized erythroderma with bullous formation

Liver stage (based on bilirubin level)\*:

0: \<2 mg/dL

2-3 mg/dL 3.01-6 mg/dL 6.01-15.0 mg/dL \>15 mg/dL

GI stage\*:

0: No diarrhea or diarrhea \<500 mL/day

Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD Diarrhea 1000-1499 mL/day Diarrhea \>1500 mL/day Severe abdominal pain with or without ileus \* If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1.

GVHD grade:

0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4

Chronic GVHD is classified as the occurrence of mild, moderate, or severe chronic GVHD per 2005 NIH Consensus Criteria (Filipovich et al. 2005)

Wuhan Union Hospital, China

Cytopenia

Anemia

Leukopenia

Thrombocytopenia

Leukocyte Disorders

Blood Platelet Disorders

Peter Bader, M.D.

This is a prospective, non-randomized multi-center multi-national study to evaluate the chimerism measured by STR and SNP in patients with hypoplastic RC and normal karyotype transplanted with a preparative regimen of reduced intensity.

Primary objectives:

* To study hematopoietic chimerism in whole blood and different cell population (CD14, CD15, CD 56, CD3, CD19) as well as in dendritic cells and regulatory T-cells after SCT with RIC in patients with RC
* To compare the results of chimerism obtained with standard STR PCR (sensitivity 1%) with those obtained with SNP PCR (sensitivity 0.1- 0.01%)

Secondary objectives:

* To evaluate the relationship between mixed chimerism and hematological engraftment, OS and EFS
* To study the impact of mixed chimerism in plasmacytoid dendritic and regulatory T-cells on the incidence of acute and chronic GVHD

Research Question 3.1.1 Chimerism and post transplant outcome During the past 3 decades, SCT has become a well established treatment procedure for many malignant and hematopoietic disorders in children and adults.1-8 After transplantation, it has been of central interest whether the newly developed hematopoietic system is of recipient or donor origin. The investigations of the genotypic origin of post transplant hematopoiesis are called chimerism analysis. Originally, it was believed that complete donor hematopoiesis is essential to maintain engraftment after allogeneic SCT in humans.9 In the last decades, however, it became evident that donor and recipient hematopoiesis could coexist after allo-SCT in the recipient. This state of coexistence of hematopoietic cells is called mixed chimerism which might end in an "autologous recovery". In patients with refractory cytopenia SCT after myeloablative conditioning regimen allowed prompt and sustained engraftment in virtually all patients. In this disease relapse has become a very rare event. Consequently, transplant related mortality and long term squeals have become major obstacles yet to be overcome to improve the children's well being and the prognosis of the disease. In SCT with RIC, the reduction of early and late toxicity may be counterbalanced by delayed engraftment, graft rejection, mixed chimerism and GVHD.

Graft rejection It is well known that less myeloablative conditioning regimens predispose for a higher rate of mixed chimerism. Consequently, graft rejection or non engraftment is a major cause of treatment failure.

Sensitization to minor histocompatibility antigens by prior transfusions of blood products can increase this risk. The rapid development of complete chimerism in NK-cells and T-cells seems to play an important role to achieve sustained engraftment specifically in patients transplanted with a dose reduced preparative regimen. Therefore, it is important to elucidate the development of post transplant chimerism in different cell subpopulations. This will allow following and documenting proper engraftment, and will detect early hints of ongoing graft rejection.

Graft versus host disease The occurrence of GVHD is influenced by many well known factors. Although the use of nonmyeloablative SCT can reduce the severity of GVHD, GVHD remains a major complication. In our pilot study using the reduced intensity preparative regimen in RC, the probability for developing GVHD grade IIIV was 0.48. It is accepted that in comparison to myeloablative SCT, in reduced intensity preparative regimens higher proportions of host immune hematopoietic cells may persist. While donor-derived alloreactive lymphocytes are being infused, these autologous cells might possibly serve as host antigen presentation for continuous stimulation of donor T-cells. Consequently, it was speculated by the group Shapira and Slavin10 that GVHD may be similarly amplified by reduced conditioning followed by intentional administration of host cells. This hypothesis was tested in a preclinical animal model. Increased incidence of GVHD, higher mortality and increased levels of chimerism were observed in recipients reconstituted with additional host cells, particularly with non-irradiated spleen cells. Graft-versus-Leukaemia (GVL) effect was not impaired by post transplant cell administration. These results suggested that GVHD may be amplified by recipient cell infusion using either irradiated or viable stimulatory host cells. This could possibly explain the higher than anticipated incidence of GVHD and consequently the rapid displacement of host cells with conversion to 100% donor type cells in reduced intensity SCT. The present study will therefore investigate whether autologous antigen presenting cells (Auto-APC) do survive the conditioning regimen and favour to occurrence of GVHD.

Hematopoietic chimerism will be investigated from PB samples. Prior to transplant 5 ml EDTA PB from patient and donor are required and will be sent to the laboratory of the Coordinating Investigator (P.B.). Post transplant PB samples (5 -10 ml EDTA blood) from day +30 (4 days), +60(4 days), +100 (7 days) and +180 (7 days) will also being sent to the laboratory of the Coordinating Investigator (P.B.) From EDTA PB cell subpopulations will be isolated and DNA will be extracted and stored for further investigations.

Serial Analysis of Chimerism in Patients With Refractory Cytopenia (RC) Transplanted With Reduced Intensity Conditioning (RIC)

Serial Analysis of Chimerism in Patients With Refractory Cytopenia (RC) Transplanted With Reduced Intensity Conditioning (RIC) EWOG MDS SCT RC RIC-06

Charlotte Niemeyer, MD

Prof. Dr. Charlotte Niemeyer, MD

Hematologic Neoplasms

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Myeloproliferative Disorders

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Chronic Myeloid Leukemia

Chronic Myeloproliferative Disorders

Antirheumatic Agents

Tacrolimus

Cyclophosphamide

Plerixafor

Lenograstim

Mycophenolic Acid

Thiotepa

Adjuvants, Immunologic

Calcineurin Inhibitors

Enzyme 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.

Orca Biosystems, Inc.

Stanford University

Immune System Diseases

Infections

Lymphoma

Precursor Cell Lymphoblastic Leukemia-Lymphoma

Leukemia, Lymphoid

Lymphoma, Non-Hodgkin

Lymphoma, Mantle-Cell

Lymphoma, Follicular

Lymphoma, B-Cell, Marginal Zone

Hodgkin Disease

Burkitt Lymphoma

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphoma, B-Cell

Communicable Diseases

Epstein-Barr Virus Infections

Virus Diseases

Herpesviridae Infections

DNA Virus Infections

Tumor Virus Infections

Lymphosarcoma

Acute Lymphoblastic Leukemia

Lymphoblastic Lymphoma

Mantle Cell Lymphoma

Follicular Lymphoma

Marginal Zone Lymphoma

Hodgkin Lymphoma

Acute Leukemia of Ambiguous Lineage

Gray Zone Lymphoma

B-cell Lymphoma

Bendamustine Hydrochloride

Experimental: Cyclophosphamide and Bendamustine Control: Cyclophosphamide

Interventions:

* Drug: Bendamustine
* Drug: Cyclophosphamide

After transplant, given intravenously on day +4 as part of Phase Ib.

Bendamustine

After transplant, given intravenously on day +3 as part of Phase 1b.

Emmanuel Katsanis, MD

The purpose of this study is to evaluate the safety of progressively substituting day +3 and +4 post-transplant cyclophosphamide (PT-CY) with post-transplant bendamustine (PT-BEN) in myeloablative (MAC) haploidentical hematopoietic cell transplantation (HHCT) for patients with hematological malignancies.

The goal of the Phase 1 component of the study is to evaluate the safety of progressively substituting post-transplant cyclophosphamide (PT-CY) given on Days +3 and +4 with bendamustine (PT-BEN). The Phase I component of the study has been completed.

The Phase Ib component of the study will continue to evaluate the safety and efficacy of subjects who receive PT-BEN on Days +3 and +4 at the maximum tolerated dose determined by Phase I. The Phase Ib component of the study has been completed.

Approximately, 18-36 subjects will be treated as part of Phase I and 15 as part of Phase Ib. Approximately 18 subjects will be used as controls, subjects that receive no PET-BEN, for direct comparison. Total, approximately 38-56 treatment and control patients and 38-56 donor subjects will be enrolled.

This study will follow the standard-of-care bone marrow transplant (BMT), with the only exception being to progressively substitute post-transplant cyclophosphamide (on Days +3 and +4 after BMT) with bendamustine. Six dose levels were planned for the Phase I component of the study, consisting of a combination of sequentially reduced doses of cyclophosphamide (PT-CY) and increased doses of bendamustine (PT-BEN) initially on Day +4 after BMT, followed by the same sequential reduction and increase on Day +3. An interim analysis was performed after cohort 3 was completed in Phase I and included a preliminary comparison between treatment and control groups. Phase Ib will evaluate patients treated with PT-CY on day +3 and PT-BEN on day +4.

Control patients will be patients that have declined to participate in the main trial but will receive haploidentical BMT with the current standard of two days of PT-CY (and no PT-BEN) and will be consented for the immune monitoring studies only.

Haploidentical BMT With Post-Transplant Cyclophosphamide and Bendamustine

A Phase I/Ib Study of Haploidentical Bone Marrow Transplant With Post-Transplant Cyclophosphamide and/or Bendamustine

Examine the effects of PT-BEN on immune reconstitution following human haploidentical BMT.

Immune reconstitution will be studied prospectively. Viral and fungal prophylaxis and treatment will be done according to our BMT programs guidelines

T cell immune reconstitution (CD4, cluster of differentiation 8 (CD8), Treg, NK), B cell and myeloid cell reconstitution will be evaluated serially until 6 months post-BMT

Gather data on Incidence of bacterial, fungal and viral infections/reactivations

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Reduced Intensity Conditioning Regimens for Acute Myeloid Leukemia and Myelodysplastic Syndrome	NCT05674539	Acute Myeloid L... Myelodysplastic... Allogeneic Hema...	Fludarabine and... Fludarabine and...	18 Years -	Wuhan Union Hospital, China
Serial Analysis of Chimerism in Patients With Refractory Cytopenia (RC) Transplanted With Reduced Intensity Conditioning (RIC)	NCT00682799	Refractory Cyto... Reduced Intensi... Myelodysplastic... Hematopoietic S...		- 215 Months	University Hospital Freiburg
Reduced Intensity Conditioning Regimens for Acute Myeloid Leukemia and Myelodysplastic Syndrome	NCT05674539	Acute Myeloid L... Myelodysplastic... Allogeneic Hema...	Fludarabine and... Fludarabine and...	18 Years -	Wuhan Union Hospital, China
Reduced Intensity Conditioning Regimens for Acute Myeloid Leukemia and Myelodysplastic Syndrome	NCT05674539	Acute Myeloid L... Myelodysplastic... Allogeneic Hema...	Fludarabine and... Fludarabine and...	18 Years -	Wuhan Union Hospital, China
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
Haploidentical BMT With Post-Transplant Cyclophosphamide and Bendamustine	NCT02996773	Acute Lymphobla... Acute Myelogeno... Myelodysplastic... Chronic Myeloge... Lymphoma,Non-Ho... Lymphoma, Hodgk... Lymphoma, Folli... Marginal Zone L... Large Cell Lymp... Mantle-Cell Lym... Gray Zone Lymph... Burkitt Lymphom... High Risk Undif...	Bendamustine Cyclophosphamid...	4 Years - 30 Years	University of Arizona

Spots Global Cancer Trial Database for reduced intensity conditioning (ric)