Brentuximab-related apoptotic colopathy

The introduction of new treatments in haematological malignances, from targeted monoclonal antibodies to immune checkpoint inhibitors, has led to an increase in adverse effects (AEs)1Mallepally N. Abu-Sbeih H. Ahmed O. et al.Clinical features of rituximab-associated gastrointestinal toxicities.Am J Clin Oncol. 2019; 42: 539-545Crossref PubMed Scopus (7) Google Scholar,2Gonzalez R.S. Salaria S.N. Bohannon C.D. et al.PD-1 inhibitor gastroenterocolitis: case series and appraisal of immunomodulatory gastroenterocolitis.Histopathology. 2017; 70: 558-567Crossref PubMed Scopus (132) Google Scholar where gastrointestinal toxicities are some of the most commonly reported. Little is known about the pathological characteristics during AEs with brentuximab, an anti-CD30 targeted antibody-drug coniugate.3Scott L.J. Brentuximab vedotin: a review in CD30-positive Hodgkin lymphoma.Drugs. 2017; 77: 435-445Crossref PubMed Scopus (66) Google Scholar Brentuximab has been approved by the United States Food and Drug Administration and the European Medicines Agency (EMA) for relapsed classical Hodgkin lymphoma (CHL) and relapsed systemic anaplastic large cell lymphoma.4Berger G.K. McBride A. Lawson S. et al.Brentuximab vedotin for treatment of non-Hodgkin lymphomas: a systematic review.Crit Rev Oncol Hematol. 2017; 109: 42-50Crossref PubMed Scopus (52) Google Scholar The most frequent AEs of brentuximab are peripheral sensory neuropathy and neutropenia3Scott L.J. Brentuximab vedotin: a review in CD30-positive Hodgkin lymphoma.Drugs. 2017; 77: 435-445Crossref PubMed Scopus (66) Google Scholar while gastrointestinal complications range from enterocolitis, with possible erosions/ulcerations and haemorrhage, to bowel obstruction and perforation due to neutropenic colitis. A 49-year-old woman was found to have enlarged latero-cervical lymph nodes and worsening pruritus associated with marked weight loss. After nodal biopsy, a diagnosis of clinical stage IIIsB (diffuse supra-diaphragmatic lymphoadenopathy and splenomegaly) classic Hodgkin’s lymphoma, mixed cellularity variant, was made. First line treatment was six cycles of ABVD protocol (adriamycin, bleomycin, vinblastine and dacarbazine), however an end of protocol positron emission tomography (PET) scan showed refractory disease with a biopsy positive mediastinic mass. Second line treatment consisted of BeGev protocol (bendamustine, gemcitabine and vinorelbine) followed by high-dose therapy with autologous stem-cell transplantation (ASCT) and complete remission of disease. Early consolidation therapy with brentuximab vedotin 1.8 mg/kg every 3 weeks was programmed; however, after 8 days from the first dose, the patient reported severe diarrhoea (scale 3 according to the Common Terminology Criteria for Adverse Events V.4)5National Institutes of Health; National Cancer InstituteCommon Terminology Criteria for adverse Events (CTCAE) V.4.https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/Archive/CTCAE_4.0_2009-05-29_QuickReference_8.5x11.pdfGoogle Scholar and abdominal pain. An infectious aetiology was excluded by serology and stool testing. Furthermore, C-reactive protein was normal and all liver and renal function tests were within normal range. Due to non-resolving symptoms, the patient underwent colonoscopy which showed diffuse, mild erythema without evident ulcerations. Biopsies were taken from the right and left colon showing preserved crypt architecture associated with slight expansion of the lamina propria by a mixed inflammatory infiltrate composed of lymphocytes, eosinophils and scattered plasma cells. Focal neutrophilic cryptitis was present, associated with withering of crypts and reactive epithelial changes. Numerous apoptoses in the crypt basal portions, sometimes more than one per crypt, were the predominant lesion observed in all large bowel biopsies (Fig. 1A–C). Immunohistochemistry for cytomegalovirus (CMV) was negative and immunostaining for CD3 showed a normal quota of intraepithelial T-lymphocytes (<20/100 epithelial cells). A diagnosis of apoptotic colopathy with focal active colitis and mild eosinophilic infiltrate was formulated, possibly drug related. Treatment with brentuximab was suspended with complete resolution of symptoms occurring within a few days. Apoptotic colopathy is an umbrella term describing a pattern of injury featuring crypt epithelial apoptoses (i.e., degenerating dust or cellular debris, or apoptotic bodies, in the crypt epithelium)6Karamchandani D.M. Chetty R. Apoptotic colopathy: a pragmatic approach to diagnosis.J Clin Pathol. 2018; 71: 1033-1040Crossref PubMed Scopus (13) Google Scholar and numerous different classes of anti-neoplastic drugs (e.g., mycophenolate, anti-PD-1/PD-L1 antibodies and CTLA-4 inhibitors) are correlated with this pattern. Brentuximab vedotin is an antibody drug conjugate composed of the CD30-specific chimeric immunoglobulin G1 monoclonal antibody ligated to monomethyl auristatin E (MMAE), an anti-microtubule agent. CD30-brentuximab vedotin ligation on the cell surface, leads to cytosolic internalisation where lysosome-based enzymes cleave the peptide and release free MMAE which binds tubulin, thereby causing arrest of the G2/M phase of the cell cycle. This induces cell apoptosis of the CD30-expressing tumour cells.3Scott L.J. Brentuximab vedotin: a review in CD30-positive Hodgkin lymphoma.Drugs. 2017; 77: 435-445Crossref PubMed Scopus (66) Google Scholar It is interesting to note that numerous apoptotic figures were seen in the colonic epithelium in this case. An important differential diagnosis in the setting of apoptotic colopathy is graft versus host disease (GVHD) as apoptoses are its histological hallmark. GVHD has been reported to complicate haematopoietic stem cell transplant (HSCT) in about 30–70% of allogenic bone marrow transplant recipients.7Washington K. Jagasia M. Pathology of graft-versus-host disease in the gastrointestinal tract.Hum Pathol. 2009; 40: 909-917Crossref PubMed Scopus (151) Google Scholar,8Salomao M. Dorritie K. Mapara M.Y. et al.Histopathology of graft-vs-host disease of gastrointestinal tract and liver: an update.Am J Clin Pathol. 2016; 145: 591-603Crossref PubMed Google Scholar A GVHD-like syndrome, which is clinically and histologically indistinguishable from allogeneic GVHD, has also been described in autologous stem cell transplantation (ASCT) and involves the gastrointestinal tract in about 4–13% of cases.9Holmberg L. Kikuchi K. Gooley T.A. et al.Gastrointestinal graft-versus-host disease in recipients of autologous hematopoietic stem cells: incidence, risk factors, and outcome.Biol Blood Marrow Transplant. 2006; 12: 226-234Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Symptomatic onset of ASCT related GVHD-like gastrointestinal syndrome occurs within a mean time of 15 days from transplant and usually responds to steroids. In the present case, a GVHD apoptotic colopathy was excluded due to the late onset of symptoms (onset at 3 months after ASCT) and response to brentuximab suspension without steroid use. In conclusion, apoptotic colopathy is a morphological pattern of response of the colonic mucosa to various types of treatments. The present case describes a rare cause of apoptotic colopathy in an ASCT patient who developed gastrointestinal symptoms after the first dose of brentuximab, with complete resolution of diarrhoea following its withdrawal. To the best of our knowledge, this is the first histological description of brentuximab related colitis. The authors state that there are no conflicts of interest to disclose and no funding sources.