An Unwanted Companion to Transplant Medicine: Post-transplant Lymphoproliferative Disorder

Post-transplant lymphoproliferative disorder (PTLD) is a cruel companion to both solid organ transplantation and hematopoietic stem cell transplant in both pediatric and adult patients. With the steadily increasing numbers of transplants occurring in pediatric patients in the United States each year, the incidence of PTLD is also increasing. The risk for PTLD in solid organ transplant is anywhere from 2 to 15 percent, with percentages varying based on the organ or organs and other factors.

Because of its expertise and success with transplant medicine as a whole, UPMC Children’s Hospital of Pittsburgh has high annual volumes of pediatric transplants and so sees and treats transplant patients with PTLD more so than many other centers.

“Small bowel transplants have the highest incidence of PTLD, likely because of the relatively higher immunogenic nature of the organ when compared to the liver, for example. UPMC Children’s transplant program for small bowel is one of the largest in the United States. Therefore, we treat PTLD patients frequently and have a number of protocols and trials in progress that guide our care while we work to find new, better therapies to combat the condition,” says Erika Friehling, MD, assistant professor of pediatrics and fellowship program director in the Division of Pediatric Hematology/Oncology.

Dr. Friehling joined the Division of Pediatric Hematology/Oncology as a faculty member in 2013 after completing her fellowship training at UPMC Children’s under the supervision of A. Kim Ritchey, MD.

A 2015 recipient of the American Society of Pediatric Hematology/Oncology Clinician Educator Award, Dr. Friehling devotes a great deal of her time to educating residents and fellows, and she has a special interest in PTLD from both a research and clinical care perspective, having authored several recent papers on the subject.

PTLD Risk Factors

While PTLD can occur with any solid organ transplant, and while small bowel incidence is higher than other organs, a full 90 percent of all cases are of the Epstein-Barr virus (EBV) positive, CD20-positive variety. “Most cases of PTLD are EBV-driven,” says Dr. Friehling. Under normal circumstances, EBV infection would likely be of no consequence. However, in transplant patients who are on immuno-suppressive regimens to prevent organ rejection, the immunosuppression itself is a risk factor.

Another potential risk factor appears to be age. A younger patient’s native immune system is relatively more naïve than that of older patients, and this might predispose younger transplant patients to acquire PTLD. The evidence is not firm yet on this aspect of PTLD, but researchers are actively pursuing a better understanding of this potential pathway to disease.

The Clinical Conundrum of Immuno-suppression and Treating PTLD

Cases of PTLD can be curable, but it becomes a delicate balance in treating these patients because of the need for immunosuppression to preserve transplant organ function. “The importance of a collaborative approach to disease management is highlighted by cases of PTLD. Moreover, it matters which organs are involved for optimal management. If PTLD arises in a liver transplant patient, we can typically decrease immune suppression for a time to combat the PTLD without the likelihood of immediate organ rejection. However, heart transplant patients are entirely different. Stopping immune suppression can lead to organ rejection and potentially life-threatening complications. The approach to care is incredibly nuanced. We have cases that require almost daily modification of the care plan, balancing the needs for immuno-suppression and treatments for lymphoma simultaneously. It is a challenging and complex set of circumstances,” says Dr. Friehling.

Clinical Trials in Progress

UPMC Children’s is one of approximately 25 centers in the United States participating in a clinical trial that is investigating the use of rituximab in combination with cytotoxic T-lymphocyte grafts of latent membrane protein (LMP)-specific T cells to combat PTLD in pediatric solid organ transplant patients.

The trial, which is currently recruiting patients, is sponsored by the Children’s Oncology Group and the National Cancer Institute. Patients must have EBV-positive, CD-20 positive cases of PTLD to qualify for enrollment.

“Once enrolled in the trial, patients will first receive a three-week regimen of rituximab immunotherapy. At the end of the first three weeks, if the PTLD has improved, they will continue receiving rituximab. However, if at the end of the first three weeks the PTLD has not improved, they are eligible to receive the LMP-specific T cell infusions,” says Dr. Friehling.

For complete study details and protocols, please visit ClinicalTrials.gov and search under trial number NCT02900976.

Further Reading

More of Dr. Friehling’s research into PTLD can be found in the following published papers.

Epperly R, Ozolek J, Soltys K, Cohen D, Rakesh G, Friehling E. Treatment of Pediatric Plasma Cell Myeloma Type Post-transplant Lymphoproliferative Disorder With Modern Risk-Directed Therapy. Pediatr Blood Cancer. 2018 Oct; 65(10): e27283.

Stanley K, Friehling E, Ranganathan S, Mazariegos G, McAllister-Lucas LM, Sindhi R. Post-transplant Lymphoproliferative Disorder in Pediatric Intestinal Transplant Recipients: A Literature Review. Pediatr Transplant. 2018. Aug; 22(5) e13211.