Ruxolitinib Penetrates Blood Brain Barrier and Reduces the Cytokine Storm in Patients With Haemophagocytic Lymphohistiocytosis

Testing of a hypothesis for osmotic opening of the blood-brain barrier.

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Practice of central nervous system prophylaxis and treatment in acute leukemias in Spain. Prospective registry study

Peripheral T-Cell Lymphoma Involvement of the Central Nervous System: Impact of Novel Therapeutics on Clinical Outcomes

Outcomes of Patients with Diffuse Large B Cell and High-Grade B Cell Lymphomas with Synchronous CNS and Systemic Involvement at Diagnosis Treated with High-Dose Methotrexate and R-CHOP: A Single-Center Retrospective Study

Prospective study on the practice of central nervous system prophylaxis and treatment in non-Hodgkin’s lymphoma in Spain

PurposeThe aim of this study was to identify the risk factors for central nervous system (CNS) involvement in systemic diffuse large B-cell lymphoma (DLBCL) patients and to explore prognostic for DLBCL patients with CNS involvement (relapse or progression).Patients and methodsThis was a retrospective cohort study in our hospital. Data were collected from all DLBCL patients diagnosed in our institutes from January 2013 to June 2018. Clinical information was collected from medical records.ResultsThe participants included 138 patients with DLBCL. Among them, 38 patients were diagnosed as CNS lymphoma, including 15 patients exhibited CNS involvement while DLBCL was pathologically confirmed, and 23 patients developed CNS lymphoma during or after initial chemotherapy. The median disease-free interval to CNS involvement was 13 months. Multivariate analysis identified elevated serum lactate dehydrogenase (LDH) level [hazard ratio (HR)=4.035; 95% confidence interval (95% CI): 1.147–14.195] was an independent predictor of CNS involvement. The median progression-free survival (PFS) and overall survival (OS) time of DLBCL patients with CNS involved were 12.5 months and 22 months, respectively. Multivariate prognostic analysis showed that eastern cooperative oncology group (ECOG) score>2(P=0.018; HR=7.333; 95% CI: 1.424–42.002), elevated serum LDH level (P=0.046; HR=6.510; 95% CI: 1.035–40.949), deep lesion (P=0.005; HR=10.957; 95% CI: 2.050–58.569), and CNS with systemic involvement (P=0.023; HR=2.730; 95% CI: 1.151–6.479) were independent poor prognostic factors for the patients. The cases with lymphocyte absolute count >0.75×109/L (HR=0.047; 95% CI: 0.003–0.732) had better prognosis. The OS of DLBCL patients with secondary CNS lymphoma was inferior to DLBCL patients without CNS involvement. There was no significant difference between the patients with CNS and extra-CNS involvement. There was no significant difference between the patients with CNS involvement and stage III-IV DLBCL cases without CNS lymphoma.ConclusionIn conclusion, elevated serum LDH was independent high-risk factor for secondary CNS lymphoma. For DLBCL patients with CNS involvement, ECOG score>2, elevated serum LDH level, deep lesion, lymphocyte absolute count ≤0.75×109/L and CNS with systemic involvement retained a significant association with outcome.

Clinical Significance of the Presence of Occult CNS Involvement Assessed by Cytofluorometry in Patients with Non Hodgkin's Lymphoma and High Risk of CNS Relapse

Monitoring of CNS involvement in AML using ultrahigh-sensitivity next-generation sequencing of cell-free DNA

Disease characteristics and outcomes of acute lymphoblastic leukemia (ALL) in adults with central nervous system (CNS) involvement

CNS Status at Diagnosis Can Identify Acute Myeloid Leukemia Patients with Poor Induction Outcomes

Central Nervous System Involvement in Adult Acute Lymphoblastic Leukemia (ALL) at Diagnosis and/or at First Relapse: Results from the GET-LALA Group.

The worldwide incidence of multiple myeloma (MM) has been rising continuously, representing an overall increase of 126% from 1990 to 2016 in almost all regions, regardless of socio-demographic status and availability of sensitive diagnostic techniques.1 Though remarkable progress has been made, the disease is still currently incurable. Nearly 13% of patients will develop extramedullary disease due to the natural accumulation of mutations, evolutionary pressure or the development of sanctuaries where tumour cells are protected from therapeutic drugs.2 In particular, central nervous system (CNS) involvement is a critical prognostic indicator, with overall survival of less than 6 months.3-9 Because of its rarity, there is no consensus on the optimal treatment. Radiotherapy is the subject of controversy, in terms of both efficacy and toxicity. In addition, most available treatments, including cytotoxic agents, monoclonal antibodies, immunomodulators and proteasome inhibitor agents, have a very-low distribution in the cerebrospinal axis, blocking an effective, curative treatment.10 Several studies have tested intrathecal injections of methotrexate and cytarabine, commonly used in lymphoma CNS involvement, but with limited success, largely due to the poor efficacy of these agents against plasma cell disorders.11, 12 Thiotepa, a well-known alkylating agent, has been used intravenously for decades, especially for the conditioning of MM autologous stem cell transplantation (ASCT).13 Additionally, it has also been injected intrathecally for the treatment of leptomeningeal metastases, without any serious adverse effects, notably in the case of breast cancer.14 Here we have conducted a retrospective, single-centre study to evaluate the safety and efficacy of intrathecal infusion of thiotepa in 13 consecutively diagnosed cases of CNS-invasive MM (CNS-MM). This study was conducted in full compliance with the principles of the Declaration of Helsinki with oral consent of the patients. Between October 2017 and March 2020, 13 consecutive patients with CNS-MM (eight harbouring cranial nerve palsies, two altered mental status, one numb chin syndrome, one radiculoneuritis and one paresthesia) were identified at Saint Louis Hospital in Paris (Table I). CNS involvement was defined either by the presence of atypical dystrophic plasma cells in the cerebrospinal fluid (CSF) (confirmed by flow cytometry if necessary) and/or clinic-radiological manifestations.3-9, 15, 16 The median age of those with CNS involvement was 62 years [range 52–72 years]: three at MM diagnosis, one at relapse and nine in refractory MM (most of the time after one ASCT plus one salvage therapy). Aggressive initial disease was observed in all cases with one third of revised international staging system (R-ISS) 3 and two thirds of R-ISS 2 [three harbouring t(4;14), two del17p/TP53 mutation, two amp1q21/del1p32, one t(9;14) and one t(14;20)]. Magnetic resonance imaging or computed tomography documentations were available for 12 of the 13 patients and revealed two (15%) with intraparenchymal plasmacytomas, three (23%) with leptomeningeal and nine (69%) with osteodural infiltrations. Treatment strategies, which varied according to patient characteristics and drug availability, are shown in Table I. All patients received intrathecal injections of thiotepa and methylprednisolone in combination with systemic therapy. Thiotepa was administered intrathecally (IT) at a total dose of 10 mg associated with 40 mg of methylprednisolone weekly until a CNS response or disease progression. A median number of three injections [range 1–8] was performed for each patient. An ASCT was performed front-line for two (15%) patients with CNS-MM at diagnosis of MM. For eight (62%) patients, radiotherapy was performed for focal lesions that were observed on imaging. The CNS-MM criteria response was defined as the cytological clearance of plasma cells from the CSF, or a complete radiological response, or a partial radiological response associated with normalization of CSF protein level and/or pleocytosis and/or clinical manifestation. The systemic response was described in accordance with the criteria of the International Myeloma Working Group. A CNS response was observed in 85% of the study population: neurological symptoms regressed in eleven (85%) patients, radiological and biological responses were observed in eight (62%) cases. In five (38%) cases, CSF was cleared at the cytological level. Among the eleven responders, 80% experienced CNS relapse in a context of systemic progression. After relapse or progression of the CNS-MM disease, four of the 13 (31%) patients continued to receive second-line therapy for CNS-MM and one of 13 (8%) a third-line therapy. None of the patients underwent allogeneic stem-cell transplantation. At the time of evaluation, seven (54%) patients were alive. Finally, post CNS-MM survival was calculated with a median follow-up period of 20 months [range 2–141 months]. The median post CNS-MM overall survival, using the Kaplan-Meier method from the date of the first thiotepa injection to the date of last follow-up or death, was estimated at 17 months (Fig 1). None of the patients had specific complications, such as cytopenias, associated with thiotepa IT use nor signs of poor tolerance, except for one patient in pain who received scopically guided injections after two IT injections. In conclusion, this study highlights the need to reconsider our practices in the management of CNS invasion of MM. The number of cases of CNS-MM seems to be increasing since the use of new anti-plasma cell treatments, as evidenced by the latest published incidence rates, which average around 2–3%.8 An effective treatment has still to be found since most recent anti-myeloma agents have a poor diffusion across the blood–brain barrier. Here we report the first analysis of intrathecal thiotepa in CNS-MM. Although this retrospective analysis is not designed for studying efficacy, feasibility and toxicity associated with systemic treatments, there is currently no standard of care to compare with in this infrequent situation. Thus, overall survival after CNS-MM treatment appears to be at least twice that observed in previously published studies, of which more than half used intrathecal injection with methotrexate, cytarabine and methylprednisolone.3-9 These encouraging results could be explained by a majority of focal invasive dural damage. However, the biological and radiological evidence surrounding this clinical outcome appears to reflect the efficiency of the alkylating agent thiotepa. In this regard, patient no 6 was refractory to seven injections of cytarabine, methotrexate and methylprednisolone, but was responsive to thiotepa IT. As in breast cancer, the safety of intrathecal thiotepa seems to be confirmed as there is no excess of toxicity from the combination with systemic therapy nor radiotherapy. CNS-MM involvement is still an issue and may rapidly lead to death. In those cases, systemic therapy and the association with intrathecal injections seems to us to be the optimal strategy especially with the use of thiotepa, in accordance with two recent studies.3, 15 Moreover, radiotherapy of the target lesions should be also considered, particularly if the lesions are symptomatic. Prospective, multicentre studies are essential to improve the survival of these patients and to provide a better understanding of the CNS penetrance of current and future anti-myeloma agents.

Central nervous system involvement in Mantle Cell Lymphoma: A retrospective multicenter cohort study from the spanish geltamo group

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