Intrathecal Injections Of Methotrexate Research Articles

Testicular lymphoma: A case report

Primary testicular lymphoma (PTTL) is a rare and aggressive form of extraganglionic malignant non-Hodgkin's lymphoma (NML). It accounts for 1% of malignant non-Hodgkin's lymphomas, 2% of extranodal lymphomas and 5% of malignant testicular tumours. LTP is the most common form of testicular malignancy in men over 60. An enlarged inguinal orchiectomy should be performed for diagnostic and therapeutic purposes(1). Adjuvant treatment is based on systemic chemotherapy, administration of rituximab in the presence of CD20+ cells and intrathecal injection of methotrexate for neuro-meningeal prophylaxis. In this article, we report a case of testicular lymphoma in a 73-year-old patient who underwent inguinal orchiectomy followed by systemic and intrathecal CHOP chemotherapy.

Pediatric Patients with High-Risk B-Cell ALL in First Complete Remission May Benefit from Less Toxic Immunotherapy with Blinatumomab - Results from Randomized Controlled Phase 3 Trial AIEOP-BFM ALL 2017

Background: One of the key questions in trial AIEOP-BFM ALL 2017 focused on the reduction of treatment-related complications by replacing parts of the highly intensive consolidation phase by two courses of Blinatumomab (Blina) in a prospective randomized trial. Herein, we report the toxicity profile of B-cell acute lymphoblastic leukemia (B-ALL) patients (pts) with high-risk (HR) characteristics pending final outcome data. Patients and Methods: 728 pts with HR B-ALL were enrolled from July 15, 2018 to October 31, 2022 in this multicenter trial run in 8 different countries. Patients were included in the HR group in view of the presence of at least one of the following criteria: induction failure; high levels of minimal residual disease (MRD) at day 15 of induction, or at the end of induction (EOI), or at the end of consolidation (EOC); presence of KMT2A::AFF1, of IKZF1+ and positive MRD at EOI (Stanulla et al, JCO 2018), TCF3::HLF, or hypodiploidy. B-ALL pts with one or several of these characteristics represented 20.8% of all pts aged 0-18 years of age with B-ALL. After a 4-drug induction phase, and two weeks of consolidation treatment, patients were randomized to receive Bortezomib in addition to standard consolidation (not part of this report). Before treatment continued with intensive consolidation block HR-1', MRD was analyzed in order to identify patients eligible for subsequent hematopoietic stem cell transplantation (HSCT) based on MRD results. After block HR-1', all B-ALL HR pts were randomized to receive either two courses of consolidation (blocks HR-2', and HR-3'), or two 28-day courses of Blina at 15µg/m 2/d administered by continuous IV infusion (with a 2-week treatment-free interval). Two intrathecal injections of methotrexate (MTX) for CNS prophylaxis were given on days 1 and 29 of each Blina course, respectively. Out of 728 HR B-ALL pts, 619 pts were eligible for randomization [reasons for non-eligibility were: Event (death or relapse) before randomization was due (26), Down syndrome (25; scheduled for a non-randomized intervention with Blina), presence of TCF3::HLF (3; could receive any alternative therapy including Blina), discontinuation/substantial change of preceding therapy (23) or other protocol exclusion criteria (32)]. 572 pts were randomized (92.4% of those eligible). One pt assigned to the experimental arm (EA) and 4 pts assigned to the control arm (CA) received the other arms, respectively. Results: Toxicity was evaluated in randomized pts according to treatment administered during the randomized phase, respectively, until next element started: 268 pts were treated in the control and 281 in the EA (see Table). 16 of them switched in/after the first Blina cycle to the HR blocks due to toxicity or poor response to Blina (due to increasing MRD, >=1x10 -4). Medically relevant adverse reactions of special interest (ARSI) according to MedDRA (specified in the protocol) were evaluated in the randomized treatment phases (CA: HR-2‘/HR-3‘ block, EA: 2 Blina cycles). ARSI were recorded in 61 of 268 pts in the CA (22.8%, 71 ARSI) and in 29 of 281 pts in the EA (10.3% [p<0.001], 33 ARSI); 3 of the 33 ARSI in the EA were related to HR blocks and were observed in 3 of the 16 pts that switched to HR blocks. Life-threatening SAR were seen in 14 pts of the control group (5.2%) and in no patient in the EA (p<0.001). Conclusions: Taken together, these results show for the first time in newly diagnosed pts with HR B ALL, the favorable toxicity profile previously reported with Blinatumomab in pediatric relapsed ALL (Locatelli F et al, JAMA 2021; Brown P et al, JAMA 2021). We have demonstrated that the toxicity profile of Blinatumomab is much more favorable as compared to the intensive chemotherapy approach using HR-blocks. If upcoming analyses of outcome data will show no inferiority of the EA, blinatumomab replacement of some of the intensive chemotherapy blocks will become the new standard of care for treatment if newly diagnosed patients with HR B-ALL.

Intrathecal injection of methotrexate and dexamethasone for vasculitis granuloma of the fourth ventricle: a case report and literature review.

Granulomatosis with polyangiitis (GPA) is a pauci-immune small vessel vasculitis characterised by neutrophil-mediated vasculitis and granuloma. The presence of intracranial parenchymal space-occupying lesions is rarely seen in GPA patients. In this manuscript, we report a case of GPA with granuloma of the fourth ventricle accompanied by obstructive hydrocephalus. Treatment with glucocorticoids (GCs) and multiple immunosuppressants cyclophosphamide (CYC), mycophenolate mofetil (MMF), and rituximab (RTX) showed poor efficacy in this case. After removal of the granuloma by craniotomy, GPA relapsed within 3months. Under the premise of GC and MMF treatment combined with intrathecal injection of dexamethasone (DXM) and methotrexate (MTX), the intracranial granuloma gradually shrank, and the patient's general condition was alleviated, showing that this is an effective treatment method. Key Points • To date, there are few reports of granulomatous vasculitis combined with granuloma of the fourth ventricle, and our case is the second. • In this case, multiple immunosuppressants and rituximab were ineffective treatments, and the intracranial granuloma was effectively controlled by intrathecal injection of dexamethasone (DXM) and methotrexate (MTX). • Based on this report, it can be suggested that intrathecal injection is effective in treating patients with GPA and central nervous system involvement, but large-scale sample studies are needed.

The influence of intrathecal injection of methotrexate and dexamethasone on neuropsychiatric systemic lupus erythematosus (NPSLE): a retrospective cohort study of 386 patients with NPSLE

BackgroundNeuropsychiatric involvement is one of the major concerns in systemic lupus erythematosus (SLE). The therapeutic effect of intrathecal treatment of methotrexate and dexamethasone has been investigated in some exploratory studies, but its influence on the long-term prognosis of neuropsychiatric SLE (NPSLE) remains unknown.MethodsThis was a propensity score-matched retrospective study. Outcomes at discharge and time free from NPSLE relapse or death were evaluated by multivariate logistic regression, survival analysis, and Cox regression as appropriate.ResultsAmong 386 hospitalized patients with NPSLE, the median [IQR] age was 30.0 [23.0–40.0] years, and 342 patients (88.4%) were female. Of those, 194 patients received intrathecal treatment. Patients in the intrathecal treatment group had higher Systemic Lupus Erythematosus Disease Activity Index 2000 scores (median 17 vs. 14 points, IQR 12–22 vs. 10–19 points, P <0 .001) and were more likely to receive methylprednisolone pulse therapy (71.6% vs. 49.5%, P < 0.001) than those who did not receive intrathecal therapy. Intrathecal treatment was associated with a higher probability of survival and being free from NPSLE relapse than control treatment among the 386 unmatched patients (P =0.042 by log-rank test) and within 147 propensity score-matched pairs (P =0.032 by log-rank test). In the subgroup of NPSLE patients with increased levels of protein in cerebrospinal fluid, intrathecal treatment had a positive influence on their prognosis (P < 0.001).ConclusionsIntrathecal treatment of methotrexate and dexamethasone was associated with a more favorable prognosis of NPSLE and may serve as a valuable additional therapy for NPSLE patients, especially for those with elevated levels of protein in cerebrospinal fluid.

R-CHOP Chemotherapy Including Biosimilar Rituximab (Redditux ®) for De-Novo Diffuse Large B-Cell Lymphoma Patients: Real-Life Single Center Experience

BackgroundThe biosimilar rituximab (Redditux) was approved in Turkey for all indications of the reference molecule (MabThera) in March 2018. Large clinical trials and real-life experiences are lacking in hematological malignancies.AimsWe aimed to evaluate the efficacy and safety of Redditux in de-novo diffuse large B-cell lymphoma (DLBCL).MethodsOur institution decided to provide Redditux for hematological indications since February 2019. We retrospectively analyzed medical records of 51 consecutive de-novo DLBCL patients (pts) diagnosed between February 2019 and September 2019 in the hematology department of Istanbul University Istanbul Medical Faculty. We compared the response rates with historical controls treated with MabThera-CHOP at Cerrahpaşa Medical Faculty. Our study was approved by I.U. Istanbul Medical Faculty Ethical Committee (2019/1454).ResultsA total of 51 pts without CNS involvement received Redditux-CHOP. Median follow-up was 24 months (range: 8-31). A median of 6 cycles of biosimilar (range: 4-8) was administered. Four pts with high CNS-IPI score received four intrathecal methotrexate injections and 13 pts had additional radiotherapy for their initial bulky disease. The patient characteristics and response rates of the Redditux and historical MabThera cohorts are summarized in Table 1.Apart from 6 cases who were refractory to Redditux-CHOP, 8 pts had progressive disease (6 with CR, 1 with PR and 1with SD) in the follow-up. The median time to relapse was 11.5 months for 6 cases who had CR following first-line treatment. Five of 8 cases with PD experienced CNS relapse. Their CNS-IPI score (Schmitz et al. J Clin Oncol 2016) were low in 2 pts, intermediate in 2 pts and high in 1 patient. Of 11 pts with bone involvement at the time of diagnosis, three cases had CNS relapse (p=0.028). Two pts with CNS relapse were treated with intrathecal chemotherapy only due to their poor performance status. Eight pts received salvage combination chemotherapy [R-ICE (n=3); R-benda (n=3); R-DHAP (n=1); MATRix (n=1)] and two of them responded. One of these 2 cases underwent auto-SCT and the other proceeded to allo-SCT; however, he died during conditioning treatment.Ten pts died in the follow-up. Causes of death were progressive disease (n=7, two cases with CNS involvement), infection during allo-conditioning (n=1), post-COVID herpes zoster infection (n=1) and unknown (n=1).The 24 month PFS and OS rates were 75.8% (95% CI: 0.61-0.85) and 80.3% (95% CI: 0.67-0.89) for Redditux cohort, respectively. In the historical MabThera group, the 24 month PFS and OS rates were 85.2 (95% CI: 0.79-0.90) and 81.4% (95% CI: 0.75-0.86), respectively.For pts with high R-IPI score in the Redditux cohort (3-5); the 24-month PFS and OS rates were 54.2% (95% CI: 0.29-0.74) and 55.6% (95% CI: 0.31-0.75), respectively. In the historical Mabthera group, the 24-month PFS and OS rates were 68.7% (95% CI: 0.53-0.80) and 59.4% (95% CI: 0.47-0.70), respectively. Although the PFS rates seems to be worse in high R-IPI cases receiving Redditux, the difference was not significant (p=0.18; Figure 1).AEs were reported in 51% (n=26) of patients. Most common AE was grade 2 infusion reactions (shivering, nausea, fever) requiring medical intervention in 20% of pts, accompanied with rash in half of them. Grade 3&4 AEs were leucopenia (n=2; 4%), neutropenia (n=20; 39%) febrile in 2 cases, anemia (n=6; 12%), thrombocytopenia (n=3; 6%). Grade 2 pneumonia (n=2) and urinary tract infections (n=2) were other infectious complications.ConclusionAlthough the PFS rate at 24 months in high-IPI group treated with Redditux seems to be lower compared to MabThera treated historical control group, survival rates were not significantly different. Our results should be cautiously evaluated due to small sample size. Compared to the original trial of MabThera added to CHOP based regimen, (Coiffier et al N Eng J Med. 2002), our CR rates in stage 2-4 pts seem to be slightly lower (70.7% vs 76%), although the OS rates are quite similar (86.3% vs 82%). Grade 3&4 neutropenia requiring empirical administration of G-CSF was 39% in our cohort. Infusion reactions were observed in 20% of pts, which was reported to be around 30% with original molecule (Patel et al. Clin Lymphoma Myeloma Leuk 2019). The CNS relapse rate was relatively high (9.8%) in our cohort. Prospective randomized clinical trials are needed to determine the efficacy and safety profile of Redditux. [Display omitted] DisclosuresFerhanoglu: Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Primary Breast Diffuse Large B-Cell Lymphoma in a 42-Year-Old Female: A Case Report and Review of Literature

Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is a rare localized extranodal lymphoma. It is mainly diagnosed by pathological examination due to the lack of specific clinical and imaging manifestations. Whole-body positron emission tomography-computed tomography (PET-CT) is widely used in determining clinical staging and guiding clinical treatment. As part of comprehensive treatment, targeted therapy with rituximab, intrathecal methotrexate injection and consolidation radiotherapy remain controversial in treating PB-DLBCL, but the comprehensive treatment based on full-course of chemotherapy is still widely used as the first-line treatment. Comprehensive treatment often leads to a sharp decline in the immunity of elderly patients with malignancy. In this situation, surgery may be a good chance to improve their life quality without serious complications. We present a rare case of PB-DLBCL during the coronavirus disease 2019 (COVID-19) pandemic. The patient underwent chest CT scan to screen COVID-19 and a mass of left breast was accidentally found. Because of the city lockdown policy in Wuhan, she did not seek medical help until noticing that the mass was gradually enlarged. Both ultrasonography and mammography indicated that the lesion was breast cancer. However, ultrasound-guided core needle biopsy revealed diffuse large B-cell lymphoma of breast and PET-CT scan showed that the lesion was a primary hypermetabolic tumor of left breast. The patient subsequently received comprehensive treatment based on six cycles of rituximab-cyclophosphamide, hydroxydaunomycin, oncovin, prednisone (R-CHOP) chemotherapy. J Med Cases. 2021;12(5):181-185 doi: https://doi.org/10.14740/jmc3660

ETMR-11. A CASE OF PRIMARY DIFFUSE LEPTOMENINGEAL PRIMITIVE NEUROECTODERMAL TUMOR

BACKGROUNDPrimary diffuse leptomeningeal primitive neuroectodermal tumor (PDL PNET) is a rare embryonal brain tumor which arises primarily in the meninges without an intraparenchymal mass. Few previous reports of this condition exist, and the clinical outcomes are poor. We herein report a case of a child with PDL PNET and present a cursory review of the literature. CASE: A 3-year-old female patient was seen at a local clinic due to vomiting, headaches, and seizures. As a head MRI revealed hydrocephalus but no mass, acute encephalopathy was initially diagnosed. She received steroid pulse therapy, but the symptoms progressed to hallucination and lethargy. Another MRI at the 1-month follow-up revealed diffuse leptomeningeal enhancement. Thereafter she was transferred to our hospital. A spine MRI revealed spinal dissemination. She underwent a dura mater biopsy, and the pathological analysis led to the diagnosis of PDL PNET. She received chemotherapy consisting of vincristine, cyclophosphamide, etoposide, cisplatin, and intrathecal methotrexate injections two months after the initial presentation. The progressive hydrocephalus was managed with external ventricular drainage. Two weeks after the first cycle of chemotherapy the hydrocephalus resolved, and the external ventricular drainage was removed. A follow-up MRI showed that the leptomeningeal enhancement decreased during the four cycles of chemotherapy without radiotherapy. The patient is scheduled to receive high-dose chemotherapy as consolidation therapy.CONCLUSIONPDL PNET is extremely rare, and its diagnosis is often delayed. Treatment of PDL PNET is very difficult due to its aggressive course, and surgical resection is impossible. Early diagnosis may help improve outcomes.

First Results of an Open Label Phase II Study to Evaluate the Efficacy and Safety of Inotuzumab Ozogamicin for Induction Therapy Followed By a Conventional Chemotherapy Based Consolidation and Maintenance Therapy in Patients Aged 56 Years and Older with Acute Lymphoblastic Leukemia (INITIAL-1 trial)

Introduction: Acute lymphoblastic leukemia (ALL) represents around 5% of all newly diagnosed leukemia in patients between 55 and 70 years of age. Despite recent advances especially in younger patients, the prognosis of older patients with ALL remains dismal, even after moderately intensive chemotherapy. Due to increasing toxicity and infection rates in older patients, dose intensification of induction treatment often is no justifiable option. Consequently, new treatment options are needed to improve the survival of older ALL patients. Methods: This open label phase II study of the German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia (GMALL) is currently activated in 14 centers in Germany. Patients aged &amp;gt;55 years with newly diagnosed acute B lymphoblastic leukemia, with the exception of Philadelphia-chromosome or BCR-ABL positive ALL or Burkitt's or mixed phenotype acute leukemia, are eligible. Leukemic blasts must have CD22 surface expression of at least 20%. No previous ALL-specific treatment, with the exception of corticosteroids and/or single dose vincristine and/or up to 3 doses of cyclophosphamide (cycloph.) plus standard prephase treatment are allowed. The 1st induction cycle consists of inotuzumab ozogamicin (InO) 0.8 mg/m2 on day1 and 0.5 mg/m2 on days 8 and 15 together with dexamethasone 10 mg/m2 (days 7-8, days 14-17) and 1 intrathecal injection of methotrexate (MTX), cytarabine (AraC) and dexamethasone (Dexa). The 2nd and 3rd induction cycle consist of InO 0.5 mg/m2 on days 1, 8 and 15 plus intrathecal injection of MTX/AraC/Dexa. Response evaluation is scheduled after each cycle. Patients achieving a complete remission are offered to receive 5 conventional consolidation therapies (3 x ID-MTX/asparaginase; 2 x ID-AraC) and one reinduction therapy (idarubicine/AraC/cycloph./Dexa) in combination with rituximab (for CD20+ ALL), followed by a maintenance therapy with 6-mercaptopurine/MTX. The primary endpoint is is event free survival (EFS) at 12-months follow-up. An event is any of the following: persisting bone marrow blasts after 2 cycles of InO, relapse or death. An event rate of ≤40% at 12 months follow-up is considered to qualify the experimental treatment as very promising for additional testing. Under the assumption of one-sided type I error of 5% and 80% power, 42 evaluable patients were needed for primary endpoint analysis. The INITIAL-1 trial is registered with ClinicalTrials.gov, identifier: NCT03460522. Results: As of July 2020, 31 patients have been included, with induction results available for 29 patients. Median age at initial diagnosis was 64 years (range 56-80 years). Twenty-five patients were diagnosed with a common- and 4 with a pro-B lymphoblastic leukemia. Median CD22 expression on leukemic blasts was 70% (range 21-99%). Due to suspected therapy related liver toxicities, 1 patient received 1 induction cycle and 1 patient 2 induction cycles (both were in remission after the 1st induction). All other patients completed induction therapy and achieved complete remission (CR/CRi) mainly after the 1st induction. Results of minimal residual disease (MRD) measured by PCR are available for 23 patients, with 17 being MRD-negative after induction. So far, 4 events have been reported (2 deaths in remission and 1 relapsed ALL in the 1st year of treatment; one relapsed disease in the 2nd year). With a median follow-up of 242 days, the probability of OS at 1 year is 82.4 %. Two patients received an allogeneic stem cell transplantation in ongoing 1st remission. With regard to adverse events (AEs) during induction therapy 1, 2 and 3, most common AEs ≥CTC 3 reported were leukocytopenia (in 64%, 33% and 13% of all cases, respectively), anemia (54%, 28%, 13%), thrombocytopenia (68%, 17%, 26%) and elevation of liver enzymes (31%, 22%, 20%). Conclusion: Replacement of conventional induction chemotherapy by InO is feasible, results in promising remission rates, and may reduce the risk of early morbidity and lethality, particular in older patients with acute B lymphoblastic leukemia. Disclosures Stelljes: Amgen: Consultancy, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Wäsch:Pfizer: Consultancy; Amgen: Consultancy; Janssen: Consultancy. Haenel:Amgen, Novartis, Roche, Celgene, Takeda, Bayer: Honoraria. Lenz:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Agios: Research Funding; AQUINOX: Research Funding; Novartis: Consultancy; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem: Research Funding; Morphosys: Consultancy, Honoraria, Research Funding. Brüggemann:Affimed: Research Funding; Regeneron: Research Funding; Celgene: Consultancy; Roche: Consultancy; Incyte: Consultancy; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Goekbuget:Gilead: Consultancy; Kite: Consultancy; Servier: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Erytech: Consultancy; Amgen: Consultancy, Research Funding. Alakel:Pfizer: Consultancy. OffLabel Disclosure: Inotuzumab ozogamicin for induction therapy (1st line therapy)

Bilateral refractory subdural hygromas following intrathecal methotrexate injections for B-Cell Acute Lymphocytic Leukemia

BackgroundSubdural hygroma (SDG) is an important complication after intrathecal injections of medications. SDG develops because of a cerebrospinal fluid leak into subdural space. Case descriptionWe report a case of 69 years old male who presented to the hospital with changes in mental status and hemodynamic instability. The patient was a known case of B-Cell Acute Lymphoblastic Leukemia (B-ALL) and was undergoing intrathecal injections of methotrexate (MTX) and intensive chemotherapy. Patient focal neurological deficits were correlated with the neuroimaging findings which showed bilateral subdural hygromas. He has received intrathecal injections of MTX almost 6 weeks ago. Surgical drainage of subdural hygroma was done but the refractory nature of hygroma left the patient with residual mass effects and neurological deficits. ConclusionAs physicians, we should be aware of a fatal but rare complication of intrathecal injections and one of them this patient developed as SDG.

The Use of Ommaya Reservoirs to Deliver Central Nervous System-Directed Chemotherapy in Childhood Acute Lymphoblastic Leukaemia.

Prophylactic eradication of central nervous system (CNS) leukaemia is the current standard of care in treating childhood acute lymphoblastic leukaemia (ALL). This is conventionally achieved through regular lumbar punctures with intrathecal injections of methotrexate into the cerebrospinal fluid (CSF). Ommaya reservoirs are subcutaneous implantable devices that provide a secure route of drug delivery into the CSF via an intraventricular catheter. They are an important alternative in cases where intrathecal injection via lumbar puncture is difficult. Among UK Paediatric Principal Treatment Centres for ALL we found considerable variation in methotrexate dosing when using an Ommaya reservoir. We review the current safety and theoretical considerations when using Ommaya reservoirs and evidence for methotrexate dose adjustments via this route. We conclude by summarising the pragmatic consensus decision to use 50% of the conventional intrathecal dose of methotrexate when it is administered via Ommaya reservoir in front-line ALL therapy.

Liposomal Cytarabine Induces Less Neurocognitive Dysfunction Than Intrathecal Methotrexate in an Animal Model.

Liposomal cytarabine is currently being tested clinically as an alternative to intrathecal (IT) methotrexate (MTX) for preventing relapse within the central nervous system among patients with acute lymphoblastic leukemia. To compare the toxicity and cognitive deficits caused by IT MTX versus liposomal cytarabine, juvenile Long Evans rats were treated with IT injections of MTX 1 mg/kg×4 doses over 8 days, or liposomal cytarabine 0.8 mg once. Mean concentrations of free cytarabine in cerebrospinal fluid remained above the cytotoxic threshold of 0.4 μM for 2 weeks after dosing. Animals treated with liposomal cytarabine exhibited normal recognition and spatial memory 4 weeks after injection. In contrast, exposure to IT MTX led to impaired cognitive function. In addition, mean hematocrit on day 11 was significantly lower in the MTX-treated animals (30.8%; 95% confidence interval, 27.0%-34.7%; n=6) compared with that in the liposomal cytarabine-treated animals (39.5%; 95% confidence interval, 38.4%-40.6%; n=6; P<0.0001). Our data suggest that liposomal cytarabine induces fewer neurocognitive deficits and less acute hematologic toxicity compared with IT MTX. Liposomal cytarabine may therefore have therapeutic advantages over IT MTX, if it is equally effective in preventing relapse.

Abstract P1-17-09: Leptomeningeal disease in ER+HER2- metastatic breast cancer patients: A review of the cases in a single institute over a 14-year period

Abstract Background: Leptomeningeal disease (LMD) is a pattern of central nervous system (CNS) metastasis that occurs in metastatic breast cancer (MBC) patients (pts). Some reports have revealed that it occurs more frequently in pts with estrogen receptor-positive (ER+), HER2-MBC than in pts with other subtypes. However, in such ER+HER2-MBC pts, LMD mainly occurs in the terminal stage of the disease; thus, the details of LMD have not been well described. Methods: We reviewed the medical records of ER+HER2-MBC pts who were treated from 2002 to present, with the aim of assessing the incidence, background and outcomes of LMD. Statistical analyses were performed using the chi-squared test, Kaplan-Meyer method, log-rank test and a multivariate COX regression analysis. Results: We identified a total of 369 ER+HER2-MBC pts, and 102 (27.6%) developed CNS metastasis. LMD developed in 32 (8.7%) pts, with the median time to LMD of 778 days (95% confidence interval [CI] 335-1221; range 0-3757 days) from the diagnosis of MBC. In most cases (28, 87.5%), LMD was accompanied by bone metastasis, and 24 pts (75.0%) showed metastasis to the skull. Thirteen pts (40.6%) had accompanying brain metastasis (BM) at the diagnosis of LMD. The majority of the pts had symptoms (25, 78.1%), and their accompanying extra-CNS lesions showed progression (23, 71.9%). Palliative radiotherapy (RT) was introduced in 27 pts (84.4%), with 4 pts (12.5%) receiving whole CNS RT. The intrathecal injection of methotrexate was introduced to one patient. The median overall survival (OS) from the diagnosis of LMD was 104 days (95% CI 38-170); however, when limited to pts without BM (N = 19), the median OS was 146 days (95%CI 79-213). All of the pts died, and the causes of death were as follows: CNS lesion progression, n=10 (31.3%); cachexia, n=9 (28.1%); respiratory failure, n=8 (25.0%); hepatic failure, n=4 (12.5%) and infection, n=1 (3.1%). There was no significant relationship between the time to LMD and OS after the diagnosis of LMD (Spearman's ρ=0.55, not significant). The multivariate analysis did not reveal any specific factors—such as the patient age, the presence of any symptom(s) at the diagnosis of LMD, the distribution of extra-CNS lesion(s) or the control of extra-CNS lesion(s)—that affected OS after the diagnosis of LMD. As a control, 70 ER+HER2-MBC pts who developed BM without LMD (BM-only group) within the same observation period were analyzed. The median time to BM was 611 days (95%CI 404-818), and it did not differ from that of pts with LMD (LMD-group) to a statistically significant extent (P &amp;gt;0.1). The BM-only group showed superior OS after the diagnosis of their CNS lesions in comparison to LMD-group (median, 295 days and 104 days, respectively, P &amp;lt;0.001). At the diagnosis of the CNS lesion, the LMD-group showed a higher rate of CNS symptoms (P &amp;lt;0.01), a lower rate of liver metastasis (P &amp;lt;0.05), a higher rate of bone metastasis (P &amp;lt;0.05) and a higher rate of skull metastasis (P &amp;lt; 0.01). Conclusion: Our retrospective analysis at a single institute revealed that the prognosis of LMD in pts with ER+HER2-MBC was still extremely poor. The data suggest that LMD is distinct from BM in terms of its pathology and response to therapy. Citation Format: Watanabe J, Mitsuya K, Hayashi N, Nakasu Y. Leptomeningeal disease in ER+HER2- metastatic breast cancer patients: A review of the cases in a single institute over a 14-year period [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-17-09.

Utility and Safety of Intrathecal Methotrexate Treatment in Severe Anti-N-methyl-D-aspartate Receptor Encephalitis: A Pilot Study.

Background:Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a treatable autoimmune neurologic syndrome that occurs with or without tumor association. However, some severe cases are refractory to systemic immunotherapy. This pilot study aimed to evaluate the utility and safety of intrathecal methotrexate injection for severe patients with anti-NMDAR encephalitis who did not respond to first-line immunotherapy.Methods:Intrathecal injections with methotrexate and dexamethasone were performed weekly in four legible patients within consecutive 4 weeks. Cerebrospinal fluid (CSF) was collected at baseline and each time of intrathecal injection for identification of anti-NMDAR antibody titers.Results:Significant clinical improvement was observed in three patients associated with a stepwise decrease of CSF anti-NMDAR antibody titers (maximum: 1/320 to minimum: 1/10). After 2 months of follow-up, they were able to follow simple commands and had appropriate interactions with people (modified Rankin scale [mRS] of 0–2). At 12 months of follow-up, they all had returned to most activities of daily life (mRS of 0), and no relapses were reported. One patient showed no clinical improvement and died of neurologic complications.Conclusions:Intrathecal treatment may be a potentially useful supplementary therapy in severely affected patients with anti-NMDAR encephalitis. Further large cohort study and animal experiment may help us elaborate the utility of intrathecal injection of methotrexate and its mechanism of action.

Prophylactic Scrotal And Contralateral Testicular Radiation Therapy Prevents Local Relapses in Primary Testicular Lymphomas

Primary testicular lymphoma is a rare form of extranodal lymphoma typically expressing B-cell markers. The contralateral testis and the central nervous system are common localizations of relapses. The purpose was to evaluate the benefit of prophylactic scrotal radiation therapy (RT). Patients with primary testicular lymphoma were identified from the institutional electronic database, by submitting keywords in a search engine. Eligibility was limited to adults (age > 18 years), and diffuse large B cells subtype. Patient’s clinical data were retrospectively reviewed. Survivals were estimated using the Kaplan-Meier method and compared using log-rank tests. Forty-eight patients were included. The majority of the patients had localized disease (Ann-Arbor stage I-II, 85.4%). Orchiectomy was performed in all cases. Their mean age at diagnosis was 61.4±14.4 years. Median follow-up was 67.7 months (range 5.6-317.2). No patient presented with B symptoms and no central nervous system involvement was documented at diagnosis. International prognostic indexes were 0 in 31.3% of the patients, 1 in 45.8%, 2 or 3 in 10.4% and 4 in one patient (2.1%). Anthracycline-based chemotherapy was administered to 81% of patients, 29.1% had rituximab associated. Prophylactic intrathecal injections of methotrexate were administered to 48% of patients. Scrotal irradiation was given to 37.5% of patients, following chemotherapy. The target volumes comprised the scrotum and contralateral testis. The mean dose was 33.3±.2.9 Gy (range: 30-36). No local relapse was reported among the patients who received scrotal radiotherapy whereas 8 failures (16.7%) where observed in those who did not. The 5-year local control rates were 100% and 81.9% respectively, in the groups of patients with and without prophylactic RT (n=30, and n=18, P=0.034). In the subgroup of patients with stage I-II diseases (n=41), 5-year local control rates were 100% in those who received RT (n=15) and 80.4% in the remaining ones (n=26, P=0.05). Prophylactic scrotal and contralateral testicular RT is effective in preventing local relapses in primary testicular lymphoma.

Subdural Hematoma Associated with Dasatinib and Intrathecal Methotrexate Treatment in Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia.

Dasatinib has been associated with an increased risk of bleeding, with the most prominent risk noted in patients with advanced-stage chronic myeloid leukemia and thrombocytopenia. We herein report two cases of Philadelphia chromosome-positive acute lymphoblastic leukemia in which a subdural hematoma developed in association with low-dose (40-50 mg/day) dasatinib treatment and lumbar puncture for intrathecal methotrexate injection. Both patients were in complete remission, with normal platelet counts and coagulation status. We suggest that dasatinib, even at a low dose, may impair platelet aggregation and that lumbar puncture may increase the risk of a subdural hematoma (occasionally bilateral) in patients receiving dasatinib.

A Prospective, Self-Controlled and Randomized Study about the Optimal Timing of Leucovorin Rescue after High Dose Methotrexate Management

Background and objectives: Methotrexate (MTX) is a folic acid reductase inhibitor widely used. Peripheral infusion of high dose MTX (HD-MTX) could prevent the central nervous system recurrence of leukemia and NHL. Due to the blood brain barrier, only 1-3% of MTX in the peripheral blood can enter the cerebrospinal fluid. Improving the peripheral MTX drug dosage helps to improve MTX concentration in the cerebrospinal fluid. However, high concentration of MTX has serious side effects to normal organs. Leucovorin (CF) rescue is given to reduce the toxic effect of methotrexate on normal cells. During high dose MTX therapy, monitoring of serum concentration of MTX and timely CF rescue therapy are mandatory so as to maximum the efficacy of MTX and minimize the toxicities. Due to the lack of randomized clinical trials with large sample, the safe dose and most appropriate time of leucovorin rescue treatment are of no consensus. In order to study the effect of different time of leucovorin rescue treatment on the serum concentration of MTX, we carried out this study.Patients and methods: We included patients who had pathological diagnosis of non-Hodgkin's lymphoma and indications to receive HD-MTX as single agent or component in combined regimen consecutively from October 2011 to June 2014 at our hospital. Patients were randomized to receive CF rescue at the sixth hour after MTX infusion in the first course and twelfth hour in the second course or the twelfth hour in the first course and sixth hour in the second course. A dosage of 3.5 g/m2 of MTX was provided. Adequate hydration, alkalization and monitoring of laboratory tests were administered. Intrathecal injection of MTX plus cytarabine and dexamethasone were given after MTX infusion. 100mg of CF was given at the first time, then 30mg of CF were given every 6 hours for a total of 7 times until the plasma concentration of MTX were lower than 1×10-7 mol/L. Blood samples were collected at 2, 12, 18, 24, 28, 72 hours after the beginning of MTX infusion. High performance liquid chromatography was used to test the plasma concentration of MTX.Results: There were 23 male patients and 12 female patients with a mean age of 41 years. Most of patients were diagnosed as diffuse large B cell lymphoma (65.7%). Eleven cases (31.4%) had central nervous system invasion at the time of HD-MTX treatment. Twenty-one patients (51%) had more than one extra-nodal lesion. Sixteen patients were randomly to be rescued at the sixth hour in the first course then the twelfth hour in the second course. Nineteen patients were randomly to be rescued at the twelfth hour in the first course then the sixth hour in the second course. The plasma concentration of MTX of patients rescued at the sixth hour at the time of 2, 12, 18, 24, 48 hours were 5.21±0.36×10-5 mol/L, 8.01±0.635×10-5 mol/L, 4.57±1.67×10-6 mol/L, 1.43±0.83×10-6 mol/L, 0.1±0.1×10-6 mol/L, respectively; The plasma concentration MTX of patients rescued at the twelfth hour at the time of 2, 12, 18, 24, 48 hours were 5.46±0.34×10-5 mol/L, 8.65±0.663×10-5 mol/L, 5.4±0.93×10-6 mol/L, 1.12±0.21×10-6 mol/L, 0.1±0.24×10-6 mol/L, respectively. There was no significant difference of MTX concentration level between patients treated with different CF rescue timing, P >0.05. Most of patients achieved maximal MTX concentration at the twelfth hour, and descended to be lower than the minimal effective concentration at the eighteenth hour. At the forty-eighth hour, majority of patients had MTX concentration being in a safe range. The rate of grade 3 to 4 adverse reactions including neutropenia, anemia, thrombocytopenia and grade 1 to 2 side effects including neutropenia, thrombocytopenia, mucositis, fatigue, and MTX discharge delay were higher when patients were rescued with CF at the twelfth hour, though P >0.05.Conclusion: Most of patients treated with high dose MTX reached the maximum MTX concentration at the twelfth hour after MTX infusion, and descended to be under the minimal effective concentration at the eighteenth hour, then to be in the safe range at the forty eighth hour. No significant difference of MTX concentration was found between patients rescued with CF at the sixth hour or the twelfth hour. However, adverse reactions were lower when patients were treated with CF rescue at the sixth hour. It seems a better choice to give patients CF rescue at the sixth hour after MTX infusion. DisclosuresNo relevant conflicts of interest to declare.

Parkinsonism as a Manifestation of Neuropsychiatric Systemic Lupus Erythematosus: A Case Report and Literature Review

Involvement of the central nervous system in systemic lupus erythematosus has been well documented. Parkinsonism as a manifestation of central nervous system lupus is rare. In this article, we report a 17-year-old girl who developed parkinsonism within one month of the onset of systemic lupus erythematosus, and presented with expressionless facies, bradykinesia, marked rigidity, and hypermyotonia. Magnetic resonance imaging showed abnormity in bilateral basal ganglia, external capsule, insular lobe, and lateral hippocampus symmetrically. Methylprednisolone pulse therapy, intravenous cyclophosphamide, and intrathecal injection of methotrexate plus dexamethasone were prescribed. Two months later, the patient returned with complete clinical recovery of neuropsychiatric symptoms and signs.

Clinical Course of Cerebral Venous Thrombosis in Adult Acute Lymphoblastic Leukemia

Venous thromboembolism (VTE) is a frequent complication in patients with acute lymphoblastic leukemia (ALL). A significant proportion of patients develop cerebral venous thrombosis (CVT). To investigate risk factors for and the clinical course of CVT in ALL patients, we describe all cases of CVT which occurred in a well-defined cohort of 240 adults, treated for newly diagnosed ALL in the HOVON (Dutch-Belgian Hemato-Oncology Cooperative Group)-37 study. We conducted a nested case-control study to explore the relevance of early symptoms and risk factors for CVT in ALL patients. Nine of 240 patients developed CVT (4%). CVT occurred during or shortly after L-asparaginase therapy (in 8 cases) and shortly after intrathecal methotrexate injections (in all cases) during cycle I of remission induction treatment. CVT was associated with prior headache and seizures. In 5 of 9 patients with CVT, headache before the diagnosis of CVT occurred within 3 days after lumbar puncture and initially had a postural character. CVT is relatively common in adult ALL patients. Our data suggest that CVT in adult ALL patients results from the additive effects of multiple risk factors, with a particular role for asparaginase and the effects of lumbar punctures for intrathecal therapy.

Very high levels of lactate dehydrogenase at diagnosis predict central nervous system relapse in acute promyelocytic leukaemia

Very high levels of lactate dehydrogenase at diagnosis predict central nervous system relapse in acute promyelocytic leukaemia

Pituitary Gland: Do Anticancer Drugs Sit in the Turkish Saddle?

TO THEEDITOR:WithinterestwehavereadthestudybyZelleret al 1 in Journal of Clinical Oncology. In their cross-sectional study, the authors compared regional brain volumes in 130 adult long-term survivors of childhood acute lymphoblastic leukemia (ALL) with thoseinhealthycontrols.Inthisstudy,ALLsurvivorshadbeentreated withchemotherapyconsistingofvincristine,methotrexate,andantracyclines. To prevent CNS leukemia, most ALL survivors had received intrathecal injections of methotrexate, whereas only 13.8% of the survivors had received cranial irradiation. Structural magnetic resonanceimagingshowedsmallervolumesofmultiplebrainstructuresin long-term survivors of childhood ALL compared with matched healthy controls. Although the study contained the largest number of participantstodate,Zelleretalcouldnotidentifyetiologicfactorsthat