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Hematopoietic cell transplantation results in many late complications
Chronic graft-versus-host disease, relapse and new malignancies are primary concerns for survivors of hematopoietic cell transplantation.
Transplantation techniques, including tissue matching and supportive care strategies, have improved the immediate outcomes with hematopoietic cell transplantation, but new data indicate the emergence of late complications in some of the treated patients.
Immune reconstitution and the potentially devastating consequences of chronic graft-versus-host disease underlie many issues, but patients can also suffer cardiovascular and pulmonary problems, relapses of the original malignancy or new cancers. Physicians who treat patients who have undergone HCT have a long list of prevention and treatment issues to keep in mind.
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The most common late complication after allogeneic HCT is chronic graft-versus-host disease, which affects 30% to 70% of allogeneic HCT patients who survive more than 100 days. “It is the underlying mediator of a variety of long-term complications that can affect the quality of life of the survivors,” said Smita Bhatia, MD, MPH, chair and professor of population sciences at City of Hope Cancer Center in Duarte, Calif. “It increases the risk many-fold for many complications down the road.”
Chronic GVH disease can affect almost every organ system in the body. Most often it manifests first in the skin, although the mouth, liver, gastrointestinal tract and eyes also are commonly affected.
“There can even be lung involvement, and people do believe that the kidney and heart can be involved,” said Stephanie J. Lee, MD, MPH, of the Transplant Clinic at Fred Hutchinson Cancer Research Center in Seattle. “Really it is almost any organ system. Some are quite rare, but you can always find a report out there attributed to GVH disease.”
Chronic GVH disease has a median time to onset of four to six months after HCT, but as many as 10% of cases are diagnosed after more than one year. A National Institutes of Health consensus conference in 2005 standardized the criteria for diagnosis of GVH disease and also established a clinical scoring system for the disease.
Each organ or site affected is given a score from zero to three, representing mild, moderate and severe involvement of the organ system. Lee said that the results from the consensus conference stop short of strict guidelines for treatment, “because there isn’t a whole lot of comparative data that we can use. The guidelines are really more for clinical trials. … We think more studies need to be done.”
High morbidity, mortality rates
The high rates of morbidity and mortality associated with GVH disease are due to both the immunodeficiency and organ dysfunction the disease causes as well as the medications used to treat it. Although treatment can be local if GVH disease is treated before multiple organ systems are involved, beyond that, systemic therapy generally begins with corticosteroids for immunosuppression at 1 mg/kg per day. Some researchers have estimated that about 90% of patients who will respond to the initial steroid therapy will do so within three months.
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For patients who do not respond or in whom improvements plateau, there is little phase-3 evidence to date regarding secondary medications. Phase-2 studies and case reports have indicated some efficacy with a number of medications, and some large phase-3 studies to determine optimal secondary therapy are underway, Lee said. For any patient who requires secondary treatment, the prognosis is poor compared to initial responders, she said.
“It’s a little bit of a wild, wild West when you get to secondary therapy,” Lee said. “If we can encourage patients to try and participate in trials so we can learn more … that will be helpful for everybody.”
In general, muting the symptoms of GVH disease is more important than attempting to eliminate or prevent it completely. The immune effect of the transplanted cells also acts against the malignancy being treated, so, as Lee said, “some GVH disease is not necessarily a bad thing. First on [a patient’s] list of outcomes is to get rid of the cancer. If we could control the symptoms of GVH disease, patients might actually accept some chronic GVH disease in order to have a lower risk of recurrent malignancies.”
Relapse after transplant
Those recurrent malignancies represent the other major area of late critical complications following HCT. According to Navneet Majhail, MD, an assistant professor of medicine at the University of Minnesota, Minneapolis, “relapse is the most frequent cause of treatment failure following transplantation, both autologous and allogeneic. And once somebody relapses posttransplant, their prognosis is extremely poor.”
Two studies found that relapse accounted for 46% and 56% of all mortality among patients receiving an allogeneic and autologous transplant, respectively, who survived at least two years.
The risk factors for relapse after HCT depend largely on the underlying diagnosis. According to a review article by Majhail, for example, acute myeloid leukemia and acute lymphoblastic leukemia carry higher risks of relapse than chronic myeloid leukemia. Disease-specific factors also play a role; patients with Philadelphia chromosome-positive ALL or AML have higher rates of relapse.
“I cannot emphasize enough the importance of preventing a relapse to begin with,” Majhail said, noting that getting a patient who may eventually need HCT to a transplant center early in the disease course is among the most important prevention techniques. “We might say that the patient doesn’t need an immediate transplant, but it is always best to get an opinion up front so that you know what the options are.”
The treatment options for relapsing patients also vary based on underlying diagnosis as well as performance status, disease bulk and time since HCT. Some research has indicated that imatinib (Gleevec, Novartis) can be effective in patients with relapsed CML, and, in general, disease-specific chemotherapy should be considered. Donor lymphocyte infusion from the original donor can be used as a way of targeting the malignancy. Donor lymphocyte infusion, however, is not an option among patients with active GVH disease.
More recently, researchers have begun examining the use of a second transplant for treatment of relapse. Majhail said the timing of relapse is the most important issue when considering this course; if the relapse occurs within six months after transplant, he said, “outcomes following a second transplant are going to be very poor.” According to a study of second transplant for patients with relapsed acute and chronic leukemia, the five-year survival rate is 28%.
New malignancies after HCT
In general, the risk of a relapse of the original malignancy goes down as more time passes after transplant, but the risk of developing secondary cancers increases. “If the patient survives the first two years, their likelihood of long-term survival is 70% to 80%,” Bhatia said.
It is beyond those two years, though, that the incidence of new malignancies tends to rise. Bhatia said that a study conducted at City of Hope and University of Minnesota found the incidence rate of severe or life-threatening health conditions 10 years after transplantation to be 40%.
New cancers fall into three main categories: secondary hematologic malignancies, solid cancers and posttransplant lymphoproliferative disorder. This latter disorder, usually associated with Epstein-Barr virus infection, occurs almost exclusively in allogeneic transplant recipients with an overall incidence of between 1% and 2%.
Myelodysplastic syndrome and secondary AML, however, occur only among autologous transplant recipients at a rate of 5% to 15%. Majhail said that, compared with patients with non-therapy–associated MDS or AML, “these patients have much more aggressive disease and the long-term survival is less than 20%.” The first step in treatment is induction chemotherapy, and allogeneic transplant can be an option in qualified patients.
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One study of almost 20,000 HCT recipients found that secondary solid cancers have an incidence of 0.7%, 2.2% and 6.7% at five, 10 and 15 years, respectively, posttransplant. Ronald Sacher, MD, professor of internal medicine and pathology at the University of Cincinnati Academic Health Center in Ohio, said the long-term immunosuppressant drugs that HCT patients take can allow the other malignancies to form.
“If the immune system is impaired, some of the cells that have a cancer message that should be destroyed establish growth and grow out of control,” said Sacher, a member of the HemOnc Today Editorial Board.
Majhail said that the latency of the tumors does not necessarily suggest they are unrelated to the transplant. “It just takes time for some of these underlying changes to occur, for a cancer to actually manifest,” he said.
Cardiovascular, pulmonary problems
Survivors of HCT also face the risk of cardiovascular, pulmonary, renal and other complications. Some are a result of chronic GHV disease or immunosuppression, and others are due to the initial diagnoses or chemotherapy and radiation used in treatment.
One recent study published in The Journal of Clinical Oncology found that congestive heart failure occurs in more than 2% of HCT recipients, but it is most likely related to initial therapy.
“We have looked at it very carefully and came to the conclusion that even though these patients are developing congestive heart failure after transplantation, it is because of the anthracyclines that they received before undergoing the transplant that resulted in the congestive heart failure,” said Bhatia, who was involved in the study. She said that there is a clear positive dose relationship between anthracyclines and the risk of congestive heart failure.
Coronary artery disease is also a concern, but research has shown it to be related primarily to the radiation therapy given to lymphoma patients prior to HCT. Pericarditis after HCT has also been reported, but its incidence is believed to be extremely low.
Some pulmonary complications arise as a result of GVH disease. Bronchiolitis obliterans, a severe obstructive respiratory disease, has been reported in more than 8% of allogeneic HCT recipients. “It is very closely related to chronic GVH disease,” Bhatia said. “Any preventive measures have to work at reducing the incidence of chronic GVH disease in this population.”
Finally, interstitial pneumonitis can occur years after HCT and is usually associated with severe chronic GVH disease. Among autologous transplant recipients, pulmonary issues occur mainly due to pulmonary toxicity with initial chemotherapeutic agents.
Little is known about the risk of renal complications following HCT. One retrospective study of 266 patients found a cumulative incidence rate of chronic kidney disease of 27% at 10 years posttransplant. This was more than twice that of a matched general population. Some of the risk factors for chronic kidney disease in these patients include older age at transplant, female sex, hypertension and low pretransplant glomerular filtration rate.
Lifelong follow-up required
Clearly, patients undergoing HCT face a wide range of potential complications, and managing expectations is an important part of treatment. “When you think about all the risks that a patient is assuming — getting through the transplant and not having early complications and then not having the late complications and not having the cancer come back — the only person who would do that would be someone who doesn’t have a better option,” Lee said. “I think that’s part of the counseling of patients … to prepare them for what is probably not going to be perfect health after the transplant.”
If physicians keep the potential late problems in mind, some of the risks can be minimized. Bhatia stressed that care of HCT recipients does not end when the transplant is complete. “These patients need specialized, long-term follow-up, almost life-long follow-up,” she said. “You can’t ever discharge these patients from care.” – by Dave Levitan
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