Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease

AbstractWe conducted a double-blind, randomized multicenter trial to determine whether the addition of mycophenolate mofetil (MMF) improves the efficacy of initial systemic treatment of chronic graft-versus-host disease (GVHD). The primary endpoint was resolution of chronic GVHD and withdrawal of all systemic treatment within 2 years, without secondary treatment. Enrollment of 230 patients was planned, providing 90% power to observe a 20% difference in success rates between the 2 arms. The study was closed after 4 years because the interim estimated cumulative incidence of success for the primary endpoint was 23% among 74 patients in the MMF arm and 18% among 77 patients in the control arm, indicating a low probability of positive results for the primary endpoint after completing the study as originally planned. Analysis of secondary endpoints showed no evidence of benefit from adding MMF to the systemic regimen first used for treatment of chronic GVHD. The estimated hazard ratio of death was 1.99 (95% confidence interval, 0.9-4.3) among patients in the MMF arm compared with the control arm. MMF should not be added to the initial systemic treatment regimen for chronic GVHD. This trial was registered at www.clinicaltrials.gov as #NCT00089141 on August 4, 2004.

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A randomized, double-blind phase III study of ibrutinib versus placebo in combination with corticosteroids in patients with new onset chronic graft versus host disease.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps7072 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS7072-TPS7072 ◽

Cited By ~ 1

Author(s):

David Bernard Miklos ◽

Madan H. Jagasia ◽

Hildegard Greinix ◽

Bor-Sheng Ko ◽

David A. Jacobsohn ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Response Rate ◽

Systemic Treatment ◽

Underlying Disease ◽

Development Project ◽

Phase Iii ◽

Consensus Development ◽

Double Blind ◽

Host Disease ◽

Graft Versus Host

TPS7072 Background: Chronic graft versus host disease (cGVHD) is a common complication of allogeneic stem cell transplantation, with pathophysiology involving alloreactive and dysregulated T and B cells and innate immune populations. Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is indicated by the US FDA for the treatment of patients (pts) with CLL/SLL. Ibrutinib recently received breakthrough therapy and orphan drug designation for the treatment of pts with cGVHD who did not respond to one or more lines of systemic therapy. Ibrutinib reduces severity of cGVHD in murine models and recently was shown to achieve an NIH-defined overall response rate of 67% in pts with steroid relapsed/refractory cGVHD (Miklos Blood 2016). Methods: The primary objective of this Phase 3, multicenter, international, randomized, controlled, double-blind study is to evaluate the 24-week response rate of ibrutinib versus placebo in combination with prednisone. Pts with newly diagnosed moderate or severe cGVHD, as per NIH Consensus Development Project Criteria (2014), will be randomized in a 1:1 ratio to receive either oral ibrutinib (arm A) or placebo (arm B) in combination with oral prednisone. Ibrutinib or placebo will be given until unacceptable toxicity, relapse of underlying disease, death, or the need for a new systemic treatment for progressive cGVHD. Eligible study pts (age ≥12 yrs) must require systemic treatment with corticosteroids and have no prior systemic treatment for cGVHD. The primary endpoint is response rate (complete or partial response) at 24 weeks, as per NIH Consensus Development Project Criteria, and must occur in the absence of both new therapy for cGVHD and relapse/return of the underlying disease that was the indication for transplant. Secondary endpoints will assess for additional clinical benefit including corticosteroid dose reduction, improvement of Lee cGVHD Symptom Scale scores, withdrawal of all immunosuppressants, and overall survival. This study is currently enrolling pts. Funding source: Pharmacyclics LLC, an AbbVie Company. Clinical trial information: NCT02959944.

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Area-under-the-Curve-Based Mycophenolate Mofetil Dosage May Contribute to Decrease the Incidence of Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients

Journal of Clinical Medicine ◽

10.3390/jcm10030406 ◽

2021 ◽

Vol 10 (3) ◽

pp. 406

Author(s):

Giorgia Carlone ◽

Roberto Simeone ◽

Massimo Baraldo ◽

Alessandra Maestro ◽

Davide Zanon ◽

...

Keyword(s):

Mycophenolate Mofetil ◽

Cell Transplantation ◽

Graft Versus Host Disease ◽

Pediatric Patients ◽

Chronic Gvhd ◽

Area Under The Curve ◽

Control Group ◽

Study Group ◽

Host Disease ◽

Graft Versus Host

Acute graft-versus-host disease (GvHD) remains the second leading cause of death, after disease relapse, in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). The medical records of 112 pediatric patients who underwent allo-HSCT from matched unrelated and haploidentical donors were analyzed. Patients were divided into two groups, according to the GvHD prophylactic regimen used. In the control group, GvHD prophylaxis consisted of cyclosporine A (CsA) and methotrexate (MTX) or CsA and mycophenolate mofetil (MMF) at a standard daily dose of 30 mg/kg. All subjects in the study group received tacrolimus (FK506) and MMF. In this group, MMF was subjected to therapeutic drug monitoring (TDM) through mycophenolic acid (MPA) area under the curve AUC0–12. We found a statistically significant difference in both overall acute GvHD (p < 0.0001) and overall chronic GvHD (p < 0.05) incidence between the study and the control group. The initial daily MMF dose and the age at transplant in the study group proved to be inversely correlated (r = −0.523, p < 0.0001). The children under six years of age required a significantly higher daily MMF dose (p < 0.008). This study showed that pharmacological monitoring of MPA AUC0–12 concentration allowed a reduction in the incidence of acute and chronic GvHD. MMF showed age-dependent pharmacokinetics due to greater drug clearance in younger children.

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Failure-free survival after initial systemic treatment of chronic graft-versus-host disease

Blood ◽

10.1182/blood-2014-03-563544 ◽

2014 ◽

Vol 124 (8) ◽

pp. 1363-1371 ◽

Cited By ~ 32

Author(s):

Yoshihiro Inamoto ◽

Mary E. D. Flowers ◽

Brenda M. Sandmaier ◽

Sahika Z. Aki ◽

Paul A. Carpenter ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Initial Treatment ◽

Systemic Treatment ◽

Chronic Gvhd ◽

Free Survival ◽

Host Disease ◽

Graft Versus Host ◽

Key Points

Key Points Failure-free survival is a potentially useful, efficient, and robust basis for interpreting results of initial treatment of chronic GVHD.

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An endpoint associated with clinical benefit after initial treatment of chronic graft-versus-host disease

Blood ◽

10.1182/blood-2017-03-775767 ◽

2017 ◽

Vol 130 (3) ◽

pp. 360-367 ◽

Cited By ~ 23

Author(s):

Paul J. Martin ◽

Barry E. Storer ◽

Yoshihiro Inamoto ◽

Mary E. D. Flowers ◽

Paul A. Carpenter ◽

...

Keyword(s):

Partial Response ◽

Graft Versus Host Disease ◽

Clinical Benefit ◽

Initial Treatment ◽

Systemic Treatment ◽

Chronic Gvhd ◽

Host Disease ◽

Graft Versus Host ◽

Key Points

Key Points Complete or partial response at 1 year without secondary systemic treatment provides clinical benefit in patients with chronic GVHD. Success defined by this endpoint is currently observed in fewer than 20% of patients after initial systemic treatment of chronic GVHD.

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Mast Cell Involvement in Fibrosis in Chronic Graft-Versus-Host Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22052385 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2385

Author(s):

Ethan Strattan ◽

Gerhard Carl Hildebrandt

Keyword(s):

Wound Healing ◽

Mast Cell ◽

Mast Cells ◽

Graft Versus Host Disease ◽

Chronic Gvhd ◽

Fibrotic Disease ◽

Acute Leukemias ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host

Allogeneic hematopoietic stem cell transplantation (HSCT) is most commonly a treatment for inborn defects of hematopoiesis or acute leukemias. Widespread use of HSCT, a potentially curative therapy, is hampered by onset of graft-versus-host disease (GVHD), classified as either acute or chronic GVHD. While the pathology of acute GVHD is better understood, factors driving GVHD at the cellular and molecular level are less clear. Mast cells are an arm of the immune system that are known for atopic disease. However, studies have demonstrated that they can play important roles in tissue homeostasis and wound healing, and mast cell dysregulation can lead to fibrotic disease. Interestingly, in chronic GVHD, aberrant wound healing mechanisms lead to pathological fibrosis, but the cellular etiology driving this is not well-understood, although some studies have implicated mast cells. Given this novel role, we here review the literature for studies of mast cell involvement in the context of chronic GVHD. While there are few publications on this topic, the papers excellently characterized a niche for mast cells in chronic GVHD. These findings may be extended to other fibrosing diseases in order to better target mast cells or their mediators for treatment of fibrotic disease.

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Non-Relapse Mortality Among Patients Diagnosed with Chronic Graft-Versus-Host Disease: An Updated Analysis from the Chronic Gvhd Consortium

Transplantation and Cellular Therapy ◽

10.1016/s2666-6367(21)00109-3 ◽

2021 ◽

Vol 27 (3) ◽

pp. S79-S80

Author(s):

Zachariah DeFilipp ◽

Lynn Onstad ◽

Sally Arai ◽

Mukta Arora ◽

Corey Cutler ◽

...

Keyword(s):

Graft Versus Host Disease ◽

Chronic Gvhd ◽

Host Disease ◽

Graft Versus Host

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Synergism Between Mycophenolate Mofetil and Cyclosporine in Preventing Graft-Versus-Host Disease Among Lethally Irradiated Dogs Given DLA-Nonidentical Unrelated Marrow Grafts

Blood ◽

10.1182/blood.v91.7.2581 ◽

1998 ◽

Vol 91 (7) ◽

pp. 2581-2587 ◽

Cited By ~ 117

Author(s):

Cong Yu ◽

Kristy Seidel ◽

Richard A. Nash ◽

H. Joachim Deeg ◽

Brenda M. Sandmaier ◽

...

Keyword(s):

Mycophenolate Mofetil ◽

Graft Versus Host Disease ◽

Host Disease ◽

Graft Versus Host ◽

Group 4 ◽

Group 2 ◽

Total Body ◽

Host Tolerance ◽

Long Term Survivors

Abstract Mycophenolate mofetil (MMF) was evaluated either alone or combined with cyclosporine (CSP) for preventing graft-versus-host disease (GVHD) in dogs given 9.2 Gy total body irradiation and DLA-nonidentical unrelated marrow grafts. Marrow autograft studies showed gut toxicity as limiting MMF side effects. Four groups were studied for GVHD prevention: six dogs in group 1 received MMF 10 mg/kg twice daily subcutaneously (SC) on days 0 to 27. They died between 8 to 28 days from infection or GVHD; survival was better than that of 72 controls given no immunosuppression (P = .04), but not different from 19 dogs given CSP. Four dogs in group 2 received MMF as described, along with CSP at 10 to 15 mg/kg twice daily on days 0 to 27. They died at 6 to 98 days from CSP-associated toxicity, weight loss, or infection. Nine dogs in group 3 received MMF SC twice daily 6 mg/kg/d for 3 days, followed by 10 mg/kg twice daily until day 27, along with CSP as described; four died between 7 to 106 days with intussusception, infection, or GVHD, and five became long-term survivors. Six dogs in group 4 received shortened MMF (21 days) and reduced doses of CSP given through day 100. Three died with GVHD or infection between days 38 to 119, and three became long-term survivors. Results support the notion of synergism between MMF and CSP, as evidenced by stable graft-host tolerance in greater than 50% of dogs.

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Immune Mediated Cerebellar Ataxia: An Unknown Manifestation of Graft-versus-Host Disease

Acta Haematologica ◽

10.1159/000494423 ◽

2018 ◽

Vol 141 (1) ◽

pp. 19-22

Author(s):

Liat Shargian-Alon ◽

Pia Raanani ◽

Uri Rozovski ◽

Tali Siegal ◽

Shlomit Yust-Katz ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Graft Versus Host Disease ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Cerebellar Atrophy ◽

Acid Decarboxylase ◽

High Dose ◽

Host Disease ◽

Graft Versus Host ◽

Aged Woman

Neurologic complications of allogeneic hematopoietic cell transplantation (allo-HCT) include infections, cerebrovascular events, therapy-induced neurotoxicity, recurrent malignancies, and neurologic manifestations of graft-versus-host disease (GVHD). Anti-glutamic acid decarboxylase (GAD) antibody-associated cerebellar ataxia is a well-established disorder of autoimmune origin, but there are no reports in the literature of its occurrence following allo-HCT. We describe a middle-aged woman with chronic GVHD after allo-HCT who presented with a rapidly progressive cerebellar syndrome. Thorough investigation revealed only cerebellar atrophy on brain imaging and positive anti-GAD65 antibodies in serum and cerebrospinal fluid suggesting the diagnosis of anti-GAD antibody-associated cerebellar ataxia. Despite prompt treatment with high-dose corticosteroids, intravenous immunoglobulins, and rituximab, the patient’s condition rapidly deteriorated, and she died 4 months later. This case suggests that anti-GAD antibody-associated cerebellar ataxia may be a rare manifestation of chronic GVHD.

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Acute and chronic graft versus host disease after hematopoietic stem cell transplant

JBMTCT ◽

10.46765/2675-374x.2020v1n1p53-66 ◽

2020 ◽

Vol 1 (1) ◽

pp. 53-66

Author(s):

Vaneuza A. M. Funke ◽

Maria Claudia Rodrigues Moreira ◽

Afonso Celso Vigorito

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Graft Versus Host Disease ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Cell Transplant ◽

Primary Therapy ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host

Graft versus host disease is one of the main complications of Hematopoietic stem cell, involving about 50% to 80% of the patients. Acute GVHD clinical manifestations and therapy is discussed, as well as new NIH criteria for the diagnosis and classification of chronic GVHD. Therapy for both refractory chronic and acute GVHD is an important field of discussion once there is no superiority for the majority of the agents after primary therapy has failed. Hence, this review is meant to be a useful tool of consultation for clinicians who are dealing with this complex complication.

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Bone marrow transplantation for severe aplastic anemia: influence of conditioning and graft-versus-host disease prophylaxis regimens on outcome

Blood ◽

10.1182/blood.v79.1.269.bloodjournal791269 ◽

1992 ◽

Vol 79 (1) ◽

pp. 269-275 ◽

Cited By ~ 2

Author(s):

E Gluckman ◽

MM Horowitz ◽

RE Champlin ◽

JM Hows ◽

A Bacigalupo ◽

...

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Graft Versus Host Disease ◽

Randomized Clinical Trials ◽

Chronic Gvhd ◽

Severe Aplastic Anemia ◽

Term Survival ◽

Host Disease ◽

Graft Versus Host ◽

Gvhd Prophylaxis

Data for 595 patients with severe aplastic anemia receiving HLA- identical sibling bone marrow transplants were analyzed to determine the effect of pretransplant conditioning and graft-versus-host disease (GVHD) prophylaxis on outcome. Transplants were performed between 1980 and 1987 and reported to the International Bone Marrow Transplant Registry. Three conditioning regimens (cyclophosphamide alone, cyclophosphamide plus limited field radiation, and cyclophosphamide plus total body radiation) were studied; none was associated with superior long-term survival. Three GVHD prophylaxis regimens (methotrexate, cyclosporine, and methotrexate plus cyclosporine) were studied. Recipients of cyclosporine with or without methotrexate had a significantly higher probability of 5-year survival (69%, 95% confidence interval 63% to 74%) than patients receiving methotrexate only (56%, 49% to 62%, P less than .003). Higher survival with cyclosporine resulted from decreased risks of interstitial pneumonia (P less than .0002) and chronic GVHD (P less than .005). Additional risk factors adversely associated with survival included infection pretransplant (P less than .004), use of parous or transfused female donors (P less than .005), older patient age (P less than .005), and 20 or more pretransplant transfusions (P less than .006). These data may prove useful in planning randomized clinical trials and in identifying patients at high-risk of treatment failure.

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