Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Rare Diseases

Syndrome

Preleukemia

Myelodysplastic Syndromes

Cytopenia

Anemia

Leukopenia

Thrombocytopenia

Bone Marrow Diseases

Hematologic Diseases

Precancerous Conditions

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

Infections

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Immune System Diseases

Hematologic Neoplasms

Acquired Immunodeficiency Syndrome

HIV Infections

Immunologic Deficiency Syndromes

Graft vs Host Disease

Virus Diseases

Homologous Wasting Disease

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anti-Inflammatory Agents

Anti-Infective Agents

Cyclophosphamide

Prednisone

Plerixafor

Bortezomib

Busulfan

Maraviroc

Mesna

Pentostatin

Anti-HIV Agents

Anti-Retroviral Agents

Antiviral Agents

RIC+alloHCT+GVHD prophylaxis per dose levels 1, 2, and

Collection of research samples on hematopoietic donors

e-ATG 40 mg/kg/day IV on days -14 and -13. Prednisone tapering doses given orally daily: -days -14 through -12: 1mg/kg/day -days -11 and -10: 0.75 mg/kg/day -days -9 and -9: 050 mg/kg/day -day -7: 0.25 mg/kg/day Pentostatin 4 mg/m2/day IV on days -11 and -7. Cyclophosphamide 5 mg/kg orally or IV daily on days -11 through -4. Busulfan IV AUC targeted dose of 14.8-23.0 mg\*h/L, on days -3 and -2.

Cyclophosphamide 50 mg/kg IV daily Bortezomib 1.3 mg/m2 IV +6 hours and +72 hours after graft infusion Mesna 50 mg/kg IV concomitant with cyclophosphamide

GVHD prophylaxis

allo HCT

In phase 1 dose level 3 and phase 2 only: Plerixafor 240 (Micro)g/kg subcutaneously every other day, starting day +1 through day +21

Phase 1 dose level 2: 300 mg orally twice daily starting day-3 through day day+30

Jennifer A Kanakry, M.D.

Background:

People living with HIV(PLWH) are at a higher risk for cancers that may be curable with a bone marrow transplant. HIV infection itself is no longer a reason to not get a transplant, for patients who otherwise have a standard reason to need transplant.

Objective:

This study is being done to see if a new combination of drugs (cyclophosphamide, maraviroc, and bortezomib) is both safe and effective at protecting against graft-versus-host disease after bone marrow transplant. The study will also test the transplant s impact on your survival and control of your cancer.

Eligibility:

People aged 18 years and older living with HIV and a blood cancer that is eligible for a transplant. Healthy family members aged 12 or older who are half matched to transplant recipients are also needed to donate bone marrow.

Design:

The study will be done in 2 phases. The first phase will be to see if we can safely use a new combination of drugs to prevent GVHD. If the combination is safe in the first phase, the study will proceed to the second phase. In the second phase, we will see if this new combination can better protect against GVHD after transplant.

Participants will be screened. Their diagnoses, organ function and eligibility will be confirmed.

Participants will have a catheter inserted into a vein in their chest or neck. Medications and transfusions will be given through the catheter; blood will be drawn from it.

Participants will be in the hospital for 6 weeks or longer.

They will receive various drugs for 2 weeks to prep their body for the transplant.

The transplant cells will be administered through the catheter.

Participants will continue to receive drug treatments after the transplant.

Blood transfusions may also be needed.

Participants will return 1-2 times per week for follow-up visits for 3 months after discharge.

Participants will have visits 6, 12, 18, 24 months after transplant, then once a year for 5 years.

Background:

* Human Immunodeficiency Virus (HIV) infection should not be considered a barrier to hematopoietic cell transplantation (HCT) in patients who otherwise have a standard indication for HCT.
* The main historical barriers include the risk of opportunistic infections, drug interactions, and lack of donor availability.
* This study addresses these barriers by requiring adequate HIV control with anti-retroviral therapies which do not interact with the transplant medications and by utilizing HLA-haploidentical donors.
* Cellular reservoirs that harbor latent HIV are cells of hematopoietic origin, and thus HCT is a potential cure for HIV if all hematopoietic/immune cells can convert to fully donors without HIV infection of these cells.
* CCR5 receptor and CXCR4 are chemokine co-receptors that enable HIV entry into cells.
* Obtaining a CCR5-delta-32 homozygous donor lacks feasibility for the majority of people living with HIV (PLWH) requiring HCT, particularly those of minority ethnic backgrounds.
* Agents used to prevent graft-versus-host disease (GVHD) include post-transplantation cyclophosphamide (PTCy), maraviroc, and bortezomib

  * PTCy expands the donor pool by allowing HLA-mismatched donor HCT with good engraftment and low rates of GVHD. PTCy typically combined with other agents as adjuncts for GVHD prophylaxis, standardly a calcineurin inhibitor and mycophenolate mofetil
  * Bortezomib has been used in combination with PTCy as GVHD prophylaxis and may additionally inhibit HIV infection of donor cells
  * Maraviroc is used as GVHD prophylaxis, but not previously in combination with PTCy and bortezomib, and is additionally a CCR5 receptor blocker, which may inhibit HIV infection of donor cells. Maraviroc is an HIV medication used in modern ART regimens.
  * This protocol is a step-wise evaluation of a GVHD prophylaxis regimen of PTCy and bortezomib in recipients of HLA-haploidentical grafts among those who are on maraviroc, followed by a de-escalation of maraviroc to serve purely as GVHD prophylaxis
* Plerixafor is used in HCT to promote hematopoietic recovery, akin to the use of G-CSF, and is also a CXCR4 blocker, which may inhibit HIV infection of donor cells

Objective:

* To determine a safe and recommended phase II dose level regimen.
* To determine whether a PTCy-based GVHD prophylaxis regimen including maraviroc and bortezomib can maintain adequate protection against grades III-IV acute GVHD (aGVHD), evaluated at day +100.

Eligibility:

* Transplant recipient: age \>= 18 years
* Transplant recipient must be HIV seropositive
* Transplant recipient must have histologically or cytologically confirmed hematologic malignancy with a standard indication for allogeneic HCT, or hematologic malignancy with a standard indication for autologous transplant without access to autologous transplant
* There must be at least one potentially suitable HLA-haploidentical donor.

Design:

* Open-label, single institution, non-randomized, single arm phase II study
* CCR5-delta-32 status will be tested among donor options and homozygous donors will be used, if available
* Conditioning will consist of eATG 40 mg/kg/day IV on days -14 and -13, pentostatin 4 mg/m\^2/day IV on days -11 and -7, low-dose cyclophosphamide 5 mg/kg/day orally daily on days -11 through -4; busulfan IV, pharmacokinetically dosed, on days -3 and -2.
* Bone marrow is the only graft source allowed for this study.
* GVHD prophylaxis will consist of PTCy 50 mg/kg/day IV on days +3 and +4, bortezomib 1.3 mg/m\^2 IV in 2 doses at 6 and 72 hours after graft infusion for all participants. The phase I will include 2 dose levels of de-escalated maraviroc

  * Dose level 1 - PLWH on a maraviroc-containing ART regimen that starts at least 4 weeks before enrollment and continues at least through day +100
  * Dose level 2 - PLWH not on a maraviroc-containing ART regimen, treated with maraviroc 300 mg orally twice daily starting day -3 and given through day +30 purely for GVHD prophylaxis
* If successful completion of dose level 2, dose level 3 will substitute plerixafor in lieu of G-CSF to the dose level 2 regimen. Plerixafor will be given subcutaneously at 240 microgram/kg every other day, beginning at day +1 after transplant through day +21, or longer as clinically indicated, such as until ANC recovery.

Trial of Allogeneic Reduced-Intensity, HLA-Haploidentical Bone Marrow Transplantation Followed by Graft-versus-Host-Disease (GVHD) Prophylaxis With Cyclophosphamide, Bortezomib and Maraviroc for Hematologic Malignancies in People Living With HIV

A Phase I/II Trial of Allogeneic Reduced-Intensity, HLA-Haploidentical Bone Marrow Transplantation Followed by GVHD Prophylaxis With Cyclophosphamide, Bortezomib and Maraviroc for Hematologic Malignancies in People Living With HIV (PLWH)

.All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGAP

Proportion of evaluable recipients who experience grade III-IV acute GVHD at day +100 will be reported along with 80% and 95% two-sided confidence interval

Number and type of toxicities noted for participants who are evaluable

Cumulative incidence of primary and secondary graft failure based on chimerism at day +100 and 1 year post transplant

cumulative incidence of hematopoietic recovery will be based on platelet recover at day +100

Time from transplant to death of any cause and will be determined using the Kaplan-Meier method

Cumulative incidence rates will be estimated based on disease-risk index.

Time from transplant to death from any cause of other event and will be determined using the Kaplan-Meier method

Evaluation by all grades, grade II-IV, and grade III-IV

Evaluation by severity of mild, moderate, and severe

Time from transplant to disease progression and will be determined using the Kaplan-Meier method

cumulative incidence of transplant related mortality will be estimated

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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
Trial of Allogeneic Reduced-Intensity, HLA-Haploidentical Bone Marrow Transplantation Followed by Graft-versus-Host-Disease (GVHD) Prophylaxis With Cyclophosphamide, Bortezomib and Maraviroc for Hematologic Malignancies in People Living With HIV	NCT05470491	HIV Hematologic Mal...	RIC GVHD prophylaxi... allo HCT Plerixafor Maraviroc	12 Years - 120 Years	National Institutes of Health Clinical Center (CC)

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Spots Global Cancer Trial Database for ric

Every month we try and update this database with for ric cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for ric cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.