Cellular Therapy + Ruxolitinib for Graft-versus-Host Disease
Recruiting in Palo Alto (17 mi)
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase < 1
Recruiting
Sponsor: M.D. Anderson Cancer Center
Must be taking: Ruxolitinib
Disqualifiers: Chronic GVHD, Uncontrolled infections, others
No Placebo Group
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?This early phase I trial is to find out the effect of adding cord blood tissue-derived mesenchymal stromal cells (cb-MSCs) to ruxolitinib in treating patients with acute graft versus host disease that does not respond to steroid therapy (steroid-refractory). Ruxolitinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. cb-MSCs are a type of tissue helper cell that can be removed from donated umbilical cord blood tissue and grown into many different cell types that can be used to treat cancer and other disease, such as graft versus host disease. This trial aims to learn if adding cb-MSCs to ruxolitinib may help control steroid-refractory acute graft versus host disease.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, it seems that you must not have been on ruxolitinib for more than 96 hours before starting the trial.
What data supports the effectiveness of the treatment Cellular Therapy + Ruxolitinib for Graft-versus-Host Disease?
Research on natural killer (NK) cell-based therapies shows promise in treating post-transplant relapse of myeloid diseases, with NK cells expanding and persisting in the body, which may suggest potential benefits for similar cellular therapies in managing graft-versus-host disease.
12345Is the combination of cellular therapy and ruxolitinib safe for treating graft-versus-host disease?
Ruxolitinib has been used in patients with graft-versus-host disease (GVHD) who did not respond to steroids, and while it is generally tolerable, some serious side effects like infections, sepsis, and respiratory issues have been reported. In a study, 68.3% of patients with acute GVHD and 33.9% with chronic GVHD experienced serious adverse events.
678910How is the drug Ruxolitinib unique in treating graft-versus-host disease?
Ruxolitinib is unique because it is a targeted therapy that works by inhibiting specific proteins (called Janus kinases) involved in the immune response, which can help reduce inflammation and immune system overactivity in graft-versus-host disease. This mechanism is different from traditional treatments that broadly suppress the immune system.
211121314Eligibility Criteria
This trial is for patients aged 12-80 with acute graft versus host disease that's not improving with steroids, specifically affecting the lower GI tract or liver. They must have a certain level of kidney function and be able to consent. Women who can get pregnant and men must use birth control. People with skin-only GVHD, uncontrolled infections, significant oxygen needs, allergies to certain animal products, or using other treatments are excluded.Inclusion Criteria
I can care for myself but may need occasional help.
I can give my consent, or my legal representative can, for this trial.
I am between 12 and 80 years old.
+3 more
Exclusion Criteria
I do not have any infections, or if I do, they are under control with no worsening signs.
I have a skin condition caused by a recent transplant.
I have been diagnosed with new onset chronic graft-versus-host disease.
+4 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Patients receive ruxolitinib orally twice daily. In Arm 2 and Arm 3, patients also receive cb-MSCs intravenously twice weekly over 4 consecutive weeks.
4 weeks
8 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment, including assessments of GVHD status and incidence of infections.
6 months
Regular follow-up visits
Participant Groups
The study tests adding cord blood tissue-derived mesenchymal stromal cells (cb-MSCs) to ruxolitinib in treating steroid-refractory acute graft versus host disease after stem cell transplant. It explores whether cb-MSCs combined with ruxolitinib can better manage the condition compared to standard treatments.
3Treatment groups
Experimental Treatment
Active Control
Group I: Arm 3 (ruxolitinib, higher dose ds-MSCs)Experimental Treatment2 Interventions
Patients receive ruxolitinib PO BID as in Arm 1. Patients also receive higher dose of cb-MSCs IV for up to 60 minutes twice weekly (at least 3 days apart) over 4 consecutive weeks for 8 total doses.
Group II: Arm 2 (ruxolitinib, lower dose ds-MSCs)Experimental Treatment2 Interventions
Patients receive ruxolitinib PO BID as in Arm 1. Patients also receive lower dose of cb-MSCs IV for up to 60 minutes twice weekly (at least 3 days apart) over 4 consecutive weeks for 8 total doses.
Group III: Arm 1 (ruxolitinib)Active Control1 Intervention
Patients receive ruxolitinib PO BID for at least 3 days and may consider tapering after 6 months of therapy if response occurs and therapeutic corticosteroid doses have been discontinued.
Ruxolitinib is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Jakafi for:
- Intermediate or high-risk myelofibrosis
- Polycythemia vera
- Steroid-refractory acute graft-versus-host disease
- Chronic graft-versus-host disease
- Vitiligo
🇪🇺 Approved in European Union as Jakavi for:
- Intermediate or high-risk myelofibrosis
- Polycythemia vera
- Steroid-refractory acute graft-versus-host disease
- Chronic graft-versus-host disease
- Non-segmental vitiligo
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
M D Anderson Cancer CenterHouston, TX
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Who Is Running the Clinical Trial?
M.D. Anderson Cancer CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
[The outcomes of the thirty patients with refractory leukemia treated with related HLA haploidentical stem cells transplantation]. [2014]To assess the outcomes of the therapy for patients with refractory leukemia with HLA haploidentical stem cells transplantation.
Natural killer cell alloreactivity in HLA-haploidentical hematopoietic transplantation: a study on behalf of the CTIWP of the EBMT. [2022]Human leukocyte antigen (HLA) class-I mismatches that trigger donor-versus-recipient natural killer (NK)-cell alloreactivity reduce the incidence of leukemia relapse and improve survival of acute myeloid leukemia patients after T-cell-depleted HLA-haplotype mismatched ("haploidentical") hematopoietic transplantation. In murine graft-versus-host disease (GvHD) models, alloreactive NK-cells also prevent GvHD. Here we report the results of a non-interventional, prospective study performed on behalf of the Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation. The study was aimed at re-assessing the role of NK-cell alloreactivity in a cohort of haploidentical transplants performed in Europe between 2012 and 2015 and composed of unmanipulated, as well as T-cell-depleted transplants. One hundred thirty-eight patients with acute myeloid or lymphoid leukemias were analyzed. Eighty-six patients received ex-vivo T-cell-depleted transplants, 52 patients received unmanipulated transplants. Fifty patients were transplanted from NK alloreactive donors, 88 from non-NK alloreactive donors. NK cell alloreactivity did not impact on GvHD/relapse-free survival (GRFS) in unmanipulated transplants (HR: 1.66 (0.9-3.1), p = 0.1). In contrast, it did impact beneficially on GRFS in T-cell-depleted transplants (HR: 0.6, (0.3-1.2), p = 0.14, interaction p
[Human leukocyte antigen mismatched hemopietic stem cell transplants for the treatment of leukemia]. [2018]To explore the feasibility of HLA mismatched hemopietic stem cell transplants for the treatment of leukemia.
Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse. [2022]BackgroundResponses to conventional donor lymphocyte infusion for postallogeneic hematopoietic cell transplantation (HCT) relapse are typically poor. Natural killer (NK) cell-based therapy is a promising modality to treat post-HCT relapse.MethodsWe initiated this ongoing phase I trial of adoptively transferred cytokine-induced memory-like (CIML) NK cells in patients with myeloid malignancies who relapsed after haploidentical HCT. All patients received a donor-derived NK cell dose of 5 to 10 million cells/kg after lymphodepleting chemotherapy, followed by systemic IL-2 for 7 doses. High-resolution profiling with mass cytometry and single-cell RNA sequencing characterized the expanding and persistent NK cell subpopulations in a longitudinal manner after infusion.ResultsIn the first 6 enrolled patients on the trial, infusion of CIML NK cells led to a rapid 10- to 50-fold in vivo expansion that was sustained over months. The infusion was well tolerated, with fever and pancytopenia as the most common adverse events. Expansion of NK cells was distinct from IL-2 effects on endogenous post-HCT NK cells, and not dependent on CMV viremia. Immunophenotypic and transcriptional profiling revealed a dynamic evolution of the activated CIML NK cell phenotype, superimposed on the natural variation in donor NK cell repertoires.ConclusionGiven their rapid expansion and long-term persistence in an immune-compatible environment, CIML NK cells serve as a promising platform for the treatment of posttransplant relapse of myeloid disease. Further characterization of their unique in vivo biology and interaction with both T cells and tumor targets will lead to improvements in cell-based immunotherapies.Trial RegistrationClinicalTrials.gov NCT04024761.FundingDunkin' Donuts, NIH/National Cancer Institute, and the Leukemia and Lymphoma Society.
Non-Ablative Chemotherapy Followed by HLA-Mismatched Allogeneic CD3+ T-Cells Infusion Causes An Augment of T-Cells With Mild CRS: A Multi-Centers Single-Arm Prospective Study on Elderly Acute Myeloid Leukemia and int-2/High Risk Myelodysplastic Syndrome Patients. [2022]To evaluate the efficacy and safety of standard or low-dose chemotherapy followed by HLA-mismatched allogeneic T-cell infusion (allo-TLI) for the treatment of elderly patients with acute myeloid leukemia (AML) and patients with intermediate-2 to high-risk myelodysplastic syndrome (MDS).
Compassionate use of ruxolitinib in acute and chronic graft versus host disease refractory both to corticosteroids and extracorporeal photopheresis. [2022]Ruxolitinib is a potent inhibitor of JAK1/2 with proven efficacy in myelofibrosis. In recent years, research in graft versus host disease (GVHD) has revealed the role of activation of JAK pathways in alloreactive lymphocytes. Some reports have shown significant responses in refractory GVHD patients.
Ruxolitinib on acute graft-versus-host disease prophylaxis after modified donor lymphocyte infusion. [2023]To evaluate the effectiveness of ruxolitinib on acute graft-versus-host disease (aGVHD) prophylaxis and its impact on graft-versus-leukemia (GVL) effect in patients after modified donor lymphocyte infusion (mDLI).
New Indication for Ruxolitinib. [2023]The kinase inhibitor ruxolitinib (Jakafi) is now approved to treat chronic graft-vs-host disease.
Safety analysis of patients who received ruxolitinib for steroid-refractory acute or chronic graft-versus-host disease in an expanded access program. [2022]Outside of clinical trials and before commercial availability for acute and chronic graft-versus-host disease (GVHD), the Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib was available to US patients with steroid-refractory GVHD through an open-label, multicenter expanded access program (EAP) sponsored by Incyte Corporation. To assess the safety of ruxolitinib, data on serious adverse events (SAEs) reported among patients in the EAP were collected. Patients ≥12 years old who received allogeneic hematopoietic cell transplantation for a hematologic malignancy and developed any-grade acute or chronic steroid-refractory GVHD received ruxolitinib at a starting dose of 5 mg twice daily (BID; acute GVHD) or 10 mg BID (chronic GVHD). At data extraction (May 8, 2020), 60 patients with acute GVHD and 549 with chronic GVHD were enrolled. In the acute and chronic GVHD cohorts, 41 (68.3%) and 186 (33.9%) patients, respectively, had ≥1 SAE. Sepsis (8.3%) and respiratory failure (6.7%) were the most common SAEs in the acute GVHD cohort, and pneumonia (4.9%), sepsis (3.8%), and lung infection (3.5%) in chronic GVHD. Infection SAEs were reported in 23.3% and 20.0% of patients with acute and chronic GVHD, respectively. Overall, these safety findings demonstrate the tolerability of ruxolitinib in steroid-refractory GVHD.
Ruxolitinib for the treatment of graft-versus-host disease. [2021]Introduction: Ruxolitinib is an oral selective JAK1/JAK2 inhibitor, initially approved by the FDA for the treatment of intermediate-2 or high-risk myelofibrosis and patients with polycythemia vera who have had an inadequate response or are intolerant to hydroxyurea.Areas covered: Accumulating evidence supports the role of JAK1/JAK2 pathways in the pathogenesis of graft-versus-host disease (GVHD), and preclinical studies have demonstrated promising efficacy of ruxolitinib in treatment/prevention of GVHD. Early clinical observations that ruxolitinib was effective in treatment of steroid-refractory (SR) acute and chronic GVHD led to the development of prospective clinical trials; Phase II REACH1 (NCT02953678), Phase III REACH2 (NCT02913261), and REACH3 (NCT03112603). Based on the data from the REACH1 trial, ruxolitinib was approved by the FDA in May 2019 for SR acute GVHD in adult and pediatric patients 12 years and older.Expert opinion: Ruxolitinib and other JAK1/JAK2 inhibitors hold promise in other treatment settings such as GVHD prevention and/or first-line therapy.
Dynamic immune profiling identifies the stronger graft-versus-leukemia (GVL) effects with haploidentical allografts compared to HLA-matched stem cell transplantation. [2022]Haploidentical stem cell transplantation (haplo-SCT) achieves superior or at least comparable clinical outcomes to HLA-matched sibling donor transplantation (MSDT) in treating hematological malignancies. To define the underlying regulatory dynamics, we analyzed time courses of leukemia burden and immune abundance of haplo-SCT or MSDT from multiple dimension. First, we employed two nonirradiated leukemia mouse models which carried human AML-ETO or MLL-AF9 fusion gene to establish haplo-identical and major histocompatibility (MHC)-matched transplantation models and investigated the immune cell dynamic response during leukemia development in vivo. We found that haplo-matching the MHCs of leukemia cells with recipient mouse T cells prolonged leukemic mice survival and reduced leukemia burden. The stronger graft-versus-leukemia activity in haplo-SCT group mainly induced by decreased apoptosis and increased cytotoxic cytokine secretion including tumor necrosis factor-α, interferon-γ, pore-forming proteins and CD107a secreted by T cells or natural killer cells. Furthermore, we conducted a prospective clinical trial which enrolled 135 patients with t(8;21) acute myeloid leukemia that displayed minimal residual disease before transplantation and underwent either haplo-SCT or MSDT. The results showed that the haplo-SCT slowed the kinetics of the leukemia burden in vivo and reduced the cumulative incidence of relapse compared with MSDT. Ex vivo experiments showed that, 1 year after transplantation, cytotoxic T lymphocytes from the haplo-SCT group had higher cytotoxicity than those from the MSDT group during the same period. Our results unraveled the role of immune cells in superior antileukemia effects of haplo-SCT compared with MSDT.
The Evolution of T Cell Depleted Haploidentical Transplantation. [2020]Work on bone marrow transplantation from haploidentical donor has been proceeding for over 20 years all over the world and new transplant procedures have been developed. To control both graft rejection and graft vs. host disease, some centers have preferred to enhance the intensity of the conditioning regimens and the post-transplant immune suppression in the absence of graft manipulation; others have concentrated on manipulating the graft in the absence of any additional post-transplant immune suppressive agent. Due to the current high engraftment rates, the low incidence of graft-vs.-host disease and regimen related mortality, transplantation from haploidentical donors have been progressively offered even to elderly patients. Overall, survivals compare favorably with reports on transplants from unrelated donors. Further improvements will come with successful implementation of strategies to enhance post-transplant immune reconstitution and to prevent leukemia relapse.
Transplantation tolerance induced by "mega dose" CD34+ cell transplants. [2019]Early studies in murine models and more recent clinical data in heavily pretreated leukemia patients have shown that escalation of hematopoietic progenitor cells can overcome major genetic barriers and enable rapid and durable engraftment of haploidentical 3-loci mismatched transplants without graft-versus-host disease. In vitro studies suggest that veto cells within the progenitors population most likely mediate this facilitating effect. Leukemia relapse is relatively low in patients with acute myeloid leukemia (AML) but is greater in adults with acute lymphoblastic leukemia (ALL). Donor NK cells most likely mediate the resistance to relapse in patients with AML who are recipients of haploidentical transplants. Immune reconstitution in adults but not in children is slow as in adult recipients of HLA matched unrelated bone marrow transplants. The "mega dose" concept was also shown recently to be useful for tolerance induction in sublethally irradiated mice, so as to effectively overcome the marked resistance presented by the large number of lymphocytes surviving the sublethal conditioning. Thus, allogeneic chimeras generated by transplantation of large doses of Sca1+Lin- cells, permanently accept allogeneic donor type skin grafts. However, the numbers required to attain this desirable goal may not be easily collected from human donors. Nonalloreactive T cells synergize with murine Sca1+Lin- cells and might, therefore, enable achievement of engraftment of haploidentical transplants in sublethally conditioned patients.
Clearance of Hematologic Malignancies by Allogeneic Cytokine-Induced Killer Cell or Donor Lymphocyte Infusions. [2020]Well-established donor lymphocyte infusion (DLI) and novel cytokine-induced killer (CIK) cell therapy for the treatment of relapsing hematologic malignancies after allogeneic hematopoietic stem cell transplantation (HSCT) were compared with respect to feasibility, safety, and efficacy. Altogether, a total of 221 infusions were given to 91 patients (DLI, n = 55; CIK, n = 36). T cell recovery was significantly improved after CIK cell therapy (P