Rituximab, Methotrexate, Procarbazine and Lomustine (R-MPL) for the Treatment of Primary CNS Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 48-49
Author(s):  
Eyal Lebel ◽  
Neta Goldschmidt ◽  
Tali Siegal ◽  
Alexander Lossos ◽  
Moshe Gatt ◽  
...  
Keyword(s):  
Medical Center ◽  
Performance Status ◽  
Primary Cns Lymphoma ◽  
Response To Treatment ◽  
Cns Lymphoma ◽  
High Dose ◽  
Cell Transplant ◽  
Rare Type ◽  
End Of Treatment ◽  
Grade 3

Introduction: Primary central nervous lymphoma (PCNSL) is a rare type of non-Hodgkin lymphoma that may involve the brain, spinal cord, leptomeninges and vitreous. The median age at diagnosis is in the fifth decade and most patients (pts) present with significant neurologic deficit and a low performance status. The optimal treatment of PCNSL is controversial. High dose methotrexate (HDMTX) is a standard treatment of PCNSL and is more effective when given in combination with other CNS-penetrating medications, which, however, add to the toxicity of the treatment. We aimed to evaluate the effectiveness and the safety of the combination of rituximab, HDMTX, procarbazine and lomustine (R-MPL) in pts with PCNSL. Patients and methods: We retrospectively reviewed the files of PCNSL pts treated in Hadassah Medical Center, Jerusalem, Israel, between the years 2006-2019. The medical records were reviewed for demographic details and initial disease characteristics (age, sex, performance status, laboratory results, cerebrospinal fluid (CSF) content and tumor location), and for therapeutic details including chemotherapy protocol, toxicity, response to treatment and survival. We excluded pts who could not receive HDMTX. The R-MPL is a 42-day cycle protocol, consisting IV Rituximab 375 mg/m2 on days 1, 15 and 28, IV HDMTX 5 g/m2 (3.5 g/m2 for pts > 60 Years (y)) on days 2, 15 and 29, PO procarbazine 100 mg/m2 (60 mg/m2 for pts > 60 y) on days 3-9, PO lomustine 60 mg/m2 (40 mg/m2 for pts > 60 y) on day 2. Six to nine intrathecal (IT) injections of MTX / cytarabine were included for pts with positive CSF cytology, tumor adjacent to ventricles, or per physician's decision. Rituximab was given for no more than 8 doses in total. A total of 3-4 courses of R-MPL were given. Responsive pts could proceed to autologous stem cell transplant (ASCT) with TECAM conditioning or 2 cycles of intermediate dose cytarabine (IDAC, 1.5 g/m2), 2 doses in each cycle. Those who achieved less than CR or had significant toxicity to R-MPL received additional ifosfamide/etoposide or high dose cytarabine or temazolamide or topotecan. Radiation was given only for salvage. Results: Fifty-two pts were included in the study. Median age was 62 years (range 28-94). Three (6%) had leptomeningeal involvement, thirteen (25%) had vitreoretinal involvement, 30 (58%) had involvement of the deep brain. Mean ECOG, IELSG and MSKCC scores were 1.98, 2.53 and 1.94 respectively. The median number of HDMTX doses was 8 (range 3-16). Forty-five (87%) pts completed at least one 42-day cycle of R-MPL. Among this group, 29 (64%) pts received at least 3 IT injections, 12 (27%) underwent ASCT, 10 (22%) received IDAC, and 7 (16%) received other chemotherapies. The median follow-up was 27 months (m) (range 0.4-140m). The overall response rate (ORR) was 79% (41/52), and the complete response (CR) rate was 52% (27/52). The median progression free survival (PFS) was 15.5m and the median overall survival (OS) was 27m. Among the 45 pts who received at least one R-MPL cycle, the ORR was 87% (39/45), the CR rate was 60% (27/45), the median PFS was 84m and the median OS was not reached (figure 1). Known prognostic factors correlated with OS: age (p<0.01), ECOG performance status (p<0.01), CSF protein (p=0.01) and IELSG/MSKCC scores (p=0.05/0.04). Patients who received at least 3 IT injections had a trend to longer PFS (32.4m Vs 19.2m, p=0.09), and a significant OS benefit (48.6m Vs 20.8m, p<0.01). In a multivariable model, the effect of IT injections was independent of age, sex and IELSG score, and attenuated by number of HDMTX doses. ASCT/IDAC did not improve PFS/OS, however numbers were small. Achieving CR at the end of treatment strongly correlated with PFS/OS, but timing of best response (after one 42-day cycle Vs later) did not. Grade 3-4 adverse events included infections (21%) and kidney injury (13%). Two pts died during therapy, both in the 1st cycle due to disease progression. Ten pts (19%) discontinued therapy due to toxicity. No treatment related mortality (TRM) was documented. Conclusions: The R-MPL protocol achieved a favorable ORR/PFS/OS as described, with reasonable grade 3-4 toxicity and no TRM. The advantage of ASCT/IDAC could not be assessed due to small number of pts. IT injections (at least 3) and achievement of CR at the end of treatment correlated with survival. The R-MPL protocol was reported in previous trials only among the elderly, and should further be evaluated in all age groups. Disclosures Goldschmidt: Abbvie Inc: Consultancy, Research Funding.

scholarly journals Management and outcome of primary CNS lymphoma in the modern era

Neurology ◽  
2020 ◽  
Vol 94 (10) ◽  
pp. e1027-e1039 ◽  
Author(s):  
Caroline Houillier ◽  
Carole Soussain ◽  
Hervé Ghesquières ◽  
Pierre Soubeyran ◽  
Olivier Chinot ◽  
...  
Keyword(s):  
Karnofsky Performance Status ◽  
Performance Status ◽  
Real Life ◽  
Primary Cns Lymphoma ◽  
Whole Brain Radiotherapy ◽  
Progression Free Survival ◽  
Population Based ◽  
Cns Lymphoma ◽  
High Dose ◽  
Population Based Study

ObjectiveReal-life studies on patients with primary CNS lymphoma (PCNSL) are scarce. Our objective was to analyze, in a nationwide population-based study, the current medical practice in the management of PCNSL.MethodsThe French oculo-cerebral lymphoma network (LOC) database prospectively records all newly diagnosed PCNSL cases from 32 French centers. Data of patients diagnosed between 2011 and 2016 were retrospectively analyzed.ResultsWe identified 1,002 immunocompetent patients (43% aged >70 years, median Karnofsky Performance Status [KPS] 60). First-line treatment was high-dose methotrexate-based chemotherapy in 92% of cases, with an increasing use of rituximab over time (66%). Patients <60 years of age received consolidation treatment in 77% of cases, consisting of whole-brain radiotherapy (WBRT) (54%) or high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) (23%). Among patients >60 years of age, WBRT and HCT-ASCT consolidation were administered in only 9% and 2%, respectively. The complete response rate to initial chemotherapy was 50%. Median progression-free survival was 10.5 months. For relapse, second-line chemotherapy, HCT-ASCT, WBRT, and palliative care were offered to 55%, 17%, 10%, and 18% of patients, respectively. The median, 2-year, and 5-year overall survival was 25.3 months, 51%, and 38%, respectively (<60 years: not reached [NR], 70%, and 61%; >60 years: 15.4 months, 44%, and 28%). Age, KPS, sex, and response to induction CT were independent prognostic factors in multivariate analysis.ConclusionsOur study confirms the increasing proportion of elderly within the PCNSL population and shows comparable outcome in this population-based study with those reported by clinical trials, reflecting a notable application of recent PCNSL advances in treatment.

A Detailed Evaluation of Transplant-Related Toxicities and Outcome for Patients with CNS Lymphoma (CNSL) Consolidated with High-Dose Therapy and Autologous Stem Cell Transplantation (HDT-ASCT) Using Thiotepa, Busulfan (Bu), Cyclophosphamide (TBC) Conditioning

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4354-4354
Author(s):  
Michael Scordo ◽  
Valkal Bhatt ◽  
Meier Hsu ◽  
Antonio M. Omuro ◽  
Matthew J. Matasar ◽  
...  
Keyword(s):  
Research Funding ◽  
Secondary Malignancy ◽  
Cns Lymphoma ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Kaplan Meier ◽  
Clinically Significant ◽  
Grade 3

Abstract Background: HDT-ASCT with TBC conditioning has emerged as a common consolidation strategy for patients (pts) with relapsed/refractory (rel/ref) primary (PCNSL) or secondary (SCNSL) (Welch et al, Leuk & Lymph 2014). In a prospective study, chemosensitive PCNSL pts in first remission after induction with R-MPV (rituximab, MTX, procarbazine and vincristine) proceeding to HDT-ASCT with TBC conditioning, experienced an encouraging 2-year PFS and OS of 75% and 81%, respectively (Omuro et al, Blood, 2015). Three of these patients experienced transplant-related mortality (TRM, 11.5%), which appears greater than HDT-ASCT for other lymphomas. The purpose of this report is to correlate characteristic toxicities of TBC conditioning for CNSL to pre-HDT-ASCT clinical variables. Methods: The MSKCC IRB approved this retrospective chart review. Eligible pts (n=34) were ≥ 18 years of age with PCNSL or SCNSL that was chemosensitive to induction therapy after which they proceeded to HDT-ASCT conditioned with TBC between December 2006 and April 2015. All pts included were treated outside of prospective clinical trials. Clinically significant grade 3-5 non-hematologic toxicities per CTCAE 4.0 occurring in >20% of pts were recorded from the initiation of conditioning until 6 months post ASCT (Figure 1). Pre-HDT-ASCT variables for analysis include: age, gender, disease (PCNSL or SCNSL), Karnofsky performance status (KPS), hematopoietic cell transplant comorbidity index (HCT-CI), number of prior regimens, prior use of whole-brain radiotherapy (WBRT), and disease status prior to HDT-ASCT (CR/CRu or PR). We evaluated the association of these pre-HDT-ASCT characteristics with the number of clinically significant grade 3-5 non-hematologic toxicities (≥4 vs. <4) using FisherÕs exact test. We further estimated progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier methods. Results: Thirty-three patients (97%) experienced ≥ 1 grade 3-5 non-hematologic toxicity. Febrile neutropenia (grade 3) occurred in 32 pts (94%). Of all pre-HDT-ASCT variables, only the number of prior regimens (>2) was significantly associated with incurring more grade 3-5 non-hematologic toxicities, p=0.04 (Table 1). With a median follow-up for survivors of 12 months (range, 1.5-86.2 months), PFS was 79% (95% CI, 65-96) and OS was 82% (95% CI, 68-98) at 1 year (Figures 2 and 3). During the follow-up period, there were 7 pt deaths: 4 died of disease, 2 died secondary to TRM (5.9%), and one died of a secondary malignancy (squamous cell carcinoma) 86.2 months after HDT-ASCT. There were no progression events beyond 12 months. In a limited subset analysis wherein n=22 had first dose bu pharmacokinetics evaluated, pre-HDT-ASCT variables were not associated with higher bu AUC levels, though 64% of these pts required a dose reduction. Conclusions: We reaffirmed that HDT-ASCT with TBC conditioning is effective consolidation for CNSL, but it is associated with more grade 3-5 non-hematologic toxicity in pts having had >2 prior regimens. Risk-adapted dose attenuation of TBC conditioning for this group of pts may mitigate observed toxicity. Table 1. Association of Pre-ASCT Variables & Grade 3-5 Non-hematologic Toxicities Number of Clinically Significant Grade 3-5 Toxicities Pre-ASCT Variables All (N=34) Fewer than 4 (N=21) 4 or more (N=13) p-value Age 0.71 <60 23 (68%) 15 (71%) 8 (62%) ≥60 11 (32%) 6 (29%) 5 (38%) Gender 0.72 Female 13 (38%) 9 (43%) 4 (31%) Male 21 (62%) 12 (57%) 9 (69%) Disease 0.30 PCNSL 19 (56%) 10 (48%) 9 (69%) SCNSL 15 (44%) 11 (52%) 4 (31%) KPS 0.99 ≥80 32 (94%) 20 (95%) 12 (92%) <80 2 (6%) 1 (5%) 1 (8%) BMT HCT CI 0.99 ≤2 17 (50%) 11 (52%) 6 (46%) >2 17 (50%) 10 (48%) 7 (54%) Number of Prior Regimens 0.04 ≤2 21 (62%) 16 (76%) 5 (38%) >2 13 (38%) 5 (24%) 8 (62%) WBRT 0.17 No 28 (82%) 19 (90%) 9 (69%) Yes 6 (18%) 2 (10%) 4 (31%) Disease state prior 0.99 CR/CRu 29 (85%) 18 (86%) 11 (85%) PR 5 (15%) 3 (14%) 2 (15%) Figure 1. Analysis of Grade 3-5 Non-Hematologic Toxicities Figure 1. Analysis of Grade 3-5 Non-Hematologic Toxicities Figure 2. Kaplan-Meier Curve for PFS Figure 2. Kaplan-Meier Curve for PFS Figure 3. Kaplan-Meier Curve for OS Figure 3. Kaplan-Meier Curve for OS Disclosures Bhatt: Spectrum: Consultancy. Moskowitz:GSK: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding.

Rituximab, methotrexate (MTX), procarbazine, and vincristine (R-MPV) followed by consolidation high-dose chemotherapy (HDC) and autologous stem-cell transplant (ASCT) for newly diagnosed primary CNS lymphoma (PCNSL).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2008-2008 ◽  
Author(s):  
Antonio Marcilio Padula Omuro ◽  
Denise Correa ◽  
Craig Moskowitz ◽  
Matthew J. Matasar ◽  
Lisa Marie DeAngelis ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Primary Endpoint ◽  
Primary Cns Lymphoma ◽  
Unknown Etiology ◽  
Cns Lymphoma ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Induction Regimen

2008 Background: In our previous study in newly diagnosed PCNSL, induction chemotherapy with MTX and cytarabine followed by consolidation HDC (carmustine, etoposide, cytarabine, melphalan [BEAM]) with ASCT without radiotherapy resulted in only 50% of pts transplanted, reflecting low efficacy of induction chemotherapy, and short intent-to-treat (ITT) median PFS (=6m). In this phase II trial, we sought to optimize this strategy by utilizing a more effective induction regimen (R-MPV) and a more aggressive HDC regimen (Soussain et al). Methods: Pts received 5-7 cycles of R-MPV (MTX: 3.5g/m2) and if a partial or complete response was achieved, HDC with thiothepa, cyclophosphamide and busulfan was given, followed by ASCT and no radiotherapy. The primary endpoint was ITT 1 year event-free survival (promising: 75%, non-promising: 50%; 90% power, significance=0.05). Follow-up included comprehensive neuropsychological evaluation. Results: Accrual has been completed (N=32 pts, median age 57 [range 23-67], median KPS=80). Following R-MPV, 17 pts achieved a CR, 13 pts a PR and two pts progressed. A total of 25 (78%) pts were transplanted; the reasons for not receiving transplant were progressive disease (N=2), poor performance status/ physician’s decision (N= 2), mobilization failure (N=1) and consent withdrawn (N= 2). One pt who withdrew consent relapsed and received HDCASCT for salvage. Two (8%) pts died from early complications of ASCT (Stevens-Johnson: one, sepsis: one) and one pt experienced a fatal late colitis of unknown etiology. In the ITT population, the median EFS and OS have not been reached after a median follow-up of 22 months. The 1 year EFS was 78% (95%CI 58-90) and the 2y OS was 76% (95% CI 54-89). No pt has developed delayed neurotoxicity. Conclusions: R-MPV induction regimen resulted in improved response rates, allowing 78% of pts to receive HDC-ASCT. Although more toxic, this regimen resulted in excellent disease control and survival in the ITT population, far exceeding the efficacy of our previous transplant study. The primary endpoint was met, warranting further investigation.

scholarly journals Alternative Consolidation Strategy after High Dose Methotrexate, Rituximab and Temozolamide in Primary CNS Lymphoma - the Henry Ford Experience

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-5
Author(s):  
Joyce Philip ◽  
Shivani Sharma ◽  
Vijayalakshmi Donthireddy
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplant ◽  
Primary Cns Lymphoma ◽  
Autologous Stem Cell Transplant ◽  
Cns Lymphoma ◽  
High Dose ◽  
Cell Transplant ◽  
High Dose Methotrexate ◽  
Dose Methotrexate

Background: Treatment for primary CNS lymphoma involves a methotrexate-based induction therapy followed by consolidation. The optimal consolidation treatment after induction with a high dose Methotrexate (HD-MTX), Rituximab and Temozolomide regimen has not been fully established. The CALGB 50202 regimen using Etoposide and Cytarabine consolidation was associated with significant toxicity. We sought to review the results of alternative consolidation regimens and evaluate the progression free survival and overall survival. Methods: A retrospective cohort study was conducted to evaluate the efficacy of alternative consolidation regimens such as autologous stem cell transplant and HDMTx alone. Patients diagnosed with primary CNS lymphoma between November 2012 and March 2019 were identified. All patients received the same induction chemotherapy based on the CALGB 50202 protocol. Data was collected for baseline characteristics, progression free survival and overall survival. Results: 38 patients had a diagnosis of primary CNS lymphoma. 15 patients received treatment as per the CALBG 50202 induction protocol with high dose Methotrexate, Rituximab and Temozolomide. Of the 15 patients, 11 patients (69%) achieved a complete remission (CR) after induction therapy. 7 patients received an autologous stem cell transplant for consolidation, 5 patients received HD-MTX alone for consolidation and one patient was placed on Lenalidomide maintenance. 2 patients did not receive any consolidation therapy due to progressive disease and/or death. At a median follow up of 2.7 years for the entire cohort, median PFS was 31.7+ months and median OS was 32.5+ months. At a median follow up of 2.7 years for patients who were consolidated with an autologous stem cell transplant, median PFS and median OS was 27.2+ and 32.5+ months respectively. At a median follow up of 5.5 years for patients who were consolidated with treatments other than transplant, median PFS and OS was 65.6+ months. There were no deaths attributed to treatment related toxicity. To date, 4 patients of the entire cohort have died, with a median survival time among surviving patients of 3.6 years (range, 0.68-7.05 years). There were no deaths attributed to treatment related toxicity. Conclusion: Patients with primary CNS lymphoma who received induction therapy as per CALGB 50202 regimen and received alternative consolidation therapies with either autologous stem cell transplant or HD-MTX based consolidation achieved prolonged PFS and OS comparable if not superior to the Etoposide and Cytarabine consolidation. Results of the ongoing CALGB 51101 trial will determine the utility of EA consolidation. Disclosures No relevant conflicts of interest to declare.

scholarly journals NQPC-5 Does high-dose methotrexate-based chemotherapy for relapsed primary CNS lymphoma increase a risk of leukoencephalopathy with prior whole brain radiotherapy?

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi22-vi22
Author(s):  
Keiichi Kobayashi ◽  
Nobuyoshi Sasaki ◽  
Kuniaki Saito ◽  
Yuki Yamagishi ◽  
Naomi Hanayama ◽  
...  
Keyword(s):  
Performance Status ◽  
Primary Cns Lymphoma ◽  
Central Nervous System Lymphoma ◽  
Whole Brain Radiotherapy ◽  
Progression Free Survival ◽  
Cns Lymphoma ◽  
High Dose ◽  
Whole Brain ◽  
Brain Radiotherapy ◽  
Study Results

Abstract Backgrounds: Standard care for primary central nervous system lymphoma (PCNSL) comprises high-dose (HD) methotrexate (MTX) -based chemotherapy with or without consolidation whole brain radiotherapy (WBRT). HD-MTX administration following WBRT has been suggested to increase a risk of leukoencephalopathy. However, given that there are no other agents with efficacy similar to or better than MTX, patients with relapsed PCNSL may often be treated with regimens containing HD-MTX if the initial MTX treatment achieved a long-term complete remission. Here, we retrospectively analyzed prevalence and an extent of white mater damages in association with prior WBRT in patients with relapsed PCNSL treated with HD-MTX based therapy. Patients & methods: Among 79 patients with relapsed/refractory PCNSL in a total of 162 patients with newly-diagnosed PCNSL treated in our institution from April, 2000 to February, 2021, 35 patients were identified with evaluable KPS, MMSE, and Fazekas scale data at both baseline and follow-up periods. Of the 35 patients, 22 were treated with chemotherapy at a relapse (10 with prior WBRT, while 12 without WBRT), and were included in this preliminary study. Results: In the WBRT group (male/female: 5/5), median age was 65 years (range, 45–73), initial median KPS was 70 (40–90), and median WBRT dose was 27 Gy (23.4–40). Median progression-free survival (mPFS) was 11.8 months, and median overall survival (mOS) was not reached. In the non-WBRT group (M/F 8/4), median age 75 (62–84), initial mKPS 80 (50–90), mPFS 16.2 m, and mOS not reached. Initial KPS and MMSE score tended to be worse in WBRT group, presumably due to enrichment of patients with poorer performance status and more comorbidities. A decline in the Fazekas score was not associated with MMSE deterioration.Conclusions: The preliminary analysis was not informative enough, and further extensive imaging analysis will be exploited.

Treatment of Primary CNS Lymphoma with Induction High-Dose Methotrexate, Temozolomide, Rituximab Followed by Consolidation Cytarabine/Etoposide: A Pilot Study with Biomarker Analysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1364-1364 ◽  
Author(s):  
Samar Issa ◽  
Arthur Shen ◽  
Jon Karch ◽  
Cigall Kadoch ◽  
Marc Shuman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Performance Status ◽  
Primary Cns Lymphoma ◽  
Immunohistochemical Analysis ◽  
Cns Lymphoma ◽  
High Dose ◽  
Whole Brain Irradiation ◽  
Whole Brain ◽  
Brain Irradiation ◽  
Biomarker Analysis

Abstract Background: There is no consensus on the optimal treatment for patients diagnosed with primary CNS lymphoma (PCNSL). The goals of this study were: to determine the safety and efficacy of a methotrexate (MTX)-based induction therapy followed by high-dose consolidation chemotherapy and the elimination or deferral of whole brain irradiation, to identify molecular markers in PCNSL which predict sensitivity to chemotherapy and outcome. Methods: 23 newly diagnosed, CD20-positive, immunocompetent PCNSL patients were treated with combination high-dose intravenous MTX (8 gm/m2), temozolomide (150 mg/m2/day) and intravenous rituximab (375 mg/m2) (MTR). Patients in complete remission (CR) after eight courses of MTX were offered consolidation with high-dose cytarabine (2 g/m2 x 8 doses) and etoposide (40 mg/kg over 96 hours) (AE). Candidate markers of outcome in PCNSL were identified by gene expression profile analysis of an independent, multicenter dataset of PCNSL tumors. Immunohistochemical analysis of one of these markers, death-associated protein-1 (DAP-1), was performed on paraffin sections of tumors from 18 of the patients treated with the MTR regimen. Results: MTR induction followed by AE consolidation was well tolerated with no treatment-related mortality or evidence for neurotoxicity. Thirteen patients (56.5%) attained CR with induction; 8 received consolidation; 5 in CR refused AE. Median progression-free (PFS) and overall survival (OS) has not yet been reached with a median follow-up of 33 months. Karnovsky performance status (KPS) correlated with improved survival (p<0.0281). Expression by lymphoma cells of DAP-1, a regulator of apoptosis, was associated with improved progression-free survival (p<0.03) and overall survival (p<0.038). Conclusions: Combination MTR followed by AE is well tolerated in PCNSL. PFS appears at least similar to regimens that contain whole brain irradiation. A multi-center study has been initiated to further evaluate this regimen. DAP-1 may be a tumor suppressor whose expression in PCNSL predicts a favorable response to MTX-based therapy.

Treatment of Primary CNS Lymphoma With Methotrexate and Deferred Radiotherapy: A Report of NABTT 96–07

2003 ◽  
Vol 21 (6) ◽  
pp. 1044-1049 ◽  
Author(s):  
Tracy Batchelor ◽  
Kathryn Carson ◽  
Alison O’Neill ◽  
Stuart A. Grossman ◽  
Jane Alavi ◽  
...  
Keyword(s):  
Tumor Therapy ◽  
Single Agent ◽  
Primary Cns Lymphoma ◽  
Entire Group ◽  
Cns Lymphoma ◽  
High Dose ◽  
Ocular Involvement ◽  
Karnofsky Performance Score ◽  
End Point ◽  
Grade 3

Purpose: A multicenter, phase II study of single-agent, intravenous methotrexate in newly diagnosed non-AIDS-related primary CNS lymphoma was conducted in the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium. Methods: Methotrexate (8 g/m2) was initially administered every 2 weeks. The primary end point was radiographic CR or PR, as defined by standard radiographic criteria, and secondary end points were survival and drug-related toxicity. Results: Twenty-five patients were enrolled with a mean age of 60 years and median Karnofsky Performance Score of 80. Three of 14 patients who underwent lumbar puncture had malignant cells on CSF cytopathology, and five of 25 patients had ocular involvement. Two patients could not be evaluated for the primary end point because of the absence of measurable disease in one and death before radiologic imaging in another. All patients have completed the treatment program or progressed. Among 23 patients, there were 12 CR (52%), five PR (22%), one (4%) with stable disease, and five progressions (22%) while on therapy. Seven patients died of tumor progression, and two died of other causes. Median progression-free survival was 12.8 months. Median overall survival for the entire group had not been reached at 22.8+ months. The toxicity of this regimen was modest, with no grade 3 or 4 toxicity in 13 of 25 patients, grade 3 toxicity in eight of 25 patients, and grade 4 toxicity in four of 25 patients after 287 cycles of chemotherapy. Conclusion: These results indicate that high-dose methotrexate is associated with modest toxicity and a radiographic response proportion (74%) comparable to more toxic regimens.

Complete Response After High-Dose Methotrexate-Based Chemotherapy as a Major Prognostic Factor for Primary CNS Lymphoma: An Exploratory Analysis of the LNHCP93 Trial of the Groupe d'Etude Des Lymphomes De l'Adulte.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 101-101
Author(s):  
Hervé Ghesquières ◽  
Celine Ferlay ◽  
Agathe Bajard ◽  
Catherine Sebban ◽  
David Perol ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factor ◽  
Performance Status ◽  
Primary Cns Lymphoma ◽  
Complete Response ◽  
Cns Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Status Number

Abstract Abstract 101 Background: Treatment of primary CNS lymphoma (PCNSL) is based on high-dose methotrexate (HD-MTX) containing chemotherapy (CT) followed by brain radiotherapy (RT). Initial CT allowed 30% to 63% of complete response (CR) in recent large series. After CT, consolidation RT can increase the CR rate up to 80%. Despite this high rate of response after initial treatment, the outcome of patients remained poor. The impact of the quality of response on outcome is not well known as well as the outcome of PR patients who converted to CR after RT. We assessed these questions in patients with newly diagnosed PCNSL treated with HD-MTX-containing CT followed by RT in the prospective LNHCP93 GELA study. Methods: 99 patients were treated in this prospective phase II study between 1995 and 2002. Patients younger than 61 years received C5R protocol (Blay et al. Blood 1995), Patients aged 61-70 years received reduced doses of C5R protocol and patients older than 70 years received a specific schedule with MTX, vepeside and cyclophosphamide. After CT, brain RT was planned: 20 Gy whole brain and a 36 Gy boost to the tumor bed. Responses after CT and after RT were evaluated by MacDonald criteria. Evaluation of response was made at time of the beginning of RT, 21-35 days after the last course of CT, and one month after the end of RT. Results: Median age of the 99 PCNSL patients was 63 years (range, 20-82), 51% were male, 51% had performance status >1, and 58% had involvement of deep structures of brain. Forty-five patients were younger than 61 years, 36 were aged 61-70 years and 18 older than 70 years. After a median follow-up 83 months, median overall survival (OS) and progression-free survival (PFS) were 33 and 20 months, respectively. Seventeen patients (17%) died of acute toxicity during CT; 3 patients (3%) did not receive RT; 8 patients (8%) progressed or had stable disease after CT and 3 patients (3%) had no available data. Thus, 68 patients were assessable for this exploratory study with thirty-six patients (36%) in PR and 32 patients (32%) in CR after CT. Sixteen of PR patients converted to CR after RT (44% of PR patients after CT). Median OS of patients in CR and PR after CT was 80 and 34 months with a 5-year OS probability of 65% and 29%, respectively (p=0.02). Median PFS of patients in CR and PR after CT was 60 and 21 months with a 5-year PFS probability of 56% and 17%, respectively (p=0.03). In univariate and multivariate analysis, age and response were the two prognostic factors for OS but not performance status, number of tumors at diagnosis, site of tumor (involvement of deep structures). Only response to CT was predictive of PFS in multivariate analysis but not age, performance status, number of tumors, site of tumor at diagnosis. 5-year OS was 65% for CR patients before RT compared to 31% and 28% for PR patients who converted to CR after RT and for patients not in CR after RT, respectively (p=0.06). The 5-year PFS probability was 56% for CR patients before RT compared to 13% and 20% for patients who converted to CR after RT and those not in CR after RT, respectively (p=0.09). Conclusion: Despite the inherent bias of response analysis as a prognostic factor, this analysis of a prospective study of PCNSL patients showed that only patients achieving CR after CT may experience long term survival. This study also showed that PR patients who converted to CR after RT had a poor outcome, similar to patients that did not reach a CR after chemoradiotherapy. Disclosures: No relevant conflicts of interest to declare.

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