Intracerebellar Granulocytic Sarcoma Presenting as a First Manifestation of Relapse in Chronic Myelogenous Leukemia (CML) During Imatinib Mesylate Therapy: A Case Report and Literature Review.
Authors: Pimentel Agustin , Forman Daniel A , Swierczynski Sharon L , Donato Anthony A , Le Brian 
Published: October 2019

Abstract
Abstract 4289

Introduction
Granulocytic sarcoma (GS) is an unusual solid tumor of extramedullary localization consisting of immature granulocytic precursors. It is mostly encountered in the course of acute myelogenous leukemia (AML), myelodysplastic or myeloproliferative disorders, with an estimated incidence of 7.9% in CML (Terjanian et al). GS can occur before, concomitantly, or after the overt development of these hematologic disorders. Most common localizations are lymph nodes, bones, skin and soft tissues, but there is paucity of published data of isolated intracranial GS manifesting as relapse in CML.

Case report
A 34-year-old male with Philadelphia chromosome-positive (Ph+) CML diagnosed in August 2005 in the chronic phase of the disease. After initiation of imatinib therapy at doses of 400 mg/d he achieved complete hematologic, cytogenetic and molecular responses. He remained in clinical remission for 3 years when he presented with bifrontal headache and dizziness. Physical exam revealed no abnormalities. Peripheral blood count showed WBC 9,200/mm3 with normal differential and no immature forms, platelet 180,000/mm3, and hemoglobin 14.4 g/dl. Magnetic resonance imaging of the brain revealed a 3.8 cm enhancing mass lesion within the left cerebellar hemisphere. He underwent posterior fossa exploration with resection of the solid tumor. Microscopic examination of the cerebellar mass demonstrated a diffuse cellular infiltrate of atypical mononuclear cells with high nuclear to cytoplasmic ratios and fine, immature chromatin, consistent with blasts. Flow cytometric analysis confirmed that the majority of the cells in the specimen were composed of blasts which coexpressed the CD33 and CD4 markers. Fluorescence in situ hybridization analysis on the cerebellar tissue detected the presence of BCR/ABL rearrangement in 60% of nuclei. Taken together, the morphologic, immunophenotypic, and molecular features are diagnostic of a myeloid sarcoma representing transformation of chronic myeloid leukemia.

Discussion
A literature search was performed to identify all cases of intracranial GS in patients with diagnosis of CML reported in medical literature. Only 3 cases were identified in the literature to date. This case appears to be the first described in the imatinib mesylate era. Table 1 summarizes the clinical data of these previously recorded cases and the present case.
Pharmacokinetic analyses (Pfeifer et al, Leis at al, Wolff et al) have demonstrated that imatinib poorly penetrates the blood–brain barrier, with resultant CNS drug levels significantly lower than corresponding plasma levels. Measured CSF levels were below the concentration required for 50% inhibition of the BCR–ABL tyrosine kinase activity, suggesting that Ph+ leukemic patients treated with this selective tyrosine kinase inhibitor are at high risk of CNS relapse even in the setting of complete remission of systemic disease.
This case illustrates an unusual site of recurrence of CML. To our knowledge, this is the first case of a granulocytic sarcoma presenting as a solitary parenchymal brain tumor in a patient receiving imatinib for CML. Noticeably, CNS relapse occurred despite lack of systemic evidence of disease. As described in human and animal model studies this may be the result of effective systemic antileukemic activity of imatinib therapy, but with limited activity in the CNS. Poor penetration of imatinib into the cerebrospinal fluid may allow the CNS to become a sanctuary reservoir for relapse of Ph+ CML.

Disclosures:
No relevant conflicts of interest to declare.