Gerald Illerhaus

High-Dose Chemotherapy With Autologous Stem-Cell Transplantation and Hyperfractionated Radiotherapy As First-Line Treatment of Primary CNS Lymphoma

PURPOSEnTo improve survival and reduce toxicity in primary CNS lymphoma (PCNSL) treatment, we conducted a multicenter phase II study with early high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) followed by hyperfractionated whole-brain radiotherapy (WBRT) for newly diagnosed PCNSL patients younger than 65 years of age.nnnPATIENTS AND METHODSnChemotherapy included three steps: three cycles of methotrexate (8 g/m2); cytarabine (AraC; two doses of 3 g/m2) and thiotepa (40 mg/m2) followed by stem-cell harvest; HDT with carmustine (400 mg/m2) and thiotepa (two doses of 5 mg/kg body weight) followed by ASCT. WBRT (45 Gy, two doses of 1 Gy/d) was administered for consolidation.nnnRESULTSnThirty patients with PCNSL younger than 65 years of age (median, 54 years; range, 27 years to 64 years) were enrolled (nine pilot-phase; 21 phase II). Twenty-eight patients responded to methotrexate: six patients with complete remission (CR), 15 patients with partial remission (PR), and seven patients with stable disease (SD) with clinical improvement. Of 26 patients proceeding to AraC and thiotepa, 10 patients achieved CR, 14 patients achieved PR, one patient experienced SD with clinical improvement, and one patient suffered disease progression. Twenty-three patients received HDT plus ASCT, resulting in 15 patients with CRs and eight patients with PRs. After WBRT, 21 of 21 patients had CRs. One patient died from liver failure after methotrexate. HDT was well tolerated apart from WHO grade 3/4 cytopenia. With a median follow-up of 63 months (range, 4 months to 84 months), 5-year overall survival probability is 69% for all patients and 87% for the 23 patients receiving HDT plus ASCT. The 5-year probability of relapse-related death is 21% for all patients (n = 30) and 8.7% for patients treated with HDT plus ASCT (n = 23).nnnCONCLUSIONnSequential systemic methotrexate and AraC and thiotepa followed by HDT plus ASCT and hyperfractionated WBRT is very effective with little toxicity as initial therapy for PCNSL.

High-dose methotrexate combined with procarbazine and CCNU for primary CNS lymphoma in the elderly: results of a prospective pilot and phase II study

BACKGROUNDnTo improve survival of elderly patients with primary central nervous system lymphoma (PCNSL), we conducted a phase II study with high-dose methotrexate (MTX) combined with procarbazine and CCNU. To reduce neurotoxicity, whole-brain irradiation was reserved for patients not responding to chemotherapy.nnnPATIENTS AND METHODSnHigh-dose MTX was applied on days 1, 15, and 30, procarbazine on days 1-10, and CCNU on day 1. Study treatment comprised up to three 45-day cycles. There was no lower limit of Karnofsky performance status (KPS).nnnRESULTSnThirty patients with PCNSL (n = 29) or primary ocular lymphoma (n = 1) were included (median age 70 years, range 57-79 years). The median initial KPS was 60% (range 30%-90%). Best documented response in 27 assessable patients were 12 of 27 (44.4%) complete remissions, 7 of 27 (25.9%) partial remissions, and 8 of 27 (29.6%) disease progressions. Two patients died of probable treatment-related causes. With a median follow-up of 78 months (range 34-105), the 5-year overall survival is 33%. Eight of 30 patients (26.7%) are currently alive and well, six without signs of leukoencephalopathy.nnnCONCLUSIONnThe combination of high-dose MTX with procarbazine and CCNU is feasible and effective and results in a low rate of leukoencephalopathy. Comorbidity and toxicity remain of concern when treating PCNSL in elderly patients.

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

study I After a median follow-up of 140 months, 10/30 patients are still alive. Median survival was reached after 104 months. Fiveand 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. Fiveand 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.

Prognosis of patients with primary central nervous system lymphoma after high-dose chemotherapy followed by autologous stem cell transplantation

High-dose chemotherapy followed by autologous stem cell transplantation has been shown to be feasible and highly effective in newly diagnosed primary central nervous system lymphoma. In this retrospective multicenter study, we investigated prognosis and baseline risk factors in patients with primary central nervous system lymphoma who underwent this treatment approach. We retrospectively analyzed 105 immunocompetent patients with primary central nervous system lymphoma who underwent high-dose chemotherapy followed by autologous stem cell transplantation with or without whole brain radiotherapy as first-line consolidation treated at 12 German centers between 1997 and 2011. We estimated survival rates and investigated the impact of age, performance status, serum lactate dehydrogenase level, and deep brain involvement on overall and progression-free survival. Patients were additionally categorized into three prognostic groups according to the Memorial Sloan Kettering Cancer Center prognostic model. After a median follow up of 47 months, median progression-free survival and overall survival was reached after 85 and 121 months; 2- and 5-year survival rates were 82% and 79%, respectively. The Memorial Sloan Kettering Cancer Center prognostic model did not predict survival. Only age revealed some evidence of prognostic relevance. Overall response rate was 95%; of those patients with progressive disease before high-dose chemotherapy, 7 of 20 achieved ongoing complete remission after therapy without whole brain radiation therapy. Transplantation-associated mortality was 2.8%. High-dose chemotherapy followed by autologous stem cell transplantation is a highly effective and safe treatment modality for selected primary central nervous system lymphoma patients. Superiority compared to standard chemotherapy still warrants further investigation.

18F-FDG PET Is an Independent Outcome Predictor in Primary Central Nervous System Lymphoma

Primary central nervous system (CNS) lymphoma is an aggressive non-Hodgkin lymphoma with poor prognosis. We evaluated pretreatment 18F-FDG PET as a prognostic marker in primary CNS lymphoma. Methods: Forty-two immunocompetent patients with newly diagnosed primary CNS lymphoma who underwent pretreatment 18F-FDG PET were retrospectively analyzed. Baseline status and response to treatment were evaluated by MR imaging. Tumor maximum standardized uptake values were assessed by volume-of-interest analyses using an automatic isocontour definition. A 10-step semiquantitative visual rating system (metabolic imaging lymphoma aggressiveness scale, or MILAS) was used to assess primary CNS lymphoma metabolism as a marker of clinical aggressiveness. Logistic regression, log-rank testing, and multivariable Cox regression were used to investigate the association between 18F-FDG uptake and tumor response and survival. Results: Mean maximum standardized uptake value correlated linearly with MILAS. The distribution of patients according to MILAS (0–9) was 0%, 28.6%, 23.8%, 21.4%, 11.9%, 4.8%, 7.1%, 0%, 0%, and 2.4%. There was no correlation between MILAS and response to treatment. Respective 2- and 5-y survival rates were 52% and 32% for progression-free survival (PFS) and 64% and 50% for overall survival (OS). A cutoff at MILAS 3 was a good separator for PFS (median: 54.7 mo [≤3], 3.8 mo [>3], P = 0.0272) and OS (median: not reached [≤3], 13.8 mo [>3], P = 0.131). In multivariable analyses, increasing MILAS was significantly associated with shorter PFS (hazard ratio, 1.49, P = 0.006) and OS (hazard ratio, 1.43, P = 0.018). Conclusion: Increased pretreatment 18F-FDG uptake may offer new opportunities for baseline risk evaluation in untreated primary CNS lymphoma.

The prognostic value of serum methotrexate area under curve in elderly primary CNS lymphoma patients

Studies on pharmacokinetics and pharmacodynamics of high-dose methotrexate chemotherapy (HD-MTX) in elderly primary central nervous system lymphoma (PCNSL) patients are rare. MTX exposure time has recently been proposed as an outcome determining factor in PCNSL. We investigated 49 immunocompetent PCNSL patients (female Nu2009=u200930, male Nu2009=u200919, median age 73xa0years) who were treated according to HD-MTX-based protocols. A two-compartment pharmacokinetic model was used to describe the MTX clearance. Response to treatment was assessed by MRI. We used multivariable models to investigate the association between MTX exposure and tumor response as well as survival. Dose normalized MTX peak serum levels [Cmax, μmol/L g] and dose normalized area under the curve [AUCdn, μmol h/L g] were higher in females than in males, respectively [59.4 (f) vs. 48.1 (m), Pu2009<u20090.001; 373.2 (f) vs. 271.9 (m), Pu2009=u20090.008]. Increasing AUC was inversely correlated with tumor response. AUC values above 2,126xa0hu2009μmol/L were independently associated with shorter overall and progression-free survival [hazard ratio (HR), 4.56, 95xa0% CI 1.74–11.94; HR 2.87, 95xa0% CI 1.18–7.00]. Exceedingly high MTX AUC levels can have a negative impact on progression-free and overall survivals in elderly PCNSL patients.

High-Dose Chemotherapy and Stem Cell Transplantation for Primary CNS Lymphoma

The treatment of patients with CNS lymphoma has posed a challenge since this entity was first described. Several issues have complicated the management of these patients. First, it is important to define whether the lymphoma is confined to the CNS (primary CNS lymphoma, PCNSL) or whether there is co-existent or pre-existent systemic lymphoma (stage IV or secondary CNS lymphoma, respectively). Second, it is important to define the histological subtypes of lymphoma involving the CNS since multiple histologies are known to occur in the CNS and the treatment can vary depending on the histology.