Alice McCarthy

When Karissa Eifert’s mother died in 2015 of hereditary diffuse gastric cancer (HDGC) caused by an inherited (also termed “germline”) mutation in the CDH1 gene, Eifert’s gynecologist proactively suggested she get genetic testing. Because of Eifert’s family history of breast cancer and her mother’s diagnosis, the doctor opted for a full panel of genetic screening.

A few weeks after, Eifert was told she had a mutation in the CDH1 gene. She was just 34 years old. Each year, about 27,000 people in the United States receive a diagnosis of stomach cancer. A very small percentage — 1% to 3% — have HDGC. The most common cause of the disease is the presence of a germline hereditary mutation in the CDH1 gene, which leads to an increased risk of diffuse stomach cancer and lobular breast cancer.

“About 20% to 40% of people who appear to have HDGC have an inherited mutation in the CDH1 gene,” says Dr. Jeremy Davis, a surgical oncologist at the National Cancer Institute (NCI) and lead investigator of the NCI’s Research Study for Hereditary Stomach Cancer.

The CDH1 gene directs development of a protein called epithelial cadherin, or E-cadherin. Found on cells that line the stomach and other organs, E-cadherin causes neighboring cells to stick to each other and form tissues. It can also function as a receptor involved in growth control. When the CDH1 gene is mutated, it causes abnormal, nonfunctional E-cadherin proteins that allow cells to grow and divide. It also increases the chances of cancer cells proliferating into the stomach wall and spreading throughout the organ.

More than 120 inherited types of CDH1 mutations are linked with HDGC.

Carriers of the CDH1 mutation have an elevated risk of developing either HDGC or, in women, lobular breast cancer, usually with onset before the age of 40. But not all patients with HDGC carry CDH1 gene mutations.

“The risk of getting gastric cancer (if you have a CDH1 mutation) is not 100%,” adds Davis. “But statistically, we think that your risk is much, much higher than the average population.” The latest evidence finds that these individuals have a 30% to 50% risk of developing HDGC by age 80. For women, the risk of lobular breast cancer is approximately 40% to 55% by age 80.

Genetic testing and counseling are two preliminary steps when a physician sees a patient with early-onset stomach cancer, lobular breast cancer or a family history of stomach cancer. For these patients, testing for the CDH1 mutation is often the first genetic test.

“We might recommend the panel if we are not totally sure what we are looking for, but we suspect a hereditary gene syndrome is involved,” Davis explains. “That is especially true if the CDH1 test comes back negative.”

Eifert’s family history of cancer concerned her, “but I had no clue I had (a mutation in) the CDH1 gene,” she says. “I consider having that information to be a gift that my mother didn’t have.”

Kate King-Scribbins, who received a diagnosis of lobular breast cancer at age 32, also went through genetic testing before discovering that she was positive for a CDH1 mutation. While lobular breast cancer is the second most common type of breast cancer, it is 30 times less common to derive it from the CDH1 mutation compared with more common gene mutations like BRCA2.

“My mother had breast cancer, but she did not have CDH1,” she says, explaining that the CDH1 mutation came from her father’s side, with several family members having early breast cancer. “They were going to test only for BRCA1/2, but I wanted to push for all of the genes — given my family history — so I got the whole gene panel. That’s when I learned I had the CDH1 mutation.”

“For patients who have a family history of stomach cancer and the CDH1 (mutation), the recommendation is to have a total gastrectomy or removal of the stomach,” Davis explains.

The decision to act on the discovery of a CDH1 mutation is influenced by many factors. If cancer is already present, the treatment choices are fairly straightforward: surgery usually followed by appropriate chemotherapy. When the CDH1 mutation is discovered but the patient has not developed any cancer, choices are more varied — especially if they have a family history of HDGC. They can either elect for gastrectomy (total removal of the stomach) or a period of intensive surveillance with endoscopy every 12 months.

Eleven months after Eifert’s diagnosis, she opted for a total gastrectomy at the NCI at the age of 35. “My endoscopies were actually clear, but I wanted to move forward with the total gastrectomy,” she explains. “I wanted to beat (HDGC) to the punch.” The first year after surgery was hard; during that time, she experienced intense bile reflux and rapid weight loss. “I also lost the desire to eat since I was frequently nauseous,” she says.

Eifert is now 18 months post-surgery and has been working regularly with a dietitian. “I feel like my old self again,” she says, noting that she lives a fairly active lifestyle of hiking in Rapid City, South Dakota. “I have most of my energy back and eat most things. Eating is less of a chore, which makes a huge difference for me mentally. I now enjoy and crave food again.”

After her surgery, however, Eifert received a diagnosis of stage 1A gastric cancer after a pathology on her stomach showed small areas of precancerous cells. Of note, she has not needed further treatment.

After undergoing a mastectomy, chemotherapy and radiation treatment for lobular breast cancer and learning she had the CDH1 mutation, King- Scribbins joined Davis’ HDGC clinical study at the NCI, which is focused on learning the best ways to screen for and treat the disease. Like Eifert, she opted for a gastrectomy. “The whole process has definitely taken its toll. I lost both breasts, my stomach and ultimately my gall bladder,” King-Scribbins says about her three years of surgeries and recovery. “I wasn’t about to go through all that treatment for breast cancer and then let stomach cancer take me out.”

Patients who do not wish to immediately move to surgery — either for a total gastrectomy to prevent diffuse stomach cancer or mastectomy to prevent lobular breast cancer — instead undergo intensive surveillance.

“The decision when to have a gastrectomy when you may be 25 years old is a heavy burden,” says Dr. Fabian Johnston, division chief of gastrointestinal oncology at Johns Hopkins Medicine in Baltimore. He adds that he sees many patients who choose surveillance until they are in their early 30s or the risk of cancer increases.

During the procedure, a tube is inserted into the stomach through the mouth. Samples of stomach tissue are collected and analyzed in a lab for the presence of abnormal cancerous signet-ring-shaped cells. In HDGC, these cells grow and often cluster together in the diffuse pattern associated with the disease.

The decision between surgery and monitoring is further complicated because individuals with the CDH1 mutation may undergo prophylactic gastrectomy: the removal of the stomach prior to known evidence of cancer. “When we do random biopsies, we will find precancerous cells about 40% of the time if we just happen to hit the right spot,” Davis adds, noting that he usually finds cancer cells in 95% of patients who have had prophylactic gastrectomy.

Because HDGC is not symptomatic until it is relatively advanced, endoscopy can be useful for catching some cancers at an early stage. “Anyone with the CDH1 mutation should get the endoscopy when they are diagnosed and every year after that for monitoring,” explains Dr. Daniel Sussman, professor of clinical medicine in the gastroenterology division at the University of Miami Health System. “The drawback of using endoscopy for surveillance is that we biopsy only certain areas of the stomach and can miss these early cancer cells.”

“That tells me that endoscopy is not that great if we only find them 40% of the time as opposed to 95%.”

For this reason, patients with HDGC or those with the CDH1 mutation are advised to seek care at a medical center experienced in monitoring, diagnosing and treating HDGC. This includes seeing an advanced endoscopist trained to monitor HDGC with specialized endoscopy scopes created to visualize hard-to-see cancerous cells.

For women with the CDH1 mutation or with stomach cancer diagnosed when they were young, breast cancer screening is recommended as early as age 30. “We recommend starting with breast MRI since lobular breast cancers are more insidious than diffuse breast cancer, and they are harder to identify on mammography,” Johnston explains. Since her CDH1 diagnosis and gastrectomy, Eifert has been alternating between mammography and breast MRI screening tests every six months. “At this point, I’m not certain what steps I may take in the future,” she says, referring to prophylactic mastectomy. “I’m in the early stages of learning and formulating a plan.”

Since her diagnosis, KING- SCRIBBINS has dedicated herself to helping others who also received a diagnosis of gene mutation
at a young age. 

As research into the genetics of the disease sheds more light on this rare cancer, some important questions remain. “We still don’t know who should definitely choose a prophylactic gastrectomy,” Davis explains. “Although the risk between CDH1 and HDGC is well established, beyond that, we cannot yet provide individual risk assessments.”

Because some patients with the gene mutation never develop HDGC, it is also important to find out why. “Since we know we almost always find early signs of HDGC after gastrectomy, why do some of them appear to be relatively indolent and others are very aggressive?” asks Sussman. “We need to understand that so we can, hopefully, intervene and perhaps find ways to prevent advanced cancer.”

Another relative unknown is what other genetic mutations may contribute to HDGC. Although CDH1 has the longest and strongest association with the cancer, other genetic mutations have been linked to it over the past several years.

Today, Eifert is back to work as an interior designer and counsels others with similar diagnoses through her blog, Reverie Rising. Having battled insurance issues and the lack of resources in her area, she advises others to be informed, follow their instincts, advocate for themselves, push for what they need and look for answers in online Instagram and Facebook communities and from specialty medical centers. “Having the knowledge, it gives you the power to determine how you want to handle your options. So many people don’t have the opportunity to proactively influence their outcomes, but you can with a CDH1 diagnosis,” she says.

Similarly, King-Scribbins — who talks more about her journey on her blog, “My Pink Genes,” where she also provides helpful resources for others with the disease — is committed to helping others. “I don’t want (others) to feel as alone as I did going through this at such a young age,” she says.

For more news on cancer updates, research and education, don’t forget to 

Articles

Knowing they’ve inherited a genetic mutation for stomach or breast cancer gives patients the power to plan ahead.

Looking Forward: Patients With Genetic Mutations Are Empowered to Make Plans

As stem cell transplantation (SCT) becomes more common, it has also become safer. This is great news for the more than 40,000 people who receive a SCT worldwide each year. People receiving SCT are living longer after transplantation, often with improved quality of life immediately after treatment. But as the numbers of people surviving SCT increase, long-term and late effects may also become more common.

Researchers have pinpointed some of the most common late-term effects after SCT, including:

Chronic graft-versus-host disease (cGVHD)

Chronic infections, such as fungal infections

Metabolic and endocrine disorders (metabolic has to do with the metabolism, and endocrine refers to tissue, such as the pituitary, thyroid, and adrenal glands, that makes and releases hormones that travel in the bloodstream and control the actions of other cells or organs)

“One of the reasons it is becoming clearer to us that we have to concentrate on the later effects of transplantation is that we thankfully have more survivors from the transplant process itself,” says Robert Soiffer, MD, clinical director of the Center for Hematologic Oncology at Dana-Farber Cancer Institute in Boston. 

Better supportive therapies, including advances in antifungal medication, boost the strength of the immune system, helping patients rebound more quickly. And over the past decade, more people receive less-intensive chemotherapy or radiation prior to transplant. This practice reduces the chances of acute toxicity, infections, and other serious illness or death. 

“One of the results of all this progress is that, as we get more survivors, we are seeing complications that can occur much later, often 10 to 20 years afterwards,” explains Soiffer.

“The bad news is that over the long-term, SCT survivors are at risk for some complex late effects,” says Leona Holmberg, MD, PhD, of the clinical research division at Fred Hutchinson Cancer Center in Seattle. These patients have a disrupted immunological reconstitution, susceptibility to infection, secondary cancer risk (skin and other cancers), chronic organ dysfunction, metabolic [and endocrine] issues, and quality of life issues.

For these reasons, researchers are studying the relationship between SCT and possible long-term effects—and possible ways to prevent them or reduce risk.

About one third to one half of allogeneic transplant recipients develops acute GVHD, which can occur within the first three months after the transplant 

and manifest as skin rashes, mouth sores, diarrhea, and muscle aches.

Patients receiving an allogeneic transplant—when patients receive stem cells from a donor&mdash;are at risk for graft-versus-host disease (GVHD), where the donor cells recognize the recipient’s cells and tissues as foreign and attack them

Sometimes, however, the condition becomes chronic and can lead to serious long-term problems including damage to the liver and lungs, or even death. Chronic GVHD is defined as either beginning more than 90 to 100 days after the transplant or when the acute condition extends beyond 90 days after transplantation. 

Many of the treatments for cGVHD center on modulating the immune system. T-cells, a type of white blood cell of the immune system, can cause harm to the patient’s body after an allogeneic transplant. Doctors can treat cGVHD with T-cell depletion—where patients receive antibodies targeted to the donated T-cells to simply reduce their number and activity.

Researchers are also looking at targeting another type of white blood cell, B-lymphocytes, to see if removing these cells may have a potential role in cGVHD. Clinical studies with Rituxan (rituximab), an agent approved to treat B-cell lymphomas, are ongoing for both therapy and prevention of cGVHD.

Additional immune therapies used to treat cGVHD include interleukin-2 and sirolimus, a drug used to prevent organ transplant rejection. Sirolimus has sparing effects on regulatory T-cells, which may make it useful in treating cGVHD. Also, extracorporeal photopheresis (ECP), a procedure used to treat cutaneous T-cell lymphoma, may be beneficial for treating cGVHD. With ECP, a person’s blood is treated with light-inducible drugs outside of the body. It is then passed under ultraviolet A radiation and reinfused into the body. This technique allows for larger numbers of donor regulatory T-cells. Studies suggest use of ECP earlier in the treatment course may be most beneficial. 

Cardiac, lung, and metabolic issues are increasingly recognized as a long-term consequence of SCT.

“Following stem cell transplantation, we see accelerated atherosclerosis leading to increased risk for heart attacks,” says Soiffer. Survivors are also more likely to develop chronic cardiotoxicity in the form of pericarditis and congestive heart failure if they have received cardiotoxic drugs or radiation as part of their treatment with transplantation. Additionally, patients who have received chest radiation in the form of mantle or mediastinal radiation are at increased risk for long-term heart problems.

The use of immunosuppressive medications also increases the risk for cardiovascular issues, as well as metabolic disorders. “Those drugs can somehow influence development of the metabolic syndrome,” says Soiffer. Patients with metabolic syndrome have higher blood sugar and cholesterol and overall abnormal lipid profiles.

In addition, about 10 percent of patients with cGVHD develop lung inflammation from three months to two years post-transplant.

Development of secondary solid tumors 10 to 30 years after transplant, particularly allogeneic, is a serious potential complication. Tissue damage resulting from previous radiation or inflammation as well as immunosuppression may be largely the cause. Those at the highest risk include patients who received total body irradiation or have cGVHD.

“We have always seen an increased number of skin cancers,” says Soiffer. “But there is also an increased risk of epithelial cancers (mouth cancers, gastrointestinal tract cancers), and breast and lung cancers.”

Cataract development is more common in SCT patients who received total body irradiation or steroids to treat GVHD. Another long-term effect of steroid treatments is bone loss (osteoporosis) and increased fracture risk, which can be addressed by using approved drugs such as bisphosphonates. Similarly, the chemotherapy and/or radiation given during SCT procedures unfortunately can leave patients infertile. 

“As transplants have improved drastically in the last several years, we have more patients living longer, staying in remission from their underlying care, and the patient care focus changes to long-term survivor management issues,” says Holmberg.

And those issues don’t always involve cancer. “As patients are living longer from their disease, we have to make sure they are living well apart from non-oncologic issues,” says Soiffer.

Over time, SCT patients tend to return to their general practitioner or internist for medical care.

“As we become more cognizant of these long-term complications, programs need to be put in place to track these patients,” says Soiffer. “We increasingly have the ability to do this—in part because of better database tools&mdash;so we should get a better sense of long-term follow-up.”

Certainly surviving the immediate cancer crisis after successful SCT is cause for great happiness and hope. “But we have to remain vigilant for other issues, particularly starting within a year of transplant that we are screening them for a whole variety of issues such as blood pressure, cholesterol, diabetes, colorectal, breast, prostate, and cervical cancers,” says Soiffer.

The American Society for Bone and Marrow Transplantation recommends all SCT survivors seek care from physicians capable of providing general care and that associated with hematologic oncology.

“As health providers, we need to take the lead on this and remain vigilant and help our patients remain vigilant for an extended time beyond their transplant to ensure the best quality of life for the long-term,” Soiffer says. 

Learn more about the various treatment approaches in 

“What’s New With Stem Cell Transplants?”

Monitoring and managing effects of transplantation can be a waiting game.

Managing the Long-Term and Late Effects of Transplantation

In the mid-1970s, a group of pathologists and clinicians from around the world  gathered several times to discuss a set of blood disorders with a strong  resemblance to leukemia but with notable differences. Known as the  French-American-British (FAB) Cooperative Group, this assembly created a  classification in 1976, which it refined and expanded in 1982, that defined  myelodysplastic syndromes (MDS).  

The designations gave doctors the ability to better diagnose and treat MDS  patients. But even as doctors were able to better classify MDS, patients were  still without effective treatments. That’s not quite true anymore. In the past  two years, the Food and Drug Administration approved several therapies, and  others are undergoing testing, offering some patients the prospect of a better  quality of life, and possibly changing the natural course of the disease.

Chet Hodge, a 71-year-old aerospace engineer from Mesa, Arizona, was  diagnosed five years ago with a mild form of MDS and felt wiped out most of the  time. Despite receiving more than five blood transfusions to restore his blood  cell numbers, relief was only partial. He was soon put on Revlimid®  (lenalidomide), one of three new medications for a disease notoriously lacking  options. “Within a month of taking the drug my blood cell counts started coming  back up,” says Hodge, who hasn’t had a transfusion in four years.

MDS occurs when mutated stem cells in the bone marrow produce dysfunctional  blood cells called blasts, resulting in low numbers of one or  more blood cell types, including red blood cells, white blood cells or  platelets. (“Myelo” refers to marrow and “dysplasia” means abnormal.)

The resulting blood cell deficiencies, or cytopenias, explain the first symptoms  typically seen with the disease: extreme fatigue, weakness, bruising,  infections, bleeding and fever. “I was fatigued by 11 in the morning,” recalls  Hodge. “I seriously considered retiring.”

But Hodge and many others like him are now enjoying lives relieved from many  of these symptoms thanks to Revlimid, Vidaza® (azacitidine) and Dacogen™  (decitabine). “These three drugs have changed the landscape of MDS treatment,”  says John Bennett, MD, a long-time MDS researcher at the University of Rochester  in New York and chairman of the MDS Foundation. They offer startlingly positive  results in some of the patients who respond to them. In Hodge’s case, not only  did his fatigue fade but so did any sign of disease. “It put me in a complete  remission,” he says.

Even with successes, MDS remains an extremely difficult disease to treat for  the majority of people, cautions Charles Schiffer, MD, professor of medicine and  oncology at the Barbara Ann Karmanos Cancer Institute at Wayne State University  School of Medicine in Detroit. MDS is usually a progressive illness, so  approximately 20 percent of patients eventually develop acute myeloid leukemia  (AML). For this reason, MDS was formerly classified as a preleukemia.

While the majority of doctors today consider MDS a type of cancer, some  institutions, such as Stanford Comprehensive Cancer Center, still do not  classify the disease as a malignancy, which can be confusing for many patients.  Further research and classification of MDS is creating more of a distinction  between MDS and benign blood disorders, leading to the disease being formally  defined as cancer by the National Cancer Institute, World Health Organization  and numerous cancer institutions and organizations. “MDS is a malignant bone  marrow disorder,” says Dr. Bennett. “We need to get that out more.”

While an estimated 10,000 to 15,000 new cases of MDS are diagnosed each year  in the United States, slightly more often in men, some experts estimate the  number is actually much higher. “I think we really have a population of 20,000  to 25,000, and that is the tip of the iceberg,” says Dr. Bennett. “There may be  another 50,000 to 100,000 elderly Americans who probably have undiagnosed MDS.”  Combine the aging baby boomer population with improved diagnostics to identify  MDS patients more precisely and the number of people diagnosed with MDS will  inevitably increase.

Though the average age of MDS diagnosis is 70, the  disease can strike younger people. “I was 51 when I was diagnosed,” says Robin  Whittemore of Easley, South Carolina. Whittemore developed therapy-related, or  secondary, MDS following breast cancer treatment she received several years  prior that included Adriamycin® (doxorubicin), a drug that carries a risk of  secondary cancer. Whittemore is among the approximately 20 percent  of secondary MDS cases with a known cause: exposure to certain types of  chemotherapy or radiation treatment for previous cancers; exposure to certain  chemicals, such as benzene; and Fanconi anemia, a rare congenital disease.

While researchers know genes play a role in the majority of primary MDS  cases, the cause is largely unknown. “Perhaps it may be because we live in an  environment where the bone marrow is continually being challenged over decades  by radiation, occupational hazards and other influences that are poorly  identified,” says Dr. Bennett. The ability of the bone marrow DNA to optimally  repair itself is limited. The repair enzymes eventually age, says Dr. Bennett,  leading to a situation where the next alteration is inadequately repaired and  sooner or later a person ends up with a damaged blood stem cell that grows at  the expense of normal cells.

MDS is actually multiple disorders wrapped up in one. After diagnosis, the  International Prognostic Scoring System, developed in the late 1990s by Dr.  Bennett and colleagues, helps provide a prognosis and defines four risk groups  for both overall survival and AML evolution: low, intermediate-1, intermediate-2  and high risk. Survival for most people with MDS can be less than six months to  more than 10 years, depending on the subtype.

The main options available to MDS patients in the past were blood  transfusions, antibiotics to prevent infection and blood cell growth factors,  drugs designed to jumpstart blood cell production. Today, almost all patients  still receive blood transfusions, but transfusions don’t provide long-term  relief and repeated red blood cell transfusions often leave patients with  iron-rich blood, a serious condition if left uncorrected. (The approval  of Exjade® [deferasirox], the first oral drug designed to reduce iron overload,  now makes the consequences of transfusion therapy less intrusive by replacing  traditional infusion-based pump therapy.)

Donor stem cell transplant—currently the only curative treatment for MDS&mdash;may  not be realistic for this older population. But a recent push to  find less toxic yet effective treatments led to the three notable drug  approvals.

Originally told she had as few as three months to live without a stem cell  transplant, Whittemore entered a clinical trial for Dacogen, an intravenous drug  just approved in May. “I figured it might give me more time to find a donor,”  she says. This latest drug approval for MDS came after three separate trials in  about 270 patients total found that blood counts completely or partially  normalized in about 22 percent of Dacogen-treated patients. Whittemore was among  that percentage and is now transfusion-free, receiving growth factor injections  as needed to boost her blood counts. She still battles fatigue, particularly the  week after treatment. “But,” she says, “compared with breast cancer  chemotherapy, this treatment was a breeze.”

While she waits for a suitable donor, Whittemore, a jewelry artisan, focuses  her artistic energy on creating cancer awareness designs. “I created the Second  Chance bracelet because of the second chance at life after virtually being given  a death sentence.” New schedules and doses of Dacogen are now being evaluated  that may be even more effective.

Other chemotherapy drugs for MDS include Vidaza and an older drug called  cytosine arabinoside (ARA-C). The response rates are comparable between Dacogen,  Vidaza and cytosine arabinoside, says Dr. Bennett, but the newer agents cause  far fewer side effects. “Currently it’s hard to make a judgment whether one is  better than the other.”

Normal cells rely on tumor suppressor genes to ensure normal cellular  functioning and growth, but since many of these tumor suppressors have been  silenced in MDS cells, abnormal growth occurs. Dacogen and Vidaza interfere with  the DNA process that silences these crucial genes, thus restoring tumor  suppressor function and normal functioning of the cell. Common side effects of  both drugs include nausea, anemia and thrombocytopenia.

Although Dacogen and Vidaza are approved for all MDS types, in practice, only  patients with more advanced disease typically receive these drugs. Singling out  Vidaza, MDS researcher Alan List, MD, says the most striking thing is the drug’s  ability to delay or suppress the development of leukemia. “Its best effects are  going to be in people who are higher-risk patients for whom you have to extend  survival and control the potential for leukemia evolution,” says Dr. List,  division chief of malignant hematology at H. Lee Moffitt Cancer Center and  Research Institute in Tampa.

The May 2004 approval of Vidaza served as fortunate timing for Ernie Widmann,  a 69-year-old investment consultant from suburban Philadelphia who was diagnosed  with MDS in late 2005. After five cycles of daily Vidaza treatment, Widmann’s  blood counts improved to the point where his doctors took him off the drug.  “They were pretty intense injections,” he recalls. “But after the first couple  of treatments my numbers rebounded.” He has remained transfusion-free since his  last treatment. In general, about 30 to 50 percent of patients receiving Vidaza  see improvements in their blood cell counts.

Beyond the impact on DNA processes, researchers suspect an overly exuberant  immune system may partly explain why the bone marrow produces abnormal blood  cells in some types of MDS. Younger, low-risk patients respond particularly well  to treatment aimed at weakening the immune system. 

Revlimid, a once-daily  oral derivative of Thalomid® (thalidomide), works by enhancing the effect of  erythropoietin, the body’s regulator of red blood cells, says Dr. List. Revlimid  is most effective against the subtype for which it was approved late last  year—5q deletion MDS, a mild type of MDS where chromosome 5 lacks a portion of  DNA. It reduces the need for transfusions in about two-thirds of patients, and  eliminates the 5q deletion chromosomal abnormality in up to 75 percent of  patients, including Chet Hodge. “I was astounded when I had a bone marrow sample  three months after starting the drug that showed no sign of the 5q deletion,”  says Hodge.

In MDS patients without the 5q deletion, the results of Revlimid are not as  robust, but trials show about 27 percent of patients become transfusion-free and  44 percent have some improvement in their blood cell counts. The drug’s main  side effects are rash, fatigue and neutropenia (low neutrophil count), a side  effect managed well by growth factor treatment.

Immunosuppressive approaches under investigation for MDS (primarily low-risk  MDS) include antithymocyte globulin, steroids and the antitumor necrosis factor  therapies, Remicade® (infliximab) and Enbrel® (etanercept).

Now with several proven agents at their disposal, researchers believe  combining drugs may enhance survival and possibly suppress disease progression.  Vidaza and Dacogen are already in clinical testing with various other drugs.  “We’re where Hodgkin’s disease researchers were in the early 1970s—they had a  lot of agents that worked. They had to put treatments together to improve on  that,” says Dr. List.

Possibly joining the next wave of MDS therapies is Telintra™ (TLK199), an  oral drug that promotes blood cell growth, and farnesyl transferase inhibitors  Zarnestra® (tipifarnib) and Sarasar™ (lonafarnib), which interfere with enzymes  involved in activating cancer-promoting genes.

“When you get your first drug approved for a disease, it suddenly attracts  interest,” says Dr. List. And from that first drug has come the beginnings of a  menu of MDS therapies. Experts agree it is unlikely Vidaza, Dacogen and Revlimid  are the final answer in MDS treatment, but the research continues, and for Dr.  List, “this is just the beginning.”

Perhaps [the cause of primary MDS] may be because we live in an environment where the bone marrow is continually being challenged. 

Deep in the bone marrow lies the reason for blood disorders classified as myelodysplastic syndromes&mdash;stem cells gone awry.

Treatment Boost for MDS

About half of MDS patients are cured after allogeneic stem cell transplantation,  a procedure where blood stem cells from a donor replace abnormal stem cells and  produce the needed healthy blood cells. But serious side effects from the  procedure and donor availability restrict many patients from taking this  treatment route.

Side effects from the intense chemotherapy and/or total body  radiation prior to transplant, known as conditioning treatment, may pose a  problem, while the risk of graft-versus-host disease, where the new donor cells  recognize the patient’s existing cells as foreign, creates a post-transplant  problem. Stem cells nearly identical to the patient, whether from a sibling or  matched unrelated donor, provide the best probability of success. Because  matched donors are difficult to find—less than a quarter of patients eligible  for a stem cell transplant have matched sibling donors&mdash;research continues for  other methods.

Recent improvements in conditioning treatments may make transplant  available to more patients. Using lower doses of chemotherapy or radiation,  sometimes called a minitransplant, gives the opportunity for a transplant to  older patients, who without treatment would have an average survival time of  less than 18 months.

Stem cell transplant is used to treat people with intermediate-1,  intermediate-2 and high-risk MDS. The age limit, previously 55, is reaching  about 65—and even higher in select cases&mdash;because patients aren’t suffering  problems previously encountered with the higher-intensity conventional  transplants.

Worldwide databases have registered more than six million  unmatched donors, and new techniques are allowing better matching between donor  and patient and reducing mortality and the incidence of graft-versus-host  disease. 

Allogeneic stem cell transplantation and improvements in conditioning treatments may make transplant available to more patients and lower risk of severe side effects.

Cure Becomes Less Risky

No one would argue the current design of clinical trials in the United States  isn’t a big improvement over history, since early experiments in medicine  involved unscientific and inefficient methods for assigning patients to  treatments.

“Up until about 60 years ago—when the randomized trial came into  existence&mdash;the standards in medical research were shoddy at best,” says Donald  Berry, PhD, chairman of the department of biostatistics at M.D. Anderson Cancer  Center in Houston. “Information was collected by anecdote and superstition more  than science.”

But some leading cancer researchers find current designs outdated. “It’s  clear the current designs are inadequate, particularly in cancers in which we  desperately need to make progress more rapidly,” says Francis Giles, MD, chief  of developmental therapeutics within the department of leukemia at M.D.  Anderson. “We certainly can do better.”

The statistical method used almost exclusively to design and monitor clinical trials is called the frequentist method. These trials include a set number of patients randomized to one of two or more treatment groups and is conducted for a pre-determined length of time, with results assessed at select endpoints. “But at the end of these trials, you usually wish you had done something different,” says Dr. Berry.

Drs. Berry and Giles believe Bayesian trials—studies that allow for changes in the trial as it progresses&mdash;are a major step forward. The concept is certainly not new, having been named after the Reverend Thomas Bayes, a Presbyterian minister and mathematician, who outlined the method in an article published in 1763. In a Bayesian-based trial, the study adapts to statistical information created during the course of the trial. Before the trial starts, investigators design a flow chart of actions if certain events become statistically dominant.

“In Bayesian trials, you have to consider all the possibilities ahead of time and plan for alternatives,” explains Dr. Berry, who wrote about the Bayesian method in the January 2006 issue of 

. For example, if it becomes statistically clear that one treatment group is having more success, fewer new patients are recruited into the less-favorable group and those currently in that group can switch or choose another study altogether. Similarly, if a treatment appears to be superior at a particular dose, other doses are phased out. And if serious toxicity arises in a treatment, patients migrate to another treatment or dose. By declaring a success or failure earlier, Dr. Berry says the result is more likely to be statistically accurate. Frequentist trials almost never use information accrued during the trial to affect the course of the study.

Dr. Berry says the traditional trial method has had enormous and appropriate impacts in medical research. “I don’t want to lose that, but there are problems with it.” So far, more than 200 Bayesian-based clinical trials have been proposed or conducted at M.D. Anderson, and other researchers are embracing the concept, including the Cancer and Leukemia Group B research group.

While the Food and Drug Administration accepts Bayesian-based clinical trials when assessing the safety and efficacy of new medical devices, only one drug—the heart medication Pravigard PAC&mdash;has ever been approved based on the Bayesian approach. But movements are afoot at the FDA for using these study designs for drug approvals.

Janet Woodcock, MD, the FDA’s deputy commissioner for operations, says the FDA believes Bayesian approaches should be incorporated into clinical trial design for drug testing because of the targeted therapy boom. “The trial approaches we use now are probably not the best ones for the new science we are bringing to cancer.” She points to Tarceva (erlotinib) and Iressa (gefitinib), both of which treat lung cancer, as examples. “We put patients into a study and find that 10 percent benefit. But we don’t know which 10 percent. What we want to do is figure out in advance who benefits and not expose those who don’t.”

An important missing link, she says, is the availability of diagnostic tests that can tell in advance of therapy what cancer pathways are active in a particular patient’s disease. “We [at the FDA] do not want to be a roadblock, but if we don’t have the tools to know who can benefit from a drug, we will not be able to approve new drugs,” says Dr. Woodcock.

“I see no rationale to further delay moving to these designs,” says Dr. Giles, who is currently involved in eight Bayesian-based leukemia studies. “They are more ethical, more patient-friendly, more conserving of resources, more statistically desirable. I think the next big issue is to get the FDA to accept them as the basis for new drug approvals.”

 Some cancer researchers are questioning whether clinical trial designs should be updated.

Alice McCarthy

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