Lindsey, Heather H.
Post-transplant lymphoproliferative disease (PTLD) can be a serious and potentially deadly complication of hematopoietic stem cell or solid organ transplantation, making a better understanding of the condition and its treatment essential to patient care.
The highly atypical ...Image Tools
“For a rare cancer, this disease has made amazing strides in the past decade, with better understanding of the disease process, new treatments, and better outcomes,” said Donald E. Tsai, MD, PhD, Associate Professor of Medicine in the Division of Hematology/Oncology at the Hospital of the University of Pennsylvania and coauthor (with Courtney D. DiNardo, MD) of a recent review article on the topic in Current Opinion in Hematology (2010;17:368-374).
Understanding PTLD Risk
Post-transplant lymphoproliferative disease is a malignancy caused by an over-immunosuppressed immune system, with most cases related to the Epstein-Barr virus (EBV).
Because transplant patients experience prolonged immunosuppression to prevent graft rejection, they are vulnerable to EBV-driven, uncontrolled B-cell expansion, Dr. Tsai explained. “Moreover, the EBV serostatus of both the donor and recipient are important factors in determining a patient's risk for developing PTLD.”
JOHN SWEETENHAM, MD ...Image Tools
A comprehensive understanding of PTLD risk factors is essential to managing the condition, said John Sweetenham, MD, Professor of Medicine in the Department of Hematologic Oncology and Blood Disorder and Vice-Chair for Clinical Research at the Cleveland Clinic Taussig Cancer Institute. Higher levels of immunosuppression and younger age are two such factors.
The type of organ transplant is also a factor—specifically, according to the assessment of the literature by Drs. Tai and DiNardo, heart-lung and intestinal transplants are associated with a high risk of PTLD development; renal transplants with the lowest; and lung, heart, liver, and pancreas transplants fall in between.
Joachim Deeg, MD, a member of the Clinical Research Division of Fred Hutchinson Cancer Research Center and Professor of Medicine at the University of Washington School of Medicine, noted that hematopoietic stem cell transplant (HSCT) patients at high risk include those receiving severe immunosuppressive transplant regimens with in vivo T-cell depletion or who are given in vitro T-cell depleted donor grafts. Additionally, certain HLA-mismatched patients have a higher probability of EBV reactivation.
The challenge of treating PTLD is that it is not any one disease, said Thomas G. Gross, MD, PhD, Professor and Gordon Teter Chair for Pediatric Cancer Research at Ohio State University School of Medicine and Chief of the Division of Hematology/Oncology/BMT at Nationwide Children's Hospital.
The World Health Organization Classification categorizes the condition into four groups:
* Early lesions or reactive hyperplasia.
* Polymorphic PTLD or polyclonal disease.
* Monomorphic PTLD or monoclonal disease of B-cell or T-cell origin.
* Classic Hodgkin lymphoma-type PTLD.
Treatment approaches vary greatly due to the heterogeneous biology of the disease and patient population, especially when considering the differences between hematopoietic stem cell and solid organ transplant recipients, Dr. Gross said. Consequently, addressing standards of care is difficult.
However, the most common treatments for PTLD are generally a reduction in immunosuppression, and use of rituximab and chemotherapy, agreed the experts interviewed for this article.
Reduction in Immunosuppression
Most practitioners who are taking care of patients with PTLD will base treatment on whether the disease is monomorphic or polymorphic, Dr. Sweetenham noted. If the disease is polymorphic, many physicians will consider reducing immunosuppression.
“Reduction in immunosuppression is an easy initial approach to take in PTLD patients and is a treatment strategy often used in large academic centers,” Dr. Tsai said. However, it may be overlooked elsewhere in the medical community. Doctors may assume PTLD patients have regular lymphomas and give them chemotherapy treatments right away, often without reducing immunosuppression first or in some cases not at all.
This treatment is not without risk, though, Dr. Gross cautioned. “Life-threatening rejection of the transplanted organ or graft-versus-host disease can occur.”
Response to reduction in immunosuppression may depend on several risk factors. For example, a retrospective analysis that Dr. Tsai and colleagues conducted of 42 PTLD patients who underwent this treatment approach and had excision of local disease, found that elevated lactate dehydrogenase, organ dysfunction at diagnosis, and multiorgan PTLD predicted poor response (Transplantation 2001;71:1076-1088).
Additionally, patients with no risk factors had an 89% chance of treatment response, while those with one risk factor had a 60% chance, and those with two or three risk factors had no chance of response.
The monoclonal antibody rituximab is often used to treat PTLD if patients do not respond to reduced immunosuppression, but the two approaches may also be used together, Dr. Deeg said.
Dr. Tsai explained that rituximab reduces abnormal B-cell proliferation and uses an immune system attack, avoiding the toxicity of conventional chemotherapy.
While rituximab may have fewer side effects than chemotherapy, patients treated with rituximab still have relapse rates of 15% to 25%, Dr. Gross noted.
Overall, recipients of rituximab for PTLD experience complete response rates of 35% to 70%, according to Dr. Tsai's assessment of the literature of mostly solid-organ transplant patients. Additionally, he said, subset analyses indicate that this treatment is also an effective option in HSCT recipients.
Rituximab may also be given to such patients to help prevent PTLD. “Physicians try, of course, to prevent the development of PTLD and do so quite effectively by monitoring patients very closely for EBV reactivation,” Dr. Deeg said, noting that high-risk patients should be checked at least once or twice a week.
If there is a significant titer rise—for example, more than 1,000 copies/ml—the approach at Fred Hutchinson is to use rituximab in a preventive manner, he said.
Screening patients with polymerase chain reaction for EBV and intervening with rituximab preemptively before full-blown disease develops has been an important advancement in reducing mortality in bone marrow transplant patients, Dr. Gross said.
If PTLD is behaving like an aggressive lymphoma or is monomorphic, the patient will probably need chemotherapy, which will also likely induce immunosuppression, Dr. Sweetenham said.
“Typically patients don't tolerate chemotherapy very well and are more at risk of complications such as infection. It's usually possible to take patients off their regular immunosuppression during chemotherapy, as long as this is done in close collaboration with the transplant physician.”
Chemotherapy is often the treatment of last resort for PTLD, said Dr. Deeg. “The major reason being that in the setting of hematopoietic stem cell transplantation, the donor-derived marrow may have limited reserve early after transplantation and may be more sensitive to chemotherapy. So there's a fear of wiping out the transplanted marrow.” This concern is relevant because most PTLD occurs within the first six to nine months after HSCT, he said.
However, in the setting of solid organ transplantation, chemotherapy has been used with some success, and a patient's own marrow is in place and appears to tolerate more aggressive treatment.
According to the Tsai and DiNardo review paper, chemotherapy regimens, generally those used for non-Hodgkin's lymphoma, are associated with response rates of 33% to 75% in refractory PTLD patients who had received a solid organ transplant. However, morbidity from this treatment can result in a 33% to 50% chance of treatment-related mortality, he said.
Dr. Gross said that reducing immunosuppression while receiving chemotherapy or adjusting chemotherapy doses may help to decrease morbidity. A lower-dose regimen is well tolerated and appears to be effective in most children who do not respond to first-line therapy.
He and his colleagues conducted a study in 36 pediatric patients with PTLD who underwent solid organ transplant and were refractory to first-line treatments (JCO 2005;23:6481-6488). The low-dose regimen of chemotherapy resulted in an overall response rate of 83%, although the relapse rate was 19%, but with no treatment-related mortality.
Adding rituximab to chemotherapy is another common approach to treating PTLD because the monoclonal antibody has no life-threatening side effects, Dr. Tsai said.
Treatments Under Evaluation
Two novel approaches are available for PTLD—arginine butyrate with antiviral treatment; and EBV-specific cytotoxic T-cell therapy.
Using antivirals with arginine butyrate is certainly of interest, noted Dr. Deeg. When PTLD was first described, researchers found that polyclonal disease sometimes responded to antiviral therapy. “One could inhibit viral replication and propagation at the polyclonal stage, but once the disease became monoclonal, there was very little that could be achieved.”
Dr. Tsai said that because the majority of cases of PTLD are linked to EBV, targeting the condition with antiviral drugs may seem like a reasonable approach, but it turns out antiviral antibiotics alone don't work for PTLD.
Patients with PTLD have EBV that is in a latent or sleeping phase, rather than in an active or lytic phase, he continued. Antivirals are effective only in the lytic phase of infection when the viral enzyme thymidine kinase is present. However, arginine can induce EBV thymidine kinase transcription, making latent EBV infection susceptive to the antiviral drugs. A Phase 2 study of this approach has just started at the University of Pennsylvania, he noted.
Dr. Sweetenham said that while interesting, the benefits of newer antiviral approaches with arginine butyrate remain unclear.
Cytotoxic T-cell therapy is another potential treatment for PTLD patients, he added. Cytotoxic T lymphocytes can recognize latent and active viral EBV antigens and prevent reactivation.
After allogeneic HSCT, patients with PTLD can acquire T-cells from their original donor to provide a global immune system boost, which cures about two out of three people, but this global T-cell treatment raises the risk of GVHD, Dr. Tsai said. To avoid this risk, EBV-specific cytotoxic T-cells can be grown and selected in a lab, making the T cells specific for EBV only.
EBV-specific cytotoxic T-cell therapy has been around for more than a decade and has been demonstrated to be effective in bone marrow transplant recipients, said Dr. Gross. However, in solid organ transplant recipients, this therapy does not appear to have a lasting benefit, since transferred EBV-specific T-cells do not survive in the patient.
“This may be due to lack of immunologic space for antitumor cells or due to the chronic immunosuppression required in these patients, he said.
JOACHIM DEEG, MD, ex...Image Tools
Additionally, Dr. Tsai noted, solid organ transplants donors are often not alive anymore and cannot provide cytotoxic T-cells to patients. A third party's stem cells may not be perfectly HLA-matched, which can also be problematic.
While in theory, EBV-specific cytotoxic T-cell therapy may be a safe, curative treatment for HSCT recipients, in practice it has logistical challenges. “It takes about two months to grow cells in a lab, and a lot of patients need them today,” he said.
Additionally, local community hospitals may not have the facilities to grow cells—”they would need a dedicated T-cell research facility, which is cost prohibitive for all but the largest academic medical centers.”
Central Bank of HLA Types of EBV-specific Cytotoxic T-Cells
To circumvent the logistic and cost issues related to EBV-specific cytotoxic T cell therapy, researchers in Scotland have established a central bank of the 100 most common HLA types of EBV-specific cytotoxic T-cells. A similar bank in the United States would require a larger inventory of T cells given the diversity in HLA types relative to that seen in Scotland, noted Dr. Tsai. Additionally, the cost of setting up a bank and running it 24 hours a day for the only 100 to 200 PTLD patients a year who need this treatment may be prohibitive.
Still, Dr. Tsai concluded, “there is a lot of hope in the five- to 10-year horizon that further novel treatments such as arginine butyrate, which is now in Phase II trials, or EBV-specific cytotoxic T cells will advance the field even more.”
© 2010 Lippincott Williams & Wilkins, Inc.