Out of the millions of people who suffer from end stage renal failure worldwide every year, only a third are eligible for kidney transplants. The ability to perform transplants between donors and recipients with different blood types has increased the possibility of performing live donor transplants, made possible by effective new drugs being used during the desensitization process. Modern methods of desensitization are based on the application of apheretic techniques combined with immunosuppressive drugs such as Rituximab, a chimeric anti-CD20 antibody, which has a key role in B lymphocyte depletion. Severe infusion related reactions due to the administration of Rituximab are reported in approximately 10% of patients (1). Such reactions restrict the use of the drug. Therefore, it is common practice to test alternative B cell depleting therapies. We reported on the first clinical case of a patient undergoing desensitization protocol for kidney disease transplantation AB0 incompatible with Ofatumumab, a fully humanized monoclonal anti-CD20 antibody, given as an alternative B-cell depleting treatment.
A 41-year-old male diagnosed with end stage kidney disease due to nephroangiosclerosis was presented to our transplant center for live kidney donation accompanied by his mother: a potential, healthy, willing AB0 incompatible kidney donor. The patient was on regular, peritoneal dialysis for the last 18 months and also had ischemic heart disease treated with dual stent placement approximately one year before. Immunological tests [complement-dependent cytotoxicity lymphocytotoxicity crossmatches (CDC-LT, CDC LB), luminex DSA, Match-HLA], were performed in the recipients. Table 1 gives demographic and immunological data of the donor and recipient. After finding the donor and recipient eligible for transplantation, we proceeded with the desensitization protocol by using the Stockholm model (Tydel et al. AJ of Transplantation 2005; 5:145-148) (2) and the Johns Hopkins Hospital model (Montgomery et al. N Engl J Med 2011;365:318-326) (3) as a guideline. This protocol states that all AB0 incompatible recipients must have received the anti-CD20 antibody (Rituximab) for four weeks before the transplant. Then, two weeks before the patients must have received plasmapheresis to reduce the anti-ABO antibody. Most recipients received plasmapheresis 4 to 5 times (range, 2–9 times) until the isoagglutinin anti-ABO antibody ratio was ≤1:8.
The qualifying patient was admitted to our department and administered Rituximab (375 mg/m2 i.v.) as part of the desensitization protocol but despite the antihistamine, anti-inflammatory, and steroid i.v. premedication given prior (Methylprednisolone 250 mg, Chlorphenamine 10 mg and Paracetamol 1 g), he displayed an adverse infusion reaction: high fever, tremors, malaise and dyspnea.
Due to the impossibility of continuing the treatment with Rituximab, we decided to complete the procedure using another anti-CD20 antibody (Ofatumumab), after a period of clinical oversight. One month after the Rituximab reaction, the patient started a new desensitization therapy which consisted of Ofatumumab (300 mg i.v. 35 days before the transplant and 2000 mg i.v. 28 days before the transplant), six sessions of apheresis and a low dose intravenous immunoglobulin (0,5 g/Kg).
The intravenous dose of Ofatumumab was administered following doses of antihistamine, anti-inflammatory, and steroid i.v. premedication (Methylprednisolone 250 mg, Chlorphenamine 10 mg and Paracetamol 1 g). The patient tolerated the administration without reaction and it was possible to complete the cycle of desensitization without any side effects. The plasmapheresis sessions were performed on alternate days, up to the achievement of a sufficiently low antibody blood titer (≤1:8). In our clinical case six apheresis sessions (5 plasma-exchange and 1 cascade filtration) were necessary in order to achieve sufficiently low isoagglutinins levels and proceed to transplantation. The graphics 1 and 2 shows the pharmacological and apheresis procedural results: a progressive decrease in isoagglutinins levels.
The triple immunosuppressive therapy was started on the first day of the plasmapheresis through oral administration of Tacrolimus (0,15 mg/Kg/day), Mycophenolic Mophetil (1000 mg x 2/day) and Prednisone (25 mg/day). On the day of the renal transplantation Basiliximab, an anti-CD25 antibody, was administered at a dose of 20 mg i.v., and then readministered on the fourth post-operative day as induction therapy.
After the desensitization protocol the patient underwent a renal transplant from an incompatible living donor with no surgical complications. The target trough level for tacrolimus was 10-15 ng/mL during the early postoperative period, but this decreased to 6-10 ng/mL after 3 months. Trimethoprim-sulfamethoxazole was used for prophylaxis for Pneumocystis jiroveci pneumonia for 6 months. No prophylaxis for CMV was performed because the patient was CMV-IgG positive.
The clinical course was characterized by a good functional recovery with creatinine values that reached 1.6 mg/dl after 1 month. Levels of IgG isoagglutinin anti-B were rechecked periodically after transplantation, and were at 1:2. Six weeks after transplantation, the patient developed a symptomatic reactivation of the cytomegalovirus for which he is undergoing antiviral therapy.
The percentage of severe infusion reactions following treatment with Rituximab is approximately 10%. Ultimately, this side effect restricts the use of the drug. Rituximab, a chimeric monoclonal antibody (murine and human), consisting of a glycosylated immunoglobulin with a constant region of human origin and a variable region sequence of murine origin (4). The study of anti CD20 alternative is important in order to find alternative treatment options. Currently, three fully humanized anti-CD20 antibodies are available: Ofatumumab, Obinutuzumab and Ocrelizumab (5). There is no experience in the use of these drugs in renal transplantation.
Ofatumumab is a human monoclonal antibody (IgG1) that binds specifically to an epitope encompassing both the small and large extracellular loops of the CD20 molecule. The binding of Ofatumumab to the membrane-proximal epitope of the CD20 molecule induces recruitment and activation of the complement pathway at the cell surface, leading to complement-dependent cytotoxicity and resultant lysis of cells (6, 7). It was also observed that Ofatumumab can induce lysis in cells Rituximab-resistant expressing CD20. As a fully humanized antibody, Ofatumumab may avoid immunogenic reactions (8).
Today Ofatumumab is approved and used in malignant hematological disorders with encouraging results especially in those patients resistant or intolerant to treatment with Rituximab (9–10–11–12–13). In immune-mediated pathologies, there are sporadic clinical cases in which Ofatumumab treatment was administered. These include studies on pediatric Rituximab resistant nephrotic syndrome (14), treatment of lupus nephritis (15) and vasculitis ANCA-associated (8). In all these trials the Ofatumumab had a good clinical efficacy and is tolerated well. This is the first use of Ofatumumab in kidney transplantation protocol and our case report suggests that is a valid alternative B cell depleting agent, especially in patients who are intolerant to Rituximab due to infusion related reactions. Further studies are needed to secure and define the role of Ofatumumab and other emerging anti-B cell therapies in kidney transplantation.
- Vogel WH, et al. Infusion reactions: Diagnosis, Assessment and Management. Clinical Journal of Oncology Nursing 2010, 10.1188/10.CJON.E10-E21
- Tyden G, et al. Implementation of a Protocol for ABO-Incompatible Kidney Transplantation – A Three-Center Experience With 60 Consecutive Transplantations. AJ of Trasplantation 2005; 5:145-148
- Montgomery RA, Lonze BE, King KE, et al. Desensitization in HLA-incompatible kidney recipients and survival. N Engl J Med 2011; 365:318-326
- Pescovitz MD. Rituximab an Anti-CD20 Monoclonal Antibody: History and Mechanism of Action Journal of Transplantation 2006; 6: 859–866
- Knepper TC, et al. Novel and expanded Oncology drug approvals of 2016-part 2: new options in the management of hematologic malignancies. Oncology, 2017, 15;31(2)
- Capuano C, Romanelli M, et al. Anti-CD20 therapy acts via Fc γRIIIA to diminish responsiveness of human natural killer cells. Cancer Reserch 2015, 75(19); 4097-108.
- Tomita A. Genetic and epigenetic modulation of CD20 expression in B-cell malignancies: molecular mechanisms and significance to rituximab resistance. J Clin Exp Hematop 2016, 56(2):89-99
- McAdoo SP, Bedi R, et al. Ofatumumab for B cell depletion therapy in ANCA-associated vasculitis: a single-centre series. Rheumatology 2016, 55:1437-1442
- Linden MA, Bachanova V, et al. Trasformed large B-cell lymphoma in rituximab-allergic patient with chronic lymphocytic leukemia after allogenic stem cell transplant: successful treatment with ofatumumab. Leuk Lymphoma 2013 January, 54(1): 174-176.
- Laurenti L, Innocenti I, et al. New developments in the management of chronic lymphocytic leukemia: role of ofatumumab. Onco Targets and Therapy 2016, 9 421-429
- Barth MJ, Mavis C, et al. Ofatumumab exhibits enhanced in vitro and in vivo activity compared to Rituximab in preclinical models of mantle cell lymphoma. Clinical Cancer Reserch 2015, 21(19) 4391-7
- Czuczman MS, Fayad L, et al. Ofatumumab monotherapy in rituximab refractory follicular lymphoma: results from a multicenter study. Blood 2012, 119(16):3698-3704
- Bologna L, Gotti E et al. Ofatumumab is more efficient than rituximab in lysing B chronic lymphocytic leukemia cells in whole blood and in combination with chemotherapy. The Journal of Immunology 2013, 190:231-239
- Biswanath Basu MD, et al. Ofatumumab for rituximab resistant nephrotic syndrome. The New England Journal of Medicine 2014, 370, 13.
- Loberg Haarhaus M, Svenungsson E, et al. Ofatumumab treatment in lupus nephritis patients. Clinical Kidney Journal 2016, vol.9, no. 4, 552-555