Clinical Outcome of Neoplastic Meningitis Associated with Breast Cancer

Background Neoplastic meningitis (NM) is considered as a terminal event with poor prognosis. Its impact in clinical oncology is growing. Objective To analyze the clinical outcome of patients with carcinoma breast diagnosed with NM. Materials and Methods This study was an observational study in breast cancer patients diagnosed with NM. Patients with typical clinical symptoms and signs with either presence of cerebrospinal fluid (CSF) cytology positive for neoplastic cells or typical radiological features of leptomeningeal involvement in the presence of neurological symptoms or signs were taken as leptomeningeal metastasis (LM) or NM. The estimation of survival was done by Kaplan–Meier method. Results Out of 1,200 patients diagnosed with carcinoma breast during the study period, 15 developed NM. The median age of study population was 51 (range: 44–55) years. Most common presentations were headache (47%), vomiting (47%), diplopia (20%), seizure (20%), and cerebellar signs (7%). Seven (46%) patients were hormone receptor positive, four (30%) were HER2 (Human epidermal growth factor receptor 2) positive and seven (46%) were triple-negative breast cancer. Median time to develop LM from the time of diagnosis of breast cancer was 6 (range: 3–8) months. Nine patients (90%) had features of NM in CSF cytology. Thirteen patients received palliative whole brain radiotherapy (20 Gy in five fractions). Nine out of 12 patients received single-agent Capecitabine as first-line chemotherapy after palliative radiation therapy (RT). Intrathecal methotrexate was given for seven patients. The median overall survival was 3 (range: 0.5–4) months. Conclusion LM is a very aggressive metastatic disease with poor outcome. There is an unmet need for proper guidelines and an overwhelming necessity for a better focus on research for new modalities of disease in this scenario.

Familial Hemophagocytic Lymphohistiocytosis Secondary to PRF1 Mutation

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that causes systemic inflammation which can progress to multiorgan failure and death. Symptoms and signs commonly seen in HLH include high fever, hepatosplenomegaly, pancytopenia, and hypertriglyceridemia. This report describes the 8-month clinical course of a 17-year-old male with G6PD deficiency who presented with intermittent high fever of unknown origin for 8 months accompanied by pancytopenia and bilateral lower limb weakness. A pathogenic homozygous missense mutation (c.1081A > T p.(Arg361Trp)) in the PRF1 gene was detected by whole exome sequencing (WES). The brain and the whole spine MRI showed leptomeningeal enhancement at different levels involving both the brain and the spine. Therefore, a diagnosis of familial HLH type 2 with CNS involvement was confirmed. Accordingly, treatment with dexamethasone, cyclosporin, and etoposide in addition to intrathecal methotrexate and hydrocortisone was given. The patient showed a dramatic response with significant neurological improvement of the bilateral lower limb weakness. Genetic analysis has helped the patient’s family with appropriate genetic counselling. This case highlights the importance of immediate treatment with immunosuppressants and the high clinical suspicion of physicians regarding HLH in areas where consanguinity is common.

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.

A Phase II Study Evaluating Safety and Efficacy of Polatuzumab Vedotin in Combination with Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone in Patients with Previously Untreated Double and Triple Hit Lymphoma

Background: Double hit lymphoma (DHL) accounts for approximately 10-14% of diffuse large B cell lymphoma (DLBCL) and is characterized by the presence of rearrangements affecting MYC and either BCL2 and/or BCL6 by FISH. The complete response (CR) rate with standard R-CHOP is very poor at 20%, with dismal long-term progression-free (PFS) and overall survival (OS). Aggressive chemotherapy regimens including R-EPOCH, R-HyperCVAD/MA, and R-CODOX-M/IVAC have been evaluated in retrospective studies and have demonstrated better PFS compared to R-CHOP. However, no OS benefit is noted. Moreover, these regimens are associated with significant toxicity and cannot be used in a substantial proportion of patients due to advanced age and comorbidities, and have not been evaluated in prospectively studies. Therefore, new therapeutic modalities, which are better tolerated, are indeed needed to improve outcomes in this high-risk population. Polatuzumab vedotin (PoV) is a CD79b-directed antibody-drug conjugate delivering monomethyl auristatin E (MMAE). PoV either as a single agent or with bendamustine and rituximab (BR) demonstrated encouraging activity in relapsed refractory DLBCL with an overall response rate (ORR) of approximately 50%. Given the promising activity, PoV has been combined with rituximab, cyclophosphamide, doxorubicin, prednisone (R-CHP) in a phase 1b/2 trial, and has shown a favorable safety and tolerability profile. Study design and Methods: This is a phase II, multicenter, open label study of PoV 1.8 mg/kg in combination with standard doses of R-CHP in patients with untreated double or triple hit lymphoma. One cycle of R-CHOP prior to enrollment is allowed. Key eligibility criteria include patients aged > 18 years with previously untreated double or triple hit lymphoma, ECOG PS 0 to 2, measurable FDG-avid disease. Key exclusion criteria are DLBCL NOS subtype, primary mediastinal or Burkitt's lymphoma, and CNS involvement. A total of 49 patients will be enrolled. All patients will receive PoV with R-CHP every 3 weeks for a total of 6 cycles with intrathecal methotrexate for CNS prophylaxis. The primary endpoint is CR rate. Key secondary endpoints are PFS, OS, ORR, duration of response, and safety and tolerability of the combination. Disease response will be assessed by the Lugano response criteria. The study is currently enrolling. ClinicalTrials.gov Identifier: NCT04479267. Disclosures Modi: Genentech: Research Funding; Seagen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees. Pregja: Janssen: Consultancy; Regeneron: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Intellia: Consultancy; Caelum: Consultancy; Alnylam: Consultancy; Eidos: Consultancy; BMS: Research Funding. Ramchandren: pharmacyclics: Consultancy, Research Funding; Trillium: Research Funding; curis: Research Funding; BMS: Consultancy; MERCK: Consultancy, Research Funding; seattle genetics: Consultancy, Research Funding.

Myelopathy associated with intrathecal methotrexate

A 21-year-old man developed progressive and bilateral lower limb numbness, gait impairment and urinary incontinence over 10 days. He had received intrathecal methotrexate 20 days previously for acute lymphoblastic B-cell leukaemia, following 7 months of systemic chemotherapy. MR scan of the spinal cord showed bilateral symmetric and extensive T2/fluid attenuated inversion recovery (FLAIR) increased signal involving the dorsal columns in the thoracic cord. His serum folate concentration was at the lower end of the normal range. We stopped the intrathecal chemotherapy and gave folate; after a few days, he progressively improved. Myelopathy is an important adverse effect of intrathecal methotrexate, which may cause clinical and imaging features resembling subacute combined degeneration of the spinal cord. CNS infiltration must be excluded, intrathecal chemotherapy stopped and deficiency of folate or vitamin B12 treated as appropriate.

Aggressive CD5-Positive Primary Bone Marrow Diffuse Large B-Cell Lymphoma with Leukemic Presentation

Primary bone marrow diffuse large B-cell lymphoma is an exceedingly rare form of non-Hodgkin lymphoma. It may demonstrate a leukemic presentation, and a proportion of cases have CD5 expression. The prognostic implications of this CD5-positivity remain unknown. Here, we present a 78-year-old man who presented with circulating peripheral blood lymphoma cells and a hypercellular marrow involved by diffuse large B-cell lymphoma, germinal center B-cell subtype. The patient responded favorably to six cycles of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) and intrathecal methotrexate. He unfortunately relapsed in several enlarged inguinal lymph nodes and succumbed to the lymphoma approximately one year after diagnosis, demonstrating the particularly aggressive clinical course of his disease.

Cytotoxic Lesion in the Splenium of Corpus Callosum Secondary to Subacute Methotrexate Neurotoxicity

Methotrexate neurotoxicity can present with a wide spectrum of neurologic symptoms and brain magnetic resonance imaging (MRI) typically demonstrates cerebral edema, demyelination, multifocal white matter necrosis, and atrophy relatively selective for the deep cerebral white matter. Here, we report a case of subacute methotrexate neurotoxicity in a 40-year-old man with B cell acute lymphoblastic leukemia. Brain MRI showed cytotoxic lesion in the splenium of corpus callosum and left middle cerebellar peduncle. Patient significantly improved 24 hours after receiving oral dextromethorphan. Methotrexate neurotoxicity should be suspected in any symptomatic patient receiving high dose of methotrexate or intrathecal methotrexate therapy. Dextromethorphan should be considered in these patients as it can modulate the excitatory responses to homocysteine and its metabolite which are usually elevated in such patients.