Hodgkins Lymphoma Awareness

My Journey Battling Cancer & Graft vs. Host Disease
Fighting for my life each day against the odds

I have decided to dedicate a page on my site to graft versus host disease.  This is my primary focus now.  I am fighting for my life because I have chronic GVHD.  It can be very hard to understand what this means for someone that has never heard of it before.  Not many people know about this disease and therefore there isn't many treatments for it and it can be life threatening just like cancer.  I'm hoping that by posting more information about GVHD it will spread awareness and make others see that research is much needed.

I have found the following information at this site and posted it in full: http://www.ibmtindy.com/faq/graft.htm

Graft-Versus-Host Disease

What Is Graft-Versus-Host Disease?

Patients who receive a stem cell transplant from an identical twin donor, are infused with stem cells that are truly identical to their own. All other recipients of donor stem cells, whether from HLA-identical sibling donors, or from matched unrelated donors, will be infused with stem cells that are different from the patient's own stem cells. The human immune system is based on recognition of "self" against "different" or "foreign". Immune systems are trained to attack and destroy "foreign" proteins, whether they are bacteria, viruses, cancer cells, or transplanted tissues. Thus, the differences between the tissues of the patient and the stem cells of the donor lead to a fight and attempts of one to destroy the other. The patient's tissues (host tissues) will try to destroy the stem cells. This process is called "rejection" and is more frequent as the donor and recipient are less well matched. Rejection of the stem cells results in failure of the new stem cells to grow and produce sufficient blood cells. The patient continues to have low white cell and platelet counts and continues to be at risk of infection and bleeding. Repeating the transplant is the only way of helping the patient. Often the re-transplant does not succeed in raising the white cells fast enough to prevent fatal infections. Fortunately, rejection is uncommon, since the issues of the patient have been suppressed by the chemotherapy and radiation given to destroy the malignant cells ("preparative regimen").

A "reversed rejection" can also occur. Under this scenario, the healthy donor stem cells recognize the patient's tissues as foreign and attack them. This is the "transplant against the patient", or "Graft-versus-Host" reaction. The complication is called "Graft-versus-Host Disease" (GvHD).

What Types Of GvHD Exist?

Commonly, GvHD is divided into acute GvHD and chronic GvHD. Acute GvHD occurs within the first 100 days after transplant, but most often between 25 and 60 days after stem cell infusion. Chronic GvHD occurs beyond day 100 after transplant. Acute GvHD can lead to chronic GvHD, but chronic GvHD may occur without any evidence of previous acute GvHD. The chronic variant of GvHD may occur up to several years after transplant, indicating that the "fight" between donor stem cells and patient tissues can continue for years. In fact, at some level the fight between donor and recipient will never stop. The donor stem cells will never feel completely at home. In patients receiving a graft from an HLA-identical sibling, ultimately the donor stem cells will function quite normally. Patients who received grafts from HLA-mismatched donors will remain at an increased risk of infections for many years.

What Are The Symptoms Of Acute GvHD?

When acute GvHD develops, white cells ("lymphocytes") from the stem-cell graft move towards target tissues. Through direct contact or through proteins produced by these cells ("lymphokines"), the target tissues get damaged. The major targets are the skin, bowel, and liver. The skin is often the first tissue that shows signs of attack. Skin rash develops, often starting on the palms, soles, and behind the ears. Other parts of the body, such as scalp, upper chest and back, and abdomen may follow. Some patients will have redness of their entire skin. A skin biopsy (small biopsy of skin, about 1/8" in diameter) usually confirms the diagnosis, but the clinical picture is quite typical.

The second tissue that can be involved is the bowel. This leads to diarrhea and abdominal cramps. The diarrhea is caused by loss of cells that cover the inside of the bowel, leading to loss of fluids and proteins from the body. The small bowel, particularly the last part of it (jejunum and ileum), is the main target of the GvHD reaction. Cramps start when a large area of bowel has lost its cover ("mucous membrane") and peristalsis becomes less organized. Diarrhea can vary from one loose stool a day to 2 gallons of diarrhea! In severe cases of diarrhea, it is difficult to support the patient through the loss of fluid and nutrients. The damaged gut is also an easy entry port for bacteria and fungi.

The third tissue involved by acute GvHD is the liver. Patients develop jaundice, because the bile ducts become clogged and bile backs up into the blood instead of being excreted into the bowel. The jaundice is itself not life-threatening, but the liver can be damaged by the GvHD reaction. Other tissues, such as lung, adrenal glands, and pancreas can also show signs of acute GvHD, but their significance is uncertain.

How Do You Grade GvHD?

In order to grade the severity of GvHD, a staging system was developed in the 1970's. This system, which originated at the Fred Hutchinson Cancer Center in Seattle, looks at involvement of skin, gut, and liver. The skin involvement is scored as percentage of total skin that is inflamed. Gut involvement is determined by amount of diarrhea per 24 hours, and liver involvement by the serum level of bilirubin. The mildest grade of GvHD is grade I, the worst is grade IV. Grade I has little effect on survival and may not need any treatment, whereas survival of patients with grade III or IV is clearly worse. A common cut-off is grade 0-I against grade II, III and IV. A more recent classification distinguishes grades A (mildest) through D (worst).

What Is Done To Prevent GvHD?

Several drugs and procedures may be used to try and prevent acute GvHD. IBMT physicians use daily cyclosporine therapy to decrease the frequency and severity of acute GvHD. Cyclosporine therapy starts on the day before transplant (day –1) and is given as daily I.V. infusions over 4 hours. Once the patient is stable and can take oral medications, the cyclosporine is switched to therapy by mouth: the drug Gengraf® is given twice a day. Capsules are either 100 mg or 25 mg. The switch to oral medication happens between 15 and 30 days after transplant. In most patients, Gengraf is continued until at least day 90 after transplant, but in many patients this drug needs to be continued much longer.

Many patients will also receive an antibody that attacks T-lymphocytes, both those in the patient’s blood (to prevent rejection) and those in the stem-cell product (to prevent GvHD). Thymoglubulin® is an antibody made in rabbits against human T-lymphocytes. This antibody is used in many patients who receive transplants from either related or unrelated donors. For donor transplants with a less aggressive preparative regimen, the monoclonal antibody Campath 1H® is used.

How Do You Treat GvHD?

Acute GvHD of grade I does not need specific therapy, except perhaps a skin cream to decrease the inflammation. If grade II (or worse) is present, the first-line of therapy are steroids. Typically, Solumedrol® is given through I.V. injections twice a day. When GvHD stabilizes, the Solumedrol is switched to oral prednsione. The dose of prednisone is slowly tapered over the next weeks to months. For acute GvHD that is unresponsive to steroids, other drugs are used. One example is ATGAM®, which is given by I.V. infusion daily for 4 days.

Why Is GvHD Dangerous?

Acute GvHD can be very dangerous, and is the single most important transplant-related cause of death after allogeneic stem cell transplant. The danger of severe acute GvHD is multifactorial. First, severe GvHD of the gut causes extensive damage to the lining cells of the bowel. Thus, micro-organisms, such as bacteria and fungi, can invade the body and may cause a fatal infection. Second, voluminous diarrhea may result in a loss of important nutrients, electrolytes, and fluid. Third, the GvHD reaction suppresses the new immune system. Finally, the treatment necessary to control the GvHD in itself will further suppress the new immune system. Therefore, many patients suffering from severe acute GvHD will ultimately die from infections with bacteria, fungi, or viruses.

Why Is GvHD Not "All Bad"?

As described above, acute GvHD is a possibly dangerous complication. However, the GvHD reaction also has positive aspects. While attacking the tissues of the patient, the new stem cells will often also attack the cancer cells that still may be present after transplant. This was first documented in acute leukemia, and this phenomenon has been called "graft-versus-leukemia" effect. Similar effects have been observed in malignant lymphoma, myeloma, and perhaps even some solid tumors. For certain diseases, such as chronic myelogenous leukemia (CML), the graft-versus-leukemia (GvL) effect may well be the most important reason that allogeneic transplants are successful in curing the disease. With increasing difference between donor and patient, the risk of GvHD increases. This may well mean that also the chance of GvL effect increases. In recent years, transplant physicians have learned to apply the GvL effect to treat or prevent disease recurrence after stem cell transplant by the infusion of donor white cells (DLI = Donoir Lymhocyte Infusions). Chronic GvHD may be even more important to prevent disease relapse than acute GvHD.

What Are Symptoms Of Chronic GvHD?

Chronic GvHD tends to have a much more insidious start. The skin may become hardened, and the joint less flexible. Sometimes abnormal liver function tests are the first sign, or some difficulty swallowing. Many patients develop dry mouth and/or dry eyes ("sicca syndrome"). Chronic GvHD may develop out of more acute GvHD, or may start without any history of prior acute GvHD. By definition, chronic GvHD starts after day 100, but the first symptoms may not start until 1 or 2 years after transplant.

What Are Risks Of Chronic GvHD?

The hardened skin and limited flexibility of joints are difficult to treat, sine they involve scarring of the skin. Therefore, preventing them with physical therapy is very important. If liver function abnormalities exist for too long, scarring of the liver may also occur. Patients with chronic GvHD continue to be at risk of serious infections. The dry mouth increases the risk of tooth decay, and the dryness of the eyes may lead to cornea damage.

What Is The Therapy Of Chronic GvHD?

Physical therapy, sufficient exercise, and good personal hygiene are very important in the treatment of chronic GvHD. Drug therapy consists of prednisone, often in combination with cyclosporine. In some patients, Imuran® (azathioprine) and/or Cellcept® (mycophenolate mofetil) are also used. All these medications are given by mouth. The minimum treatment lasts 6 months, but often much longer periods of treatment are necessary.

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I also found an article online at http://bloodjournal.hematologylibrary.org/cgi/content/full/105/11/4200  It is from the Dana Farber Cancer Institute. Please click on the link to read the article.

REVIEW IN TRANSLATIONAL HEMATOLOGY
New approaches for preventing and treating chronic graft-versus-host disease
Stephanie J. Lee

From the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

 

 

Research Needed For GVHD

Research is MUCH needed for Graft versus Host Disease. There is not much known about the disease. There is so much efforts being put into treatments for cancer, but the side effects from treatments for the cancer need to be looked at as well.  I am hoping to spread awareness about GVHD to others and help get this some much needed attention for research.


http://www.marrow.org/PHYSICIAN/Adv_in_Auto_Allo_Tx/Imprv_Mgmt_of_Graft-Versus-Hos/index.html

Treatment of chronic GVHD

Primary therapy for chronic GVHD is administration of steroids, usually cyclosporine and prednisone. Clinical trials investigating treatments of steroid-refractory chronic GVHD using the following drugs have reported success rates of between 25% and 50%:

  • Tacrolimus

  • Mycophenolate mofetil

  • Antithymocyte globulin (ATG)

  • Thalidomide

  • Daclizumab

  • Extracorporeal photopheresis

  • Infliximab

  • Clofazimine [9,10]

In 2006, a National Institutes of Health (NIH) Consensus Conference established guidelines for diagnosis, ancillary therapy and supportive care in chronic GVHD. The Conference reports outlined proposed treatments for symptoms and gives recommendations for patient education, preventive measures, and appropriate follow-up. Also developed were standard criteria for the diagnosis of chronic GVHD and a proposed new clinical scoring system that describes the extent and severity of chronic GVHD for each organ or site.

In all, six consensus documents were produced, and they are excellent resources for physicians wishing to learn more about chronic GVHD. [11-16]

http://www.lymphomation.org/bmt-gvhd.htm

"Chronic graft-versus-host disease (GVHD) is the most serious and common long-term complication of allogeneic hematopoietic stem cell transplantation (HCT), occurring in 20% to 70% of people surviving more than 100 days.1,2 Approximately half of affected people have 3 or more involved organs, and treatment typically requires immunosuppressive medications for a median of 1 to 3 years. Because of higher treatment-related (nonrelapse) mortality, chronic GVHD remains the major cause of late death despite its association with a lower relapse rate.3,4bloodjournal.org

Many risk factors exist that can predispose patients to chronic GVHD. These include: 
• prior acute GVHD • older donor/recipient age • HLA mismatch • use of an unrelated donor • viral infection (eg, cytomegalovirus) • splenectomy • DLI • use of blood as a source of stem cells.

Early Treatment Intervention Is Key: Initial studies reported by Sullivan et al indicated that treatment with corticosteroids alone used late in the course of chronic GVHD resulted in a 23% survival probability at 3 years after transplantation [7] compared to 76% if treatment was administered earlier in the course of the disease [8].

http://www.dcmsonline.org/jax-medicine/2000journals/nov2000/graft.htm

(Bits & pieces taken from full article)

Graft Versus Host Disease - Pathophysiology & Management

Amarin Alexander, M.D. & Shirley Wong, Pharm.D.

 

Introduction

First described in irradiated mice infused with donor cells in the 1950's, graft versus host disease has been the bane of scientists' existence from the beginning of allogeneic bone marrow transplantation (BMT). The presence of immunocompetent donor cells in an immunocompromised host may cause a number of symptoms and cellular changes often leading to acute or chronic rejection, termed Graft Versus Host Disease (GvHD). In the intervening years, as our understanding of the immune system has progressed, so has our ability to control, or limit the process of GvHD. As well, over the last 50 years, we have unearthed a beneficial phenomenon termed "Graft versus Tumor" (GvT), a consequence of GvHD that may lead us down new paths of cancer therapy.1,2

GvHD

Billingham in 1966 proposed the requirements under which GvHD can occur, later summarized by Ferrara and Deeg: `the graft must contain immunologically competent cells, the recipient must express tissue antigens that are not present in the transplant donor, and the recipient must be incapable of mounting an effective response to destroy the transplanted cells.'3,4 Today we know that the mediators of GvHD are T cells, human leukocyte antigens (HLAs) in the host, and the host being typically immunocompromised either chemically or physiologically (as in the case of neonates). While there are cases of GvH-like syndromes in autologous and syngeneic transplants, these are typically mild.10 Thus, allogeneic BMT is overwhelmingly the most common setting in which clinically significant GvHD is seen.

Extensive work on HLA antigens over the years has demonstrated that the better the HLA class I and II match, the lower the risk and intensity of the GvHD. Recently the minor HLA antigens have also been identified as contributing to GvHD. Prophylaxis of the host also has been associated with less severe GvHD. Risk factors for developing GvHD are indicated in Table 1.

In discussing GvHD, it is important to delineate between acute and chronic GvHD. The cutoff is arbitrarily set at 100 days post-BMT in clinical trials, but in practice, manifestations of both acute and chronic GvHD may be found later or earlier, respectively.5 Clinically the symptoms of both can be mild, moderate, or severe, with 100% mortality associated with the latter.


Chronic GvHD (cGvHD)

Chronic GvHD is loosely defined as GvHD occurring 100 days after transplantation. The incidence varies with HLA-matching and the source of the donor cells (bone marrow versus peripheral stem cell) but ranges from 27% to 72%.12 The symptoms may overlap those of the acute phase, and may begin to appear as late as two years after transplantation. Organ fibrosis with collagen deposition and atrophy are the hallmarks of cGvHD and thus, in its effects, cGvHD is often likened to autoimmune diseases such as lupus or scleroderma. Diagnosis may be made clinically or by biopsy and is graded either "limited or extensive," though some groups use "mild, moderate, and severe."4,12

cGvHD is generally subdivided into three categories:

  • Progressive onset: Continuation of aGvHD

  • Quiescent: Presence of cGvHD with previously resolved aGvHD

  • De novo: New onset cGvHD with no prior aGvHD

Prognosis is generally better when the cGvHD is de novo, that is, without any prior acute phase. Poor prognosis is associated with older patients and resistance to GvHD treatment.6 Other factors associated with poor prognosis in cGvHD are listed in table 3.

Clearly, the incidence of cGvHD varies according to many of the same factors affecting aGvHD. Additionally, CMV infection in the host or donor, and previous aGvHD are associated with increased incidence of cGvHD.6 Interestingly, donor age and recipient radiation source or dose do not appear to influence the incidence of cGvHD. Abnormalities of cellular immunity and selective epithelial attack are contributors to cGvHD. Decreased thymic function of the host due to age or pre-transfusion chemoradiotherapy has lead some to propose extra-thymic production of T lymphocytes with decreased negative selection and subsequent autoreactivity as another link in cGvHD.12,13

As in autoimmune disease, skin changes can be diffuse and devastating or localized and clinically insignificant. Over 80% of patients with cGvHD will have at least skin and glandular changes. The former can develop into severe contractures, ulcers, and atrophy while the latter usually involves drying of the mucous membranes of the eyes, mouth, and urethra.6

Much work has centered around prevention of GvHD. Immunocompetent donor T cells have been identified as the chief culprit in cGvHD, with severity of the disease actually linked to the number of donor immunocompetent T cells present in the host.14 Since we know that T cells are one of the major players, T lymphocyte-depleted BMT has been studied. While these have shown promise in decreasing the incidence of GvHD, the coincident tumor relapse rates have been unsatisfactorily high. One explanation is the suppressive effect the donor T-cells have on the host's residual tumor load. It is now generally thought that the infused donor T cells may have a tumor-suppressive effect, referred to as Graft versus Tumor effect (GvT).


Treatment of GvHD

The immunosuppressive agents used to prevent GvHD also may be used to treat established GvHD. They are generally less efficacious for treatment than prophylaxis. Corticosteroids with or without cyclosporin have been the standard of treatment for cGvHD. Tacrolimus provides an effective alternative in patients with GvHD unresponsive to cyclosporin therapy.26 Antithymocyte globulin (ATG) has also been used, however its efficacy is variable and its usefulness is limited by its toxicity.10 Ursodiol has shown benefit when used on a short-term basis to treat cGvHD of the liver that is refractory to immunosuppressive therapy.27 Notably, none of the present treatments are totally effective in the majority of patients. Clinical trials are under way to define the optimal drug therapy for the management of cGvHD. Thalidomide with immunosuppressive properties has shown promising results in the treatment of cGvHD. In a clinical trial, high-risk patients who received thalidomide as primary treatment showed a 3-year survival rate of 48% which was very similar to the results reported with cyclosporin and prednisone combination therapy. 28 In addition, a phase II study has confirmed the apparent efficacy of thalidomide as salvage therapy in patients with cGvHD unresponsive to conventional treatment.29 A randomized trial of thalidomide versus placebo added to cyclosporin and prednisone therapy is currently being investigated in patients with high-risk cGvHD.10 Similar to thalidomide, clofazimine, used in leprosy and immune-mediated skin disorders, has shown activity in some patients with cutaneous and oral cGvHD as well.30

Mycophenolate, a potent immunosuppressive agent for the prevention of acute rejection in renal transplantation, has also been studied in BMT, but the results were disappointing. The use of Mycophenolate for cGvHD was associated with low response rates and high incidence of leukopenia, anemia, and thrombocytopenia.31-33

Etretinate, a synthetic vitamin A derivative, has been used in the treatment of cGvHD of the skin. Marcellus et al34 found that 74% of the patients with refractory sclerodermatous cGvHD experienced softening of the skin, flattening of the cutaneous lesions, increased range of motion, and performance status while on oral etretinate. The major side effects were skin breakdown and ulceration leading to discontinuation of therapy in 18% of the patients.

Research on the use of monoclonal antibodies against T-cell activation and proliferation during GvHD is increasing. Antibodies directed against cytokines, such as tumor necrosis factor (TNF), and their receptors, such as IL-2 receptor antagonist (Daclizumab), appear promising. Immunotoxins, such as anti-CD5-ricin targeting mature T cells, are now undergoing clinical trials.4 According to some case reports and animal studies, penicillamine, cyclophenile, halofunginone, and nedocromil sodium may have a role in the treatment of cGvHD. 12

Supportive care for patients with GvHD is also important. Topical sunscreen products to prevent worsening of skin involvement, artificial tears for ocular dryness, pilocarpine for xerostomia, and nutritional supplements for patients with severe mucositis are crucial. For patients on long-term corticosteroid therapy, estrogen replacement in women, high calcium and vitamin D intake, antiosteoporosis agents, and daily exercise are highly encouraged to decrease bone loss.35

Future Paths

Early recognition and intervention will hopefully reduce the severity of GvHD when it occurs. Of course, better HLA matching and recognizing the risk factors of GvHD will also help in reducing the incidence. Research into selectively depleting the donor lymphocyte contamination is a priority. Increased understanding in the cellular biology of lymphocytes and antigen-receptor interactions during GvHD is critical to provide new insights into the pathophysiology of the disease and aid in designing and optimizing drug therapy. In addition, host APC or MHC blockade may be another therapeutic option in the future. The role of umbilical cord stem cells, which are theoretically immunologically immature, is another area of investigation, with promising initial results.

Conclusion

Great strides in the last 50 years have led to improved outcomes in BMT recipients. In fact from this research, BMT, once reserved for leukemics, is beginning to be applied to other hematologic disorders like multiple myeloma, aplastic anemia, and sickle cell disease. Currently, immunosuppressive drug therapy is the mainstay of GvHD prophylaxis and treatment but is associated with severe toxicity. T-cell depletion of bone marrow grafts decreases the incidence of GvHD but increases the risk of engraftment failure and leukemia relapse. Unfortunately, work is still needed to prevent and manage GvHD which, together with infection, is still the major cause of morbidity and mortality in the BMT patients. Improved understanding of the immune system and inflammatory response will aid in this effort.


http://www.bmtinfonet.org/newsletters/issue67/GVHD.html

Researchers Tackle GVHD

Researchers studying graft-versus-host disease (GVHD) met in Bethesda MD June 6 to share information and recommendations for developing future clinical trials for the disease. BMT InfoNet provided suggestions on how best to include BMT survivors and others with first-hand knowledge of GVHD in the development and oversight of such clinical trials.

The meeting, which was chaired by Dr. Steven Pavletic of the National Cancer Institute and Dr. Georgia Vogelsang of Johns Hopkins School of Medicine, brought together prominent researchers to develop definitions and tools for conducting clinical trials, outline standards for the care of patients who have this disease, and guide future research. "We are laying the foundation for a new cycle of research in chronic GVHD," said Dr. Pavletic at the meeting.

Although the exact number of patients who develop chronic GVHD is not known, some estimate the number to be around 3,000 per year. In most cases, the disease is mild or moderate, but some cases are life-threatening. Even the less severe cases of chronic GVHD can profoundly affect a patient's physical and emotional well-being and lifestyle.

"Those who've been touched by GVHD have an important role to play in the development and oversight of new clinical trials," says Susan Stewart, Executive Director of BMT InfoNet. "They have unique insights about quality-of-life issues associated with the disease, the practicality of proposed treatments, and ethical issues associated with research. Theirs is an important voice in the development of future research to treat this disease."