R-MPV Followed by High-dose Chemotherapy With Thiotepa-based and Autologous Stem Cell Transplantation for Newly Diagnosed Primary Central Nervous System Lymphoma: A Single-center Experience
Ji Yun LeeJin Ho PaikKoung Jin SuhJi‐Won KimSe Hyun KimJin Won KimYu Jung KimKeun‐Wook LeeJee Hyun KimSoo‐Mee BangJong-Seok LeeJeong‐Ok Lee
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Abstract BackgroundHigh-dose chemotherapy followed by autologous stem-cell transplantation (HDC–ASCT) as a consolidation treatment is a promising approach in eligible patients with newly diagnosed primary central nervous system lymphoma (PCNSL). This study sought to assess the safety and efficacy of initial methotrexate-based chemotherapy followed by consolidation HDC-ASCT with a thiotepa-based conditioning regimen in patients with newly diagnosed PCNSL. MethodsIn this retrospective analysis, 22 patients with newly diagnosed PCNSL received chemotherapy with rituximab, methotrexate, procarbazine, and vincristine (R-MPV). Those who showed a complete or partial response subsequently received consolidation HDC-ASCT with a thiotepa-based conditioning regimen and no radiotherapy. ResultsCharacteristics of the PCNSL patients included a median age of 57 years (range: 49–67 years), Eastern Cooperative Oncology Group performance status of grade 2 or more in 9.1%, elevated lactate dehydrogenase level in 26.3%, and involvement of multiple lesions in 72.1%. About 82% of patients received six cycles of induction chemotherapy, which was well-tolerated with excellent disease control. The rate of confirmed/or unconfirmed complete response increased from 45.5% in the interim to 81.8% before HDC-ASCT. With a median follow-up of 19.6 months (range: 7.5–56.5 months), the 2-year progression-free survival and overall survival estimates were 84% and 88%, respectively. There were no treatment-related deaths. Grade 3 toxicity was recorded in 90.9% after HDC-ASCT, and the most common grade 3 adverse event was febrile neutropenia without sepsis. ConclusionsThe discussed treatment approach appears feasible in patients with newly diagnosed PCNSL, yielding encouraging results.Keywords:
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Abstract BackgroundHigh-dose chemotherapy followed by autologous stem-cell transplantation (HDC–ASCT) as a consolidation treatment is a promising approach in eligible patients with newly diagnosed primary central nervous system lymphoma (PCNSL). This study sought to assess the safety and efficacy of initial methotrexate-based chemotherapy followed by consolidation HDC-ASCT with a thiotepa-based conditioning regimen in patients with newly diagnosed PCNSL. MethodsIn this retrospective analysis, 22 patients with newly diagnosed PCNSL received chemotherapy with rituximab, methotrexate, procarbazine, and vincristine (R-MPV). Those who showed a complete or partial response subsequently received consolidation HDC-ASCT with a thiotepa-based conditioning regimen and no radiotherapy. ResultsCharacteristics of the PCNSL patients included a median age of 57 years (range: 49–67 years), Eastern Cooperative Oncology Group performance status of grade 2 or more in 9.1%, elevated lactate dehydrogenase level in 26.3%, and involvement of multiple lesions in 72.1%. About 82% of patients received six cycles of induction chemotherapy, which was well-tolerated with excellent disease control. The rate of confirmed/or unconfirmed complete response increased from 45.5% in the interim to 81.8% before HDC-ASCT. With a median follow-up of 19.6 months (range: 7.5–56.5 months), the 2-year progression-free survival and overall survival estimates were 84% and 88%, respectively. There were no treatment-related deaths. Grade 3 toxicity was recorded in 90.9% after HDC-ASCT, and the most common grade 3 adverse event was febrile neutropenia without sepsis. ConclusionsThe discussed treatment approach appears feasible in patients with newly diagnosed PCNSL, yielding encouraging results.
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Chemotherapy plus radiation therapy (RT) for primary CNS lymphoma (PCNSL) has significantly improved patient survival over RT alone, but there are late neurologic sequelae of RT, particularly in the elderly. We treated 13 patients over age 50 years (mean age 74 years) with chemotherapy alone as initial treatment for PCNSL. All received methotrexate (MTX) and procarbazine; in addition, five received thiotepa, four vincristine, and four vincristine and cytarabine. Ten achieved a complete response (CR), 2 a partial response (PR), and 1 progressed through treatment. Two patients with ocular lymphoma responded to MTX, procarbazine, and vincristine. Four of six patients who relapsed after achieving a CR or PR were treated with additional chemotherapy or RT; three achieved a CR and one a PR. Five patients remain in CR at 7.5 to 30 months, one is alive at 35 months but with progressive disease, six died of PCNSL at 5 to 30.5 months, and one died in CR of sulfur allergy 2 months after diagnosis. The Karnofsky Performance Status improved in 11 to 13 patients with treatment. Cognitive deficits were present in nine patients at diagnosis and improved in eight of these nine after chemotherapy. Only one patient developed new cognitive deficits, due to progressive tumor and possibly MTX leukoencephalopathy. Chemotherapy alone for PCNSL is effective in the elderly and eliminates the risk of RT-related neurotoxicity. RT can salvage those who relapse after chemotherapy.
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Musolino et al reported their experience with a reduced dose regimen designed for “very elderly” patients with high-risk diffuse large B-cell non-Hodgkin lymphomas.1 They treated 23 patients (median age, 77 years), most of whom were diagnosed with an advanced stage of disease and poor prognostic score, with 6 to 8 courses of dose-adjusted infusional cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy with rituximab (DA-POCH-R). This regimen is an anthracycline-based scheme whose dose intensity, compared with the CHOP regimen, is 88% for doxorubicin, 53% for cyclophosphamide, and nearly 90% for vincristine; however, 12 cycles in 9 patients were administered at reduced doses. The overall response rate was 90%, with a complete response rate of 57%; the 3-year overall survival and event-free survival rates were 56% and 54%, respectively. Hematological toxicity was manageable and nonhematological toxicity was negligible. The authors concluded that this regimen was a reasonable alternative for elderly patients who were not considered to be able to tolerate standard treatment with R-CHOP. Although we believe the study is interesting, the authors did not make specific mention of the criteria used for the recruitment of patients and, in particular, they did not mention the comprehensive geriatric assessment (CGA), based on cumulative comorbidities and the ability to perform basic and instrumental daily life activities.2, 5 In our clinical practice, we treat elderly “fit” patients with R-CHOP, and the majority of “unfit” or “frail” patients are treated with the R-VV regimen, which is comprised of rituximab plus oral vinorelbine and etoposide, and which permits appreciable results with acceptable toxicity and the avoidance of hospital admission. In conclusion, we believe that a broader application of CGA could lead to a better selection of patients and, consequently, studies with more comparable results. Alberto Fabbri MD*, Alessandro Gozzetti MD*, Luigi Rigacci MD , * Department of Hematology, University Hospital of Siena, Siena, Italy, Department of Hematology, University Hospital of Florence, Florence, Italy.
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We studied the clinical effects of high-dose methotrexate(HD-MTX)combined with rituximab and vincristine in 5 elderly patients, aged 65-83 years, with diffuse large B-cell lymphoma of the central nervous system(DLBCL CNS). Patients aged 65- 71 years were given 3.0 g/m2 of HD-MTX, while patients aged 75-83 years were given 1.5 g/m2 of the drug. All patients showed responses; 1 CR and 1 PR in MTX 3.0 g/m2 group, and 2 CRs and 1 PR in MTX 1.5 g/m2 group.
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Background: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive non-Hodgkin lymphoma that affects the brain, eyes, cerebrospinal fluid (CSF), or spinal cord without systemic involvement. Current treatments including surgery, chemotherapy and whole-brain radiotherapy often fail to achieve satisfactory effect, especially in elderly. Novel insights into the pathophysiology of PCNSL have identified key mechanisms in tumor pathogenesis including activation of the B-cell receptor pathway.Bruton’s tyrosine kinase (BTK) inhibitor zanubrutinib has been tested in clinical trials against R/R PCNSL and shows potential to be used in first-line treatment of PCNSL. Aims: To evaluate efficacy and safety of Zanubrutinib, rituximab, methotrexate and cytarabine(ZRMA regimen) in patients with primary CNS diffuse large b cell lymphoma. Methods: Retrospective study was done on patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and measurable disease who received ZRMA regimen in our hospital.Patients received four courses of ZRMA regimen every 21 days a cycle: Zanubrutinib 80mg twice daily, rituximab 375 mg/m(2) on days 0,methotrexate 3·5 g/m(2) on day 1 plus cytarabine 2 g/m(2) once daily on days 2. Patients with responsive were then received whole-brain radiotherapy, autologous stem cell transplantation or lenalidomide maintenance. Results: Between Aug 18, 2020, and Feb 28, 2022, 15 enrolled patients were assessable. At median follow-up of 10 months（3-18）, patients had a complete remission rate of 93%(14/15). The median progression-free survival (PFS) and overall survival (OS) was not reached. The only two grade 3-4 adverse events were neutropenia(7%,1/15) and f infections(7%,1/15). The ZRMA regimen was well tolerated in these treatment-naïve PCNSL patients with an acceptable safety profile. Summary/Conclusion: This retrospective study provides an evidence supporting the use of ZRMA regimen for further research in patients aged up to 70 years with newly diagnosed primary CNS lymphoma.
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Abstract BACKGROUNDS Standard of care (SOC) for primary central nervous system lymphoma (PCNSL) has been induction therapy with high-dose methotrexate (MTX)-based multiagent immunochemotherapies followed by consolidation, and we have shown that one such regimen, R-MPV-A have superior efficacy over HD-MTX alone with whole brain radiotherapy (WBRT). While SOC for secondary CNS involvement of systemic diffuse large B-cell lymphoma (DLBCL)(SCNSL) has not been established. Here we report the outcome of R-MPV-A for patients with SCNSL. PATIENTS AND METHODS Fifteen patients with SCNSL treated with R-MPV-A from January 2014 to January 2019 in Kyorin University Hospital were eligible. Prior treatment for systemic DLBCL was mostly R-CHOP. Response and survival outcomes were evaluated. RESULTS Median age was 68.0 y (55–84), male/female 6/9, median KPS 70 (40–90), histopathological confirmation was achieved in 12 patients (80%; biopsy 11). RMPV (rituximab+MTX+procarbazine+vincristine) 3 cycles in 3, 4–7 cycles in 6, 8 cycles in 5. WBRT and cytarabine were delivered in 6 and 9 patients, respectively. R-MPV resulted in 6 CRs/CRus, 5 PRs, 1 SD, and 2 PDs (Response rate 73%). R-MPV-A including consolidation led to 9 CRs/CRus, 2 PRs, 1 SD, and 2 PDs (complete response rate 60%). With median F/U period of 11.2 m (0.1–51.5), 1y-PFS and 2y-PFS of R-MPV-A were 66.0% and 56.6%, 1y-OS and 2y-OS were 72.2% and 72.2%, respectively. Median PFS/OS were not reached. Consolidation cytarabine was associated with better outcome. Three deaths occurred during the treatment (20%; two during R-MPV with aged 70s, KPS 40 and 50; one presented MTX clearance delay). No other serious adverse events were observed. CONCLUSIONS These results suggest the certain efficacy of R-MPV-A for SCNSL. Being heavily pretreated frequently, precautions should be taken to identify high risk cases.
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Introduction. Induction chemotherapy (CT) for primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS) is based on the use of methotrexate in high doses. An optimal consolidation strategy involves high-dose chemotherapy followed by autologous haematopoietic stem cell transplantation (auto-HSCT). The most effective conditioning regimen comprises a combination of chemotherapy agents including thiotepa. Aim. To present the authors’ experience of applying auto-HSCT/TBC in patients with primary DLBCL of the CNS. Methods. The prospective study CNS-2015 was carried out among 20 patients aged 20–52 years (median 42 years old) from 2015 to 2019. The male/female ratio came to 13/7. The somatic status of 17 (85 %) patients was 0–1 on the ECOG scale. Only 3 (15 %) patients showed the somatic status of 4 points. According to the criteria of the MSKCC prognostic system, 18 (90 %) and 2 (10 %) patients were assigned to the low-risk and medium-risk groups, respectively. Results. All patients included in the study received 3–5 cycles of chemotherapy with high doses of methotrexate, vincristine, procarbazine and rituximab (R-MPV), as well as underwent auto-HSCT following TBC-based conditioning regimen (thiotepa, busulfan, cyclophosphamide). Prior to auto-HSCT, 15 and 5 out of 20 patients having completed induction chemotherapy achieved complete remission and partial remission, respectively. Following auto-HSCT, complete remission was achieved in 5 patients with an initial partial response to treatment. All patients underwent temozolomide maintenance therapy for 2 years. With a median follow-up of 17 (1–46) months, 18 patients are alive and in remission. Two patients, who relapsed 4 and 5 months after auto-HSCT and achieved no response to the second line of chemotherapy and radiation therapy, died 24 and 26 months after auto-HSCT. Conclusion. R-MPV is an effective treatment for patients with primary DLBCL of CNS, which is not accompanied by severe toxicity. The use of high-dose chemotherapy with TBC allows a high remission rate to be achieved. The mortality associated with treatment in the group of patients included in the study came to 0 %.
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