ARE FINGERS TOO LONG ON TRIGGERS?
A case of oxaliplatin induced immun-mediated thrombocytopenia
Introduction
Oxaliplatin is a third-generation platinum anti-neoplastic agent, which is used in the treatment of colorectal, gastric, and biliary tract cancers with combination other chemotherapy drugs. The most common side effects for this agent is peripheral neuropathy, myelosuppression, nausea, and vomiting. Thrombocytopenia may be seen in more than 70% of patients receiving with oxaliplatin combining chemotherapy regimen. This side effect of oxaliplatin is usually moderate, self-limited and related to myelosuppression (1). Only 3%-4% of patients experience a grade 3-4 thrombocytopenia with the life-threatening bleeding (1,9,10).
In rare cases grade 4 thrombocytopenia can occur suddenly in approximately 24 hours due to immune mediated reactions (2).This rare life-threatening side affect occur by Type II hypersensitivity reactions. This reaction is usually seen after long term usage of oxaliplatin-based chemotherapy. Here we present our case of immune-mediated thrombocytopenia associated with oxaliplatin.
CASE
A 56 year old man diagnosed stage IV rectum cancer which had liver metastasis. He had a palliative surgery because of bowel obstruction after initial diagnostic approach. The pathological specimen of the patient evaluated as K-Ras wild type. The patient was given neo-adjuvant FOLFIRI plus Bevacizumab chemotherapy regimen for the conversion of the border-line resectable liver metastases. After the 6 cycles of chemotherapy (3 months),partial response was seen radiologically. The patient was undergone surgery for the metastasectomy of the liver metastases, but R0 resection can not be achieved. With this reason FOLFIRI plus Bevazicumab regimen continued for 6 cycles more. Progression was detected radiologically after the total 12 cycles of FOLFIRI+Bevazicumab treatment. So that, second-line mFOLFOX6 plus Cetuximab regimen was started. After 12 cycles (6 months) second line treatment, partial response achieved with reduction in marker levels, tumor shrinkage in radiological studies and improvement in clinical performance status. As the maintenance therapy oxaliplatin and cetuximab regimen was continued for 8 cycles. As the 21th cycle of oxaliplatin plus cetuximab regimen in which patient had normal thrombocyte and neutrophile count in the morning; 8 hours after the chemotherapy patient had been taken to the emergency service with petechia, vigorous gastrointestinal and nasal bleeding.(Picture-1,2) No allergic reaction was seen in the physical examination like urticaria, angioedema, wheezing or rush. The thrombocyte levels was 3000 at µl. The patient was hospitalized for gastrointestinal bleeding and received thrombocyte transfusions and methylprednisolone . After two days hospitalization thrombocyte levels stabilized and gastrointestinal bleeding stopped.(Figure-1) No anti-thrombocyte antibodies performed because of unavailability of the test. The fast reduction in thrombocyte count in 12 hours time was considered for oxaliplatin associated immune-mediated thrombocytopenia. After this reaction, oxaliplatin stopped and the chemotherapy was changed to capesitabine plus cetuximab regimen. The thrombocyte levels was normal with this chemotherapy regimen. No adverse reaction was seen.
Picture-1: Petechial hemorrhagic lesions on physical examination
Picture-2: Mucosal bleeding dependent to thrombocytopenia at Emergency service
Figure-1: The course of Thrombocyte counts of the patient on the days of chemotherapy and hospitalization
DISCUSSION
All grades of thrombocytopenia is reported as an adverse reaction up to 70% of patients who have oxaliplatin combining chemotherapy regimen (1,9,10). This side effect have seen about 30% in oxaliplatin monotherapy.
Myelosuppression is the main cause of thrombocytopenia related to oxaliplatin, which represents generally moderate and asymptomatic thrombocytopenia. In some patients, hepatic sinusoid damage by oxaliplatin leads to portal hypertension and results the splenic sequestration of platelets. Immune-mediated mechanism is the third reason of thrombocytopenia which is quite rarely occurs during oxaliplatin infusion or soon after that (11). This rare side affect occur by Type II hypersensitivity reactions when antibodies (IgG and/or IgM) recognize surface antigens on host cells and mediate cell lysis via complement and phagocytic cells. Especially, glycoprotein IIb/IIIa glycoproteins is targeted by the production of oxaliplatin-dependent specific antibodies.
This type of reaction usually presents with signs and symptoms of hemolytic anemia, thrombocytopenia and/or leukopenia was described previously in patients receiving oxaliplatin-based chemotherapy after a prolonged exposure (2-8). The findings from the clinical evaluation will usually be sufficient for the diagnosis of oxaliplatin induced thrombocytopenia without the need to test for specific antibodies. The treatment must be started rapidly to avoid complications , because fatal cases have been reported in published studies.
In April-June 2016, a review article published by Erdem et. al showed clinical features of 42 cases immune mediated thrombocytopenia due to oxaliplatin use. One of patients was their institution original case report and 41 case reports of the rest had been detected in Pubmed screening. According to this review, most of the patients were female( 54.7%), the age of patients was differ from 38 to 83 years and the emerge of the reaction changes from sudden onset to 24 hours. The infusion numbers of oxaliplatin which the reaction occurred was differed second to thirtieth cycle (average 15 cycle). The steroids, transfusion, IVIG, G-CSF, hydration and fresh frozen plasma was used most of the patients. Three patients had been died due to complications of thrombocytopenia while all other cases recover with the supportive treatment (12). Twenty six patient were diagnosed isolated acute immune thrombocytopenia (AIT) and the others were Evan’s Syndrome (ES,9 patients), Hemolytic Uremic Syndrome (HUS,3 patients), and Thrombotic Thrombocytopenic Purpura (TTP,3 patients).
Recently, in september 2016, published a systematic review(13) the largest series (61 patients) reported to date. In this review, oxaliplatin immune-ınduced syndrome was divided four subgroups; drug mediated thrombotic microanjiopaties (TMAs; HUS, TTP, and dissemine intravascular coagulation), Evan’s Syndrome (ES), ısolated immune hemolytic anemia (IHA), and isolated acute immune thrombocytopenia (AIT). In 7 of cases (11.5%) were diagnosed ES, in 13 of cases (21.3%) TMA, in 13 of cases (21.3%) IHA, and in 28 of cases (45.9%) AIT. No information had been reported about diagnosis of only 1 case. Of the 61 patients, 56 (91.8%) had received oxaliplatin based chemotherapy for metastatic colorectal cancer. The median age of patients was 60 years and most of the patients were female( 57.9%). Anti-thrombocyte antibodies was positive in 87.7% (49 patient) of the patients. The average number of oxaliplatin cycles were 16.7. When oxaliplatin was administered as a rechallenge treatment, the chemotherapy cycles number until the onset immune induced syndrome was threefold lower than first time exposure to oxaliplatin. Three of patients has been died for thrombocytopenia .
In our case, after the prolonged exposure to oxaliplatin (21 cycles), the sudden onset of thrombocytopenia with very low levels of thrombocytes fits to the immune-mediated destruction of thrombocytes. Also the quick recovery of thrombocyte levels with steroid treatment supported the immune-mediated reaction.
In conclusion, oxaliplatin induced immune-mediated thrombocytopenia is a rare side effect but life threatening complication. Also the allergic reactions like of fever, rash and bronchospasm can accompany the immune-mediated thrombocytopenia. A physician who uses oxaliplatin as a treatment option should keep in mind the possibility immune-mediated thrombocytopenia which may cause life-threatening bleeding. Especially the long term use of oxaliplatin (median >10 cycles) may alert the physician for immune-mediated adverse effects.