Treatment dilemma for survivors of rituximab-induced bowel perforation in the setting of post-transplant lymphoproliferative disorder

Abstract

Post-transplant lymphoproliferative disorder (PTLD) is a recognised complication of solid and haematopoietic stem cell transplant. It consists of a heterogeneous group of lymphoid neoplasms that arises secondary to post-transplant immunosuppression. Although there is no definite standard of care for the optimal treatment for PTLD, rituximab, a monoclonal antibody, with and/or without chemotherapy (usually CHOP=cytoxan, doxorubicin, vincristine, prednisone) has become a routine part of the treatment of any CD20 (+) PTLD, with response rates similar to chemotherapy with decreased toxicity. A rare and often lethal, complication of rituximab therapy for PTLD is bowel perforation secondary to tumour lysis of lymphoma involving the intestine. A small number of cases of bowel perforation have been reported, with very few documented survivors. The risk for recurrent perforation in the setting of ongoing rituximab treatment is unknown. There is sparse data supporting how to best treat the survivors.

Background

Post-transplant lymphoproliferative disorder (PTLD) is a lymphoma that develops due to pharmacological immunosuppression after a solid organ or haematopoietic stem cell transplant. The reported incidence of PTLD is variable, and is most strongly associated with the organ transplanted and level of immunosuppression.^{1 2} The incidence of PTLD in renal transplant is roughly 1%–2%. The cumulative incidence inclusive of all organ transplants is 1% at 18 months and almost 5% at 15 years.³ PTLD is the second most common malignancy after a solid organ transplant, following non-melanoma skin cancers, and about 70% of cases are associated with Epstein-Barr virus (EBV).^{4 5} Due to multiple subtypes and low prevalence, data regarding optimum disease management is sparse.

The treatment goal of PTLD is to eliminate the disease while preserving the transplanted graft. The first-line treatment is immune suppression reduction, for which only about half of the patient population will exhibit a response. Recent data supports early use of rituximab, a chimeric anti-CD20 IgG monoclonal antibody, either as a monotherapy or in combination with chemotherapy, radiation, or surgery.^{2 4 6} Chemotherapy is reserved for more aggressive forms of PTLD due to its high morbidity and mortality, with treatment-related mortality reported to be 25%–50%. The addition of rituximab in the treatment regimen has improved overall survival from 30%–50% to greater than 60%.²

Though generally well-tolerated, rituximab has been demonstrated to cause tumour lysis syndrome and bowel perforation.² In 2006, rituximab had been linked to 37 cases of gastrointestinal perforations based on about 730 000 patient exposures with the majority of the cases occurring in patients with lymphoma. In most of these cases, patients had multiple risk factors for perforation, such as chemotherapy or secondary to the disease itself, so it could not be concluded that the rituximab was the causative agent.^{3 7} There are limited documented cases of bowel perforation after rituximab therapy for PTLD and often outcomes and future management are often not discussed.^{3 8 9}

The treatment of patients with PTLD who respond to rituximab but who have incurred rituximab-induced complications, is a clinical dilemma. Tumour lysis causing perforation can be viewed as evidence for rituximab effectiveness. Options after a rituximab-induced complication include withholding further treatment and allowing the PTLD to progress, combination chemotherapy, or resumption of rituximab alone. Chemotherapy has higher morbidity in the setting of perforation and generally cannot be started immediately after surgery. Resuming rituximab may be a less toxic and more effective option with the caveat that one cannot predict the risk of recurrent perforation.

Case presentation

A 52-year-old woman with an extensive and complicated medical history including lupus, lupus nephritis status post three kidney transplants (1984, 1991, 2007), squamous cell anal cancer treated with chemoradiation (2005) and recurrent squamous cell carcinoma of skin treated topically presented with vague complaints of abdominal discomfort over a 2-month period. The patient had positive EBV titers and her immunosuppression regimen for her renal transplant consisted of tacrolimus and azathioprine.

A CT scan of the abdomen and pelvis revealed enlarged, hypermetabolic left supraceliac lymph nodes, multiple hypermetabolic lesions within the transplanted kidney, the liver (>15 lesions) and hypermetabolic lymph nodes throughout the abdomen suspicious for malignancy. Ultrasound-guided biopsy of the renal lesion revealed a CD20 (+) monomorphic PTLD consistent with a diffuse large B cell lymphoma. Azathioprine was stopped. A bone marrow biopsy and aspiration was negative for lymphoma. Given the overall frail condition of the patient, chemotherapy was not initiated and she was started on weekly rituximab 375 mg/m². The first dose was uneventful with no complications. However, 24 hours after the second dose of rituximab she developed acute-onset, severe abdominal pain and she was referred to the emergency department.

On examination, she had diffuse abdominal tenderness with guarding and rebound, consistent with peritonitis. A CT of the abdomen and pelvis demonstrated thickened and inflamed loops of ileum with diffuse intraperitoneal air. The patient was taken emergently to the operating room for an exploratory laparotomy.

Treatment

In the operating room tumour implants were found on the small bowel and bladder with a small bowel perforation at the site of one of the tumour implants. A small bowel resection with primary anastomosis was performed. The pathology revealed monomorphic B cell PTLD (large B cell lymphoma) focally involving the small bowel wall with perforation.

Outcome and follow-up

The patient made an uneventful recovery. Immunosuppression was continued with tacrolimus and the patient was maintained on broad-spectrum antibiotics. A positron emission tomography (PET)/CT scan done 1 month after discharge and after only two weekly doses of rituximab at 375 mg/m², demonstrated a complete resolution of the previously seen hypermetabolic hepatic and small bowel lesions with decreased metabolic activity in the renal transplant (figure 1). With the absence of fluorodeoxyglucose (FDG) uptake in the abdomen, rituximab was resumed 7 weeks after the surgery. A third PET scan done after six additional doses of weekly rituximab showed no FDG-avid lesions including in the transplanted kidney. She remains in complete remission as of this writing at 1 year from her initial diagnosis.

Figure 1.

Positron emission tomography/CT scan pre-rituximab and post-rituximab treatment. The top images are pre-treatment. The bottom images are after only two doses of rituximab.

Discussion

The initial approach to treating PTLD is to reduce immunosuppression while maintaining the viability of the allograft. However, this may be impracticable in patients such as ours, with a history of organ rejection, or when the graft is crucial for survival. As of 2005, conventional cytotoxic chemotherapy which is known to be curative for many non-PTLD lymphomas has been shown to have treatment-related deaths in about 25% of patients. The recommended approach for monomorphic CD20 (+) PTLD is presently rituximab with chemotherapy (usually CHOP) concurrently or sequentially. However, for candidates with asymptomatic disease or those not fit to receive chemotherapy, single agent rituximab has been the preferred approach.² Despite the fact that our patient’s lymphoma was initially rapidly growing, rituximab as a single agent was used given her comorbidities.

Subsequent studies demonstrate mixed results regarding improved prognosis with rituximab.⁵ Because of the low incidence and complexity of the disease, data is sparse. Evens et al found significantly improved progression-free survival and overall survival in patients with PTLD treated with rituximab-based therapy in a multi-centre retrospective analysis in 2010. Since then, rituximab-based therapy has become a primary treatment for many patients.¹⁰

There have been several case reports of rituximab-induced bowel perforation in PTLD in patients with gastrointestinal involvement as these patients are at risk of gastrointestinal perforation from tumour lysis.³ In a majority of the case reports, patients with rituximab-induced bowel perforation either expired or no discussion regarding subsequent treatment is offered. A PubMed query of ‘rituximab-induced bowel perforation’ revealed seven cases reports of patients of different ages after various organ transplants. In these case reports, two patients expired,^{3 11}three survived,^{8 12 13} and for two patients outcomes were not specified.^{9 14} For those who survive, the conundrum arises whether to continue a treatment that may effectively eradicate PTLD but with perhaps prohibitively high morbidity and mortality. This risk for recurrent perforation is unknown.

As the cohort of patients with transplanted organs increases and the incidence of PTLD increases, the management of patients who survive rituximab-induced bowel perforation needs to be clarified. Rituximab-based therapy is frequently used as a first-line agent and thus further investigation to identify which patients are at highest risk for perforation and how to manage patients surviving rituximab-induced perforation is needed.

Learning points.

• Rituximab-induced bowel perforation in post-transplant lymphoproliferative disorder (PTLD) is a rare entity with a high mortality rate.

• Treatment for survivors presents a novel clinical quandary; bowel perforation could be considered proof of disease response but patients and providers risk recurrent perforation with continued therapy.

• As PTLD becomes more common studies should focus on determining patients at highest risk for bowel perforation, how to reduce risk, and the recurrent risk of perforation if treatment is to be continued.