Central Nervous System Specific Characteristics and Outcomes in Acute Myeloid Leukemia Patients with Neurologic Involvement

Introduction:

Rates of leukemic central nervous system (CNS) involvement in acute myeloid leukemia (AML) are lower than in acute lymphoblastic leukemia, with estimates ranging from about 1.1% - 32%, based largely on differences in lumbar puncture (LP) screening protocols. Although risk factors for CNS AML and the prognostic implications are widely documented, the CNS specific characteristics and outcomes with intrathecal (IT) therapy have not been previously reported.

Methods:

We retrospectively identified patients at The Mount Sinai Hospital with CNS AML, defined as having leukemic blasts in the cerebral spinal fluid (CSF), as identified by flow cytometry or cytology, or as having atypical immature myeloid cells in the CSF with either concerning imaging findings or neurologic symptoms. Patients with neurologic symptoms with imaging findings suggestive of CNS disease, but no CSF diagnosis, were excluded.

Patient, disease, and treatment-related variables were summarized by the median and range; categorical variables were summarized by n (%). The Kaplan-Meier method was used to estimate the median times to event for outcomes including CSF blast clearance and overall survival (OS).

Results:

A total of 25 patients were identified with CNS AML, with a median age of 57 years and 52% male. Seventy-six percent of patients had de novo AML, 20% AML secondary to myeloproliferative neoplasm or myelodysplastic syndrome, and 4% (n=1) had acute promyelocytic leukemia. Baseline characteristics previously associated with CNS AML were frequently observed, including monocytic differentiation (28%), elevated LDH (84%), and WBC >100K (36%). The most common karyotype abnormality was trisomy 8 (32%) with 46% having a normal karyotype and 24% having a complex karyotype. The most common mutations were FLT3 (56%), TET2 (32%), NPM1 (32%), and SRSF2 (20%) (Table 1).

Of the 25 patients, 56% had CD34+ blasts and 44% had atypical myeloid cells in the CSF accompanied by either imaging findings or neurologic symptoms; 40% of all patients had imaging findings concerning for leukemic infiltration. Fifty-six percent of patients were diagnosed with CNS disease before or during induction, whereas 44% were diagnosed at time of relapse. Neurologic symptoms were reported in 76% of patients, with headache being the most common (36%), followed by vision changes (24%), radicular pain (16%), and hearing loss/tinnitus (12%). Other neurologic symptoms recorded include vertigo, seizure, hemorrhage and altered mental status.

Systemic AML therapy received during or immediately after CNS diagnosis was 7+3 (56%), 7+3+midostaurin (16%), hypomethylating agent (HMA) + venetoclax (12%), HMA monotherapy (12%), and all-trans retinoic acid + idarubicin (4%). Eighty-four percent of patients received at least one dose of IT methotrexate, 52% at least one dose of IT cytarabine, and 40% at least one dose of both. The median number of IT doses received was 4 with a range of 0-31. Twelve percent of patients received 1 dose, 38% received between 2-5 doses, 25% received 6-10 doses, 12% 11-15 doses, 12% 15+ doses, and 4% received no intrathecal therapy.

Of the 23 patients that had repeat LPs, 96% achieved CSF clearance with a median number of IT doses before clearance of 1 (range 0-9) and a median time to CSF clearance of 3.79 weeks (95% CI 2.14 to 5.29) (Figure 1). Of those patients who had CSF clearance, 16% of patients (n=4) had CSF relapse with concurrent bone marrow relapse. All 4 of these patients were FLT3+. Of the 18 patients with baseline neurologic symptoms at time of CNS diagnosis, 56% had improvement in original symptoms, 33% had no improvement, and 11% had no clear documentation of clinical symptoms post-IT therapy. The median overall survival after CNS diagnosis was 6.53 months (4.1-Not Reached) for patients diagnosed before/during induction and 3.55 months (2.75-Not Reached) for patients diagnosed at relapse.

Discussion:

In the present study, IT therapy was shown to be rapidly effective in clearing blasts and atypical myeloid cells from the CSF. Furthermore, neurologic symptoms improved in a majority of patients that received IT therapy. Lastly, a minority of patients had CSF relapse which were all accompanied by BM relapse. Prospective clinical trials and multi-center retrospective cohort studies with greater sample size are needed to further fill the gaps in treatment and outcomes for AML patients with CNS disease.

Bar-Natan:Incyte: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Amgen: Research Funding. Silverman:Celgene/BMS: Research Funding; Takeda: Research Funding; Gilead/Forty-Seven: Research Funding. Kremyanskaya:BMS: Research Funding; Kura: Research Funding; Incyte: Consultancy, Research Funding; Kronos: Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Research Funding; Chimerix: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Ionis: Research Funding. Mascarenhas:Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Consultancy, Research Funding; Prelude Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos: Consultancy, Research Funding; Sierra Oncology: Consultancy; Forbius: Research Funding; CTI BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy; Galecto: Consultancy; Merck: Research Funding; Merus: Research Funding; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy; AbbVie: Consultancy, Research Funding; Janseen: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Imago: Consultancy; Roche: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.