scholarly journals Dose-Adjusted EPOCH-R and Mid-Cycle High Dose Methotrexate for Patients with Systemic Lymphoma and secondary CNS Involvement

2016 ◽  
Vol 179 (5) ◽  
pp. 851-854 ◽  
Author(s):  
Dai Chihara ◽  
Nathan H. Fowler ◽  
Yasuhiro Oki ◽  
Michelle A. Fanale ◽  
Luis E. Fayad ◽  
...  
Keyword(s):  
High Dose ◽  
High Dose Methotrexate ◽  
Cns Involvement ◽  
Dose Methotrexate ◽  
Systemic Lymphoma

Long Term Outcomes of Rituximab, Temozolamide, and High-Dose Methotrexate for Lymphoma Involving the Central Nervous System

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2701-2701
Author(s):  
Sarah Jordan Nagle ◽  
Nirav N. Shah ◽  
Alex Ganetsky ◽  
Daniel J. Landsburg ◽  
Sunita Dwivedy Nasta ◽  
...  
Keyword(s):  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Initial Response ◽  
Response Assessment ◽  
Response To Therapy ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Cns Involvement ◽  
Dose Methotrexate

Abstract Background Management of patients (pts) with primary central nervous system lymphoma (PCNSL) and those with secondary CNS involvement by diffuse large B cell lymphoma (DLBCL) present a therapeutic challenge. There is no clear standard of care but traditionally initial treatment of PCNSL involves induction with intravenous high-dose methotrexate (HD-MTX) followed by consolidation including whole brain radiation therapy (WBRT), cytarabine, or autologous stem cell transplant. This approach has been associated with significant toxicities, especially the risk of cognitive dysfunction with WBRT. Treatment of secondary CNS involvement by DLBCL may depend on the extent of concomitant systemic disease, but HD-MTX is often the backbone of therapy. We report results of our institutional approach in pts with PCNSL and secondary involvement of the CNS by DLBCL using a prolonged course of rituximab, temozolamide, and HD-MTX (RTM) without consolidation. Methods We conducted a retrospective cohort study describing outcomes of pts with PCNSL or secondary CNS DLBCL who were treated on the RTM protocol. Eligible pts are treated with rituximab 375 mg/m2 on day 1 in combination with HD-MTX 8 g/m2 (days 1 and 15) and temozolamide 150 mg/m2 (days 1-5) in 28-day cycles. HD-MTX is administered with leucovorin rescue and adjusted for creatinine clearance. Initial response assessment is usually after 2 cycles with brain MRI. Once a complete response (CR) has been achieved, the day 15 HD-MTX is omitted from future cycles. Pts typically complete a total of 6-12 cycles, at the discretion of the clinician, without further planned consolidation. Descriptive and survival analyses using the Kaplan-Meier methodology were performed (STATA 13). The primary endpoints, overall survival (OS) and progression free survival (PFS) were estimated from the date of the first treatment with RTM to death, progression, or date of last follow-up. A log-rank test was utilized to compare OS/PFS between pts with PCNSL versus secondary CNS DLBCL. A Cox proportional hazard analysis was performed to evaluate the effect of patient level variables on OS. Clinical response was evaluated using International Workshop on Response Criteria for PCNSL (Abrey, J Clin Oncol 2005). Results We identified 46 pts who received RTM at our institution between 2009 and 2014. Twenty-seven (59%) pts had PCNSL and 19 (41%) pts had secondary CNS DLBCL. The median age at diagnosis was 61 years (range 21-85) with 50% males. Treatment was well tolerated. Two (4%) pts discontinued treatment prematurely and 7 (15%) pts required a dose reduction in HD-MTX due to toxicity. Toxicities included transaminitis, acute renal failure, infection, fatigue, and cytopenias. In pts with PCNSL, all received RTM as their initial treatment. Best response to therapy in this group was as follows: 19 (70%) had a CR, 3 (11%) had PR, 3 (11%) had SD and 2 (7%) had PD. The overall response rate was 81%. All patients with secondary CNS DLBCL had received prior systemic therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. Best CNS response to therapy in this group was as follows: 7 (37%) had CR, 2 (11%) had PR, 1 (5%) had SD, and 9 (47%) had PD. The overall response rate was 47%. For the entire cohort, the median OS was 41 months (m) and median PFS was 8 m. Compared with secondary CNS DLBCL, patients with PCNSL had a significantly longer median OS (54 m vs. 5 m; p<0.01) (Figure 1). PFS was also significantly longer for pts with primary versus secondary CNS DLBCL (22 m vs. 2 m; p=0.02) (Figure 2). Univariate cox analysis demonstrated that sex and age did not impact OS but pts who were in a CR or PR at initial response assessment compared to SD or PD had a hazard ratio for OS of 0.12 (95% CI: 0.05 to 0.29, P<0.01). Conclusions In our cohort, pts with PCNSL had excellent outcomes using a prolonged course of the RTM regimen without the toxicities of consolidation with radiation or high dose chemotherapy. These outcomes did not translate to pts with secondary CNS DLBCL, which may be consistent with the different biology and aggressive nature of this subgroup in addition to the prior therapies received. Early response assessment is vital to assess prognosis pts as those who respond within 2 cycles of therapy have an improved OS. This data suggests that RTM without further consolidation is an acceptable alternative regimen for PCNSL. Future prospective studies are needed to validate our findings. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Ganetsky: Onyx: Speakers Bureau. Dwivedy Nasta:Millenium: Research Funding; BMS: Research Funding. Mato:Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; Celgene Corporation: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy. Schuster:Gilead: Research Funding; Janssen: Research Funding; Hoffman-LaRoche: Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Svoboda:Celgene: Research Funding; Seattle Genetics: Research Funding; Immunomedics: Research Funding; Celldex: Research Funding.

scholarly journals Systemic high-dose methotrexate plus ifosfamide is highly effective for central nervous system (CNS) involvement of lymphoma

2008 ◽  
Vol 88 (2) ◽  
pp. 133-139 ◽  
Author(s):  
Lars Fischer ◽  
Agnieszka Korfel ◽  
Philipp Kiewe ◽  
Martin Neumann ◽  
Kristoph Jahnke ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Cns Involvement ◽  
Dose Methotrexate ◽  
Highly Effective

scholarly journals A Single Institution Experience of Treating Patients with High Dose Methotrexate for Primary CNS Lymphoma and with Secondary CNS Involvement

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 31-32
Author(s):  
Tanya L Lalani ◽  
Ashley D. Staton ◽  
Andrew P. Dalovisio ◽  
Laura E. Finn ◽  
Ambuga Badari ◽  
...  
Keyword(s):  
Stem Cell ◽  
Performance Status ◽  
Primary Cns Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Cns Involvement ◽  
Ebv Infection ◽  
Dose Methotrexate ◽  
Cell Transplants

Primary CNS lymphoma is a rare condition, with annual incidence of about 1400 cases in the US. Patients with aggressive systemic lymphomas also have high incidence of CNS involvement, with poor overall prognosis. Use of high dose methotrexate based therapies has substantially altered the outlook for these patients. We present the outcomes data of patients with primary CNS lymphoma and those with secondary CNS involvement treated with high dose methotrexate from a single , FACT accredited academic transplant center. We reviewed patients treated at our center over a 42 month period between Jan 2017- June 2020. There were 19 patients with primary CNS lymphoma and 24 with secondary CNS involvement who received high dose methotrexate. There were equal number of men and women, and were mostly Caucasian. Median age at diagnosis was 60 years. Majority were HIV negative (95%). 3 of the 19 patients had EBV infection at the time of diagnosis. Majority had performance status of ECOG 1 (range: 0-4). 1 patient had CNS lymphoma in the post transplant setting (had bilateral lung transplant). 2 out of 19 patients had concurrent solid organ malignancies. 17 patients (90 %) had newly diagnosed primary CNS lymphoma. 2 patients (10 %) had relapsed disease. Patients received a median of 6 induction treatments (range 1-12) . Majority of patients (17/19) received high dose methotrexate with rituximab. 1 patient received only high dose methotrexate. 1 patient received methotrexate, procarbazine, rituximab and vincristine (R MPV). 5 patients (26%) progressed during induction. There were 7 deaths (37 %) during induction phase. Majority of the deaths occured early during induction. Majority had partial response. 1 patient had complete response . No patient has received stem cell transplant. There were no chemotherapy delays due to COVID 19 . No patient with primary CNS lymphoma was hospitalized or died due to COVID 19. 1 patient elected to defer chemotherapy due to fear of contracting COVID 19 in the hospital. No patient received the full,planned doses of high dose methotrexate during induction. Dose reductions were due to poor performance status or impaired renal function. Consolidation was mainly with high dose methotrexate. Those progressing received whole brain radiation, Ara C , or best supportive care. The PFS and OS are being evaluated at the time of this submission. There were 24 patients with secondary CNS involvement . 12 had concurrent systemic and CNS involvement. 12 patients had history of systemic lymphoma but with CNS only relapse. There were equal males and females. Median age at diagnosis was 64 years. (range 33-81). They had good performance status, with majority having PS of ECOG 1 (range 1-3). Majority were caucasian. There were 4 patients (17%) with EBV infection. 2 patients (8 %) had HIV. They received a median of 2 high dose methotrexate inductions (range: 1-10). 4 patients (17%) eventually received stem cell transplants. PFS, survival data are being evaluated at the time of this submission. In general, high dose methotrexate was well tolerated in both primary CNS lymphoma and systemic lymphoma with CNS involvement. Stem cell transplants are still being done infrequently for these patients. Disclosures Finn: Jazz Pharmaceuticals:Speakers Bureau;Celgene:Speakers Bureau;Seattle Genetics:Speakers Bureau.

scholarly journals The Outcome of Diffuse Large B-Cell Lymphoma with CNS Involvement at Diagnosis, Single-Center Experience

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-29
Author(s):  
Mubarak A Almansour ◽  
Saif Saif ◽  
Ziyad Alhrbi ◽  
Abdulrhamn Alhwaity ◽  
Ahmed Almasrahi ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Cns Involvement ◽  
Extranodal Involvement ◽  
Large B Cell Lymphoma ◽  
Dose Methotrexate ◽  
Large B Cell

Introduction Central nervous system involvement is uncommon in diffuse large B cell lymphoma but always associated with a poor prognosis. We reviewed the risk of CNS involvement at diagnosis, clinical features, and survival outcome of patients with diffuse large B cell lymphoma with CNS involvement. Patients and Methods All patients with diffuse large B cell lymphoma from January 2005 to December 2019 at Princess Noorah Oncology Center were retrospectively reviewed. We included patients 15 years old or over, with biopsy-proven diffuse large B cell lymphoma. Patients with HIV disease, double or triple hit lymphomas, or Burkitt's like lymphomas were excluded. CNS involvement was confirmed by clinical, brain imaging, cerebrospinal fluid flow cytometry or biopsy Results A total of 406 patients with DLBCL were identified. The median age was 58 years. The majority of patients had stage III and IV disease (68%) and had more than one site of extranodal involvement (66%). The majority of the patients had intermediate to high IPI (66%) and elevated LDH (67%). A large proportion of patients had high CNS IPI (36%), and a minority of patients received either intravenous prophylaxis high dose methotrexate (11%) or Intrathecal methotrexate (3%). The majority of patients were treated with R-CHOP chemotherapy (92%). In total, 17 (4%) patients had CNS involvement: 9 patients (2.2 %) at diagnosis and 8 (2%) at relapse. All the nine patients who had CNS involvement at diagnosis had advanced-stage disease except one patient. Six patients had another extranodal involvement. Four out of nine patients had a non-germinal center phenotype, and all four patients had parenchymal rather than leptomeningeal involvement. All the patients received R-CHOP chemotherapy alternating with high dose methotrexate except one patient who received palliative treatment. Five out of nine patients achieved CR and survived. For those patients who had CNS relapse, the median time to relapse was 11.8 months (range 6 to 19 months), and most of the patients experienced a relapse in the first 6-13 months. All patients had an advanced stage, extranodal involvement, intermediate to high CNS-IPI, and only two of them received high dose methotrexate, and one patient received radiotherapy. Only two patients are alive: one patient received high dose methotrexate and high dose Ara C followed by high dose chemotherapy and autologous stem cell transplant. Another patient received salvage R-ESHAP for systemic relapse alternating with intrathecal MTX and waiting for stem cell transplant. The 5-year overall and progression-free survival rates for the entire DLBCL group were 84% and 73 %, respectively. Conclusion CNS involvement in diffuse large B cell lymphoma carries a poor prognosis. Aggressive CNS-directed therapy should be considered, especially in young fit patients. Disclosures No relevant conflicts of interest to declare.

High-Dose Therapy (HDT) with Hematopoietic Stem Cell Transplantation (HSCT) Is Effective Therapy for Patients with Non-Hodgkin Lymphoma (NHL) and Central Nervous System (CNS) Involvement

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1358-1358 ◽  
Author(s):  
R. Gregory Bociek ◽  
Peerapon Wong ◽  
Fausto R. Loberiza ◽  
Philip Bierman ◽  
Julie M. Vose ◽  
...  
Keyword(s):  
Overall Survival ◽  
Conflicts Of Interest ◽  
B Cell Lymphoma ◽  
Leptomeningeal Disease ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Cns Involvement ◽  
Hematopoietic Stem ◽  
Dose Methotrexate ◽  
Sensitive Relapse

Abstract Abstract 1358 Patients with NHL and CNS involvement have a poor prognosis when treated with conventional therapy. We performed a retrospective review of the Nebraska Lymphoma Study Group database to identify patients with NHL and CNS involvement who underwent HSCT. CNS involvement was defined as the presence of lymphomatous cells in cerebrospinal fluid, clear evidence of leptomeningeal disease by imaging studies, or biopsy proven parenchymal disease. Between January 1991 and December 2006, 24 such patients underwent HDT/HSCT. The median age at transplantation was 43 years (range 20–61). Fifty four percent of patients had diffuse large B-cell lymphoma. Sixty three percent of patients had parenchymal CNS involvement. CNS directed therapy as part of salvage prior to transplantation included intrathecal chemotherapy in 19 patients, high-dose methotrexate in 15 patients, and cranial irradiation in 10 patients. All but one patient achieved CNS remission prior to transplant. Twenty patients underwent autologous HSCT and four underwent allogeneic HSCT. The majority of patients were conditioned with carmustine, etoposide, cytarabine and melphalan (BEAM). At a median follow-up of 67 months for surviving patients (range 35–224 mo) the 1-year progression-free survival (PFS) is 50% (95% confidence interval [CI] 30–67) and the 5-year PFS is 38% (95% CI 20–56). The 1-year overall survival (OS) is 65% (95% CI 44–80) and the 5-year overall survival is 52% (95% CI 31–70). Eleven patients have relapsed and all relapses occurred within 13 months of HSCT. Thirteen patients remain alive and in remission. There have been 9 deaths due to disease recurrence and one death with no evidence of relapse. Among 15 patients who received high-dose methotrexate as part of CNS directed therapy the 5-year probability of PFS was 47% (95% CI 23–68) compared with 22% (95% CI, 3–51) in 9 patients not receiving high-dose methotrexate (p = 0.24). For patients transplanted as consolidation of initial therapy (n = 9) the 3-year probability of PFS was 63% (95% CI 29–96) compared with 36% (95% CI 0–71) for 12 patients transplanted in sensitive relapse (p = 0.36). Those same 9 patients had an 88% probability of survival at three years post transplant (95% CI 65%-100%) compared with 33% (95% CI 0–68) for the 12 patients with sensitive relapse (p = 0.046). In conclusion patients with NHL and CNS involvement who undergo HDT/HSCT appear to have similar outcomes to patients transplanted without CNS involvement. Patients destined to relapse appear to do so relatively soon after transplantation. Patients who received high-dose methotrexate as CNS directed therapy prior to transplant had a trend toward superior PFS compared with those receiving only intrathecal methotrexate, CNS irradiation, or both. Disclosures: No relevant conflicts of interest to declare.

High-dose methotrexate-induced reversible grade 4 hyperbilirubinaemia and transaminitis in an adolescent with Burkitt Leukaemia

2021 ◽  
Vol 14 (1) ◽  
pp. e237512
Author(s):  
Sanjeev Khera ◽  
Randhir Ranjan ◽  
Sateesh Ramachandran ◽  
Ajay Beriwal
Keyword(s):  
Liver Injury ◽  
Clinical Significance ◽  
Short Latency ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Drug Induced ◽  
Common Cause ◽  
Drug Induced Liver Injury ◽  
Dose Methotrexate

Symptomatic drug-induced liver injury (DILI) is an uncommon problem. Direct DILI is dose-related, predictable with short latency (hour to days) and is generally associated with transient and reversible transaminitis without jaundice. Antimetabolites including methotrexate are a common cause for direct DILI. Hepatotoxicity associated with high-dose methotrexate (HD-MTX) is generally transient and includes reversible elevation of transaminase in up to 60% and associated hyperbilirubinaemia (≤grade 2) in 25% of courses and therefore is of no clinical significance. Severe grades of DILI with HD-MTX (grade ≥4) are extremely rare. We describe an adolescent with Burkitt leukaemia who had reversible grade 4 DILI including hyperbilirubinaemia postfirst course of HD-MTX. Rechallenge with two-third dose of HD-MTX in subsequent chemotherapeutic cycle did not cause recurrence of DILI.

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