CML was first diagnosed in January 2005 with a blast crisis. The patient was subsequently treated with imatinib. In November 2005, therapy was changed to cytosine arabinoside and mitoxantrone followed by hydroyurea due to a second blast crisis. Since February 2006, the second generation tyrosine-kinase inhibitor (TKI) dasatinib induced a hematological remission (chronic phase) until a one antigen mismatched (C-allele locus) unrelated allogeneic hematopoietic stem cell transplantation (SCT) was performed in May 2006. After SCT, she developed a series of epileptic seizures owing to posterior reversible encephalopathy syndrome (PRES) and developed severe critical illness polyneuropathy. At this time point, the analysis of the CSF was normal (1 cell/μl, total protein 355 mg/l) pointing neither to inflammation nor to a relapse. After initial severe tetraplegia, she reconstituted during intensive rehabilitation therapy and could use her arms independently, but did not regain her ability to walk. Up to November 2007, the patient received immunosuppressive therapy with ciclosporine and low dose prednisolone was administered until May 2008 because of a mild hepatic graft-versus-host disease. Cognition remained unimpaired. In all follow-up hematological visits after transplant, CML was regarded to be in remission (major cytogenetic and major molecular).
In November 2008, a progressive cognitive decline within a period of 6 months was noticed which led to a neurological consultation. The patient was mutistic and apathetic showing psychomotorical impairment and pathologically inadequate laughter. Moreover, orientation regarding time and place was impaired, but spastic tetraplegia was unchanged. MRI revealed a hydrocephalus with signs of high brain pressure (Figure 1 A-C). A lumbar puncture showed an elevated total cell count (389 cells /μl) and total protein (1154 mg/l) with an increased pressure of 26.5 cm H2O. Thus, 30 ml of CSF was drained leading to a significant cognitive improvement.
CSF microbiology excluded an infectious cause of the pleocytosis. In the differential count of CSF, about 50% immature blasts were counted and 65% myeloid precursor cells (CD7/CD33 double positive) were detected by FACS-analysis. However, the peripheral blood differential count was normal and did not point to a systemic hematological relapse of CML. The BCR-ABL/ ABL ratio (real time PCR) in CSF was 61.44% (and 0.0025% in the bone marrow).
The malresorptive hydrocephalus was at first treated with shunt surgery since the hydrocephalus was thought to be the major pathophysiologic factor causing cognitive decline in the patient. Following surgery, the CSF cell count fell to 66 cells/μl. However, after initial cognitive improvement, the patient showed a secondary deterioration. At this time point, leukemic infiltration in the lateral ventricles walls was detected by cranial MRI (Figure 1 D-F). Total cell and total protein counts were 1024 cells/μl and 2923 mg/l, respectively, and 66% of the cells were CD7/CD33 double positive by FACS-analysis. In the CSF, differential count megakaryocytes, immature eosinophils and blast cells were noted. (Figure 1 G). The BCR-ABL/ABL ratio (real time PCR) in the bone marrow had increased from 0.0025% in the previous analysis to 0.07%.
Triple intrathecal therapy consisting of cytarabine (40 mg), methotrexate (10 mg), and dexamethasone (4 mg) was initiated, as described in the literature for cases of CNS relapse [2–4]. Intrathecal chemotherapy was administered twice and caused a significant decrease of total cell count and protein in the CSF (11 cells/μl, 1254 mg/l protein). Myeloid precursor cells were reduced to 19% by FACS-analysis. During follow-up examinations, cognition of the patient was much improved and she showed good participation in daily activities.
Therapy with dasatinib was begun after initial intrathecal chemotherapy, due to its ability to cross the blood–brain barrier [5] and because the major molecular response was lost in the consecutive bone marrow aspiration in February 2009 (BCR-ABL/ ABL ratio (real time PCR): 0.24%). Since then, the patient has remained neurologically stable with subjective improvement of her impaired daily activities. No hematological relapse occurred during further patient follow up and continuous dasatinib therapy. However, the patient was diagnosed with advanced vulva carcinoma in May 2011 and died in December of the same year.
