Sequential administration of anti-VEGF therapy after craniospinal irradiation and intrathecal chemotherapy for the treatment of central nervous system AML relapse after allo-HSCT: a case report and literature review

There have been few reports on the treatment of central nervous system (CNS) acute myeloid leukemia (AML) relapse. This case study demonstrates that bevacizumab may be a viable treatment option when combined with IT chemotherapy as maintenance therapy for those with CNS leukemia.

Intrathecal Chemotherapy As a Potential Alternative Treatment for Steroid-Refractory Immune Effector Cell-Associated Neurotoxicity Syndrome

Introduction Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm for patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and other hematologic malignancies. However, its use is associated with serious adverse effects including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Severe ICANS can present with aphasia, mutism, somnolence, seizures, signs of increased intracranial pressure and rarely cerebral edema. Corticosteroids (CS) and IL-6 inhibitors are first line treatment for CRS and ICANS. Prolonged CS use has been associated with decreased over-all survival in CAR T-cell treated patients. Data on effective treatments for CART T-cell induced neurotoxicity is limited, especially in steroid-refractory ICANS. Blood-brain barrier (BBB) disruption and infiltration of myeloid and immune effector cells into the central nervous system are implicated in the pathogenesis of ICANS. This likely explains the role of intrathecal chemotherapy, which has been described in literature for treatment of steroid-refractory ICANS. Here, we report the outcomes of two patients with refractory DLBCL who developed severe ICANS after receiving axicabtagene ciloleucel (axi cel) and treated with intrathecal (IT) chemotherapy. Case Presentation Our first case is of a 66 year old male with diagnosis of R/R DLBCL, who was treated with R-CHOP, followed by R-GemOx, with no response then received axi cel. Patient developed grade 2 CRS and grade 1 ICANS (National Cancer Institute Common Terminology Criteria for Adverse Effects v4.03) on day +2 post infusion, treated with tocilizumab and dexamethasone with good response initially. While tapering dexamethasone on day +5, he developed grade 3 CRS and grade 3 ICANS. Brain MRI did not show any intracranial abnormality and EEG showed no seizure activity. Lumbar puncture (LP) was done on day +7 and showed opening pressure of 32 cm H2O, and 12 lymphocytes. He was started on IV solumedrol and tocilizumab was resumed. CRS improved while neurotoxicity progressed to grade 4 prompting intubation and mechanical ventilation on day +8. On day +9, patient received intrathecal methotrexate 12 mg and hydrocortisone 50 mg. On day +12, neurotoxicity improved to grade 1 and patient was extubated on day +13. Steroid taper stopped on +17. Despite disease response, patient remained hospitalized at day +45 for deconditioning and vocal cord paralysis related to a lengthy hospital stay and intubation. He was eventually discharged, however passed away on day +49 from complications of prolonged hospitalization. Our second case is of a 69 year old female with a diagnosis of R/R DLBCL with CNS involvement, treated with RCHOP x6 followed by salvage chemotherapy with refractory disease, She then received axi cel. Patient developed grade 1 CRS on day +4, treated with tocilizumab and dexamethasone, and patient responded well. On day +9, she developed grade 2 CRS and grade 3 ICANS. At that time, dexamethasone was switched to pulse dose solumedrol and tocilizumab was continued. CT head showed no acute intracranial abnormality and EEG did not show any epileptiform activity. LP showed opening pressure of 21, and 84 lymphocytes. On day +11, patient's CRS resolved, however ICANS developed to grade 4 and patient received 12 mg intrathecal methotrexate and hydrocortisone 50 mg for steroid-refractory ICANS. The very next day, patient showed significant neurological improvement. Steroid taper was initiated and patient's ICANS resolved on day +16. MRI brain showed decrease in size of nodular enhancement along periventricular white matter and left occipital area corresponding to treatment response. She was discharged on day +28 and continues to do well one year out of axi cel infusion Conclusion Our abstract adds to the sparse literature about the use IT chemotherapy in cases with severe ICANS. It also highlights its importance as an alternative potential therapy to high doses and prolonged courses of corticosteroids which is associated with increased morbidity and mortality. Steroid-refractory ICANS has limited treatment options and further evaluation of the use of IT chemotherapy in large scale studies is warranted. Disclosures Kahn: Abbvie: Research Funding, Speakers Bureau; Astrazeneca: Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Epizyme: Research Funding, Speakers Bureau; Genetech: Research Funding, Speakers Bureau; GSK: Speakers Bureau; Karyopharm: Speakers Bureau; Kite: Speakers Bureau; Morphosys: Speakers Bureau; Sanofi: Speakers Bureau; SeaGen: Speakers Bureau. Fazal: Agios: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Janssen Oncology: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau; Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Lister: Oncology Analytics: Other: Academic Board.

Incidence and Characteristics of Central Nervous System Involvement in Adult Acute Myeloid Leukemia Patients

Features of central nervous system (CNS) involvement in acute myeloid leukemia (AML) are not well-defined. Unlike acute lymphoblastic leukemia, there are limited guidelines for the use of intrathecal chemotherapy with induction for AML, and institutional practices vary. Unfortunately, AML patients with CNS involvement often have worse outcomes compared to those without CNS involvement (Del Principe et al., 2018; Rozovski et al., 2015). It is important to better understand the incidence and predictive clinical and features of CNS involvement in AML to identify patients for diagnostic testing and intrathecal chemotherapy. This retrospective analysis evaluated the incidence and characteristics of CNS involvement in adult AML patients at our institution. CNS screening is recommended for AML patients with specific characteristics, including CNS symptoms, monocytic phenotype, FLT3-internal tandem duplication gene mutation, and hyperleukocytosis (>100,000 white blood cells per microliter). Treatment recommendations for CNS involvement include intrathecal methotrexate, intrathecal cytarabine, or a combination of both. In this IRB-approved retrospective study, medical records were analyzed from the University of Kansas Medical Center from years 2015-2020. Patients were selected by searching the electronic medical record for adult AML patients who received a diagnostic lumbar puncture. Characteristics of interest included presence of CNS symptoms, monocytic phenotype, FLT3 mutation, and hyperleukocytosis. Characteristics that prompted CNS screening were recorded for each patient. Additional data collection included next-generation sequencing (NGS), cytogenetic results, and whether CNS screening occurred during an initial diagnosis or during an AML relapse. Lastly, the number of intrathecal chemotherapy doses was recorded for each patient. The incidence of CNS involvement was determined by dividing the number of newly diagnosed AML CNS-positive patients by the total number of newly diagnosed AML patients. Screening detection rates were determined by dividing the number of CNS-positive patients with each characteristic by the total number that received a lumbar puncture. The percentage of CNS-positive patients with each characteristic was determined by dividing the number with each specific characteristic by the total number of CNS-positive patients. The number of intrathecal chemotherapy doses required for CNS clearance was determined using data only from patients that achieved CNS clearance. Forty-eight patients met current guidelines for CNS screening; 25 were CNS-positive and 23 were CNS-negative (overall screening detection rate of 52%). The incidence of CNS involvement among all newly diagnosed adult AML patients was 3.24%. Screening detection rates were 58% for patients with 3 characteristics, 60% for 2 characteristics, 45% for CNS symptoms, and 30% for monocytic phenotype. Not enough patients presented with the FLT3 mutation or hyperleukocytosis in isolation to calculate accurate detection rates. The CNS-positive group consisted of 28% with 3 characteristics, 24% with 2 characteristics, 20% with CNS symptoms, 12% with monocytic phenotype, 4% with FLT3 mutation, 4% with hyperleukocytosis, and 36% were screened during a relapse rather than at initial diagnosis. Two patients were CNS-positive without any of our characteristics of interest (screened due to extramedullary involvement at presentation and the other was screened as part of pre-transplant evaluation). Seventeen patients achieved CNS clearance with 41% requiring 1 dose of intrathecal chemotherapy, 35% requiring 2 doses, and 24% requiring more than 2 doses. NGS and cytogenetic results did not reveal any additional associations. This data indicates that current AML CNS screening guidelines appear to properly identify a patient population at risk for CNS involvement. At our institution, 52% of screened patients were CNS-positive. This analysis also revealed a diverse distribution of characteristics among AML patients with CNS involvement, and patients commonly presented with multiple risk factors. These results emphasize the need for ongoing research to further delineate CNS involvement risk factors in AML. This data will be used for current policy analysis at our institution and potentially prospective studies to better evaluate outcomes for AML patients with CNS involvement. Figure 1 Figure 1. Disclosures Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding.

Can We Lower the Platelet Threshold of ≥50x10 9/L for Performing a Lumbar Puncture Safely in Patients with Hematological Malignancies?

Introduction: Lumbar punctures (LP) are routinely used to administer intrathecal chemotherapy for children and adults with hematologic malignancies. The platelet threshold at which an LP can be safely performed is a heavily debated topic. A platelet count of ≥50x10 9/L is a widely accepted threshold for other image-guided procedures [1]. In this patient population achieving this platelet count can be challenging. Previous studies failed to report any increase in the incidence of post-procedure adverse events in patients with a platelet count below this threshold who undergo LPs [2,3,4]. However, these prior studies were limited in their sample size for the number of LPs done in patients with platelets <50 x 10 9/L. Objective: Our study aims to identify differences in adverse events related to the administration of intrathecal chemotherapy in patients with platelet counts <50 x10 9/Lcompared to those over the transfusion threshold of ≥50x10 9/L. Methods: A retrospective chart review of all patients who received intrathecal chemotherapy under fluoroscopy guidance between January 2020 and May 2021 at Moffitt Cancer Center was performed. Patient charts were reviewed to collect information on baseline characteristics, laboratory parameters, platelet transfusions, and post-procedure outcomes. Adverse events related to LPs or platelet transfusions were compared among patients above or below the platelet threshold of 50x10 9/L. Statistical analysis was performed using chi-square test. Results: A total of 900 LPs performed on 224 unique patients were included in the study. The median age at LP was 60 years (range 20-87). 107 (47.7%) patients were females and 117 (52.3%) were males. 169 (75.5%) patients were Caucasian, 22 (9.8%) African American, 3 (1.3%) Asian, 3 (1.3%) Hispanic, and 27 (12.1%) were unknown. The hematological malignancies for which intrathecal chemotherapy was administered included: acute lymphoblastic leukemia, diffuse large B cell lymphoma, other B-Cell Lymphomas, acute myeloid leukemia, T-cell lymphomas, blast-phase chronic myeloid leukemia, mixed phenotype acute leukemia, and chronic lymphocytic leukemia (Table 1, Figure 1). The 900 LPs were divided into two cohorts based on the pre-procedure platelet count: Cohort 1 included 682 LPs (75.8%) with a pre-procedure platelet count ≥50x10 9/L, and cohort 2 included 218 LPs (24.2%) with a pre-procedure platelet count <50x10 9/L. The average laboratory parameters for the cohorts are presented in Table 2. The average platelet counts for cohort 1 and cohort 2 were 199 (range 50-838) and 32 (range 15-49), respectively. Patients with a pre-procedure platelet count of <50x10 9/L were transfused at a significantly higher rate prior to the procedure (55% vs 4.5%, p<0.0001). Only one patient experienced an adverse reaction from platelet transfusion in the form of allergic reaction with facial swelling, treated and resolved with diphenhydramine. A total of 59 post-procedure adverse events were reported but were not significantly different between the two groups (6.5% vs 6.8%, p=0.8237). No instances of epidural hematomas were reported. The most common complications included headaches (n=42), back pain or soreness (n=11) and nausea or vomiting (n=6). Only two patients experienced bleeding complications, including subarachnoid hemorrhage and subdural hemorrhage, but neither of these was directly linked to the procedure. However, the rate of traumatic taps was significantly higher in the group with platelets <50x10 9/L with observed LP RBC count ≥200 (31.2% vs 20.5%, p=0.0016), ≥500 (27.1% vs 14.6%, p<0.0001), and ≥1000 (23% vs 11.6%, p<0.0001). Conclusion: Among 900 LP procedures, a pre-procedure platelet count <50x10 9/L did not demonstrate a higher rate of hemorrhagic complications (6.5% vs 6.8%, p=0.8237) but did demonstrate a higher rate of traumatic taps. No instances of epidural hematomas were seen. However, the number of pre-procedure platelet transfusions required was higher in the group with lower platelets. In light of this, consideration should be given to lowering the platelet threshold for performing LPs. While prospective studies are necessary to confirm that a lower platelet threshold is safe, a lower platelet threshold would result in decreased burden on blood banks by reducing platelet transfusions and could potentially aid in decreasing platelet alloimmunization and subsequent sequelae. Figure 1 Figure 1. Disclosures Jaglal: Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees.

INNV-01. THE CASE OF LEPTOMENINGEAL CARCINOMATOSIS RELATED HYDROCEPHALUS MANAGED WITH SYSTEMIC AND INTRATHECAL CHEMOTHERAPY

INTRODUCTION Leptomeningeal carcinomatosis (LC) is an end-stage sequela of metastatic cancer that commonly leads to severe neurological symptoms due to hydrocephalus and commonly treated with surgery or radiation. As these procedures are invasive and have associated risks, chemotherapy could be a great alternative. We report a case of a hydrocephalus related to LC in a patient with Stage IV breast cancer that resolved after the administration of HD-MTX and intrathecal cytarabine. CASE A 64-year-old right-handed woman with Stage IV ER positive, PR positive, HER2 negative invasive lobular carcinoma of the left breast on chemotherapy with palbociclib and alpelisib who presented with mild occipital headaches, diplopia and imbalance. Imaging revealed an extensive abnormal leptomeningeal enhancement withing the posterior fossa compatible with leptomeningeal carcinomatosis. CSF cytology was consistent with metastatic adenocarcinoma. Liquid biopsy detected circulating tumor cells. During the admission for the cycle 1 of systemic chemotherapy with HD-MTX and intrathecal cytarabine, neurological status deteriorated as she became stuporous due to the newly developed moderate obstructive and communicating hydrocephalus. Surgical innervation was considered but given her response to serial Ommaya taps and dexamethasone, we proceeded with observation. Symptomatic improvement was noted within few days and confirmed on imaging showing the resolution of previously seen hydrocephalus. DISCUSSION This case highlights the role of non-invasive combination of systemic and intrathecal chemotherapy in patients with LC-related hydrocephalus aimed to preserve patient’s quality of life. No relevant disclosures.

DDRE-05. LONG-TERM OUTCOME OF INTRATHECAL CHEMOTHERAPY WITH PEMETREXED IN LEPTOMENINGEAL METASTASIS FROM NON-SMALL CELL LUNG CANCER WITH EGFR-MUTATION: A CASE REPORT

Leptomeningeal metastasis (LM) is fatal complication of non-small cell lung cancer (NSCLC) ,which has a poor prognosis and lacks effective treatments. Pemetrexed, a multitargeted antifolate agent, has demonstrated antitumor activity, a few studies have shown intrathecal pemetrexed (IP) controllable toxicities and potential promising efficacy for LM from NSCLC patients. We report a patient who diagnosed with LM from NSCLC harboring epidermal growth factor receptor (EGFR) mutation in exons 21 via typical neurological symptoms, magnetic resonance imaging (MRI) and positive cerebrospinal fluid (CSF) cytology. The curative effect of tyrosine kinase inhibitor (TKI) targeted drugs was maintained for a short time, the first-generation TKI icotinib was 4 months, and the third-generation osimertinib was 4 months. Then the patient received IP, and osimertinib continued. 30 mg of pemetrexed were implemented on day 1 every weeks for 8 weeks via lumbar puncture, then 50 mg of pemetrexed on day 1 every 4 week for 8 times. This treatment regimen resulted in the alleviation of the neurological symptoms, the CSF level of carcinoembryonic antigen also decresed without obvious side effects. At the time of this manuscript’s submission, she had maintained stable disease (SD) for more than 11 months. To our knowledge, this study provides the first clinical evidence that longterm intrathecal chemotherapy with pemetrexed providing a therapeutic approach against LM from NSCLC.

INNV-17. RESPONSE TO AVAPRITINIB IN A PEDIATRIC SPINAL CORD H3K27M-MUTANT GLIOMA PATIENT

H3K27M-mutated diffuse midline glioma (H3K27M-DMG) may arise in the pons, thalamus and spinal cord generally having a dismal prognosis. Notably, H3K27M-DMG are driven by oligodendrocyte precursor-like cells which are partly sustained by PDGFRA signaling. Co-mutations including TP53, ACVR1, PDGFRA, KIT and PI3K pathway alterations are present in a subset of cases, and molecular profiling may allow detection of additional targetable alterations. However, small-molecule inhibitors often have limited efficacy associated with low blood-brain-barrier (BBB) penetration. Here, we report on a patient with spinal, leptomeningeal disseminated H3K27M-DMG treated with avapritinib, an orally administered, BBB-penetrant and highly selective KIT and PDGFR inhibitor, provided through a compassionate-use program. Initial therapy consisted of subtotal resection, focal radiotherapy and temozolomide (TMZ) resulting in disease stabilization. Ten months after diagnosis, leptomeningeal metastases were detected, biopsied and treated with local irradiation and TMZ. The patient subsequently received systemic and intrathecal chemotherapy augmented with dasatinib. Molecular analyses of the biopsy revealed the H3F3A and TP53 mutations present in the primary tumor, as well as de novo PDGFRA and KIT amplifications with gene copy numbers of 25 and 21, respectively. Upon further disease progression, therapy with avapritinib was initiated. Assessment of treatment response according to RANO criteria after four months revealed stable disease of the target lesion in the cerebellum and partial response of all non-target lesions. Avapritinib was generally well tolerated with lower limb edema (Grade 2), small intratumoral bleeding (Grade 1) and unrelated hydrocephalus (Grade 3) as reported adverse events. As precaution, treatment was interrupted and re-initiated after one week as the bleeding was stable. A ventriculoperitoneal shunt was implanted resolving the hydrocephalus. Pharmacokinetic analyses revealed up to 65% avapritinib plasma exposure and clinically relevant levels in cerebrospinal fluid. In summary, we report on first effective therapy of treatment-resistant H3K27M-DMG with avapritinib as clinical proof of concept.