Gastrointestinal Manifestations of CML: A Systematic Review
Authors: Ali Elrazi Awadelkarim , Mushtaq Kamran , Sardar Sundus , Abdelmahmuod Elabbass , Yassin Mohamed A 
Published: November 2021

Abstract
Introduction
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by overproduction of mature granulocytes. Up to half of the patients are asymptomatic and diagnosed during routine blood investigations; others present with fatigue and non-specific symptoms. Many patients develop gastrointestinal manifestations such as abdominal pain, bloody diarrhea, and pancreatitis during the disease course. Some presentations are related to leukemia itself, while others may be related to CML treatment.
Methods
We searched the English literature (PubMed, SCOPUS, and Google Scholar) for studies, reviews, case series, and case reports of patients with CML who developed any gastrointestinal manifestations involving the gastrointestinal tract from the esophagus down to the rectum Inclusion criteria comprised of patients above 18 years of age, with CML and gastrointestinal features. Pregnant women and bone marrow transplant recipients were excluded. Search terms included chronic myeloid leukemia, chronic myelogenous leukemia, with esophagitis, pancreatitis, duodenitis, gastritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, hepatocellular carcinoma, cholangiocarcinoma, colon cancer, malignancy, hepatitis, primary biliary cholangitis, primary biliary cirrhosis, primary sclerosing cholangitis, and perforation.
Results
A total of 129 patients were included. Patient characteristics are shown in table 1. Among the gastrointestinal manifestations, the most common treatment-related complications were drug-related hepatitis followed by reactivation of viral hepatitis B, pancreatitis, and typhlitis. Hepatitis in CML was reported with different TKIs but more commonly with imatinib. Reactivation of viral hepatitis B was common, while hepatitis C reactivation was rarely reported. Pancreatitis was associated mostly with nilotinib. Colitis is seen mainly with dasatinib. Inflammatory bowel diseases, liver diseases such as primary biliary cholangitis (PBC), were variable; some occurred after CML diagnosis while others preceded the diagnosis. Malignancies like pancreatic adenocarcinoma and hepatocellular carcinoma occurred after CML.
Discussion
Gastrointestinal features in patients with chronic myeloid leukemia can be the first presenting featuring of leukemia itself, arising during the course of CML or as a complication of the treatment. Interestingly, most of these presentations have been reported in patients with CML. These include inflammatory conditions such as pancreatitis and esophagitis, reactivation of viral hepatitis to the neoplastic process, and malignancy. In patients with CML, malignant tumors in the gastrointestinal tract can be caused by leukemic infiltration. Moreover, like other myeloproliferative neoplasms, CML confers a risk of developing a second non-hematological malignancy, including colonic neoplasms.
Gastrointestinal complications can pose drastic impacts throughout the disease course; they may result in a change in the treatment, affect the prognosis, and may also be fatal, as in severe enterocolitis or fulminant liver failure. The treatment goal in patients with CML has changed significantly over the last decades. The current treatment goal is to achieve normal survival and good quality of life without the need for lifelong treatment. The improvement in CML treatment and prognosis is largely attributed to the introduction of tyrosine kinase inhibitors. However, most gastrointestinal features associated with treatment are related to tyrosine kinase. The exact pathogenesis of TKI injury is unclear but likely attributed to immune-related mechanisms. Imatinib is the first-line therapy for CML and is the most widely used TKI; however, not all the gastrointestinal features are associated with imatinib as expected. Various gastrointestinal features are prominent with other TKIs as well. Appropriately identifying which TKI is the likely trigger will help in avoiding highly suspected gastrointestinal complications or guide in switching to a safer TKI, thereby achieving treatment goals.
Conclusion
Patients with chronic myeloid leukemia can have a different gastrointestinal presentation which can alter their disease course. Such complications must be managed appropriately in order to improve outcome and quality of life in this group of patients and maintain treatment goals.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.