Graft versus Host Disease (GVHD)

Multiple mechanisms occur for antibody mediated rejection, including donors, specific antibody dependent, and independent processes that can trigger the activation of natural killer cells (NK) which leads to subsequent inflammatory and complemented mediated reactions.

After allogenic HSCT an ongoing loss of T cell and B cell immune tolerance occurs as a new immune system develops under the constant exposure to foreign host and tumor antigens.

Chronic GVHD is characterized by inflammatory and fibrotic changes in multiple organs, sharing clinical features with autoimmune disorders, such as SLE, systemic, sclerosis, and interstitial lung disease: typically refractory to classic immunosuppressants.

Presently definitions of acute or chronic graft versus host disease is based on clinical manifestations and a patient with significant diarrhea and skin rash six months after transplant has acute GVHD.

The median time to acute GVHD development is day 40.

Acute GVHD typically occurs within the first 3 to 6 months after hematopoietic stem cell transplantation, and affects the skin with rash and redness, the liver with jaundice and liver enzyme, alterations, and gastrointestinal tract with profuse, diarrhea, abdominal pain, and nausea.

With acute GVHT tissues become inflamed, due to the infiltration of activated, white cells, including macrophages.

The most worrisome G.I. symptoms is voluminous watery diarrhea, a manifestation of significant damage to the gastro intestinal epithelium.

The upper G.I. tract GVHD manifestations are much less severe than in the lower G.I. system and usually manifests as nausea and anorexia.

Rash can develop anywhere on the body, but classic areas involve the nape of the neck, the ears, the palms, and the souls.

Time presently after transplant is no longer a component of the diagnosis.

A complex process that begins with the conditioning regimen and is enhanced by multiple effective cells in the donor graft and persistent in the host.

Frontline therapy for chronic GVHD fails to induce durable responses and more than half of patients who have disease that subsequently progresses to organ damage.

Donor leukocytes form an immune response that may attack the recipients healthy tissues.

Donor leukocytes encounter foreign host issues and begin to activate and expand with the development of tissue inflammation that helps generate an inflammation that encourages an immuno logic response.

Subsequentlyy stimulation of an adaptive immune response causes clinical manifestations of acute GVHD.

Higher intensity conditioning regimens correspond to a higher risk of GVHD.

Main risk factor for GVHD is the degree of human leukocyte antigen disparity between the recipient and the donor.

Age is a risk factor for GVHD reveals higher incidence of both acute and chronic GVHD among patients who are older and when older donors are used.

Some studies suggest female donors and male recipients are associated with a higher incidence of GVHD.

Chronic GHD generally occurs at least six months after stem cell transplant and can last for many years.

Chronic GVHT involves the same organs as acute GVHD, but additionally can affect the lungs with cough and respiratory failure due to fibrosis, the eyes and mouth with dryness, connective tissues, such as the skin that thickens and mimics scleroderma, and joint or muscles with progressive stiffness.

The above organs may become sclerotic of fibrotic.

Chronic GHD is associated with high morbidity and mortality.

Requirements necessary for GVHD include that the transplanted graft must contain immunologically competent cells, the recipient must be incapable of rejecting the transplanted cells, and the recipient must express tissue antigens that are not present in the transplant donor.

GVHD syndromes associated with morbidity, escalated and prolonged immunosuppressive therapy, organ dysfunction, impared quality of life, and increased mortality.

Chronic GVHD causes inflammation and fibrosis in multiple tissues.

Chronic graft versus host disease (cGVHD) is the most common complication after allogeneic hematopoietic stem cell transplant, and substantially worsens quality of life.

More than half of long-term survivors of allogenic hematopoietic stem cell transplant develop chronic GVHD with an onset that generally occurs between three and 18 months after transplantation.

Chronic GVHD can affect any organ, but most commonly the skin, mouth, and eyes leading to disruptions and physical and functional capacity and diminished quality of life.

With chronic GVH D, skin rash and mouth sores are common initially, but damage to glands that produce tears and saliva lead to scar tissue, irritation of genitalia, damage air passages and cause liver inflammation.

The disease course for chronic GVHD is unpredictable and ranges from mild to severe alterations that last for a few months to many years.

Treatment entails corticosteroids with limited efficacy and additional toxicities.

Management may consist of daily systemic and topical anti-inflammatory other immunity suppressive agents.

Some patients do not have a response to glucocorticoids, or they become glucocorticoid dependent and standard treatments for refractory or recurrent chronic GVHD currently include Ibrutinib, ruxolitinib and belumosudil.

Patients with chronic GVHD have symptoms, including pain, fatigue, sexual dysfunction, elevated psychological distress, with up to half and 1/3 of patients expressing significant depression and anxiety.

HLA mismatch increases the risk of graft versus host disease as they incidence of acute GVHD  is  to 50% and the incidence of chronic graft vs. host disease is 50 to 60%.

Two cytokines controlled by the ROCK2 signaling pathway, IL-17 and IL-21, have a major role in the chronic GvHD response.

Acute GVHD requires the graft contain immunocompetent cells, the immunocompromised recipient is not capable of rejecting the transplant cells, and the recipient expresses tissue antigens not present in the donor (Billingham’s postulates).

One of the major determinants for the development of acute GVHD is the disparity in major and minor histocompatibility antigens, with an increasing number of missed matched antigens predicting greater risk of acute GVHD and non-relapse mortality in allogeneic hematopoietic cell transplantation.

Each human cell expresses six MHC class I alleles-one HLA-A, -B, and -C allele from each parent) and six to eight MHC class II alleles-one HLA-DP and -DQ, and one or two HLA-DR from each parent, and combinations of these.

The MHC variation is high, with at least 350 alleles for HLA-A genes, 620 alleles for HLA-B, 400 alleles for DR, and 90 alleles for DQ.

Polymorphism in non-HLA genes, cytokines TNF, IL-10, and interferon gamma,KIR polymorphism, NOD2/CARD15 gene polymorphism may all contribute to the development and severity of acute graft vs. host disease in our genetic hematopoietic cell transplantation.

Incidence of acute GVHD ranges from 26-50% among recipients of matched sibling donor grafts,and from 42-75% among recipients of matched unrelated donor grafts.

Acute disease likely mediated by donor T cells coinfused with stem cell graft and involves cellular and cytokine elements of the immune system.

Acute GVHD in SCT involves mainly the skin, gastrointestinal system and the liver.

Generally the least common organ effective is the liver.

Acute GVHD in SCT the GI involvement generally parallels the skin and liver involvement, although severe involvement can occur without gross skin and liver changes.

In G.I. involvement the major barrier between the body and the healthy bacteria is in the intestine mucosa and if it is injured bacteria can become pathogens and increase the likelihood of infections.

Malnutrition and a protein losing enteropathy may cause low serum albumin which results in profound Edema of the lower extremities and abdomen.

GI GVHD can cause symptoms such as pain, cramping, and abdominal distention can lead to ileus even small bowel obstruction.

Muscle wasting occurs from our nutrition, inactivity, and long-term use of corticosteroids.

Initial event starts with the conditioning regimen resulting in host tissue damage, release of cytokines that are proinflammatory, release of chemokines, up-regulation of adhesion molecules and the major histocompatiblity complex (MHC).

The diarrhea manifestation of G.I. graft versus host disease includes the entire G.I. epithelium of the small and large bowel that is injured and interferes with the absorption of nutrients and water.

The conditioning regimen results in host tissue damage, release of proinflammatory cytokines, upregulation of MHC and adhesion molecules and chemokine production.

The recognition by donor T cells of host alloantigens results in T cell activation, further cytokine secretion, effector cell activation result in damage to host tissues through perforin/granzyme, fas/fas ligand and other cytotoxic pathways.

Depletion of T cells in the graft prevents GvsHD due to the removal of precursor alloreactive T-cells, but the risk of Host vs Graft disease increased due to anti-graft response of host.

Depletion of T ceels leads to defective production of cytokines like GM-CSF or IL3 by donot T cells and leads to reduced engraftment rates.

Chronic GVHD occurs in 30-60% of patients after allogeneic bone marrow transplantation.i

Chronic GVHD can affect around 30% of recipients of fully matched transplants to 60-70% of recipients of mismatched transplants.

Chronic GVHD can occur three months to up to two years after transplant.

Chronic GVHD is more common among patients who experience acute GVHD.

Occurs in up to 40% of patients undergoing related donor HSCT and up to 70% of patients undergoing an unrelated HSCT.

Incidence of chronic disease likely to increase because increasing use in older patients, transplants from unrelated and mismatched related donors, peripheral blood stem cell transplants and donor lymphocyte infusions, all of which increase the likelihood of chronic GVHD.

Patients receiving bone marrow transplants have significantly less graft-vs-host disease than those who receive peripheral blood stem cell transplants with unrelated donors. (Applebaum FR et al).

The above process of higher graft-vs-host reactions is due to the higher T cell content in peripheral blood cells.

Most cases manifest within 1 month of transplant.

Acute GVHD occurs within first 100 days after HSCT.

Acute GVHD manifests by erythematosus skin eruption, cholestatic liver disease, and upper and lower G.I. involvement.

Diagnostic biopsy excludes competing diagnoses such as cytomegalovirus enteritis or drug eruption from medications.

Acute GVHD skin histology findings include lymphocytic infiltration, dyskeratotic epidermal keratinocytes and cellular apoptosis.

Acute GVHD liver pathologic changes include bile duct damage with epithelial cell drop out, and lymphocytic infiltration.

Acute GVHD G.I. pathology includes crypt cell necrosis.

Acute GVHD associated with a greater incidence and severity in donor relation, with the greatest incidence and severity in mismatched hematopoetic cell transplant between donor and recipient.

Proteomic biomarkers IL-2 receptor-alpha, TNF receptor-1, IL-8 and hepatocyte growth factor help confirm acute GVHD and have prognostic value independent of GVHD severity.

The greater the severity of acute GVHD associated with increased mortality in HCT.

Newer definition for acute GVHD include presence of acute symptoms greater than 100 days with persistent, recurrent or late-onset acute GVHD.

Chronic GVHD occurs after day 100 days after HSCT.

Chronic GVHD now symptom and manifestation based with no set time criteria.

The classification of acute vs. Chronic is unsatisfactory since may manifestations of acute disease occur later than 100 days.

Severity reflected by changes in skin, liver, intestine and lungs.

Many other organs can be involved including lymphatics, joints and mucous membranes.

Chronic disease manifested by findings similar to other autoimmune conditions with dry skin, oral lesions, nail dystrophy skin sclerosis, bile duct loss, bronchiolitis, fasciitis and skin ulcerations.

Bronchioltitis obliterans is the pulmonary form of chronic graft versus host disease after allogeneic bone marrow transplantation.

Bronchioltitis obliterans incidence maybe as high as 26% in allogeneic HSCT patients.

Induces changes in salivary composition and decreasing salivary flow reducing saliva’s protective capacity which may lead to oral mucositis.

When the gene UGT2B17 is missing from a donor’s genome, but is present in the recipient’s there is is significantly greater risk of acute graft vs. host disease arising within 100 days after bone marrow transplantation.

One study reported response rates to treatment of 61%, 53% and 50% at 6 months, 1 year and 2 years, respectively, with prevalence of chronic disease of 33% at 2 years, and 18% off immunosuppressive treatment by 2 years and 89% by 4 years.

Standard first line treatment for GVHD is high-dose glucocorticoids with response rates ranging from approximately 60% with grade II disease to 30-40% in  patients with grade IV disease.

Fewer than 40% of patients with acute GVHD have a complete response to high dose steroids.

Less than a half of patients will achieve a durable response with the use of systemic corticosteroids and a long term mortalitytally rates for patients who do not respond to corticosteroids or estimated 80% or higher.

Therapies used in the second line setting of acute GVHD include: anti-thymocyte globulins, inhibitors of Interleukin-2 Pathways, inhibitors of the tumor necrosis factor alpha, sirolimus, mycophenolate mofetil, pentostatin,mesenchymal stem cells, and exit extracorporeal photophetesis.

Treatment after allogeneic hematopoietic cell transplantation for acute GVHD during prophylactic with immunosuppressive medications is the use of systemic glucocorticosteroids as first line treatment.

For acute GVHD glucocorticosteroids effectively control inflammatory manifestations without the need for additional immunosuppressive agents and treatment can generally be withdrawn.

With persistent or recurrent GVHD, despite glucocorticosteroids, the risk for morbidity, and mortality from uncontrolled GVHD is increased, the use of prolonged glucocorticosteroids exposure persists and increased infections due to immunosuppression occur.

Chronic GVHD management includes the use of steroids, cyclosporine and FK506 (tacrolimus).

Chronic disease and/or its treatment is the leading cause of nonrelapse mortality in hematopoietic cell transplantations.

About 15% of conditions associated with chronic GVHD can become life threatening.

Primary cause of nonrelapse mortality associated with chronic GVHD is infection.

Chronic GVHD associated with poorer quality of life reduced Karnofsky performance scores, and delay in returning to work.

Cytomegalovirus seropositivity of recipient or donor, stem cell dose, age of the donor and immunosuppressive regimen all contribute to risk of disease.

In AML patients with chronic disease at 2 years have a 3 times higher likelihood to experience nonrelapse mortality than those without chronic GVHD and 1.7 times more likely to die from any cause.

Can produce antitumor effects in chronic myelogenous leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia and lymphomas.

Incidence of grade II-IV acute disease in HLA matched related transplant recipients 30-40% with mortality rate as high as 30%.

Most relevant complication besides infection following allogeneic stem cell transplantation.

Its development put patients at risk for infection for several weeks or months after engraftment.

Host disease (GVHD)-characterized by the expansion of donor lymphocytes with cytotoxicity against recipient histocompatibility antigens.

T cell lymphocytes in the incoming graft responsible for acute graft-versus-host disease.

T cell depletion techniques can decrease GVHD, but removal of graft lymphocytes concomitantly increases the risk of graft failure, relapse and opportunistic infections.

A consequence of naïve donor T cells recognizing alloantigen on host antigen presenting cells.

Dendritic cells are capable of inducing GVHD.

Acute graft-versus-disease can be abrogated by T cell depletion.

Removal of T cells associated with increased incidence of bone marrow failure and higher malignant disease relapse rates.

Macrophage infiltration of affected tissues is a biomarker for the occurrence and development of GVHD and establishes the role of macrophages in the pathogenesis of GVHD.

Macrophages are cells that present self antigens and alloantigens to T lymphocytes, initiating and perpetuating immune responses.

Following HSCT that involves radiation therapy, chemotherapy of both, the presentation of immuno genic, self peptide antigens by macrophages is enhanced due to the release of molecules from dying cells that are not normally present in extracellular milieu: this may initiate and perpetuate immune responses that lead to acute and chronic GVHD.

Macrophages contribute to sustained inflammation in chronic GVHD causing tissue damage and fibrosis through the activation of fibroblasts, which synthesize and secrete fibrotic cellular metrics molecules.

Macrophage is also stimulate T and B lymphocytes which expand pathogenic T cells and activation of B cells, which may lead to auto immunity in chronic GHD.

Ibrutinib approved for monotherapy for treatment of patients with chronic graft versus host disease after failure of one or more lines of systemic therapy.

The FDA has approved ruxolitinib (Jakafi) for the treatment of adult and pediatric patients ≥12 years of age with steroid-refractory acute graft-versus-host disease (aGVHD).

The approval is based on findings from the phase II REACH1 trial, which demonstrated that the combination of ruxolitinib with corticosteroids elicited a 57% overall response rate (ORR) at day 28 in patients with steroid-refractory aGVHD, with a complete response (CR) rate of 31%.

Ruxolitinib was administered at 5 mg twice daily, which could be increased to 10 mg twice daily if no cytopenias occurred.

Overall response rates were 82.6%, 41.2%, and 42.9%, among patients with grade 2, 3, and 4 GVHD, respectively.

About half of the people who develop acute GVHD do not respond adequately to steroids,

In the REACH2 trial group significant improvements therapy in efficacy outcomes in patients with grade II-IV glucocorticoid refractory acute GVHD. with a higher incidence of thrombocytopenia, thsn observe with control therapy.

Ruxolitinib First Agent to Show Phase 3 Benefit in Chronic Graft-Versus-Host Disease.

Ruxolitinib demonstrates improved overall response rates and failure-free survival compared with best available therapy in adolescent and adult patients with chronic graft-versus-host disease (REACH3 trial), in a population of patients with an inadequate response to steroids.

 

About half of patients with GVHD become refractory or addicted to systemic steroids, and no standard second-line therapy has been defined.

 

At week 24, overall response rates were 49.7% in the ruxolitinib group and 25.6% in the best available treatment group.

 

Median failure-free survival rates were not reached in the ruxolitinib group and was 5.7 months in the best available therapy group.

Sitagliptin (a Dipeptidyl Peptidase 4 inhibitor) added to standard immunosuppressive regimen of tacrolimus and sirolimus resulted in a low incidence of acute graf versus host disease after hematopoetic stem cell transplant from HLA matched related or unrelated donors.

Among patients undergoing allogeneic HLA matched HSCT with reduced intensity conditioning, GVHD,mfree, relapse free, survival at one year, was significantly more common among those who receive cyclophosphamide, tacrolimus, mycophenolate, than those who were received tacrolimus and methotrexate.

The addition of T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)–based graft-vs-host disease prophylaxis resulted in reduced rates of acute graft-vs-host disease in patients with hematologic malignancies receiving unrelated donor hematopoietic cell transplantation (HCT).

Agents approved for GVHD include ruxolitinib, belumosudil, ibrutinib.

For chronic graft versus host disease, mortality, rate of more than 30% occurs during follow up.

Colony stimulating factor 1(CSF 1) and interleukin-34 mediate signaling and play key rules in regulating the development and function of tissue macrophages.

CSF1R is a cell surface receptor that can be activated by colony stimulating factor 1 and is expressed in monocytes and macrophages.

The binding of CSF1 to CSF1R actively promotes the differentiation of monocytes into macrophages and the survival and proliferation of both cell types.

Excessive CSF1R a signaling and macrophage activation is implicated in inflammatory processes, and overactivation of the pathway can lead to chronic inflammation and progression of diseases such as rheumatoid arthritis, idiopathic pulmonary fibrosis, chronic graft versus host disease.

CSF1R signaling dependent monocytes and macrophages are mediators of inflammation in fibrosis in chronic GVHD and auto immune diseases.

Axatilmab, a humanized IgG4 monoclonal antibody, inhibits CSF1R signaling, and can affect differentiation and function of sites and macrophages: it use results in high incidence of response among patients with recurrent or refractory chronic GVHD.

Axatilmab suppresses the proliferation and activity of macrophages by blocking the binding of ligand  to CSF1R.

Axatilmab can induce clinical response in GVHD, including all involved organs, especially with fibrotic manifestations in the lung, esophagus, joints, fascia, and skin.