Chronic lymphocytic leukemia (CLL) occurs in older individuals with a median age at diagnosis of 72 years. In recent years, there has been considerable progress in the frontline therapy of ...elderly/physically unfit patients with CLL. The German CLL11 trial showed that addition of obinutuzumab to chlorambucil (G-Clb) prolongs progression free survival (PFS) and overall survival (OS) compared to chlorambucil alone or in combination with rituximab. More recently, obinutuzumab together with ibrutinib or venetoclax were shown to be superior to G-Clb with regard to PFS, but there was no advantage in terms of OS.
In this retrospective, multinational and multicenter co-operative study the European Research Initiative on CLL (ERIC) and the Israeli CLL Study Group (ICLLSG) evaluated the efficacy of frontline treatment with G-Clb in patients with CLL, in a “real-world” setting. Our analysis excluded CLL patients with documented del(17p) or TP53 mutations since they are no longer treated with chemotherapy.
Results: A total of 437 treatment-naïve patients with CLL from 51 medical centers located in 13 countries were included. The median age of this patient population was 75.9 years; 59.7% were men, median CIRS total score was 8 and estimated creatinine clearance 61.1 mL/min. Seventy four patients had Binet stage A (17.2%), 167 (38.8%) stage B and 190 (44.1%) stage C. Results of FISH and IGHV mutational status were available for 332 and 115 patients, respectively. High-risk cytogenetics, del(11q) was documented in 18.7% patients and IGHV-unmutated gene in 64.4%. The vast majority of patients were treated with G-Clb (N=408) and the rest with obinutuzumab monotherapy (G-monotherapy, N=29). The clinical overall response was 86.5%, including clinical complete and partial responses in 41.6% and 45.8% of cases, respectively. The median observation time was 14.1 months (m) and the median PFS of the entire cohort was 27.6m (95% CI, 24.2-31.0). The PFS for G-Clb was significantly better than G-monotherapy (P=0.001; HR=0.38, 95% CI: 0.22-0.67), being the 2-year PFS estimates 61.8% and 52.8%, respectively. The median PFS was significantly shorter for patients with del(11q) (19.2m) compared to those with normal FISH (not reached, P<0.001), del(13q) (29.9m, P<0.001) and trisomy12 (not reached, P=0.027). Patients with IGHV-unmutated had a trend for shorter PFS compared to those with IGHV-mutated gene (median PFS 25.3m vs. not reached, respectively. p=0.06). In a multivariate analysis, older age, high risk-disease, lymph nodes >5cm, G-monotherapy, reduced cumulative dose of obinutuzumab and status less than CR, were independently associated with shorter PFS. Seventy patients (16%) received a second-line treatment. The median OS for the entire cohort has not been reached yet and 2-year OS estimate is 88%.
In conclusion, in a “real-world” setting, frontline treatment with G-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were observed in patients with high-risk disease del(11q) and/or IGHV-unmutated and those treated with G-monotherapy. Thus, even today in the era of novel drugs, G-Clb can be considered a legitimate frontline treatment in unfit CLL patients with low-risk disease non-del(11q) and IGHV-mutated.
Herishanu:Roche: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Simkovic:Roche: Honoraria; University Hospital Hradec Kralove: Employment; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Honoraria. Mauro:Gilead: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Coscia:Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Research Funding. Scarfo:AstraZeneca: Honoraria; Janssen: Honoraria; AbbVie: Honoraria. Tedeschi:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen spa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; SUNESIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Honoraria. Gimeno Vázquez:JANSSEN: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Assouline:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Levato:Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria. Rigolin:Gilead: Speakers Bureau; Gilead: Research Funding; AbbVie: Speakers Bureau. Loscertales:Janssen: Honoraria; Roche: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Gilead: Honoraria. Ghia:Dynamo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria; ArQule: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno/Celgene: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Gilead: Consultancy, Honoraria, Research Funding.
Introduction: The treatment of advanced Hodgkin lymphoma (HL) has undergone many changes in recent years. The original International Prognostic Score (IPS) introduced by Hasenclever et al (1998) was ...based on a cohort of 1618 patients (pts) mainly treated with MOPP-ABV or ABVD between the years 1983 and 1992. One third (33%) of those pts also underwent involved field radiation therapy (IFRT). Staging was based on CT. The 5-y freedom from progression (FFP) results ranged between 84% and 42%, depending on the presence of 0-≥5 risk factors. The IPS has been validated in a number of studies and settings. Currently, staging is based on baseline PET/CT, which upgrades the disease stage in 15% and downgrades it in 5% of pts compared to CT scan. Positive interim PET/CT (PET-2) is predictive of an inferior prognosis in pts with early and advanced HL. Based on these findings, several studies have used a positive PET-2 as an indication for therapy escalation. However, the majority of relapses still occur in pts with negative PET-2, highlighting the need for additional prognostic markers. We evaluated baseline factors and lab results in a prospectively collected database of pts enrolled in a multicenter clinical trial (NCT00392314) where treatment was modified based on PET-2 results. The current study aimed to develop a model for refined prediction of HL progression risk in advance-disease pts with negative PET-2, using baseline risk factors.
Methods: Pts with advanced classic Hodgkin lymphoma (HL) were stratified according to their baseline IPS; treatment was modified according to PET-2 results. Pts with IPS 0-2 initially received 2 ABVD cycles and those with IPS ≥ 3 received 2 cycles of escalated BEACOPP (EB). In the former group, if PET-2 was positive without evidence of disease progression, therapy was escalated to EB with involved site radiation therapy (ISRT) given to residual masses. If PET-2 was negative in both IPS strata, 4 additional ABVD cycles were administered. We evaluated whether traditional IPS parameters continued to predict relapse when treatment was modified based on PET-2 results, and assessed the need for new cutoffs based on ROC curves using univariate and multivariate Cox proportional hazard models.
Results: Of 185 enrolled pts, 33 (18%) experienced disease progression and 27 (15%) had a positive PET-2. The 5-y PFS for the whole group, PET-2 negative and PET-2 positive subgroups was 80%, 82% and 68%, respectively (p=0.07). Eight of 33 (28%) relapsed pts had a positive Deauville score (≥3). On univariate analysis of traditional IPS parameters, male gender, age >45, stage IV disease were not found to be associated with a significantly increased hazard ratio (HR) for progression. New cutoffs for lymphocyte count and albumin level predictive of relapse were determined. The following parameters were significantly (P<0.006) associated with lower PFS on univariate analysis: albumin <3.5gm/dL, hemoglobin <10.5 gm/dL, lymphocyte count <1400 or <11% of white blood cell (WBC) count. On multivariate analysis, albumin <3.5gm/dL, lymphocyte count <1400 or <11% of WBC remained significantly associated with relapse, with adjusted HRs of 2.2 (95% CI 1.1-4.5; P<0.03) and 2.6 (95% CI 1.1-6.2; P<0.025), respectively. Hence, a score was constructed using 0, 1 or 2 of these factors. Pts with 0-1 or 2 new risk factors and negative PET-2 had a relapse rate (RR) of 10% and 42%, respectively (HR=4.7; 95% CI 4.7-11), while in pts with positive PET-2 the RR was 30% (Table 1). However, one should bear in mind that pts with IPS 0-2 initiated therapy with ABVDx2 and those with IPS≥3 initiated therapy with EBx2.
Conclusions: The current analysis, using data prospectively collected during a phase II study but analyzed retrospectively after pts had been stratified by IPS, suggests a scoring model that could refine the IPS-based identification of pts at a higher risk for disease progression, even if their PET-2 is negative. The findings imply that pts with 2 new risk factors (19% of pts) may need to initiate more intensive therapy than ABVD. However, given the retrospective nature of the analysis, its results should be interpreted with caution. The model needs to be verified in an independent cohort of pts with advanced HL using uniform treatment protocols.
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Bairey:Janssen: Consultancy.
Decreased absolute lymphocyte counts (ALCs) following frontline therapy for chronic lymphocytic leukemia may be associated with disease control, even in patients without evidence of minimal residual ...disease. We studied the prognostic significance of ALCs during the first year following treatment with fludarabine, cyclophosphamide, and rituximab (FCR). We evaluated 99 patients who achieved a partial response without lymphocytosis (<4.0 × 10
cells/μL) or better after FCR. Absolute lymphocyte counts were recorded at 3-, 6-, 9-, and 12-month posttreatment and correlated with overall survival (OS) and event-free survival (EFS). For each time point, analyses were limited to patients without lymphocytosis, so as to avoid possible biases from undocumented disease progressions. Lymphopenia (ALC < 1.0 × 10
cells/μL) at 3 m after FCR (69% of patients n = 68), was associated with a longer OS (5y OS 91% vs 64%, P = .001), as were ALC ≤ 2 × 10
cells/μL at 6 m (5y OS 85% vs 48%, P = .004) and ALC ≤ 1.8 × 10
cells/μL at 9 m (5y OS 93% vs 54%, P = .009). A normal-range ALC (≤4 × 10
cells/μL) at 12 m was also associated with a 91% 5y OS. Higher ALCs (but without lymphocytosis) were associated with shorter EFS (median EFS 27 months for ALC > 1.8 vs not reached for ALC ≤ 0.7 at 9 months, P < .0001). In conclusion, lower ALC levels in the first few months following frontline FCR therapy were associated with longer OS and EFS. Possible explanations may be that lower ALCs reflect deeper clonal suppression or protracted T
depletion. Absolute lymphocyte count levels may be a cheap and widely available prognostic marker, though the added value for clinical practice is the minimal residual disease era needs to be explored.
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