Errata Acesso aberto Revisado por pares

Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma—a long-term follow-up study

2015; Elsevier BV; Volume: 26; Issue: 3 Linguagem: Inglês

10.1093/annonc/mdv002

ISSN

1569-8041

Autores

Benjamin Kasenda, Elisabeth Schorb, Kristina Fritsch, Jürgen Finke, Gerald Illerhaus,

Tópico(s)

Glioma Diagnosis and Treatment

Resumo

Ann Oncol 2012; 23: 2670–2675 (doi: 10.1093/annonc/mds059) In the original version of this paper in the issue, an error occurred whereby several instances of the number '1' had dropped out of the PDF. The corrected sections read as below. The Publisher apologizes for the error. After a median follow-up of 140 months, 10/30 patients are still alive. Median survival was reached after 104 months. Five- and 10-year OS estimates were 67% [95% confidence interval (CI) 52% to –86%] and 42% (95% CI 28% to –65%) (Figure 1). EFS estimates after 5 and 10 years were 67% (95% CI 52% to 86%) and 40% (95% CI 25% to 62%), respectively. In the per-protocol analysis, median survival was reached after 122 months. Five- and 10-year OS probability was 83% (95% CI 69%–100%) and 56% (95% CI 39%–81%) and EFS probability after 5 and 10 years was 83% (95% CI 69%–100%) and 52% (95% CI 35%–77%), respectively. After a median follow-up of 72 months, 9/13 patients are still alive. The median survival was not reached at the time of last follow-up. Both 2- and 5-year OS estimates were 77% (95% CI 57%–100%) (Figure 2). Two- and 5-year EFS estimates were 77% (95% CI 57%–100%) and 70% (95% CI 48%–100%), respectively. In the per-protocol population, 8/11 patients are still alive. Both 2- and 5-year OS estimates were 82% (95% CI 62%–100%); 2- and 5-year EFS estimates were 82% (95% CI 62%–100%) and 73% (95% CI 51%–100%), respectively. In the entire intention-to-treat group (N = 43), after a follow-up of 110 months, the median OS was reached at 104 months. Two- and 5-year OS was 81% (95% CI 71%–94%) and 70% (95% CI 57%–85%), respectively (supplemental Figure S2, available at online). Two- and 5-year EFS was 81% (95% CI 70%–94%) and 67% (95% CI 55%–83%), respectively. In the per-protocol analysis, the median OS was reached after 122 and median EFS after 104 months. The estimated 5-year OS and EFS was 82% (95% CI 71%–96%) and 79% (95% CI 67%–94%), respectively. In multivariate Cox regression analysis, neither age [hazard ratio (HR) = 1.55, 95% CI 0.95–2.55, P = 0.08] nor KPS (HR = 1.04, 95% CI 0.83–1.30, P = 0.7284) had a significant impact on survival. However, the HR and the rather small P value for the coefficient age suggest a trend that with higher age the survival probability decreases. Of those patients achieving CR, in study I, after the last followup, additional four patients relapsed (all together 10/25; 40%, 95% CI 22%–61%). Of those, only one was successfully salvaged with a second HCT–ASCT and is ongoing CR. Regarding the per-protocol population from study I, the overall relapse rate was lower (7/22; 32%, 95% CI 0.15%–0.55%). In study II, previously one patient was reported to suffer from relapse (CNS and systemic) after achieving CR. Now, one additional female patient relapsed (altogether 2/9; 22%, 95%, CI 4%–60%), but she was successfully salvaged by immuno-polychemotherapy (rituximab, MTX, lomustine, and procarbazine). In the entire cohort, 12 of 34 patients who achieved CR relapsed (35%; 95% CI 20%–54%) and of those, six relapsed 5 years after diagnosis (18%; 95% CI 7%–35%). The relapse rate in the per-protocol population was lower, here, only 9 of 30 patients who achieved CR relapsed (30%; 95% CI 15%–50%). Figure 3 illustrates the cumulative incidence function of the probability to die of PCNSL with other causes of death as competing risk in the per-protocol population. The estimated risk of death due to PCNSL after 5 years was 15% compared with 3% of death due to other cause. The characteristics of 28 patients who survived 5 years and longer after diagnosis are summarized in supplemental Table S1 (available at online). Of those, only two who experienced a relapse were successfully salvaged and are still alive (patient 20 and 23). One female patient (44 years of age) developed late onset neurotoxicity during follow-up. She was irradiated because of only obtaining partial remission after HCT–ASCT (patient 25). One patient died due to severe neurotoxicity (patient 2). Altogether, six patients relapsed after > 5 years. During first-line treatment, five of these six patients received HCT–ASCT according to study protocol (one refused WBRT after HCT–ASCT, patient 20) and one patient (patient 8) was only irradiated due to renal failure developed after the second HD-MTX application (stable disease at that time, CR after WBRT). In these five patients who received HCT–ASCT, first CR was observed (i) during induction treatment with HD-MTX (N = 2, patients 5 and 20), (ii) after HCT–ASCT (N = 1, patient 10), and (iii) after WBRT (N = 2, patients 2 and 3). There were no apparent differences compared with all other patients regarding histology. We dichotomized our cohort in patients who received WBRT (N = 30, for consolidation N = 26, for salvage N = 4) and those who did not (N = 13) to describe the association between WBRT and clinical apparent neurotoxicity. Of those eight (19%) patients who developed neurotoxicity during the entire follow-up, all were irradiated [N = 7 (as planned in study I), N = 1 (from study II due to partial response (PR) after HCT–ASCT)]. None of the patients who solely underwent HCT–ASCT developed neurotoxicity. Furthermore, regarding efficacy, patients who received HCT–ASCT without consolidating WBRT (N = 10; two from study I, eight from study II) achieved a response rate of 100% (nine CR, one PR); 2- and 5-year OS rates were 80% (95% CI 59 to 100) and 70% (95% CI 47 to 100), respectively. The present study provides long-term data of patients with newly diagnosed PCNSL who were treated according to our previously published HCT–ASCT containing protocols [13.Illerhaus G. Marks R. Ihorst G. et al.High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma.J Clin Oncol. 2006; 24: 3865-3870Crossref PubMed Scopus (240) Google Scholar, 14.Illerhaus G. Muller F. Feuerhake F. et al.High-dose chemotherapy and autologous stem-cell transplantation without consolidating radiotherapy as first-line treatment for primary lymphoma of the central nervous system.Haematologica. 2008; 93: 147-148Crossref PubMed Scopus (167) Google Scholar]. So far, eight studies (including ours) reported outcome after HCT–ASCT containing regimens for first-line treatment in PCNSL patients [13.Illerhaus G. Marks R. Ihorst G. et al.High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma.J Clin Oncol. 2006; 24: 3865-3870Crossref PubMed Scopus (240) Google Scholar, 14.Illerhaus G. Muller F. Feuerhake F. et al.High-dose chemotherapy and autologous stem-cell transplantation without consolidating radiotherapy as first-line treatment for primary lymphoma of the central nervous system.Haematologica. 2008; 93: 147-148Crossref PubMed Scopus (167) Google Scholar, 17.Brevet M. Garidi R. Gruson B. et al.First-line autologous stem cell transplantation in primary CNS lymphoma.Eur J Haematol. 2005; 75: 288-292Crossref PubMed Scopus (50) Google Scholar, 18.Colombat P. Lemevel A. Bertrand P. et al.High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group.Bone Marrow Transplant. 2006; 38: 417-420Crossref PubMed Scopus (138) Google Scholar, 19.Montemurro M. Kiefer T. Schuler F. et al.Primary central nervous system lymphoma treated with high-dose methotrexate, high-dose busulfan/thiotepa, autologous stem-cell transplantation and response-adapted whole-brain radiotherapy: results of the multicenter Ostdeutsche Studiengruppe Hamato-Onkologie OSHO-53 phase II study.Ann Oncol. 2007; 18: 665-671Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 20.Abrey L.E. Moskowitz C.H. Mason W.P. et al.Intensive methotrexate and cytarabine followed by high-dose chemotherapy with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma: an intent-to-treat analysis.J Clin Oncol. 2003; 21: 4151-4156Crossref PubMed Scopus (245) Google Scholar, 21.Cheng T. Forsyth P. Chaudhry A. et al.High-dose thiotepa, busulfan, cyclophosphamide and ASCT without whole-brain radiotherapy for poor prognosis primary CNS lymphoma.Bone Marrow Transplant. 2003; 31: 679-685Crossref PubMed Scopus (111) Google Scholar, 22.Yoon D.H. Lee D.H. Choi D.R. et al.Feasibility of BU, CY and etoposide (BUCYE), and auto-SCT in patients with newly diagnosed primary CNS lymphoma: a single-center experience.Bone Marrow Transplant. 2011; 46: 105-109Crossref PubMed Scopus (39) Google Scholar] (supplemental Table S2, available at online). Median follow-up ranged between 15 and 63 months (number of patients, 6–30) and conditioning regimens as well as survival rates varied strongly among the studies. To our best knowledge, no other study has yet reported comparable long-term data as reported in the present analysis regarding the treatment approach using HCT–ASCT in newly diagnosed PCNSL and for the population up to 65 years, no superior outcome data were published. According to a recent review, only few studies reached a median OS of 60 months or longer [1.Morris P.G. Abrey L.E. Therapeutic challenges in primary CNS lymphoma.Lancet Neurol. 2009; 8: 581-592Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar]. Recently published long-term follow-up data of the 'Bonn Protocol' (median follow-up 100 months for surviving patients) show a median OS of 54 months for the whole study population, but the median OS for patients younger than 60 years (N = 30) has not been reached yet [23.Juergens A. Pels H. Rogowski S. et al.Long-term survival with favorable cognitive outcome after chemotherapy in primary central nervous system lymphoma.Ann Neurol. 2010; 67: 182-189Crossref PubMed Scopus (85) Google Scholar]. Another recent publication reports a median OS of 33 months after a median follow-up of 83 months; however, this prospective multicenter trial was stopped due to toxicity and slow accrual [24.Ghesquieres H. Ferlay C. Sebban C. et al.Long-term follow-up of an age-adapted C5R protocol followed by radiotherapy in 99 newly diagnosed primary CNS lymphomas: a prospective multicentric phase II study of the Groupe d'Etude des Lymphomes de l'Adulte (GELA).Ann Oncol. 2010; 21: 842-850Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar]. These examples reflect the still existing heterogeneity of outcomes which may be caused by several differences regarding treatment protocols, study design (single center versus multicenter), type of analysis (retrospective versus prospective), age limit but also baseline risk factors. In fact, besides age and KPS, which are both wellestablished clinical prognostic factors, several other factors such as serological markers but also pharmacokinetic parameters of MTX have been proposed to potentially identify risk groups [25.Hottinger A.F. Iwamoto F.M. Karimi S. et al.YKL-40 and MMP-9 as serum markers for patients with primary central nervous system lymphoma.Ann Neurol. 2011; 70: 163-169Crossref PubMed Scopus (22) Google Scholar, 26.Levy O. Deangelis L.M. Filippa D.A. et al.Bcl-6 predicts improved prognosis in primary central nervous system lymphoma.Cancer. 2008; 112: 151-156Crossref PubMed Scopus (64) Google Scholar, 27.Joerger M. Huitema A.D. Krahenbuhl S. et al.Methotrexate area under the curve is an important outcome predictor in patients with primary CNS lymphoma: A pharmacokinetic-pharmacodynamic analysis from the IELSG no. 20 trial.Br J Cancer. 2010; 102: 673-677Crossref PubMed Scopus (64) Google Scholar], but most of these findings still lack external validation from larger cohorts. Another cause of the observed heterogeneity is of course random variability due to the relatively small numbers of patients. However, with all these limitations, the now achieved median OS of 104 months for patients up to 65 years in our cohort is encouraging. Unfortunately, late relapses still occurred and one additionally needs to consider the fact that patients regarded eligible for this aggressive treatment approach are still a selected subpopulation and do not represent the majority of PCNSL patients. Especially elderly patients above 65 years who comprise about 50% of PCNSL patients are mostly not eligible for HCT–ASCT and are referred to other treatment regimens [28.Fritsch K. Kasenda B. Hader C. et al.Immunochemotherapy with rituximab, methotrexate, procarbazine, and lomustine for primary CNS lymphoma (PCNSL) in the elderly.Ann Oncol. 2011; 22: 2080-2085Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar], but thorough clinical baseline risk evaluation beyond age should be done and if elderly patients have a good performance status, they maybe also considered as candidates for HCT–ASCT. It is known that substantial proportions of patients who achieve CR experience relapse mostly during the first 2 years after diagnosis [9.Jahnke K. Thiel E. Martus P. et al.Relapse of primary central nervous system lymphoma: clinical features, outcome and prognostic factors.J Neurooncol. 2006; 80: 159-165Crossref PubMed Scopus (122) Google Scholar]. Nayak et al. recently published comprehensive data from 378 PCNSL patients; of those, 268 achieved a CR and 230 of them relapsed (86%; 95% CI 81%–90%). With regard to the narrow CI, these data give a rather good estimate of the true relapse rate. The authors further report that relapses after 5 years in CR were rare but did occur in 3.7% [8.Nayak L. Hedvat C. Rosenblum M.K. et al.Late relapse in primary central nervous system lymphoma: clonal persistence.Neuro Oncol. 2010; 13: 525-529Crossref Scopus (36) Google Scholar]. Compared with the overall relapse rate, our data compare favorably well with the data reported by Nayak et al.; however, because recurrence occurred later, our rate of patients who relapsed after 5 years is higher (18%) and only one of our patients with such late relapse has successfully been salvaged with a second HCT–ASCT containing a busulfan conditioning regimen and is in ongoing CR [29.Kasenda B. Schorb E. Fritsch K. et al.Primary CNS lymphoma–radiation-free salvage therapy by second autologous stem cell transplantation.Biol Blood Marrow Transplant. 2010; 17: 281-283Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. It seems that even after an upfront aggressive treatment approach, such as HCT–ASCT, some clonal malignant cells persist within the organism and patients are still at risk for relapse even after 5 years and longer. Although WBRT is effective in disease control, the risk for short- and long-term neurotoxicity as well as the low positive impact on OS has recently questioned its role in first-line therapy [5.Omuro A. Taillandier L. Chinot O. et al.Primary CNS lymphoma in patients younger than 60: can whole-brain radiotherapy be deferred?.J Neurooncol. 2010; 104: 323-330Crossref PubMed Scopus (54) Google Scholar, 7.Thiel E. Korfel A. Martus P. et al.High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial.Lancet Oncol. 2010; 11: 1036-1047Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar], but data from the recent randomized non- inferiority trial need to be taken with care since it was under powered and the induction treatment mainly based on HDMTX monotherapy [7.Thiel E. Korfel A. Martus P. et al.High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial.Lancet Oncol. 2010; 11: 1036-1047Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar, 30.DeAngelis L.M. Radiotherapy: has the role of WBRT in primary CNS lymphoma been settled?.Nat Rev Clin Oncol. 2011; 8: 196-198Crossref PubMed Scopus (11) Google Scholar]. In fact, dose-reduced WBRT (23.4 Gy) is reported to be not associated with neurocognitive decline but still excellent disease control for patients achieving CR after treatment according to the R-MPV regimen (rituximab, MTX, procarbazine, and vincristine) [31.Shah G.D. Yahalom J. Correa D.D. et al.Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma.J Clin Oncol. 2007; 25: 4730-4735Crossref PubMed Scopus (304) Google Scholar]. On the other hand, Bessel et al. [32.Bessell E.M. Lopez-Guillermo A. Villa S. et al.Importance of radiotherapy in the outcome of patients with primary CNS lymphoma: an analysis of the CHOD/BVAM regimen followed by two different radiotherapy treatments.J Clin Oncol. 2002; 20: 231-236Crossref PubMed Scopus (159) Google Scholar] reported compromised disease control after reducing the WRBT dose from 45 to 30.6 Gy, but the comparison between these two cohorts is difficult since induction polychemotherapies varied. As previously reported, the rate of clinical apparent neurotoxicity in our first study was relatively high (16.7%) in patients receiving both, HCT–ASCT and hyperfractionated WBRT [13.Illerhaus G. Marks R. Ihorst G. et al.High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma.J Clin Oncol. 2006; 24: 3865-3870Crossref PubMed Scopus (240) Google Scholar]. Unfortunately, the rate in patients from study I increased during long-term follow-up to 23.3%. One limitation of this analysis was the lack of prospective standardized testing for neurocognition at baseline and during follow-up, thus the reported risk for neurotoxicity might even be underestimated. However, in study II, in order to decrease the risk of neurotoxicity without lacking efficacy, we improved the protocol by adding another cycle of cytarabine/ thiotepa before stem-cell harvest and by doubling the thiotepa cumulative dose (4 × 5 mg/kg) within the conditioning regimen. In contrast to the earlier study, all patients were supposed to proceed to HCT–ASCT irrespective of their response to HD-MTX. The OS of study II was similar to the previous study with obligatory WBRT and we observed only one female patient developing severe neurotoxicity after being irradiated because of PR after chemotherapy. Of note, the 3-year OS prognosis (82%) of the per-protocol analysis of study II is comparable to that estimated for patients suffering from systemic aggressive diffuse large cell b-cell lymphoma who were at low to intermediate risk (3-year OS 81%) and treated in the rituximab era [33.M Ziepert D Hasenclever E Kuhnt Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era J Clin Oncol 2010 28 2373 2380Google Scholar]. Granted treatment-related mortality (TRM) is an issue to be considered when HCT–ASCT is applied in first-line therapy, but in both studies, we observed no deaths in association with HCT–ASCT. Additionally, following a systematic review of HCT–ASCT in systemic lymphoma, estimated TRM of 6% was not increased compared with standard chemotherapy [34.Greb A. Bohlius J. Schiefer D. et al.High-dose chemotherapy with autologous stem cell transplantation in the first line treatment of aggressive non-Hodgkin lymphoma (NHL) in adults.Cochrane Database Syst Rev. 2008; : CD004024PubMed Google Scholar]. Therefore, basing on our data, not only with regard to the lower risk of neurotoxicity but also the systemic approach of eliminating residual lymphoma cells in all possible chemotherapy sanctuaries including the cerebrospinal fluid, HCT–ASCT could be an effective alternative to WBRT as consolidation therapy. Nevertheless, results from our national multicenter trial that has recently finished recruiting (N = 81) need to be awaited. In this trial, rituximab was added to the induction treatment and WBRT was restricted to those who did not achieve CR after HCT–ASCT (NCT00647049) in accordance to study II. Sequential HD-MTX-based chemotherapy followed by carmustine/thiotepa-containing HCT–ASCT is a promising treatment option leading to remarkable median survival rates of almost 9 years in eligible patients. The role of HCT–ASCT compared with WBRT as consolidation in first-line therapy is currently under investigation in an international randomized trial (NCT01011920), which also evaluates three different combinations of induction treatments for efficacy and safety. With the improvement of chemotherapy protocols for PCNSL, another question that should be addressed in the future is whether HCT–ASCT is really superior to a potent immuno-polychemotherapy combination or may be deferred and saved as an option in case of relapse. Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma—a long-term follow-up studyAnnals of OncologyVol. 23Issue 10PreviewHigh-dose chemotherapy followed by autologous stem-cell transplantation (HCT–ASCT) is a promising approach in eligible patients with primary central nervous system lymphoma (PCNSL). We report long-term data of patients who were treated according to HCT–ASCT containing protocols. Full-Text PDF Open Archive

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