| 1. |
- 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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| 2. |
- Davenne, Tamara, et al.
(författare)
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SAMHD1 Limits the Efficacy of Forodesine in Leukemia by Protecting Cells against the Cytotoxicity of dGTP.
- 2020
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Ingår i: Cell Reports. - : Elsevier. - 2211-1247. ; 31:6
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Tidskriftsartikel (refereegranskat)abstract
- The anti-leukemia agent forodesine causes cytotoxic overload of intracellular deoxyguanosine triphosphate (dGTP) but is efficacious only in a subset of patients. We report that SAMHD1, a phosphohydrolase degrading deoxyribonucleoside triphosphate (dNTP), protects cells against the effects of dNTP imbalances. SAMHD1-deficient cells induce intrinsic apoptosis upon provision of deoxyribonucleosides, particularly deoxyguanosine (dG). Moreover, dG and forodesine act synergistically to kill cells lacking SAMHD1. Using mass cytometry, we find that these compounds kill SAMHD1-deficient malignant cells in patients with chronic lymphocytic leukemia (CLL). Normal cells and CLL cells from patients without SAMHD1 mutation are unaffected. We therefore propose to use forodesine as a precision medicine for leukemia, stratifying patients by SAMHD1 genotype or expression.
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| 3. |
- Klintman, Jenny, et al.
(författare)
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Antibody formation and specificity in Bethesda-negative brother pairs with haemophilia A.
- 2012
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Ingår i: Haemophilia. - : Wiley. - 1351-8216.
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Tidskriftsartikel (refereegranskat)abstract
- Antibodies directed towards non-neutralizing epitopes on the factor VIII protein (FVIII) may be detected in patients with haemophilia A. We evaluated the prevalence of non-neutralizing antibodies, in 201 inhibitor-negative brother pairs with severe haemophilia A, enrolled in the Malmö International Brother Study and the Haemophilia Inhibitor Genetics Study. To evaluate binding specificity of the antibodies, ELISA plates were coated with two recombinant full-length (FL) FVIII-products and one recombinant B-domain-deleted (BDD) product. Seventy-nine patients (39.3%) had a history of positive inhibitor titre measured by Bethesda assay, and FVIII antibodies were detected in 20 of them (25.3%). Additional 23 samples from subjects without a history of FVIII inhibitors were ELISA-positive corresponding to a frequency of non-neutralizing antibodies of 18.9%. The antibody response towards the different FVIII products was heterogenous, and was raised not only towards the non-functional B-domain but also towards both FL-rFVIII and BDD-rFVIII. In patients considered successfully treated with immune tolerance induction, 25.4% had remaining FVIII antibodies. The number of families with an antibody response in all siblings was increased when the total antibody response was taken into account, further supporting the concept of a genetic predisposition of the immune response. Further studies and careful monitoring over time are required to appreciate the immune response on the risk of inhibitor development or recurrence in the future.
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| 4. |
- Klintman, Jenny, et al.
(författare)
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Blodsjukdomar
- 2016. - 1
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Ingår i: Omvårdnad & medicin. - 9789144076645 ; , s. 587-621
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Bokkapitel (populärvet., debatt m.m.)
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| 5. |
- Klintman, Jenny, et al.
(författare)
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Bone mineral density in haemophilia – a multicentre study evaluating the impact of different replacement regimens
- 2022
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 28:2, s. 239-246
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Tidskriftsartikel (refereegranskat)abstract
- AimThe aim of this study was to investigate if prophylactic treatment in severe haemophilia impact on bone mineral densisty (BMD) in adults with haemophilia A/B.MethodsSubjects with haemophilia (n = 120) underwent bone-density measurement and clinical data was collected. BMD in subjects with severe haemophilia on high-dose prophylaxis (n = 41) was compared to BMD in subjects with mild haemophilia (n = 33) and to severe haemophilia treated with intermediate-dose prophylaxis (n = 32) or on-demand replacement therapy (n = 14).ResultsSubjects with severe haemophilia on high-dose prophylaxis showed BMD at total hip comparable to subjects with mild haemophilia (median BMD 955.8 and 977.4 mg/cm2 (P = .17), respectively). No difference in BMD was found related to type of prophylactic regimen (median BMD 955.8 and 942.4 mg/cm2, in high-dose and intermediate dose groups, respectively; P = .70). Subjects with severe disease treated on-demand had significantly lower BMD compared to subjects on a high-dose prophylactic regimen (median BMD 771.8 and 955.8 mg/cm2 (P = .001), respectively). BMD decreased significantly with age, regardless of severity of haemophilia disease. In a multivariate analysis, adjusted for disease status and age, type of prophylactic regimen was not significantly associated with osteoporosis development.ConclusionWe show that BMD differs in persons with severe haemophilia on propylaxis as compared to those treated on-demand, but that type of prophylactic regimen does not reflect on BMD. The difference between treatment groups was mainly explained by an age difference between groups. However, patients on prophylaxis displayed a high degree of normal BMD not far from mild haemophilia at comparative age.
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| 6. |
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| 7. |
- Klintman, Jenny, et al.
(författare)
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Combination of FVIII and by-passing agent potentiates in vitro thrombin production in haemophilia A inhibitor plasma.
- 2010
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048. ; 151:4, s. 381-386
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Tidskriftsartikel (refereegranskat)abstract
- The by-passing agents, recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (APCC), are important tools in the treatment of patients with haemophilia A and high-responding inhibitory antibodies. It has been observed clinically that in some patients undergoing immune tolerance induction the bleeding frequency decreases, hypothetically caused by a transient haemostatic effect of infused FVIII not measurable ex vivo. We evaluated how by-passing agents and factor VIII (FVIII) affect thrombin generation (TG) in vitro using plasma from 11 patients with severe haemophilia A and high titre inhibitors. Samples were spiked with combinations of APCC, rFVIIa and five different FVIII products. Combination of APCC and FVIII showed a synergistic effect in eliciting TG (P < 0·005) for four FVIII products. When rFVIIa and FVIII were combined the interaction between the preparations was found to be additive. APCC and rFVIIa were then combined without FVIII, resulting in an additive effect on thrombin production. Each product separately increased TG above baseline. In conclusion, the amount of thrombin formed in vitro by adding a by-passing agent, was higher in the presence of FVIII. Our findings support the use of FVIII in by-passing therapy to optimize the haemostatic effect.
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| 8. |
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| 9. |
- Klintman, Jenny
(författare)
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Exploring Anti-FVIII Antibodies in Haemophilia A - Role in In Vitro Haemostasis and Clinical Disease
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Haemophilia A (HA) is caused by defective synthesis of coagulation factor VIII(FVIII), which has serious effects on haemostasis; joints being the most common site of bleeding. The development of FVIII replacements has improved the situation for patients with haemophilia such that chronic arthropathy can be prevented, and life expectancy and the quality of life have increased. However, approximately 20-30% of patients suffering from severe HA develop neutralizing antibodies (inhibitors) against FVIII. Alternative treatment, using by-passing agents, is available for patients exhibiting inhibitors, although these can only be used for the short-term treatment of acute haemorrhage and as prophylaxis during surgery. Furthermore, the clinical response to by-passing products is unpredictable. Two of the studies included in this thesis evaluated the response to by-passing therapy in plasma from patients with HA. The variation in thrombin production within families was found to be significantly lower than the variation between families, indicating that a familial predisposition may influence thrombin formation in response to by-passing agents (Paper I). Moreover, FVIII clotting factors were found to potentiate the in vitro effect of by-passing agents on thrombin formation in plasma from patients with HA exhibiting inhibitors, indicating that further assessment of this treatment strategy in a clinical context is warranted (Paper II). Not all anti-FVIII antibodies have neutralizing capacity. In the studies presented in Papers III & V, non-neutralizing anti-FVIII antibodies(NNAs) were investigated in two different cohorts, using an enzyme-linked immunosorbent assay (ELISA). NNAs were detected in 18.9% of siblings with HA, and in 12.8% of unrelated HA subjects followed for four years. The antibody response was assayed using three different rFVIII products. The antibody response was found to be heterogeneous, to vary considerably between individuals (Papers III and V), and also over time (Paper V). None of the patients in the cohort with NNAs observed longitudinally developed inhibitors (Paper V). However, in one patient with moderate HA, the detection of Bethesda-negative anti-FVIII antibodies coincided with a change in bleeding phenotype four years prior to FVIII inhibitor development. This finding suggests that immunoassays may be a useful complement in evaluating the immune response to FVIII (Paper IV). The potential clinical impact of NNAs was evaluated in the long term study (Paper V), showing no association between age, F8 mutation, or the influence of immune system challenges on NNA development. Interestingly, patients with NNAs had significantly fewer bleeding episodes than NNA-negative patients (p=0.048), raising questions about the possibility of yet undefined types of anti-FVIII antibodies with protective or potentiating effects on FVIII.
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| 10. |
- Klintman, Jenny, et al.
(författare)
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Genomic and transcriptomic correlates of Richter transformation in chronic lymphocytic leukemia
- 2021
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 137:20, s. 2800-2816
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Tidskriftsartikel (refereegranskat)abstract
- The transformation of chronic lymphocytic leukemia (CLL) to high-grade B-cell lymphoma is known as Richter syndrome (RS), a rare event with dismal prognosis. In this study, we conducted whole-genome sequencing (WGS) of paired circulating CLL (PB-CLL) and RS biopsies (tissue-RS) from 17 patients recruited into a clinical trial (CHOP-O). We found that tissue-RS was enriched for mutations in poor-risk CLL drivers and genes in the DNA damage response (DDR) pathway. In addition, we identified genomic aberrations not previously implicated in RS, including the protein tyrosine phosphatase receptor (PTPRD) and tumor necrosis factor receptor–associated factor 3 (TRAF3). In the noncoding genome, we discovered activation-induced cytidine deaminase–related and unrelated kataegis in tissue-RS affecting regulatory regions of key immune-regulatory genes. These include BTG2, CXCR4, NFATC1, PAX5, NOTCH-1, SLC44A5, FCRL3, SELL, TNIP2, and TRIM13. Furthermore, differences between the global mutation signatures of pairs of PB-CLL and tissue-RS samples implicate DDR as the dominant mechanism driving transformation. Pathway-based clonal deconvolution analysis showed that genes in the MAPK and DDR pathways demonstrate high clonal-expansion probability. Direct comparison of nodal-CLL and tissue-RS pairs from an independent cohort confirmed differential expression of the same pathways by RNA expression profiling. Our integrated analysis of WGS and RNA expression data significantly extends previous targeted approaches, which were limited by the lack of germline samples, and it facilitates the identification of novel genomic correlates implicated in RS transformation, which could be targeted therapeutically. Our results inform the future selection of investigative agents for a UK clinical platform study. This trial was registered at www.clinicaltrials.gov as #NCT03899337.
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