- Email: [email protected]
Temozolomide as a Single Agent Maintenance Therapy in Elderly Patients With Primary CNS Lymphoma
Original Study
Temozolomide as a Single Agent Maintenance Therapy in Elderly Patients With Primary CNS Lymphoma Geraldine Faivre,1 Matthew James Butler,2 Isabelle Le,2 Andrew Brenner2 Abstract Optimal management of elderly patients with primary central nervous system lymphoma (PCNSL) after induction therapy is unclear. In our retrospective series of 10 patients treated with temozolomide after induction with R-MPV (rituximab, methotrexate, procarbazine and vincristine) we found a median progression-free survival of 57 months, and a median overall survival of 63 months, with moderate toxicity, which supports the idea that temozolomide might have activity for maintenance in elderly patients with PCNSL. Introduction: Optimal management of elderly patients with primary central nervous system lymphoma (PCNSL) after induction therapy is unclear. Whole-brain radiotherapy and autologous stem cell transplantation carry increased toxicity in patients older than 60 years of age, which might outweigh the benefits in this group. Temozolomide (TMZ) has established antineoplastic activity in the central nervous system in other disease states, with a favorable toxicity profile. Patients and Methods: We report efficacy and tolerability in a series of 10 patients treated off-label with TMZ maintenance after completion of R-MPV (rituximab, methotrexate, procarbazine and vincristine) treatment for or primary diagnosed PCNSL. Results: Median progression-free survival (PFS) was 57 months, 2-year PFS was 67%, and 5-year PFS was 33%. Median overall survival (OS) was 63 months, 2-year OS was 88%, and 5-year OS was 57%. TMZ was generally well tolerated, with the most common toxicity of Grade 3 or higher being thrombocytopenia in 3 patients (30%). Conclusion: These outcomes suggest that TMZ might have activity for maintenance in elderly patients with PCNSL, when more aggressive treatments are contraindicated. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2019 Published by Elsevier Inc. Keywords: Consolidation, MTX, PCNSL, R-MPV, TMZ
Introduction Primary central nervous system lymphoma (PCNSL) is challenging to manage in elderly patients. Being older than 60 years at diagnosis is known to be a negative prognostic factor,1 with lower response rates and earlier relapse.2 Moreover, elderly patients and those with comorbidities suffer high rates of treatment-related toxicity.3 Considering that almost half of PCNSL patients are 70 years old or older,3,4 there is an unmet clinical need to define optimal treatment for this population. Standard induction therapy 1
Department of Neurology Division of Hematology and Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 2
Submitted: Feb 18, 2019; Accepted: May 21, 2019 Address for correspondence: Andrew Brenner, MD, PhD, University of Texas Health San Antonio Cancer Center, 7979 Wurzbach Rd, MC 8232, San Antonio, TX 782293900 Fax: 210-692-7502; e-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2019 Published by Elsevier Inc. https://doi.org/10.1016/j.clml.2019.05.012
incorporates high-dose methotrexate (HD-MTX), usually with other cytotoxic agents, corticosteroids, and rituximab.5 This is typically followed by consolidation treatment, consisting either of whole-brain radiation therapy (WBRT) and high-dose cytarabine6 or high-dose chemotherapy with autologous stem cell transplantation (ASCT).7,8 In patients older than 60 years, WBRT is associated with a high incidence of neurotoxicity, leading to progressive ataxia and cognitive impairment,1,3 and is not recommended. ASCT remains an option for select older individuals,9 but in practice, many of these patients are poor candidates for this intensive treatment modality because of medical comorbidities and general frailty. High doses of methotrexate10 or cytarabine11 represent other consolidation options, but their use is limited by myelosuppression and other toxicities. Safe and efficient postinduction treatment for elderly patients with PCNSL remains an unmet clinical need, especially for the oldest and least fit patients. Temozolomide (TMZ) is an oral alkylating agent commonly used to treat primary brain tumors such as gliomas. It is known to
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Temozolomide Maintenance for CNS Lymphoma excluded; intrathecal chemotherapy was allowed. Ten patients met criteria for inclusion. These patients had been offered TMZ after achieving complete response (CR) or partial response (PR) after RMPV treatment. TMZ was given as a single agent at the maintenance dose of 150 mg/m2 daily on days 1 through 5 of an initial 28day cycle, and increased to 200 mg/m2 for subsequent cycles, unless limited by toxicity, with intention to give at least 6 cycles. Serial magnetic resonance imaging was performed to monitor for disease progression. Maintenance therapy was continued until progression, unacceptable toxicity, or patient preference to stop treatment. The primary end point of the study was progression-free survival (PFS), calculated from date of diagnosis to date of progression, last neurologic evaluation, or death if patients did not have disease progression, whichever came first. Overall survival (OS) was calculated from the date of diagnosis to last contact or death. Cases were also assessed for treatment-associated adverse events, using the Common Terminology Criteria for Adverse Events version 4.0, and were evaluated for neurocognitive impairment using Mini-Mental State Examination (MMSE) at baseline and after completion of TMZ treatment.
Table 1 Patient Characteristics at Baseline Characteristic
Value
Sex Male
4 (40%)
Female
6 (60%)
Median Age (Range), Y
67 (61-76)
CSF Involvement
2/6 (33%)
Ocular Involvement
1 (10%)
Performance Status ECOG 0
1 (10%)
ECOG 1
8 (80%)
ECOG 2
1 (10%)
MSKCC 2
10 (100%)
Median MMSE Score (Range)
27 (20-30)
Abbreviations: CSF ¼ cerebrospinal fluid; ECOG ¼ Eastern Cooperative Oncology Group; MMSE ¼ Mini-Mental State Examination; MSKCC ¼ Memorial Sloan Kettering Cancer Center.
effectively penetrate the blood-brain barrier, and to have a tolerable toxicity profile. It has been incorporated into induction treatment for elder individuals with PCNSL2,12; these studies showed acceptable safety, but limited efficacy. One study introduced it as a maintenance treatment in elderly patients with promising results.13 Therefore, we conducted a retrospective observational study, including 10 immunocompetent patients older than 60 years who received TMZ as a maintenance treatment after induction therapy including R-MPV (rituximab, HD-MTX, procarbazine, and vincristine).
Results Patient characteristics are reported in Table 1. Noticeable points were a sex ratio of 60% female and median age at diagnosis of 67 years (range, 61-76), with most patients with Eastern Cooperative Oncology Group performance status of 1, Memorial Sloan Kettering Cancer Center prognostic score at 2, and median MMSE at baseline at 27 (range, 20-30). All patients received 5 cycles of MPV without reduction of dose, except 1 patient who received only 3 cycles because of recurrent severe acute renal failure associated with chemotherapy. All patients were given 1 to 5 cycles of intrathecal MTX. Eight patients (80%) also received rituximab as part of the induction treatment. One patient had previously received HD-MTX with cytarabine for 1 month before seeking a second opinion and starting our study regimen. After completion of 5 cycles of R-MPV, 3 patients (30%) were in CR, 3 others (30%) in near CR, and the last 4 (40%) in PR, with an overall response rate (ORR) of 100%. Patients subsequently received a median of 6 cycles of TMZ (range, 3-12). Three patients (30%) received <6 cycles: 2 stopped after 3 cycles because of progression of disease, the fourth stopped after 5 cycles because of
Patients and Methods Patients were identified through a search of electronic medical records for all individuals older than 60 years who received a diagnosis of PCNSL at our institution between 2011 and 2017. A total of 30 cases were reviewed with new, tissue-confirmed, cases of B-cell lymphoma in the central nervous, with adequate staging imaging to exclude extra-central nervous system sites of involvement, treated with MPV (methotrexate, procarbazine and vincristine) with or without rituximab, followed by at least 1 cycle of TMZ. Methotrexate was given at a dose of 3.5 g/m2. Individuals who received WBRT or ASCT as part of initial therapy were
Table 2 Toxicities of Treatment (CTCAE Version 4.0) R-MPV Acute Renal Failure Encephalopathy Thrombocytopenia Neutropenia Infection
TMZ
Grade 3
Grade 4
Grade 3
0
1 (10%)
0
Grade 4 0
2 (20%)
0
0
0
NA
1 (10%)
1 (10%)
2 (20%)
1 (10%)
1 (10%)
0
2 (20%)
NA
NA
1 (10%)
0
Neurotoxicity Median MMSE Score (Range)
28.5 (21-30)
30 (27-30)
Abbreviations: CTCAE ¼ Common Terminology Criteria for Adverse Events; MMSE ¼ Mini-Mental State Examination; R-MPV ¼ rituximab, methotrexate, procarbazine, vincristine; TMZ ¼ temozolomide.
2
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Clinical Lymphoma, Myeloma & Leukemia Month 2019
Geraldine Faivre et al Figure 1 Progression-Free Survival (PFS) and Overall Survival (OS) Curves in 10 Elderly Patients Treated for Newly Diagnosed Primary Central Nervous System Lymphoma With R-MPV (Rituximab, Methotrexate, Procarbazine, and Vincristine) With or Without ITMTX Followed by Temozolomide. PFS and OS Were Calculated From Date of Diagnosis
Abbreviation: IT-MTX ¼ intrathecal methotrexate.
Grade 4 thrombocytopenia. Among patients who discontinued TMZ, two (20%) did because of Grade 3 or 4 thrombocytopenia (after 5 and 6 cycles, respectively), 2 (20%) because of fatigue (after 6 and 9 cycles, respectively), 1 for Grade 4 neutropenia after 6 cycles, and 3 (30%) because of CR (after completion of 6, 7, or 12 cycles, respectively). There were treatment delays in 4 patients (40%) because of thrombocytopenia (2 patients), bronchitis (1 patient), and severe allergic reaction to penicillin (1 patient). Two patients (20%) received only the 150 mg/m2 dose, with the usual dose increment withheld because of thrombocytopenia. After completion of TMZ, 8 patients (80%) were in CR and 2 (20%) had disease progression after 3 cycles. Response rates are reported in Table 2. Median follow-up was 55 (range, 16-79) months. Median PFS was 57 (range, 6.2-77) months; 2-year, 3-year, and 5-year PFS were respectively 67%, 56%, and 33% (Figure 1). Median OS was 63 (range, 16-79) months; 2-year, 3-year, and 5-year OS were respectively, 88%, 75%, and 57% (Figure 1). Median time to progression after discontinuation of TMZ was 16 (13-48). months Six patients (60%) had disease progression after 3 to 12 cycles, but only 2 (20%) while receiving TMZ treatment. Two of these had systemic recurrence without brain relapse and were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), whereas the other 4 had cerebral progression of disease (1 had systemic and brain relapse and was treated with R-
CHOP, another received TMZ with rituximab, and the last 2 were given WBRT). Four patients (40%) died, all while receiving chemotherapy for progressive or recurrent disease. Adverse events are reported in Table 2, with TMZ associated with Grade 3 (1 patient) or 4 (2 patients) thrombocytopenia in 30% of the patients, and Grade 4 neutropenia in 2 patients (20%) (1 was related to accidental overdose and the other happened after 6 cycles of TMZ). Median MMSE score after completion of TMZ was 30 (range, 27-30), with an average increase of 3 points (range, 0-10) compared with baseline. No neurotoxicity was reported.
Discussion In our study we aimed to evaluate the efficacy and safety of TMZ as single-agent maintenance treatment in elderly patients with newly diagnosed PCNSL, after completion of R-MPV as induction treatment. TMZ was generally well tolerated with moderate hematologic toxicity and no neurotoxicity. Outcomes, notable for a median PFS of 57 months, were highly favorable compared with clinical trial data of PCNSL in elderly patients, which typically report PFS in the 1-year range.11,12 Our study excluded nonresponders to R-MPV, because patients were offered TMZ maintenance therapy only if they had achieved a response (CR or PR) to induction therapy. However, we went back and analyzed all patients who met the criteria and found only 2 patients (20%) whose disease progressed with R-MVP, after 5 cycles. The outcomes in our study
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Temozolomide Maintenance for CNS Lymphoma
4
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are unfortunately not comparable with a prospective study using intention-to-treat analysis. However, a retrospective study of elderly patients who underwent ASCT, subject to a similar selection bias, showed a similar median PFS of 51.1 months.9 Furthermore, one could argue that our study might provide some evidence of therapeutic activity for TMZ, apart from survival outcomes, because 3 patients with PR and 2 with near-CR after induction achieved CR during maintenance treatment. This study might suffer from several limitations. The small sample size (n ¼ 10) has statistically weakened our findings as well as the lack of a direct comparator group. In addition, the retrospective design is vulnerable to selection bias and it could be argued that individuals might well have been selectively offered TMZ on the basis of patient and disease factors that predispose them to favorable outcomes. The nonincluded remaining patients had limited data available, a different pathologic diagnosis, or a different consolidation treatment, such as WBRT (in 2 patients). Finally, the potentially high performance status of patients before inclusion might also have participated in those optimistic results. Temozolomide was associated with moderate toxicity. Forty percent of the patients experienced a Grade 3 or 4 thrombocytopenia with TMZ. This is higher than in other studies of TMZ in PCNSL, which might reflect the higher dose of TMZ used: 200 mg/m2 in our study, versus 100 to 150 mg/m2 in previous studies.2,12,13 Most of the former studies focused on evaluating new efficient and safe induction therapies in elderly patients with PCNSL, including polychemotherapy, ASCT, and immunotherapies. WBRT is now considered as neurotoxic and usually offered as salvage therapy after disease recurrence in elderly patients.3 A few studies considered the effect of systemic maintenance or consolidation therapies. Omuro et al reported 1 retrospective study in 2007,2 in which patients aged older than 60 years were given HDMTX and TMZ (at a dose of 100 mg/m2) as induction (3 cycles) and consolidation (5 cycles) therapies.2 Median PFS was 8 months, 2-year PFS was 22%, median OS was 35 months with a median follow-up of 21 months, and ORR was 55%. Severe thrombocytopenia was noticed in 20% of patients. Eight years later, Omuro et al conducted a prospective study in which outcomes were compared in patients treated with HD-MTX plus TMZ versus MPV followed by 1 cycle of cytarabine as consolidation (MPV-A).12 Although differences were not statistically significant, there was a trend in favor of the MPV-A regimen (median PFS 9.5 vs. 6.1 months). Outcomes in the HD-MTX-TMZ group were as follows: median PFS was 6 months, 1-year PFS was 36%, median OS was 14 months, and 2-year OS was 39%. Incidence of thrombocytopenia was only 1%, and no delayed neurotoxicity was found in any groups. Finally, Pulczynski et al conducted a prospective and multicenter study with young and elderly PCNSL patients who received HD-MTX and cytarabine. Elderly patients, older than 65 years old, who achieved CR or PR after 6 cycles TMZ at 150 mg/ m2 was given as maintenance therapy.13 After a median of 11 (range, 1-12) cycles, 5 of the 15 elderly patients with maintenance therapy relapsed after achieving CR, with an ORR of 75%. In this population, 2-year PFS was 44.4% and 2-year OS was 55.6%, which were superior to the youngest group. The authors suggested that de-escalating induction treatment and introducing maintenance
Clinical Lymphoma, Myeloma & Leukemia Month 2019
TMZ in elderly PCNSL patients might improve outcomes. Severe thrombocytopenia (Grade 3 or 4) was reported in 10.6% of the patients. Two other recent studies evaluated the use of other consolidation treatments. Houillier et al reported that 3 cycles of cytarabine after 3 cycles of R-MPV were no better in terms of outcomes than rituximab with MPV-A, but added toxicity.11 Fritsch et al conducted a prospective study the same year, and described good results with maintenance procarbazine, after induction with R-MP (rituximab, methotrexate, and procarbazine) or R-MPL (R-MP with lomustine).10 Median PFS was 10.3 months with 1-year PFS of 46.3% and 2-year PFS of 37.3%; median OS was 20.7 months with 1-year OS of 56.7% and 2-year OS of 47%. Hematologic toxicity was limited, especially in the R-MP group, with severe thrombocytopenia in 5.6% of the patients. Additional studies are required to assess efficacy and tolerance of consolidation or maintenance therapy in the elderly patients who are poor candidates for aggressive treatments.
Conclusion Temozolomide is generally a well tolerated and easily administered drug, given orally for 5 days per 4-week cycle. It might be active as single-agent maintenance therapy against PCNSL in elderly patients, for whom treatment often aims to maintain a quality of life and functional independence with the best neurocognitive preservation.3 It is a potential option in elder patients with PCNSL who have achieved CR or PR with R-MPV and who wish to avoid the neurotoxicity of WBRT, especially those who are deemed poor candidates for ASCT. Larger prospective studies are required to confirm and quantify the benefit of TMZ in this setting. Ongoing studies include NCT01458730, which will investigate the efficacy and safety of an HDeMTX-based induction polychemotherapy regimen used in combination with rituximab and intraspinal liposomal cytarabine followed by TMZ, and NCT02313389, which will compare outcomes of elderly patients with newly diagnosed PCNSL, treated with rituximab, methotrexate, and TMZ as maintenance therapy after achieving CR with rituximab with MPVA induction therapy.
Clinical Practice Points Optimal management of elderly patients with PCNSL after in-
duction therapy is unclear. Standard approaches to consolidation, including WBRT and ASCT, carry significant toxicity in this population. In our retrospective series of 10 patients who were treated with TMZ after induction with R-MPV, outcomes were favorable, with a median PFS of 57 months and a median OS of 63 months, with moderate toxicity. Our results support the idea that TMZ might have activity for maintenance in elderly patients with PCNSL.
Acknowledgments The study was supported by in part by the University of Texas Health Science Center at San Antonio Cancer Therapy and Research Center through the National Institutes of Health; National Cancer Institute P30 award CA054174.
Geraldine Faivre et al Disclosure The authors have stated that they have no conflicts of interest.
References 1. Deangelis LM, Iwamoto FM. An update on therapy of primary central nervous system lymphoma. Hematol Am Soc Hematol Educ Program 2006:311-6. 2. Omuro AM, Taillandier L, Chinot O, Carnin C, Barrie M, Hoang-Xuan K. Temozolomide and methotrexate for primary central nervous system lymphoma in the elderly. J Neuro Oncol 2007; 85:207-11. 3. Roth P, Hoang-Xuan K. Challenges in the treatment of elderly patients with primary central nervous system lymphoma. Curr Opin Neurol 2014; 27:697-701. 4. O’Neill BP, Decker PA, Tieu C, Cerhan JR. The changing incidence of primary central nervous system lymphoma is driven primarily by the changing incidence in young and middle-aged men and differs from time trends in systemic diffuse large B-cell non-Hodgkin lymphoma. Am J Hematol 2013; 88:997-1000. 5. Karmali R, Nabhan C, Petrich AM, et al. Impact of treatment variability on survival in immuno-competent and immuno-compromised patients with primary central nervous lymphoma. Br J Haematol 2017; 177:72-9. 6. Morris PG, Correa DD, Yahalom J, et al. Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and longterm outcome. J Clin Oncol 2013; 31:3971-9.
7. Kasenda B, Ihorst G, Schroers R, et al. High-dose chemotherapy with autologous haematopoietic stem cell support for relapsed or refractory primary CNS lymphoma: a prospective multicentre trial by the German Cooperative PCNSL study group. Leukemia 2017; 31:2623-9. 8. Omuro A, Correa DD, DeAngelis LM, et al. R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood 2015; 125:1403-10. 9. Schorb E, Fox CP, Fritsch K, et al. High-dose thiotepa-based chemotherapy with autologous stem cell support in elderly patients with primary central nervous system lymphoma: a European retrospective study. Bone Marrow Transplant 2017; 52:1113-9. 10. Fritsch K, Kasenda B, Schorb E, et al. High-dose methotrexate-based immunochemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study). Leukemia 2017; 31:846-52. 11. Houillier C, Ghesquieres H, Chabrot C, et al. Rituximab, methotrexate, procarbazine, vincristine and intensified cytarabine consolidation for primary central nervous system lymphoma (PCNSL) in the elderly: a LOC network study. J Neurooncol 2017; 133:315-20. 12. Omuro A, Chinot O, Taillandier L, et al. Methotrexate and temozolomide vs. methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: an intergroup ANOCEF-GOELAMS randomised phase 2 trial. Lancet Haematol 2015; 2:e251-9. 13. Pulczynski EJ, Kuittinen O, Erlanson M, et al. Successful change of treatment strategy in elderly patients with primary central nervous system lymphoma by deescalating induction and introducing temozolomide maintenance: results from a phase II study by the Nordic Lymphoma Group. Haematologica 2015; 100:534-40.
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Temozolomide as a Single Agent Maintenance Therapy in Elderly Patients With Primary CNS Lymphoma Geraldine Faivre,1 Matthew James Butler,2 Isabelle Le,2 Andrew Brenner2 Abstract Optimal management of elderly patients with primary central nervous system lymphoma (PCNSL) after induction therapy is unclear. In our retrospective series of 10 patients treated with temozolomide after induction with R-MPV (rituximab, methotrexate, procarbazine and vincristine) we found a median progression-free survival of 57 months, and a median overall survival of 63 months, with moderate toxicity, which supports the idea that temozolomide might have activity for maintenance in elderly patients with PCNSL. Introduction: Optimal management of elderly patients with primary central nervous system lymphoma (PCNSL) after induction therapy is unclear. Whole-brain radiotherapy and autologous stem cell transplantation carry increased toxicity in patients older than 60 years of age, which might outweigh the benefits in this group. Temozolomide (TMZ) has established antineoplastic activity in the central nervous system in other disease states, with a favorable toxicity profile. Patients and Methods: We report efficacy and tolerability in a series of 10 patients treated off-label with TMZ maintenance after completion of R-MPV (rituximab, methotrexate, procarbazine and vincristine) treatment for or primary diagnosed PCNSL. Results: Median progression-free survival (PFS) was 57 months, 2-year PFS was 67%, and 5-year PFS was 33%. Median overall survival (OS) was 63 months, 2-year OS was 88%, and 5-year OS was 57%. TMZ was generally well tolerated, with the most common toxicity of Grade 3 or higher being thrombocytopenia in 3 patients (30%). Conclusion: These outcomes suggest that TMZ might have activity for maintenance in elderly patients with PCNSL, when more aggressive treatments are contraindicated. Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2019 Published by Elsevier Inc. Keywords: Consolidation, MTX, PCNSL, R-MPV, TMZ
Introduction Primary central nervous system lymphoma (PCNSL) is challenging to manage in elderly patients. Being older than 60 years at diagnosis is known to be a negative prognostic factor,1 with lower response rates and earlier relapse.2 Moreover, elderly patients and those with comorbidities suffer high rates of treatment-related toxicity.3 Considering that almost half of PCNSL patients are 70 years old or older,3,4 there is an unmet clinical need to define optimal treatment for this population. Standard induction therapy 1
Department of Neurology Division of Hematology and Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 2
Submitted: Feb 18, 2019; Accepted: May 21, 2019 Address for correspondence: Andrew Brenner, MD, PhD, University of Texas Health San Antonio Cancer Center, 7979 Wurzbach Rd, MC 8232, San Antonio, TX 782293900 Fax: 210-692-7502; e-mail contact: [email protected]
2152-2650/$ - see frontmatter ª 2019 Published by Elsevier Inc. https://doi.org/10.1016/j.clml.2019.05.012
incorporates high-dose methotrexate (HD-MTX), usually with other cytotoxic agents, corticosteroids, and rituximab.5 This is typically followed by consolidation treatment, consisting either of whole-brain radiation therapy (WBRT) and high-dose cytarabine6 or high-dose chemotherapy with autologous stem cell transplantation (ASCT).7,8 In patients older than 60 years, WBRT is associated with a high incidence of neurotoxicity, leading to progressive ataxia and cognitive impairment,1,3 and is not recommended. ASCT remains an option for select older individuals,9 but in practice, many of these patients are poor candidates for this intensive treatment modality because of medical comorbidities and general frailty. High doses of methotrexate10 or cytarabine11 represent other consolidation options, but their use is limited by myelosuppression and other toxicities. Safe and efficient postinduction treatment for elderly patients with PCNSL remains an unmet clinical need, especially for the oldest and least fit patients. Temozolomide (TMZ) is an oral alkylating agent commonly used to treat primary brain tumors such as gliomas. It is known to
Clinical Lymphoma, Myeloma & Leukemia Month 2019
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Temozolomide Maintenance for CNS Lymphoma excluded; intrathecal chemotherapy was allowed. Ten patients met criteria for inclusion. These patients had been offered TMZ after achieving complete response (CR) or partial response (PR) after RMPV treatment. TMZ was given as a single agent at the maintenance dose of 150 mg/m2 daily on days 1 through 5 of an initial 28day cycle, and increased to 200 mg/m2 for subsequent cycles, unless limited by toxicity, with intention to give at least 6 cycles. Serial magnetic resonance imaging was performed to monitor for disease progression. Maintenance therapy was continued until progression, unacceptable toxicity, or patient preference to stop treatment. The primary end point of the study was progression-free survival (PFS), calculated from date of diagnosis to date of progression, last neurologic evaluation, or death if patients did not have disease progression, whichever came first. Overall survival (OS) was calculated from the date of diagnosis to last contact or death. Cases were also assessed for treatment-associated adverse events, using the Common Terminology Criteria for Adverse Events version 4.0, and were evaluated for neurocognitive impairment using Mini-Mental State Examination (MMSE) at baseline and after completion of TMZ treatment.
Table 1 Patient Characteristics at Baseline Characteristic
Value
Sex Male
4 (40%)
Female
6 (60%)
Median Age (Range), Y
67 (61-76)
CSF Involvement
2/6 (33%)
Ocular Involvement
1 (10%)
Performance Status ECOG 0
1 (10%)
ECOG 1
8 (80%)
ECOG 2
1 (10%)
MSKCC 2
10 (100%)
Median MMSE Score (Range)
27 (20-30)
Abbreviations: CSF ¼ cerebrospinal fluid; ECOG ¼ Eastern Cooperative Oncology Group; MMSE ¼ Mini-Mental State Examination; MSKCC ¼ Memorial Sloan Kettering Cancer Center.
effectively penetrate the blood-brain barrier, and to have a tolerable toxicity profile. It has been incorporated into induction treatment for elder individuals with PCNSL2,12; these studies showed acceptable safety, but limited efficacy. One study introduced it as a maintenance treatment in elderly patients with promising results.13 Therefore, we conducted a retrospective observational study, including 10 immunocompetent patients older than 60 years who received TMZ as a maintenance treatment after induction therapy including R-MPV (rituximab, HD-MTX, procarbazine, and vincristine).
Results Patient characteristics are reported in Table 1. Noticeable points were a sex ratio of 60% female and median age at diagnosis of 67 years (range, 61-76), with most patients with Eastern Cooperative Oncology Group performance status of 1, Memorial Sloan Kettering Cancer Center prognostic score at 2, and median MMSE at baseline at 27 (range, 20-30). All patients received 5 cycles of MPV without reduction of dose, except 1 patient who received only 3 cycles because of recurrent severe acute renal failure associated with chemotherapy. All patients were given 1 to 5 cycles of intrathecal MTX. Eight patients (80%) also received rituximab as part of the induction treatment. One patient had previously received HD-MTX with cytarabine for 1 month before seeking a second opinion and starting our study regimen. After completion of 5 cycles of R-MPV, 3 patients (30%) were in CR, 3 others (30%) in near CR, and the last 4 (40%) in PR, with an overall response rate (ORR) of 100%. Patients subsequently received a median of 6 cycles of TMZ (range, 3-12). Three patients (30%) received <6 cycles: 2 stopped after 3 cycles because of progression of disease, the fourth stopped after 5 cycles because of
Patients and Methods Patients were identified through a search of electronic medical records for all individuals older than 60 years who received a diagnosis of PCNSL at our institution between 2011 and 2017. A total of 30 cases were reviewed with new, tissue-confirmed, cases of B-cell lymphoma in the central nervous, with adequate staging imaging to exclude extra-central nervous system sites of involvement, treated with MPV (methotrexate, procarbazine and vincristine) with or without rituximab, followed by at least 1 cycle of TMZ. Methotrexate was given at a dose of 3.5 g/m2. Individuals who received WBRT or ASCT as part of initial therapy were
Table 2 Toxicities of Treatment (CTCAE Version 4.0) R-MPV Acute Renal Failure Encephalopathy Thrombocytopenia Neutropenia Infection
TMZ
Grade 3
Grade 4
Grade 3
0
1 (10%)
0
Grade 4 0
2 (20%)
0
0
0
NA
1 (10%)
1 (10%)
2 (20%)
1 (10%)
1 (10%)
0
2 (20%)
NA
NA
1 (10%)
0
Neurotoxicity Median MMSE Score (Range)
28.5 (21-30)
30 (27-30)
Abbreviations: CTCAE ¼ Common Terminology Criteria for Adverse Events; MMSE ¼ Mini-Mental State Examination; R-MPV ¼ rituximab, methotrexate, procarbazine, vincristine; TMZ ¼ temozolomide.
2
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Clinical Lymphoma, Myeloma & Leukemia Month 2019
Geraldine Faivre et al Figure 1 Progression-Free Survival (PFS) and Overall Survival (OS) Curves in 10 Elderly Patients Treated for Newly Diagnosed Primary Central Nervous System Lymphoma With R-MPV (Rituximab, Methotrexate, Procarbazine, and Vincristine) With or Without ITMTX Followed by Temozolomide. PFS and OS Were Calculated From Date of Diagnosis
Abbreviation: IT-MTX ¼ intrathecal methotrexate.
Grade 4 thrombocytopenia. Among patients who discontinued TMZ, two (20%) did because of Grade 3 or 4 thrombocytopenia (after 5 and 6 cycles, respectively), 2 (20%) because of fatigue (after 6 and 9 cycles, respectively), 1 for Grade 4 neutropenia after 6 cycles, and 3 (30%) because of CR (after completion of 6, 7, or 12 cycles, respectively). There were treatment delays in 4 patients (40%) because of thrombocytopenia (2 patients), bronchitis (1 patient), and severe allergic reaction to penicillin (1 patient). Two patients (20%) received only the 150 mg/m2 dose, with the usual dose increment withheld because of thrombocytopenia. After completion of TMZ, 8 patients (80%) were in CR and 2 (20%) had disease progression after 3 cycles. Response rates are reported in Table 2. Median follow-up was 55 (range, 16-79) months. Median PFS was 57 (range, 6.2-77) months; 2-year, 3-year, and 5-year PFS were respectively 67%, 56%, and 33% (Figure 1). Median OS was 63 (range, 16-79) months; 2-year, 3-year, and 5-year OS were respectively, 88%, 75%, and 57% (Figure 1). Median time to progression after discontinuation of TMZ was 16 (13-48). months Six patients (60%) had disease progression after 3 to 12 cycles, but only 2 (20%) while receiving TMZ treatment. Two of these had systemic recurrence without brain relapse and were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), whereas the other 4 had cerebral progression of disease (1 had systemic and brain relapse and was treated with R-
CHOP, another received TMZ with rituximab, and the last 2 were given WBRT). Four patients (40%) died, all while receiving chemotherapy for progressive or recurrent disease. Adverse events are reported in Table 2, with TMZ associated with Grade 3 (1 patient) or 4 (2 patients) thrombocytopenia in 30% of the patients, and Grade 4 neutropenia in 2 patients (20%) (1 was related to accidental overdose and the other happened after 6 cycles of TMZ). Median MMSE score after completion of TMZ was 30 (range, 27-30), with an average increase of 3 points (range, 0-10) compared with baseline. No neurotoxicity was reported.
Discussion In our study we aimed to evaluate the efficacy and safety of TMZ as single-agent maintenance treatment in elderly patients with newly diagnosed PCNSL, after completion of R-MPV as induction treatment. TMZ was generally well tolerated with moderate hematologic toxicity and no neurotoxicity. Outcomes, notable for a median PFS of 57 months, were highly favorable compared with clinical trial data of PCNSL in elderly patients, which typically report PFS in the 1-year range.11,12 Our study excluded nonresponders to R-MPV, because patients were offered TMZ maintenance therapy only if they had achieved a response (CR or PR) to induction therapy. However, we went back and analyzed all patients who met the criteria and found only 2 patients (20%) whose disease progressed with R-MVP, after 5 cycles. The outcomes in our study
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are unfortunately not comparable with a prospective study using intention-to-treat analysis. However, a retrospective study of elderly patients who underwent ASCT, subject to a similar selection bias, showed a similar median PFS of 51.1 months.9 Furthermore, one could argue that our study might provide some evidence of therapeutic activity for TMZ, apart from survival outcomes, because 3 patients with PR and 2 with near-CR after induction achieved CR during maintenance treatment. This study might suffer from several limitations. The small sample size (n ¼ 10) has statistically weakened our findings as well as the lack of a direct comparator group. In addition, the retrospective design is vulnerable to selection bias and it could be argued that individuals might well have been selectively offered TMZ on the basis of patient and disease factors that predispose them to favorable outcomes. The nonincluded remaining patients had limited data available, a different pathologic diagnosis, or a different consolidation treatment, such as WBRT (in 2 patients). Finally, the potentially high performance status of patients before inclusion might also have participated in those optimistic results. Temozolomide was associated with moderate toxicity. Forty percent of the patients experienced a Grade 3 or 4 thrombocytopenia with TMZ. This is higher than in other studies of TMZ in PCNSL, which might reflect the higher dose of TMZ used: 200 mg/m2 in our study, versus 100 to 150 mg/m2 in previous studies.2,12,13 Most of the former studies focused on evaluating new efficient and safe induction therapies in elderly patients with PCNSL, including polychemotherapy, ASCT, and immunotherapies. WBRT is now considered as neurotoxic and usually offered as salvage therapy after disease recurrence in elderly patients.3 A few studies considered the effect of systemic maintenance or consolidation therapies. Omuro et al reported 1 retrospective study in 2007,2 in which patients aged older than 60 years were given HDMTX and TMZ (at a dose of 100 mg/m2) as induction (3 cycles) and consolidation (5 cycles) therapies.2 Median PFS was 8 months, 2-year PFS was 22%, median OS was 35 months with a median follow-up of 21 months, and ORR was 55%. Severe thrombocytopenia was noticed in 20% of patients. Eight years later, Omuro et al conducted a prospective study in which outcomes were compared in patients treated with HD-MTX plus TMZ versus MPV followed by 1 cycle of cytarabine as consolidation (MPV-A).12 Although differences were not statistically significant, there was a trend in favor of the MPV-A regimen (median PFS 9.5 vs. 6.1 months). Outcomes in the HD-MTX-TMZ group were as follows: median PFS was 6 months, 1-year PFS was 36%, median OS was 14 months, and 2-year OS was 39%. Incidence of thrombocytopenia was only 1%, and no delayed neurotoxicity was found in any groups. Finally, Pulczynski et al conducted a prospective and multicenter study with young and elderly PCNSL patients who received HD-MTX and cytarabine. Elderly patients, older than 65 years old, who achieved CR or PR after 6 cycles TMZ at 150 mg/ m2 was given as maintenance therapy.13 After a median of 11 (range, 1-12) cycles, 5 of the 15 elderly patients with maintenance therapy relapsed after achieving CR, with an ORR of 75%. In this population, 2-year PFS was 44.4% and 2-year OS was 55.6%, which were superior to the youngest group. The authors suggested that de-escalating induction treatment and introducing maintenance
Clinical Lymphoma, Myeloma & Leukemia Month 2019
TMZ in elderly PCNSL patients might improve outcomes. Severe thrombocytopenia (Grade 3 or 4) was reported in 10.6% of the patients. Two other recent studies evaluated the use of other consolidation treatments. Houillier et al reported that 3 cycles of cytarabine after 3 cycles of R-MPV were no better in terms of outcomes than rituximab with MPV-A, but added toxicity.11 Fritsch et al conducted a prospective study the same year, and described good results with maintenance procarbazine, after induction with R-MP (rituximab, methotrexate, and procarbazine) or R-MPL (R-MP with lomustine).10 Median PFS was 10.3 months with 1-year PFS of 46.3% and 2-year PFS of 37.3%; median OS was 20.7 months with 1-year OS of 56.7% and 2-year OS of 47%. Hematologic toxicity was limited, especially in the R-MP group, with severe thrombocytopenia in 5.6% of the patients. Additional studies are required to assess efficacy and tolerance of consolidation or maintenance therapy in the elderly patients who are poor candidates for aggressive treatments.
Conclusion Temozolomide is generally a well tolerated and easily administered drug, given orally for 5 days per 4-week cycle. It might be active as single-agent maintenance therapy against PCNSL in elderly patients, for whom treatment often aims to maintain a quality of life and functional independence with the best neurocognitive preservation.3 It is a potential option in elder patients with PCNSL who have achieved CR or PR with R-MPV and who wish to avoid the neurotoxicity of WBRT, especially those who are deemed poor candidates for ASCT. Larger prospective studies are required to confirm and quantify the benefit of TMZ in this setting. Ongoing studies include NCT01458730, which will investigate the efficacy and safety of an HDeMTX-based induction polychemotherapy regimen used in combination with rituximab and intraspinal liposomal cytarabine followed by TMZ, and NCT02313389, which will compare outcomes of elderly patients with newly diagnosed PCNSL, treated with rituximab, methotrexate, and TMZ as maintenance therapy after achieving CR with rituximab with MPVA induction therapy.
Clinical Practice Points Optimal management of elderly patients with PCNSL after in-
duction therapy is unclear. Standard approaches to consolidation, including WBRT and ASCT, carry significant toxicity in this population. In our retrospective series of 10 patients who were treated with TMZ after induction with R-MPV, outcomes were favorable, with a median PFS of 57 months and a median OS of 63 months, with moderate toxicity. Our results support the idea that TMZ might have activity for maintenance in elderly patients with PCNSL.
Acknowledgments The study was supported by in part by the University of Texas Health Science Center at San Antonio Cancer Therapy and Research Center through the National Institutes of Health; National Cancer Institute P30 award CA054174.
Geraldine Faivre et al Disclosure The authors have stated that they have no conflicts of interest.
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