High-dose Methotrexate-based Regimens Research Articles

Outcomes of R-MPV followed by ara-c in primary central nervous system lymphoma: A single-center retrospective analysis.

e19046 Background: Primary central nervous system lymphoma (PCNSL) lymphoma is a rare non-Hodgkin’s Lymphoma. Currently, there is no uniform consensus in the optimal management of PCNSL. In patients that can tolerate systemic therapy, induction therapy is typically done with a high-dose methotrexate-based regimen, due to evidence of better penetration of the blood brain barrier. One such regimens is high dose methotrexate combined with rituximab, procarbazine, and vincristine (R-MPV). Options for consolidation therapy include high-dose systemic therapy with stem cell rescue (ASCT), whole brain radio therapy (WBRT) and high-dose cytarabine (ara-c) with or without etoposide (EA). At our institution we utilize an R-MPV induction approach with some form of ara-c consolidation without etoposide. We aimed to execute a retrospective cohort study to analyze outcomes of this approach. Methods: All the patients diagnosed with PCNSL who received an induction regimen of R-MPV from 10/01/2020 to 06/01/2023 were included. Data was then gathered by chart review of the electronic medical record. Treatment outcomes were evaluated based on imaging with brain MRIs and PET scans. Central findings such as complete response (CR) rate, progression free survival (PFS) and overall survival (OS) were ascertained. Results: 10 charts were reviewed. 9 out of the 10 patients had a histological presentation consistent with diffuse large B-cell lymphoma; 1 patient had a diagnosis of B-cell lymphoma. In terms of demographics, the patients ages ranged from 54 to 83 years, with a median of 74 years. Complete response was achieved in 5 out of the 10 patients (CR rate of 50%), and no relapse was noted in any of these patients. 2 out of the 10 patients progressed on treatment, with 1 dying from progression of the disease. The median follow-up for patients who were still alive was 24 months. 2-year PFS was 80%, and 2-year OS was 90%. Median PFS and OS were not reached. Mean PFS and OS were 28 months and 30.5 months respectively. Conclusions: Based on our study results, the CR rate we observed for R-MPV appears consistent with existing literature on this regimen and other methotrexate-based induction regimens. Our results for R-MPV with ara-c consolidation provides similar outcomes to existing studies on treatment with different methotrexate-based induction and consolidation with ASCT, particularly the 80% PFS we observed. This percent PFS also appears similar to studies of consolidation with ara-c and EA, and superior to PFS with WBRT. Overall, these results are reassuring as in a specific set of older patients who might not be candidates for ASCT, our specific nonmyeloablative approach could be worthwhile. However, our study does have the limitation of being a single center retrospective perspective. [Table: see text]

Efficacy and Safety of Orelabrutinib-Containing Regime (TORM) As First-Line Therapy in Primary Central Nervous System Lymphoma (PCNSL): A Retrospective Analysis

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare, aggressive extranodal lymphoma with poor prognosis. Currently there is no standard therapeutic strategy for PCNSL, and high-dose methotrexate-based regimens remain the first option (Siegal et al. Acta Haematologica 2019). Recently, studies have shown that Bruton's tyrosine kinase (BTK) plays a crucial part in B cell receptor and Toll-like receptor signaling pathways, which are constitutively active in PCNSL (Shen et al. Front Oncol. 2022). BTK inhibitor has been proven effective in treating chronic lymphocytic leukemia and other B-cell lymphomas (Yoshitaka et al. Neuro-Oncology 2021). Orelabrutinib is a novel and highly selective BTK inhibitor with high cerebrospinal fluid (CSF) concentration, which has demonstrated efficacy and safety in PCNSL (Wu et al. Invest New Drugs. 2022). Thus, we conducted a retrospective study to evaluate the efficacy and safety of the orelabrutinib-containing regimens as first-line therapy for patients (pts) with PCNSL. Methods: This isa retrospective analysis of pts with PCNSL who received TORM regimens (temozolomide 150 mg/m 2 day 2-5; orelabrutinib 150 mg qd day 2-21; rituximab 375 mg/m 2 day 1; methotrexate 3.5 g/m 2 day 2; 3 weeks per cycle) as first-line induction therapy between June 2021 and April 2023. It was proposed to receive autologous stem cells transplantation (ASCT) as consolidation therapy or orelabrutinib monotherapy as maintenance after TORM therapy when deemed necessary. The primary endpoint was overall response rate (ORR) according to the International PCNSL Collaborative Group (IPCG) criteria. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: Twelve pts (8 males) with PCNSL were included, with a median age of 63.5 years (range, 40-77). All pts had a histologically confirmed diffuse large B-cell lymphoma and a history of deep intracranial lesions. 8 pts (66.7%) had non-germinal center B-cell-like subtypes. 5 pts (41.7%) had an Eastern Cooperative Oncology Group performance status of ≥2, and 10 pts (83.3%) had International Extranodal Lymphoma Study Group scores ≥2. 4 pts (33.3%) underwent ASCT after induction therapy and 4 pts (33.3%) received orelabrutinib maintenance monotherapy. As of the cut-off date (July 1, 2023), the median follow-up was 11.7 (range, 1.9-23.0) months, and median treatment cycle was 6 cycles (range, 2-9). All 12 pts were evaluated for the treatment response. An interim evaluation after 3/4 cycles was available for 12 pts, showing complete remission (CR) rate of 83.3% (10/12), partial response (PR) rate of 16.7% (2/12), giving an ORR of 100.0% (12/12, Table 1). At data cutoff, of all 12 evaluable pts, the best ORR was 100.0% (12/12), with all pts achieved CR ( Table 1). The median time to response was 1.7 (range, 0.7-2.4) months. Of 12 responders, 9 had an ongoing response, 2 developed progressive disease, and 1 died of covid-19 infection ( Figure 1). Median PFS was 22.6 months, with a 95% CI of 10.4-not reached (NR). Based one OS event, median OS was 22.6 months (95% CI, NR-NR). The most common AEs were anemia. Reported AEs were generally manageable and resolved soon after supportive treatment. AEs associated with off-target activities such as atrial fibrillation, diarrhea, and major hemorrhage were not reported. Conclusions: TORM regimens demonstrated encouraging efficacy and well-tolerated safety profile among pts with PCNSL in this retrospective study. This orelabrutinib-containing regimens may provide a potential treatment strategy for pts with PCNSL.

High-Dose Methotrexate, Ibrutinib and Temozolomide (MIT) for the Treatment of Newly Diagnosed Primary Central Nervous System Lymphoma: A Multi-Center Prospective Phase II Study

Abstract Background: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive subtype of B-cell lymphoma with poor survival. Genetic alterations often occur in the chronic active B-cell receptor signaling which mediate the response to BTK inhibition (BTKi) in PCNSL. However, the efficacy of traditional high-dose methotrexate-based regimen as a first-line treatment was suboptimal with a short effective remission time and low response rate. Therefore, we initiated this phase II trial to investigate the efficacy of novel induction combination of high-dose methotrexate (HD-MTX) plus ibrutinib and temozolomide (MIT), in the treatment of newly diagnosed PCNSL for the first time (ClinicalTrials.gov identifier: NCT04514393). Methods: Patients aged 18-75 years, newly diagnosed PCNSL and at least one measurable or evaluable lesion were enrolled. The MIT induction treatment included six cycles of HD-MTX (3.5 g/m 2, every three weeks), ibrutinib (560 mg/d, after HD-MTX clearance), and temozolomide (150 mg/m2 d1-d5, every three weeks). After the completion of the six cycles of MIT induction treatment, ASCT consolidation (only for patients < 65 years) or daily ibrutinib maintenance (560 mg/d) were administered up to two years, or until disease progression, intolerable toxicity, or death. Treatment response was evaluated by brain MRI and FDG-PET and/or cerebrospinal fluid (CSF) examination every two cycles of MIT treatment. The primary objective of this study was to evaluate the overall response rate (ORR) of MIT induction treatment. The safety profile of MIT was also investigated. At the same time, next generation sequencing (NGS) of baseline tissues and dynamic monitoring with CSF/ plasma ctDNA were performed by Nanjing Geneseeq Technology Inc. Results: Between July 2021 and October 2022, thirty-three patients were enrolled in this open-label, multi-center phase II prospective clinical study. The median age was 56 years (range: 27-75) and 17 of them were male. Eye involvement occurred in 5 patients (15%). Twenty-five patients (76%) had multiple cerebral lesions. The best ORR was 94% and complete response rate was 73%. The median follow-up was 17.5 months (range: 5.8-21.3 months) for survivors. Twenty-three patients underwent ibrutinib maintenance after 6 cycles of induction therapy. The swimmer plot of the 33 patients was shown in Figure 1. The 1-year progression-free survival was 66.4% (95%CI: 58.1-74.7%) and overall survival was 90.5% (95%CI: 85.2-95.8%) (Figure 2). Treatment-related toxicities were acceptable, with grade 3-4 neutropenia occurring in 9%, thrombocytopenia in 6%, subdural hematoma (SH) in 6%, and atrial fibrillation in 3%. The 2 patients with SH recovered following discontinuation of ibrutinib. No fungal infections and treatment-related deaths were observed. NGS of Tissue/CSF was tested in 30 patients, 19 (63%) of whom were classified as MCD subtype, 2 (7%) as BN2 subtype. The mutational profiles of baseline tissue and/or CSF samples revealed that PIM1 and MYD88 mutations were present in 75.9% and 65.5% of the entire cohort followed by BTG2 (55.2%) and CD79B (51.7%). Patients with dynamic CSF ctDNA monitoring during MIT treatment were analyzed (Figure 1). The consistence of ctDNA clearance in CSF/plasma samples and imaging complete remission was observed. Patients with clearance of ctDNA in the CSF after 2 cycles of MIT treatment achieved better PFS. Conclusions: The novel induction treatment of MIT achieved encouraging responses in newly diagnosed PCNSL patients with acceptable toxicities. The early clearance of ctDNA in CSF may be related to favorable survival. Disclosures No relevant conflicts of interest to declare.

Prognostic Factors and Outcomes of Adolescent and Adult Burkitt Lymphoma and Leukemiafrom a Low-Middle Income Country: An Experience from Hematology Cancer Consortium

The treatment of BL/L has evolved on the principles of short-course, intensive, non-cross resistant, alternating chemotherapy. These intensive high-dose methotrexate-based treatment regimens (CODOX-M/IVAC, Hyper-CVAD, BFM, LMB) have led to high response rates and cures in a significant proportion of children and young adults. The addition of rituximab has led to overall survival benefit. There is limited data that dose adjusted EPOCH-R provides a low intensity treatment option for patients who may not be able to tolerate high-dose methotrexate-based regimens. Efficacy of these regimens in real-world, more so in an LMIC setting need to be evaluated given the delays in seeking care, higher risk of treatment-related complications including infections and antecedent treatment interruptions. This retrospective multicentric study collected the data from eight-member centers of Hematology Cancer Consortium (www.hemecancer.org) using an electronic database, to analyze the clinical characteristics, treatment patterns, outcomes and prognostic factors in adolescent and adult newly diagnosed Burkitt lymphoma and leukemia diagnosed between 2012-2019 (including HIV positive). Patients who had received more than 2 weeks of chemotherapy or steroids prior to presentation were excluded. The data included demographic details, performance status (ECOG), HIV serology, bone marrow and CNS involvement, stage, treatment type, use of rituximab, response to treatment, and treatment-related mortality as assessed by the investigator of the respective centre. The primary objective was to evaluate event-free survival at 2 years. Secondary objectives were to evaluate the overall survival, impact of the treatment protocol, use of rituximab, stage, age, performance status, CNS involvement, and HIV positive status on the overall and event-free survival. A total of 312 patients were included in this study. Out of these 257 patients received treatment and were analyzed for the outcome and prognostic factors. The treated and untreated cohorts differed in age [ median age 37 years (range-25-49 years) versus 42 years (range-32-51 years); with the untreated cohort being older. Table 1 provides the baseline characteristics of the patients who received treatment. The HIV positive patients (in treated cohort) had higher LDH [median - 967.5 (range, 509- 2355) vs 589 (311-1141), p=0.003). A total of 100 (42%) patients received intensive and high-dose methotrexate-based chemotherapy, 81 (34%) patients received dose-adjusted EPOCH-based treatment whereas 56 (24%) received other low-intensity or palliative chemotherapy. Patients with HIV were largely treated with a dose-adjusted EPOCH-based regimen (25/32 patients). Patients who received a high-dose methotrexate-based regimen were younger than those who received dose-adjusted EPOCH and other lower intensity regimens (Mean age 29 years versus 42.4 and 43.9 years) At the median follow-up of 36.5 months, the 2-year EFS was 61% and 2-year OS was 73%. There was no significant difference in outcomes in HIV-positive and negative patients. On univariate analysis lack of use of rituximab and use of protocols other than high-dose methotrexate and dose-adjusted EPOCH negatively affected EFS and OS. Age had an adverse impact on the OS but not EFS whereas stage 2 or above had a negative impact on EFS. On multivariate analysis use of regimens other than high-dose methotrexate-based and dose-adjusted EPOCH was a negative prognostic factor for both EFS and OS. The HR favored high dose methotrexate and dose-adjusted EPOCH-based regimen for both EFS and OS; HR- 0.42 (95% CI,0.22,0.77) and 0.27(95% CI,0.13-0.59), respectively. Use of rituximab was associated with better OS HR-0.44(95% CI,0.21-0.93) and a trend toward better EFS - HR-0.58 (95%CI, 0.31-1.07). The treatment-related mortality was 11.2% (29/257) and high serum LDH was associated with higher mortality (p=0.003). Treatment of adolescent and adult Burkitt lymphoma and leukemia with intensive regimens (high-dose methotrexate-based) and dose-adjusted EPOCH regimen resulted in similar survival. Dose-adjusted EPOCH-based regimen was preferred in older patients. The use of rituximab in these patients adds to the overall survival benefit. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

INNV-18. PROLONGED REMISSION AFTER TREATMENT WITH SINGLE-AGENT IBRUTINIB AS MAINTENANCE THERAPY FOLLOWING SALVAGE RADIATION THERAPY FOR REFRACTORY/RELAPSE PRIMARY CNS LYMPHOMA

Abstract INTRODUCTION Primary central nervous system lymphoma (PCNSL) is a rare and aggressive disease. Standard induction therapy for PCNSL consists of a high-dose methotrexate-based (HD-MTX) regimen. For relapsed or refractory primary CNS lymphoma (r/r PCNSL), most of the non-standard treatment regimens including additional chemotherapy, stem cell transplant, or whole brain radiation therapy (WBRT) may not reach long-term remission due to intolerance of the treatment by the patients or lack of effects. Here we report a case with r/r PCNSL reached more than 50-month remission after salvage WBRT followed by single agent ibrutinib maintenance therapy. CASE REPORT: a 75-year-old female with PCNSL, experienced disease recurrence, despite undergoing multiple lines of treatment including initial HD-MTX, second-line rituximab and temozolomide, repeated HD-MTX, and a clinical trial. Because her disease was refractory to these treatment options, we decided to start WBRT as salvage therapy, which resulted in significant reduction of tumor burden. Prior studies, however, showed that r/r PCNSL patients who underwent salvage WBRT alone had a median survival of only 1-2 years. Therefore, to extend the remission after salvage WBRT, she opted to try ibrutinib, a Bruton’s tyrosine kinase inhibitor with past success in treating r/r PCNSL patients, as maintenance therapy after salvage WBRT. She tolerated well and decided to be off the treatment after 18 month-maintenance therapy. The patient has been stable clinically. She has since survived for more than 50 months after the completion of salvage WBRT plus maintenance therapy with ibrutinib. DISCUSSION Compared to prior reports of 11 to 16 months of median survival after salvage WBRT alone for r/r PCNSL, our case has had prolonged survival, which supports the potential positive effect of ibrutinib as maintenance therapy for r/r PCNSL after salvage WBRT

Clinical characteristics, prognostic indicators, and survival outcomes in intravascular lymphoma: Mayo Clinic experience (2003-2018).

Intravascular lymphoma (IVL) is a rare extranodal non‐Hodgkin lymphoma. We performed a retrospective analysis of 55 IVL patients who were treated at our institution 2003–2018. Median age at diagnosis was 68 years, and 64% were males. The most frequent presenting symptoms were skin rash 43% and weight loss 30%. MRI brain on IVL patients with CNS involvement (CNS‐IVL) showed multifocal involvement in 76% (13/17). 89% (17/19) of non‐CNS‐IVL patients with abnormal FDG‐PET had biopsy of an avid lesion resulting in definitive diagnosis. The top diagnostic biopsy site was the bone marrow (45%). 56% had multiorgan involvement. Based on CNS involvement, 36.5% (20/55) had CNS‐IVL and 63.5% (35/55) had non‐CNS‐IVL. CNS‐IVL group consists of clinically isolated CNS involvement (CNS‐only IVL) (22%;12/55) and mixed clinical CNS and peripheral site involvement (M‐IVL) (14.5%; 8/55). Non‐CNS‐IVL group consists of clinically isolated skin involvement (skin‐only IVL) (9%; 5/55) and peripheral IVL with or without skin involvement (P‐IVL); (54.5%; 30/55). Skin involvement was predominantly in the lower extremities. Pathologically, 89% (48/54) were B‐cell IVL. Rituximab + high‐dose methotrexate‐based regimen were used in 75% (12/16) of CNS‐IVL patients and RCHOP in 60% (17/28) of non‐CNS‐IVL patients. Estimated 5‐year progression free survival (PFS) and overall survival (OS) for the entire cohort were 38.6% and 52%, respectively. Skin‐only IVL was associated with excellent survival. Platelet count <150x109/L, age > 60Y, and treatment without Rituximab were poor prognostic factors. Further research is necessary to identify novel therapies.

New Treatment Approaches in Relapsing/Refractory Primary Central Nervous System Lymphomas

Background: Primary central nervous system lymphoma (PCNSL) is a rare disease that affects the brain, leptomeninges, spinal cord, cerebrospinal fluid, or vitreoretinal compartment without evidence of systemic disease. Although some treatment success is achieved with high dose methotrexate-based regimens, the prognosis is still poor. In this respect, new therapeutic approaches are needed. Methods: The clinical data of 6 patients diagnosed with primary central nervous system lymphoma in a hematology center of a university hospital were analyzed for 3 years. Ibrutinib monotherapy was applied to these 6 refractory patients as the last-stage treatment. The results were analyzed. Results: 6 patients (5 women, 1 man) with relapsed and refractory PCNSL received ibrutinib as monotherapy. As initial treatment, 3 patients received high-dose methotrexate + rituximab, 1 patient received MATRix (Rituximab, Methotrexate, Cytarabine, Thiotepa), 1 patient received high-dose methotrexate, and then only one patient received radiotherapy (RT). Two patients were consolidated with autologous transplantation and one patient with RT. All patients received treatment at a dose of 560 mg. No serious side effects have been detected. 5 patients who received ibrutinib monotherapy for the shortest 1 month and the longest 24 months died. The patient, who has been on ibrutinib monotherapy for 11 months, is being followed up stably. Conclusions: We have seen the therapeutic benefit of ibrutinib as monotherapy in our refractory patients. However, we believe that using ibrutinib as part of combination therapy at the initial stage of the disease will yield better results.

Fotemustine-Containing Regimens Versus Regimens Based on High-Dose Methotrexate in Newly Diagnosed PCNSL

Objective: This study was conducted to compare the effectiveness and safety of fotemustine-containing regimens and high-dose methotrexate-based regimens in newly diagnosed primary central nervous system lymphoma(PCNSL). Methods: From April 2012 to April 2020, 88 patients with PCNSL who received fotemustine-containing regimens and regimens based on high-dose methotrexate were retrospectively assessed in this study.47 patients were treated with fotemustine-containing regimens, of which 25 patients were treated with R-FPD (Rituximab , formustine, pemetrexed, dexamethasone) regimen, and the other 22 patients were treated with FVD (formustine, vincristine,dexamethasone) regimen. 41 patients were treated with high-dose methotrexate-based regimens, of which 26 patients were treated with MA(Methotrexate ,Cytarabine ) regimen, of which 8 patients were treated with R-MT(Rituximab ,methotrexate ,temozolomide)regimen,of which 5 patients were treated with R-MA(Rituximab ,methotrexate ,Cytarabine) regimen, and the other 2 patients were treated with RM(Rituximab ,methotrexate) combined Zebutinib regimen. Results: In the fotemustine-containing regimen groups (n=47), 18 cases were complete response(CR), 19 cases were partial response(PR), 6 cases werestable disease (SD), 4 cases were disease progression (PD), objective response rate(ORR )was 79%, and diease contral rate(DCR) was 91%.10 cases were CR in the high-dose methotrexate groups (n=41) , 17 cases of PR, 7 cases of SD, 7 cases of PD, ORR was 66%, DCR was 83%.there was no significant difference in ORR (79%vs66%, P=0.176)and DCR(91%vs83% , P=0.226) between the two groups.No significant difference was observed in the 2-year PFS rate (19.4%vs10%, P=0.149) and 3-year OS rate (24%vs15%, P=0.200) between the two groups. The main adverse reactions in the high-dose methotrexate groups were myelosuppression and mucositis. In the fotemustine-containing regimen groups, myelosuppression was the main adverse reaction. The incidence of leukopenia of grade 3 and above in the high-dose methotrexate groups and fotemustine groups was 54% and 23%, respectively. The high-dose methotrexate groups had more severe leukopenia (P= 0.001). The incidence of mucositis in the high-dose methotrexate groups (68%) was significantly higher than that in the fotemustine group (26%). Conclusion: The fotemustine-containing regimens for the treatment of newly diagnosed PCNSL has the similar efficacy to the high-dose methotrexate group, with fewer adverse reactions, better safety and tolerability, and may be a feasible regimen. DisclosuresNo relevant conflicts of interest to declare.

Improvement of outcomes of an escalated high-dose methotrexate-based regimen for patients with newly diagnosed primary central nervous system lymphoma: a real-world cohort study.

PurposeHigh‐dose methotrexate (HD‐MTX)-based chemotherapy regimen is the first-line treatment of primary central nervous system lymphoma (PCNSL). At present, doses of MTX in the range of 3.5–8 g/m2 are frequently used. However, the optimal dose of methotrexate for PCNSL remains controversial. The purpose of this real-world study was to compare the efficacy and toxicity of HD-MTX in patients with untreated PCNSL.MethodsImmunocompetent adults with newly diagnosed PCNSL between January 2015 and December 2018 were investigated and followed up to June 2019. All patients’ initial treatments were based on HD‐MTX chemotherapy regimens.ResultsA total of 73 patients were reviewed. For patients who received HD-MTX at 8 g/m2 vs.3.5 g/m2, the complete response (CR) rates were 68.29% vs 43.75% (p = 0.03), and the median PFS times were 17.7 months vs 9.05 months (HR=0.455, 95% CI 0.239–0.865, p=0.016). There was no significant difference in OS between the two groups. Serious adverse effects were uncommon and clinically manageable.ConclusionThere is a correlation of treatment response and clinical outcomes between the dosage of MTX in initial induction therapy in newly diagnosed PCNSL. MTX dose of 8 g/m2 provided a higher CR rate and PFS benefits with acceptable adverse effects.

Primary and secondary central nervous system mature T- and NK-cell lymphomas

Primary central nervous system (CNS) mature T- and NK-cell lymphomas are rare, only comprising 2% to 3% of all primary CNS lymphomas. Among them, peripheral T-cell lymphoma, not otherwise specified, anaplastic large cell lymphoma (ALCL), and extranodal NK/T-cell lymphoma (ENKTL) are the commonly reported histological subtypes. Secondary CNS T-cell lymphoma generally affects about 5% of patients with T- or NK-cell lymphoma, with some exceptions. Acute and lymphomatous subtypes of adult T-cell leukemia/lymphoma (ATLL) have high risk of CNS progression, may affect up to 20% of patients; ALK-positive ALCL with extranodal involvement >1 also has high risk of CNS progression. However, the impact and the optimal methodology of CNS prophylaxis remain unclear in systemic T-cell lymphomas. There are little data on the treatment strategy of primary and secondary CNS T-cell lymphoma. Treatment strategy derived from B-cell CNS primary lymphoma is generally used; this includes induction therapy with high-dose methotrexate-based regimens, followed by high-dose chemotherapy with autologous stem cell transplant in fit patients. There are unmet needs for patients who are not fit for intensive chemotherapy. The prognosis after CNS progression in T-cell lymphoma is dismal with the median overall survival of less than 1 year. New agents targeting T-cell lymphomas are emerging and should be tested in patients with mature T- and NK-cell lymphoma who suffer from CNS involvement.

High-dose methotrexate-based regimens and post-remission consolidation for treatment of newly diagnosed primary CNS lymphoma: meta-analysis of clinical trials

With the exception of high-dose methotrexate (HD-MTX), there is currently no defined standard treatment for newly diagnosed primary central nervous system lymphoma (PCNSL). This review focused on first-line induction and consolidation treatment of PCNSL and aimed to determine the optimal combination of HD-MTX and the long-term beneficial consolidation methods. A comprehensive literature search of MEDLINE identified 1407 studies, among which 31 studies met the inclusion criteria. The meta-analysis was performed by using Stata SE version 15. Forest plots were generated to report combined outcomes like the complete response rate (CRR), overall survival, and progression-free survival. We also conducted univariate regression analyses of the baseline characteristics to identify the source of heterogeneity. Pooled analysis showed a CRR of 41% across all HD-MTX-based regimens, and three- and four-drug regimens had better CRRs than HD-MTX monotherapy. In all combinations based on HD-MTX, the HD-MTX + procarbazine + vincristine (MPV) regimen showed pooled CRRs of 63% and 58% with and without rituximab, respectively, followed by the rituximab + HD-MTX + temozolomide regimen, which showed a pooled CRR of 60%. Pooled PFS and OS showed that post-remission consolidation with autologous stem cell transplantation (ASCT) was associated with the best survival outcome, with a pooled 2-year OS of 80%, a 2-year PFS of 74%, a 5-year OS of 77%, and a 5-year PFS of 63%. Next, whole-brain radiation therapy (WBRT) + chemotherapy showed a pooled 2-year OS of 72%, 2-year PFS of 56%, 5-year OS of 55%, and 5-year PFS of 41%, with no detectable CR heterogeneity throughout the entire treatment process. In HD-MTX-based therapy of newly diagnosed PCNSL, MPV with or without rituximab can be chosen as the inductive regimen, and the rituximab + HD-MTX + temozolomide regimen is also a practical choice. Based on our study, high-dose chemotherapy supported by ASCT is an efficacious approach for consolidation. Consolidation with WBRT + chemotherapy can be another feasible approach.

NCOG-59. PROGRESSION-FREE SURVIVAL AS A PRIMARY OUTCOME MEASURE TO COMPARE CONSOLIDATIVE STRATEGIES IN RELAPSED/REFRACTORY PRIMARY CNS LYMPHOMA

Abstract Relapsed or refractory primary CNS non-Hodgkin’s lymphoma (rrPCNSL) is a rare and challenging malignancy for which better evidence is needed to guide management. We present a retrospective cohort of 70 consecutive patients with rrPCNSL treated at the University of Washington between 2000-2020. HIV positive and secondary CNS lymphoma patients were excluded. During a median follow-up of 19.8 months, median overall survival (OS) was 18.30 months and median progression-free survival (PFS) was 12.67 months. At all stages of disease (diagnosis, first relapse, multiple relapses), PFS was an excellent predictor of OS. There was a small effect of age &amp;lt; 70 on PFS after initial diagnosis (PFS1), but no effect on PFS after first (PFS2) or subsequent (PFS3+) relapses. There was no effect of age &amp;lt; 60 on PFS1, PFS2, or PFS3+. Patients reinduced with high-dose methotrexate-based (HD-MTX) regimens had an overall response rate (ORR) of 86.7% and median PFS 17.2 months. For patients who responded to reinduction therapy, those consolidated with autologous stem cell transplant (ASCT) had median PFS of 30.3 months (n=11) compared with 12.1 months for other consolidation strategies (n=9), and 9.0 months for no consolidation (n=20). Although patients receiving ASCT were younger, KPS, sex, and the median number of recurrences were similar between consolidation groups. We conclude that PFS is a useful endpoint for rrPCNSL which predicts OS and is not associated with age. Using PFS as an endpoint, we did not detect a benefit to any consolidation strategy other than ASCT.

Nivolumab in Primary CNS Lymphoma and Primary Testicular Lymphoma with CNS Involvement: Single Center Experience

Background.Most patients with primary CNS lymphoma (PCNSL), an aggressive extranodal lymphoma confined to the CNS, have a poor prognosis in spite of development of chemotherapy regimens. First-line treatment consists of high-dose methotrexate-based (HD-MTX) regimen followed by consolidation with autologous stem cell transplantation or whole brain radiotherapy. Given that this tumor manifests predominantly in older patients with median age of 65 years, many patients are unable to tolerate intensive chemotherapy. Moreover, most patients eventually present with relapsed or refractory (r/r) disease. Relapse or refractory (r/r) PCNSL has a poor prognosis with median overall survival not exceeding 3.5 months (Langner-Lemercier et al, 2016) and these patients should be offered a clinical trial whenever possible. These groups are in need of safe, tolerable and effective therapeutic approaches. Primary testicular lymphoma (PTL) shares biological and clinical similarities with PCNSL and often present with CNS involvement. Such patients are also in need of new approaches, especially if they are refractory or not suitable to HD-MTX. Given high PD-1/PD-L1 expression in tumor microenvironment (Berghoff, 2014), immune checkpoint inhibitors were successfully tested in r/r PCNSL and PTL setting. However, data are still scarce and limited to case series (Nayak et al., 2017; Graber et al. 2020). Here we present Pavlov University experience of the treatment of PCNSL and PTL with CNS involvement with PD-1 inhibitor nivolumab. Methods.Eight patients, 2 men and 6 women, with PCNSL and one patient with PTL with CNS involvement treated at the Pavlov University between 2017 and 2020 were included into analysis. Median age at a diagnosis was 62 (28-66) years. Two patients (22%) had ECOG score 3-4 and therefore could not be considered for intensive MTX containing frontline treatment. In all of the cases the tumor histological type was diffuse large B-cell lymphoma. All patients had parenchymal involvement: 7 patients had multifocal disease; deep structures were involved in 2 patients. One patient had leptomeningeal involvement. Nivolumab was used in a first-line setting in 2 patients (22%). In 7 (78%) patients with relapsed/refractory disease, the median number of treatment lines prior to nivolumab was 1 (1-7). Nivolumab was given every 2 weeks in the 100 mg dose. Adverse events were defined according to NCI CTC-AE 5.0. Results.At the time of analysis, the median follow-up was 18 (3-44) months. Median number of nivolumab cycles was 10 (2-23). Seven (78%) patients had an objective response: complete response in 3 patients (33.3%) and partial response in 4 patients (44.4%). Two patients (22.2%) were refractory to treatment. Two-year overall survival (OS) was 44% with median OS of 12 months. Two-year progression-free survival (PFS) was 26% with median of PFS 12 months. Оne responder had a moderate increase of tumor volume on MRI after two months of therapy followed by complete disappearance of brain lesions on sequential imaging at 4 months after treatment initiation. Nivolumab therapy appeared safe with only one patient (11%) having severe adverse event, namely grade 3 alanine aminotransferase and aspartate aminotransferase increase. Conclusion.Nivolumab appears to be safe and effective therapy in PCNSL and PTL with CNS involvement both in first-line and r/r setting. However, in our cohort majority of patients relapsed that suggest that consolidation therapy after remission induction with nivolumab may be crucial for long-term remissions. We also demonstrate that pseudoprogression might be also observed in PCNSL during immunotherapy. Large-scale trials are needed to generate strong evidence for the use of PD-1 inhibitors in PCNSL. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Nivolumab is an anti-PD-1 inhibitor approved for classical Hodgkin lymphoma. There is early clinical data suggesting the efficiency of nivolumab in PCNS lymphoma (Nayak, 2017)

High-dose methotrexate-based regimens with or without vincristine for the treatment of primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a rare malignancy with few treatment options. One regimen used for induction is rituximab, high-dose methotrexate (HD-MTX), procarbazine, and vincristine (R-MPV). A common institutional practice is removing vincristine (VCR) from this regimen due to its poor CNS penetration and associated toxicities. The aim of this study was to evaluate how the omission of VCR from HD-MTX-based induction impacted clinical outcomes. In a retrospective review, patients with PCNSL who received HD-MTX-based induction therapy between January 1, 2010 and May 31, 2018 were evaluated. Patients were stratified according to treatment into 2 groups, VCR-containing therapy versus no VCR. The primary endpoint was complete response (CR) rate following the completion of induction chemotherapy. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse event rate. Twenty-nine patients were included: 16 patients in the VCR group and 13 in the non-VCR group. A CR was achieved in 7 (44%) and 5 (38%) (odds ratio [OR] = 1.24; 95% confidence interval [CI]: 0.28-5.53) patients, respectively. Median OS was 85.3 (95% CI: 20.2-85.3) versus 67.1 months (95% CI: 10.5-NR) and median PFS was 60.7 (95% CI: 9.4-NR) versus 23.7 months (95% CI: 4.7-NR) in the VCR group versus non-VCR group, respectively. The incidence of any grade peripheral neuropathy was higher in the VCR group. CR rate, OS, and PFS were similar between groups regardless of VCR inclusion. Adverse events were higher in the VCR group. Larger studies are required to further evaluate the efficacy of VCR in PCNSL induction regimens.

Central Nervous System Involvement of Natural Killer and T Cell Neoplasms.

Peripheral natural killer (NK) and T cell neoplasms comprise approximately 10-15% of non-Hodgkin lymphomas. There are 27 different subtypes of peripheral NK and T cell neoplasms, each of which is relatively uncommon. Treatment has been largely extrapolated from case series, retrospective reports, and paradigms developed for the aggressive B cell lymphomas. This review explores the current knowledge of the characteristics, outcome, and treatment of CNS T cell and NK neoplasms. Primary and secondary CNS NK and T cell malignancies confer significant morbidity and poor prognosis. Despite clinical heterogeneity between the 27 subtypes, high-dose methotrexate-based regimens seem most effective overall. The role of prophylaxis against secondary CNS involvement remains controversial. Autologous stem cell transplant and immunotherapy are potential for promising future therapies. Current understanding of incidence, outcome, and optimal treatment strategies for CNS T cell and NK neoplasms is limited, in large part due to their diversity and rarity. Prognosis is poor, except in a few reports of long-term survival in patients most often treated with combination therapy including high-dose methotrexate. A future prospective study on treatment and outcome in CNS T cell and NK neoplasms is needed to better define these diseases.

Central Nervous System Involvement in Peripheral T Cell Lymphoma.

Central nervous system (CNS) involvement in peripheral T cell lymphoma (PTCL) is a difficult condition to treat, both as a primary and a secondary disease. Primary CNS lymphoma (PCNSL) in PTCL is very rare, making up only 2% of all PCNSLs. The incidence of CNS relapse is generally 2-6% in all cases of PTCL, but the risk may vary by histologic subtype, and extranodal involvement > 1 has been consistently found to be a risk factor for CNS relapse. Currently, there is no consensus about indications for CNS prophylactic treatment. A high-dose systemic methotrexate-based regimen is the most commonly used treatment, with or without consolidation with high-dose chemotherapy with autologous stem cell transplantation for both primary and secondary CNS involvement. This approach, however, is generally toxic for older patients. New therapeutic approaches against PTCL are therefore needed.

Balancing relapses versus cognitive impairment in primary central nervous system lymphoma: a single-center experience

ABSTRACTObjectives: The outcomes of primary central nervous system lymphoma (PCNSL) are much improved with multi-modality regimens. Unfortunately, in limited-resource countries, chemo-radiotherapy is the only option of curative-intent treatment. This study aimed to evaluate the effects of low-dose whole brain radiotherapy (WBRT) as a consolidation on disease control and long-term neurocognitive functions.Methods: We conducted a retrospective single-center study enrolling PCNSL patients from 2011 to May 2016 to evaluate the real-life treatment outcome and neurotoxicity from treatment especially radiotherapy.Results: Thirty-seven newly diagnosed immunocompetent PCNSL patients were treated with a high-dose methotrexate-based regimen with or without WBRT. The median age was 56 (range 16–78) years old. After chemotherapy, the overall response and complete response (CR) rates were 59.5% and 43.2%, respectively. All 6 partial response (PR) patients and 6 of 16 CR patients underwent radiotherapy. In 22 patients who achieved CR, the progression-free survival (PFS) of patients without WBRT was significantly inferior to the WBRT group with the hazard ratio of 4.7 (95% confidence interval 1.14–19.82, p = 0.03). The 3-year PFS were 35% and 78.75%, respectively, but there was no difference in overall survival. The serial Montreal Cognitive Assessment evaluations (20–72 months post chemotherapy) of 10 long-term CR patients revealed one dementia among three patients without WBRT and five mild cognitive impairments in seven patients with WBRT. Except for the dementia case, all the other patients can perform daily activities without assistance.Conclusion: The low-dose WBRT consolidation is associated with lower PCNSL relapses with only mild neurocognitive toxicity.

Promising treatment results with blood brain barrier disruption (BBBD) based immunochemotherapy combined with autologous stem cell transplantation (ASCT) in patients with primary central nervous system lymphoma (PCNSL).

Primary central nervous system lymphoma (PCNSL) is a rare brain tumour with a dismal prognosis. Several phase II studies with high-dose methotrexate-based regimens have shown promising early results, but in all hospital-based data published so far, the disease outcome has been poor. Patients with relapsed or refractory disease have a dismal prognosis. We performed retrospective analysis to evaluate results and tolerabilities of BBBD therapy in combination with high-dose therapy supported by autologous stem cell transplantation. We analysed 25 patients (age range: 40-71years) who were treated in first or second line with BBBD therapy. When we started BBBD treatment, patients had relapsed or refractory PCNSL or they did not tolerate Bonn-like therapy. In recent years, some of the patients were treated in first line. We found promising response rates. Altogether 19 (76 %) of the patients achieved a complete response (CR). Two-year progression-free survival (PFS) and overall survival (OS) rates were 61 and 57 % respectively and the five-year OS was 47 %. Patients who were treated with a five-drug therapy had a very promising prognosis. The CR rate was 100 % in first-line therapy and 60 % in relapsed cases. These findings suggest that BBBD is a promising therapy for PCNSL, especially for patients in first line, but also for patients with relapsed or refractory disease after conventional chemotherapy, who commonly have a very poor prognosis. Treatment-related toxicity was generally manageable. Thus, BBBD followed by ASCT could be a treatment of choice in transplant-eligible patients with PCNSL.

Constant pattern of relapse in primary central nervous lymphoma patients treated with high-dose methotrexate combinations. A Finnish retrospective study

Background. Primary central nervous system lymphoma (PCNSL) is a rare brain tumour with a dismal prognosis. Several phase II studies with high-dose methotrexate-based regimens have shown promising early results, but in all hospital-based data published so far, the disease outcome is poor.Material and methods. We performed a hospital-based retrospective analysis to evaluate the long-term results of the Nordic type of Bonn chemotherapy regimen in PCNSL patients. The study included 54 patients with newly diagnosed PCNSL who received chemotherapy with curative intent as their first-line treatment.Results. We found promising response rates, 76% of the patients achieving CR and 22% patients achieving PR, with corresponding two-year EFS 53% and OS 76%. However, with longer follow-up a constant pattern of relapses was observed with only one patient remaining in primary remission after 60 months.Discussion. The finding suggests that basic biological differences exist between PCNSL and systemic diffuse large B-cell lymphoma and there is a need for consolidation or maintenance therapy after achieving a remission in patients with PCNSL.

Epstein-Barr Virus Kinase-Targeted Therapy for Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder

Abstract BACKGROUND: Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) is a rare complication of solid organ transplant, with no standard therapy. Epstein-Barr virus (EBV) is ubiquitous making the virus a candidate therapeutic target. For virus targeted therapy to be effective, antiviral agents must be phosphorylated by lytic-phase kinases BXLF1 and BGLF4. We hypothesized that lytic kinases would be constitutively expressed in PCNS-PTLD and that antiviral therapy would prove an attractive therapeutic alternative to high dose methotrexate-based regimens in patients who often have impaired organ function and poor performance status. METHODS: We investigated the safety and efficacy of EBV-kinase targeted therapy with zidovudine (AZT), ganciclovir (GCV), rituximab, and dexamethasone in patients with PCNS-PTLD. Patients with biopsy-proven PCNS-PTLD following solid organ transplantation were eligible for treatment. Immune suppression was reduced in all patients prior to treatment. Induction therapy consisted of 14 days of AZT 1500 mg IV BID, GCV 5 mg/kg IV BID, dexamethasone 10 mg IV BID and rituximab 375 mg/m2 once weekly for four weeks. Maintenance antiviral therapy was initiated on day 15 with valganciclovir 450 mg and AZT 300 mg, both twice daily. Responses were evaluated by serial brain MRIs beginning 4 weeks after initiation of treatment. Brain biopsy specimens were evaluated for expression of BGLF4 and BXLF1 by in situ hybridization or immunohistochemistry. To test the hypothesis that expression of EBV kinases conferred sensitivity to antiviral therapy, 293T cells were transfected with cDNAs (or control vectors) encoding for full length BXLF1 and/or BGLF4. Transiently transfected cells were tested for expression by immunoblot and drug sensitivity to AZT/GCV was performed by MTS and flow cytometry assays. RESULTS: Twelve patients (7 M, 5 F) with a median age of 49 were treated from 1998-2014. Transplant history included kidney (N=11), pancreas (N=2), and liver (N=1). Histology data included diffuse large B-cell lymphoma (N=7) and grade III lymphomatoid granulomatosis (N=5). EBV positivity (EBER-ISH) and CD20 expression were documented in all cases. All patients completed induction therapy. Median follow-up time and median duration of maintenance therapy were 28 months (range 2 - 143). The mean progression free survival (PFS) was 33.8 months. Overall response rate (ORR) was 83.3%. Eight patients achieved a complete response (CR) within a median time of 2 months (range 0.75 – 6 months). Two patients had a partial response (PR) with an average time to response of 1.25 months. Two patients (2/12) had progressive disease (PD). Causes of death included septic shock (n=3), pulmonary embolism (n=1), and poor functional status requiring hospice (n=1). One patient had PD at the time of death. Median overall survival (OS) was 29 months (range 2 – 143 months). Grade 3-4 toxicity was primarily hematologic, including anemia (N=4), thrombocytopenia (N=2), and neutropenia (N=5). Toxicity in the maintenance phase was generally reversible with holding therapy. Three patients required discontinuation of AZT during maintenance treatment for transfusion-dependent anemia persisting after holding AZT for 7 days or neutropenia coinciding with systemic infection. One patient had AZT discontinued due to nausea and vomiting that led to acute kidney injury. Evaluation of BXLF1, BGLF4 and LMP1 was completed in 7 patients and found to be positive in all cases. LMP1 and kinase expression occurred in mutually exclusive regions of the tumor. Expression of BXLF1 and BGLF4 led to enhanced sensitization of 293T cells to antiviral-induced growth inhibition and apoptosis. CONCLUSIONS: EBV-kinase targeted therapy with AZT, GCV, rituximab and dexamethasone appears to be effective treatment for patients with EBV+ PCNS-PTLD. We demonstrated durable responses without disease recurrence and minimal toxicity. Expression of BXLF1 and BGLF4 kinases provides a mechanistic rationale for an antiviral approach to this disease and an attractive option to replace high dose chemotherapeutic regimens with less toxic targeted therapy in patients with compromised transplant organ function. A multi-center phase II trial is in development to further investigate this regimen in patients with immune deficiency-related CNS EBV-LPD. Figure 1 Figure 1. Disclosures Porcu: Infinity: Research Funding; Seattle genetics: Research Funding; Actelion: Honoraria; Celgene: Honoraria; United States Cutaneous Lymphoma Consortium: Membership on an entity's Board of Directors or advisory committees; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees.