| 1. |
- Eketorp Sylvan, Sandra
(författare)
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Targeted therapy and outcome in chronic lymphocytic leukemia
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Despite major advances, chronic lymphocytic leukemia (CLL) is still considered incurable. Fludarabine refractory patients and those with TP53disruptions have a particularly poor prognosis. Alemtuzumab is an established treatment option for these patients. However, its use is complicated by immunosuppressive side effects. New drugs targeting cellular pathways are currently developed but there are few manufacturer-independent comparative experiments. The aim of this thesis is to gain an insight into the outcome of patients with advanced CLL and to explore new emerging drugs. In the first study, the natural history of advanced CLL in a well-defined region without external referrals was retrospectively investigated. All patients diagnosed with CLL 1991-2010 were screened and those with bulky fludarabine refractory (BFR) and double (i.e. fludarabine and alemtuzumab) refractory (DR) CLL were identified. Subjects were primary referrals within the Stockholm region. The ORR to salvage therapy was 20% and the median time to treatment failure was 6 months, both significantly lower in BFR/DR patients than in non-BFR/DR patients. Median overall-survival (OS) was 18 months; 29 months in BFR vs 13 months in DR. Our results on consecutive patients in routine clinical practice may facilitate interpretation of non-randomized trials on novel drugs in advanced-stage CLL. In the second study, the safety and efficacy of alemtuzumab, when used in routine health care in relapsed/refractory patients at experienced medical centres in a defined region, was evaluated. Records from patients diagnosed within the Stockholm region year 2000-2010 were retrospectively screened. Files from alemtuzumab treated patients were analysed in detail. Patients were heavily pretreated and the majority had fludarabine refractory disease. The median cumulative dose of alemtuzumab was 930 mg and median duration of therapy was 12 weeks. The ORR was 43% and a higher dose was associated with higher response rate. Median OS was 22.5 months. Compared with the results from previous reports, we observed a higher cumulative dose/longer duration of therapy, numerically higher response rates as well as longer survival in our regional, consecutive patients. Our results suggest that optimal patient management and patient identification may result in avoidance of early discontinuation of planned therapy and possibly better treatment outcomes. In the third study, the safety and efficacy of lenalidomide in combination with alemtuzumab was explored in a phase I study and additionally, the capacity of low-dose lenalidomide in maintaining immune functions in advanced-stage CLL patients prior and during alemtuzumab was evaluated. Tumor flare reaction occurred in some patients but there was no evidence of tumor lysis syndrome. The combination showed an acceptable safetyprofile as well as clinical activity with an overall response rate of 42%. Median progression free survival was 5 months, exceeding 12 months in 3 patients. T-cell stimulation as well as a decreased number of regulatory T cells was evident on low dose lenalidomide. Our results provide the basis for an extended phase 2 trial on this combination of drugs as well as further studies on lenalidomide as an immune-enhancing agent. In the fourth study, we provide a manufacturer independent, head-to-head comparison on sensitivity of CLL cells to a panel of emerging small targeted therapeutic molecules using highthroughput screening based on an automated fluorescence digital scanning system. Fresh CLL cells from patients with indolent or progressive disease were cultured in a unique primary cell-culture medium and the in vitro anti-tumor effects of 31 small therapeutic molecules were compared. The sensitivity to each drug showed considerable inter-patient variability. Highest mean direct killing was observed with one survivin inhibitor (YM-155), 2 BCL-2 inhibitors (ABT-199, ABT 737) and one selective CDK inhibitor (dinaciclib). Their killing capacity was similarly high in refractory and untreated patients and was significantly higher in cells with TP53disruptions. Sensitivity in bone marrow showed a high correlation to that in blood. Our results may help to identify drugs of particular interest for further clinical development.
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| 2. |
- Mattsson, Agnes, et al.
(författare)
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Idelalisib (PI3Kδ inhibitor) therapy for patients with relapsed/refractory chronic lymphocytic leukemia : A Swedish nation-wide real-world report on consecutively identified patients
- 2023
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Ingår i: European Journal of Haematology. - : John Wiley & Sons. - 0902-4441 .- 1600-0609. ; 111:5, s. 715-721
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesWe examined the efficacy and toxicity of the PI3Kδ inhibitor idelalisib in combination with rituximab salvage therapy in consecutively identified Swedish patients with chronic lymphocytic leukemia (CLL).Methods and ResultsThirty-seven patients with relapsed/refractory disease were included. The median number of prior lines of therapy was 3 (range 1–11); the median age was 69 years (range 50–89); 22% had Cumulative Illness Rating Scale (CIRS) >6 and 51% had del(17p)/TP53 mutation. The overall response rate was 65% (all but one was partial response [PR]). The median duration of therapy was 9.8 months (range 0.9–44.8). The median progression-free survival was 16.4 months (95% CI: 10.4–26.3) and median overall survival had not been reached (75% remained alive at 24 months of follow-up). The most common reason for cessation of therapy was colitis (n = 8, of which seven patients experienced grade ≥3 colitis). The most common serious adverse event was grade ≥3 infection, which occurred in 24 patients (65%).ConclusionsOur real-world results suggest that idelalisib is an effective and relatively safe treatment for patients with advanced-stage CLL when no other therapies exist. Alternative dosing regimens and new PI3K inhibitors should be explored, particularly in patients who are double-refractory to inhibitors of BTK and Bcl-2.
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| 3. |
- Sylvan, Sandra Eketorp, et al.
(författare)
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First-line therapy in chronic lymphocytic leukemia : a Swedish nation-wide real-world study on 1053 consecutive patients treated between 2007 and 2013
- 2019
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Ingår i: Haematologica. - : FERRATA STORTI FOUNDATION. - 0390-6078 .- 1592-8721. ; 104:4, s. 797-805
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate long-term outcome following first-line therapy in consecutive chronic lymphocytic leukemia (CLL) patients in a well-defined geographic area: Sweden. All patients diagnosed with CLL (2007-2013) (n=3672) were identified from national registries, screening of patient files identified all (100%) treated first line (n=1053) and for those, an in-depth analysis was performed. End points were overall response rate, progression-free survival (PFS), overall survival (OS), and safety. Median age was 71 years; 53% had Rai stage III-IV and 97% had performance status grade 0-2. Fluorescence in situ hybridization (FISH) was performed in 57% of patients: 15% had del(17p). Chlorambucil + prednisone was used in 39% (5% also received rituximab). Fludarabine+cyclophosphamide+rituximab or fludarabine+cyclophosphamide was used in 43% and bendamustine + rituximab in 6%. Overall response rate was 64%; chlorambucil 43%, fludarabine+cyclophosphamide+rituximab 84%, fludarabine+cyclophosphamide 75% and bendamustine + rituximab 75%. Median PFS and OS was 24 and 58 months, respectively, both were significantly associated (multivariate analysis) with type of treatment, del(17p), performance status, gender, age and geographical region (OS only). Chlorambucil-treated patients had a median PFS and OS of only 9 and 33 months, respectively. Chlorambucil usage declined gradually throughout the study period, but one-third of patients still received chlorambucil + rituximab in 2013. Infections >= grade III were significantly associated with treatment; chlorambucil 19% versus fludarabine+cyclophosphamide+rituximab 30%. Richter transformation occurred in 5.5% of the patients, equally distributed across therapies. This is the largest retrospective, real-world cohort of consecutive first-line treated CLL patients with a complete follow up. In elderly patients, an unmet need for more effective, well-tolerated therapies was identified.
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