Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial

Greil, Richard; Obrtlíková, Petra; Smolej, Lukáš; Kozák, Tomáš; Steurer, Michael; Andel, Johannes; Burgstaller, Sonja; Mikušková, Eva Ballová; Gercheva-Kyuchukova, Liana; Nösslinger, Thomas; Papajík, Tomáš; Ladická, Miriam; Girschikofsky, Michael; Hrubisko, M; Jäger, Ulrich; Fridrik, Michael A.; Pecherstorfer, Martin; Králíková, Eva; Burcoveanu, C; Spasov, Emil; Petzer, Andreas; Mihaylov, Georgi; Raynov, Julian; Oexle, Horst; Zabernigg, August; Flochová, Emília; Palášthy, Stanislav; Stehlíková, Olga; Doubek, Michael; Altenhofer, Petra; Pleyer, Lisa; Melchardt, Thomas; Klingler, Antón; Mayer, Jiřı́; Egle, Alexander

doi:10.1016/s2352-3026(16)30045-x

Cited by 46 publications

(43 citation statements)

References 30 publications

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“…These results are better than those obtained in our study and are most likely due to the doubled cumulative dose of rituximab given in the induction with its continued use as maintenance. In this respect, two recent controlled phase III studies have shown that induction chemo‐immunotherapy, followed by maintenance with anti‐CD20 antibodies, also prolonged PFS in patients with CLL . Later, in 2014, the Czech CLL study group also reported results in a multicenter study of 207 TN and relapsed/refractory elderly patients with CLL with comorbidities, treated with low‐dose FCR, using identical doses and the same schedule as in our study.…”

Section: Discussionsupporting

confidence: 65%

Low‐dose fludarabine and cyclophosphamide combined with standard dose rituximab (LD‐FCR) is an effective and safe regimen for elderly untreated patients with chronic lymphocytic leukemia: The Israeli CLL study group experience

Herishanu

Tadmor

Braester

et al. 2019

Hematological Oncology

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Chronic lymphocytic leukemia (CLL) is a disease of elderly patients. The fludarabine, cyclophosphamide, and rituximab (FCR) regimen is considered the treatment of choice for young fit patients with CLL; however, this combination is toxic for older patients. At the time this study was first planned and initiated, there was no standard chemo‐immunotherapy regimen regarded as standard therapy for the less fit elderly patient with CLL. Here, we conducted a single‐arm, phase II trial to examine the efficacy and safety of lower‐dose fludarabine and cyclophosphamide combined with a standard dose of rituximab (LD‐FCR) in elderly patients with previously untreated CLL. Forty patients received LD‐FCR and were included in the efficacy analysis. Two patients treated with FC alone were only included in the safety analysis. The median age was 72.7 years (range, 65.0 to 85.0). The overall response and complete response rates were 67.5% and 42.5%, respectively. Median progression‐free survival (PFS) was 35.5 months (95% CI, 29.27‐41.67). Two patients (4.8%) died during the study period. Hematological toxicities and infections were the most common complications encountered; grade 3 to 4 treatment‐related neutropenia occurred in 20 (47.6%) patients. During the entire study follow‐up, 26 patients (61.9%) had all grades of infection including six (14.3%) with neutropenic fever and eight (19%) with grade 3 to 4 non‐neutropenic infections. In conclusion, LD‐FCR is an effective and relatively safe regimen for previously untreated patients with CLL. It has the advantage of being both “time and cost limited” and, even in the era of novel agents, can still be considered when planning treatment for elderly patients without high‐risk biomarkers. However, recent results in fit elderly patients using the combination of bendamustine and rituximab which have achieved longer PFS with good safety profile must be taken into consideration in this regard.

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Section: Discussionsupporting

confidence: 65%

Low‐dose fludarabine and cyclophosphamide combined with standard dose rituximab (LD‐FCR) is an effective and safe regimen for elderly untreated patients with chronic lymphocytic leukemia: The Israeli CLL study group experience

Herishanu

Tadmor

Braester

et al. 2019

Hematological Oncology

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“…Maintenance therapy with an anti-CD20 monoclonal antibody after chemoimmunotherapy has been shown to prolong PFS, but not overall survival, and was associated with a significantly higher incidence of neutropenia and risk for infections 168 . This regimen is currently not considered the standard of care, but might be useful in patients with medical comorbidities that limit other treatment options.…”

Section: Managementmentioning

confidence: 99%

Chronic lymphocytic leukaemia

Kipps

Stevenson

et al. 2017

Nat Rev Dis Primers

413

437

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Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5+ B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow and lymphoid tissues. Signalling via surface immunoglobulin, which constitutes the major part of the B cell receptor, and several genetic alterations play a part in CLL pathogenesis, in addition to interactions between CLL cells and other cell types, such as stromal cells, T cells and nurse-like cells in the lymph nodes. The clinical progression of CLL is heterogeneous and ranges from patients who require treatment soon after diagnosis to others who do not require therapy for many years, if at all. Several factors, including the immunoglobulin heavy-chain variable region gene (IGHV) mutational status, genomic changes, patient age and the presence of comorbidities, should be considered when defining the optimal management strategies, which include chemotherapy, chemoimmunotherapy and/or drugs targeting B cell receptor signalling or inhibitors of apoptosis, such as BCL-2. Research on the biology of CLL has profoundly enhanced our ability to identify patients who are at higher risk for disease progression and our capacity to treat patients with drugs that selectively target distinctive phenotypic or physiological features of CLL. How these and other advances have shaped our current understanding and treatment of patients with CLL is the subject of this Primer.

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“…Also, likely due to the above hypothesis for discordant BM involvement, the survival of this group appeared to be prolonged by rituximab maintenance, just as this strategy improved outcome in advanced indolent B-cell lymphoma. 45, 46 It may be appropriate for patients with different types of BM disease to accept precision treatment strategies, whereas this assumption needs further study in future prospective clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Concordant bone marrow involvement of diffuse large B-cell lymphoma represents a distinct clinical and biological entity in the era of immunotherapy

et al. 2017

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In diffuse large B-cell lymphoma (DLBCL), the clinical and biological significance of concordant and discordant bone marrow (BM) involvement have not been well investigated. We evaluated 712 de novo DLBCL patients with front-line rituximab-containing treatment, including 263 patients with positive and 449 with negative BM status. Compared with negative BM disease, concordant BM adversely impacted overall and progression-free survival, probably independent of the International Prognostic Index (IPI) and cell-of-origin classification. Once BM is concordantly involved, poor prognosis was not associated with the extent of BM involvement. Conversely, patients with discordant BM showed favorable overall survival similar to stage I-II DLBCL. A BM-adjusted IPI, using three parameters: concordant BM involvement, age >60 years, and performance status >1, improves the risk stratification for DLBCL with positive BM. Intensive immunochemotherapy seemingly rendered survival benefit for patients with concordant BM, as did rituximab maintenance for the discordant BM group. Frequently revealing adverse clinical and molecular characteristics, patients with concordant BM demonstrated gene expression signatures relevant to tumor cell proliferation, migration, and immune escape. In conclusion, clinical and biological heterogeneity is seen in DLBCL with positive BM but concordant BM involvement represents a distinct subset with unfavorable gene signatures, high-risk clinicopathologic features, and poor prognosis.

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Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial

Cited by 46 publications

References 30 publications

Low‐dose fludarabine and cyclophosphamide combined with standard dose rituximab (LD‐FCR) is an effective and safe regimen for elderly untreated patients with chronic lymphocytic leukemia: The Israeli CLL study group experience

Low‐dose fludarabine and cyclophosphamide combined with standard dose rituximab (LD‐FCR) is an effective and safe regimen for elderly untreated patients with chronic lymphocytic leukemia: The Israeli CLL study group experience

Chronic lymphocytic leukaemia

Concordant bone marrow involvement of diffuse large B-cell lymphoma represents a distinct clinical and biological entity in the era of immunotherapy

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