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1.
NPJ Precis Oncol ; 2: 18, 2018.
Article in English | MEDLINE | ID: mdl-30182064

ABSTRACT

Development of antibody drugs against novel targets and pathways offers great opportunities to improve current cancer treatment. We here describe a phenotypic discovery platform enabling efficient identification of therapeutic antibody-target combinations. The platform utilizes primary patient cells throughout the discovery process and includes methods for differential phage display cell panning, high-throughput cell-based specificity screening, phenotypic in vitro screening, target deconvolution, and confirmatory in vivo screening. In this study the platform was applied on cancer cells from patients with Chronic Lymphocytic Leukemia resulting in discovery of antibodies with improved cytotoxicity in vitro compared to the standard of care, the CD20-specific monoclonal antibody rituximab. Isolated antibodies were found to target six different receptors on Chronic Lymphocytic Leukemia cells; CD21, CD23, CD32, CD72, CD200, and HLA-DR of which CD32, CD200, and HLA-DR appeared as the most potent targets for antibody-based cytotoxicity treatment. Enhanced antibody efficacy was confirmed in vivo using a patient-derived xenograft model.

3.
Leukemia ; 31(7): 1547-1554, 2017 07.
Article in English | MEDLINE | ID: mdl-27890934

ABSTRACT

Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.


Subject(s)
Early Growth Response Protein 2/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation , Adult , Aged , Female , Genes, p53 , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/classification , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Middle Aged , Proportional Hazards Models
6.
Eur J Cancer Care (Engl) ; 24(6): 898-910, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26156141

ABSTRACT

Health-related quality of life (HRQL) was evaluated in 94 patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) after myeloablative (MAC, n = 18) or reduced intensity conditioning (RIC, n = 76). HRQL was assessed with the EORTC QLQ C-30 during the inpatient period as well as during the following 3 years, i.e., at baseline and 12 times thereafter. Functional status and global quality of life decreased from baseline to weeks 2 and 3, especially role and social functions. Symptoms increased significantly during the first 3 weeks, particularly appetite loss, nausea and vomiting, diarrhoea and fatigue. It took at least 1 year for HRQL to return to the baseline level. The only function that improved significantly 3 years after HSCT was role function. Patients treated with MAC experienced significantly worse HRQL at baseline than patients treated with RIC, as well as more pain, sleep disturbance and appetite loss in weeks 3 and 4. Patients with extensive chronic graft-versus-host disease experienced reduced HRQL. These results provide a clinically useful overview of patients' HRQL during and after HSCT and indicate when they require increased support. The results demonstrate the importance of close follow-ups during the first year after HSCT to improve preventive or supportive interventions.


Subject(s)
Graft vs Host Disease , Health Status , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Quality of Life , Activities of Daily Living , Adult , Anorexia/etiology , Diarrhea/etiology , Fatigue/etiology , Female , Humans , Longitudinal Studies , Male , Middle Aged , Myeloablative Agonists/adverse effects , Myeloablative Agonists/therapeutic use , Nausea/etiology , Prospective Studies , Role , Sleep Initiation and Maintenance Disorders/etiology , Transplantation Conditioning/adverse effects , Transplantation Conditioning/methods , Transplantation, Homologous , Vomiting/etiology
8.
Leukemia ; 29(2): 329-36, 2015 Feb.
Article in English | MEDLINE | ID: mdl-24943832

ABSTRACT

Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation , Aged , Cytogenetics , DNA Mutational Analysis , Europe , Female , Gene Deletion , Humans , Male , Middle Aged , Multivariate Analysis , Phosphoproteins/genetics , Polymorphism, Single Nucleotide , Prognosis , RNA Splicing Factors , Receptor, Notch1/genetics , Recurrence , Ribonucleoprotein, U2 Small Nuclear/genetics , Time Factors , Tumor Suppressor Protein p53/genetics
9.
Blood Cancer J ; 4: e188, 2014 Feb 28.
Article in English | MEDLINE | ID: mdl-24583534

ABSTRACT

The Swedish population-based acute myeloid leukemia registry contains data from 3251 patients (excluding acute promyelocytic leukemia) diagnosed between 1997 and 2006. Informative cytogenetic data from 1893 patients were retrospectively added, including 1054 patients aged between 60 and 79 years. Clonal abnormalities were found in 57% of the informative karyotypes. Karyotypic patterns differed by age: t(8;21), inv(16) and t(11q23) were more common in younger patients, whereas loss of 5q, 7q and 17p, monosomal karyotype (MK) and complex karyotypes were more common in older patients. Loss of 5q, 7q and 17p often occurred together within MK. Patients with 5 chromosome abnormalities had worse overall survival than those with fewer abnormalities or normal karyotype in all age groups. Loss of 5q, 7q and/or 17p had, in contrast to MK, a further negative impact on survival. Multivariable Cox regression analyses on risk factors in patients <80 years with cytogenetic abnormalities and intensive treatment revealed that age and performance status had the most significant impact on survival (both P<0.001), followed by sex (P=0.0135) and a karyotype including -7/del(7q) (P=0.048).

12.
Leukemia ; 27(1): 150-8, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22922567

ABSTRACT

In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K arrays, we provide the most comprehensive DNA methylation study of CLL to date, analyzing paired diagnostic/follow-up samples from IGHV-mutated/untreated and IGHV-unmutated/treated patients (n=36) and patient-matched peripheral blood and lymph node samples (n=20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (for example, CLLU1, LPL, ZAP70 and NOTCH1), epigenetic regulator (for example, HDAC9, HDAC4 and DNMT3B), B-cell signaling (for example, IBTK) and numerous TGF-ß and NF-κB/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event.


Subject(s)
Biomarkers, Tumor/genetics , Cell Proliferation , CpG Islands/genetics , DNA Methylation , Gene Expression Profiling , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Aged , B-Lymphocytes/pathology , Case-Control Studies , Cohort Studies , DNA, Neoplasm/genetics , Disease Progression , Female , Genome-Wide Association Study , Humans , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , Prognosis
15.
Leukemia ; 25(7): 1128-34, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21502956

ABSTRACT

Our knowledge about acute promyelocytic leukemia (APL) patients is mainly based on data from clinical trials, whereas population-based information is scarce. We studied APL patients diagnosed between 1997 and 2006 in the population-based Swedish Adult Acute Leukemia Registry. Of a total of 3897 acute leukemia cases, 3205 (82%) had non-APL acute myeloid leukemia (AML) and 105 (2.7%) had APL. The incidence of APL was 0.145 per 100,000 inhabitants per year. The median age at the time of diagnosis was 54 years; 62% were female and 38% male. Among younger APL patients, female sex predominated (89% of patients <40 years). Of the 105 APL patients, 30 (29%) died within 30 days (that is, early death (ED)) (median 4 days) and 28 (26%) within 14 days from diagnosis. In all, 41% of the EDs were due to hemorrhage; 35% of ED patients never received all-trans-retinoic acid treatment. ED rates increased with age but more clearly with poor performance status. ED was also associated with high white blood cells, lactate dehydrogenase, creatinine, C-reactive protein and low platelet count. Of non-ED patients, 97% achieved complete remission of which 16% subsequently relapsed. In total, 62% are still alive at 6.4 years median follow-up. We conclude that ED rates remain very high in an unselected APL population.


Subject(s)
Leukemia, Promyelocytic, Acute/mortality , Adolescent , Adult , Age Distribution , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cause of Death , Female , Hemorrhage/etiology , Hemorrhage/mortality , Humans , Incidence , Kaplan-Meier Estimate , Leukemia, Promyelocytic, Acute/blood , Leukemia, Promyelocytic, Acute/complications , Leukemia, Promyelocytic, Acute/diagnosis , Leukemia, Promyelocytic, Acute/drug therapy , Male , Middle Aged , Mortality/trends , Prognosis , Registries , Risk Factors , Sex Distribution , Sweden/epidemiology , Time Factors , Young Adult
16.
Bone Marrow Transplant ; 46(1): 44-51, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20436517

ABSTRACT

SCF has been shown to synergize with G-CSF to mobilize CD34(+) PBPCs. In this study we report results from this combination after a phase II trial of 32 patients with malignant lymphoma randomized to receive recombinant methionyl human SCF (ancestim, r-metHuSCF) in combination with recombinant methionyl human G-CSF (filgrastim, r-metHuG-CSF) (experimental arm A) or routine chemotherapy plus filgrastim (conventional arm B). The primary objective was to evaluate the side effects and toxicity during priming and mobilization. The secondary objectives were efficacy by the level of blood-circulating PBPCs, the number of harvest days and the time to three-lineage engraftment after autografting. First, during priming 5 patients had 8 serious events, 4 in each arm. A summary of all adverse events revealed 30 (94%) patients suffering from 132 events of all grading. Second, neutropenia and thrombocytopenia was documented in arm B. Third, 9/14 (64%) patients in arm A reached the target of 5 million CD34(+) cells/kg body weight (bw) compared with 13/15 (87%) in arm B. The results represent the first randomized trial of growth factor plus chemotherapy priming and indicate that a formal phase III trial very unlikely may challenge chemotherapy plus r-metHuG-CSF priming in candidates for high-dose therapy.


Subject(s)
Graft Survival/drug effects , Granulocyte Colony-Stimulating Factor/therapeutic use , Hematopoietic Stem Cell Mobilization/methods , Lymphoma/therapy , Peripheral Blood Stem Cell Transplantation , Stem Cell Factor/analogs & derivatives , Transplantation Conditioning/methods , Adult , Aged , Antigens, CD34/blood , Drug Therapy, Combination/adverse effects , Female , Filgrastim , Granulocyte Colony-Stimulating Factor/adverse effects , Hematopoietic Stem Cell Mobilization/adverse effects , Humans , Lymphoma/blood , Male , Middle Aged , Neutropenia/chemically induced , Neutropenia/prevention & control , Peripheral Blood Stem Cell Transplantation/adverse effects , Pilot Projects , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Stem Cell Factor/adverse effects , Stem Cell Factor/therapeutic use , Thrombocytopenia/chemically induced , Thrombocytopenia/prevention & control , Transplantation Conditioning/adverse effects , Transplantation, Autologous/adverse effects , Young Adult
17.
Bone Marrow Transplant ; 46(6): 870-5, 2011 Jun.
Article in English | MEDLINE | ID: mdl-20956959

ABSTRACT

Allogeneic transplantation after reduced intensity conditioning (allo-RIC) is a treatment option for patients with Hodgkin's lymphoma (HL) relapsing after autologous transplantation. In all, 23 adult patients with HL underwent allo-RIC in Sweden between 2000 and 2007. The median number of previous treatment lines was five and 20 patients (87%) were previously autografted. TRM at 100 days and at 1 year was 13 and 22% respectively. Acute GVHD grades II-IV developed in 7 out of 23 patients (30%) and chronic GVHD in 10 out of 20 patients at risk (50%). The OS and EFS at three years was 59 and 27%, respectively. Four patients (17%) developed post transplant lymphoproliferative disease (PTLD) after a median time of 55 days (range 38-95); two of these patients later died. The study confirmed that allo-RIC is feasible, but associated with a substantial relapse rate: only 20% of the patients were still alive 7 years after the transplant. A finding of high incidence of PTLD needs to be confirmed in a larger trial that includes patients with non-HL and CLL.


Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Hodgkin Disease/therapy , Lymphoproliferative Disorders/etiology , Transplantation Conditioning/methods , Adult , Data Collection , Female , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation/methods , Hodgkin Disease/complications , Humans , Incidence , Lymphoproliferative Disorders/epidemiology , Male , Middle Aged , Survival Analysis , Sweden/epidemiology , Transplantation Conditioning/adverse effects , Transplantation, Autologous , Transplantation, Homologous , Treatment Outcome , Young Adult
19.
Bone Marrow Transplant ; 37(5): 503-10, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16415894

ABSTRACT

Sixty-nine consecutive patients (median age 54 years) were prospectively enrolled in a single-institution protocol for allogeneic transplantation with adjusted non-myeloablative fludarabine-melfalan-based conditioning including cyclosporin A and MMF, and one of three modes of serotherapy. Thirty-one donors (45%) were unrelated. The first cohort of 29 had ATG (Thymoglobulin 2 mg/kg x 3 days), the subsequent 26 had Campath 30 mg x 3 days subcutaneously, and the final cohort of 14 had 30 mg Campath once. The groups were similar as regards age, diagnosis and risk factors. Campath-patients had no acute toxicity, fewer days with fever and antibiotics, and required fewer transfusions than ATG-treated patients. 3-d-Campath patients showed lower lymphocyte counts from day +4, and CD4+, CD8+, CD19+ and NK cells recovered slower than in ATG-treated patients. More Campath patients developed mixed chimerism that required DLI. 3-d-Campath induced more serious and opportunistic infections than ATG, which resulted in a greater non-relapse mortality and an impaired overall survival despite a low tumor-related mortality. The change of the Campath dosing schedule to one dose abrogated the deleterious effect of 3-d-Campath on immune recovery, severe infections and survival. Subcutaneous Campath is simple and provides strong immune suppression with no early toxicity, but dose limitation to 30 mg once is recommended.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antibodies, Neoplasm/administration & dosage , Antilymphocyte Serum/administration & dosage , Hematopoietic Stem Cell Transplantation/methods , Transplantation Conditioning/methods , Adult , Alemtuzumab , Antibodies, Monoclonal/toxicity , Antibodies, Monoclonal, Humanized , Antibodies, Neoplasm/toxicity , Antilymphocyte Serum/toxicity , Cause of Death , Dose-Response Relationship, Drug , Female , Fever , Hematologic Neoplasms/complications , Hematologic Neoplasms/mortality , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/mortality , Humans , Killer Cells, Natural , Lymphocyte Count , Lymphopoiesis , Male , Middle Aged , Opportunistic Infections , Survival Rate , Transplantation Chimera , Transplantation Conditioning/mortality , Transplantation, Homologous
20.
Leukemia ; 20(1): 42-7, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16327841

ABSTRACT

Combination chemotherapy may induce remission from acute myeloid leukemia (AML), but validated criteria for treatment of elderly are lacking. The remission intention (RI) rate for elderly patients, as reported to the Swedish Leukemia Registry, was known to be different when comparing the six health care regions, but the consequences of different management are unknown. The Leukemia Registry, containing 1672 AML patients diagnosed between 1997 and 2001, with 98% coverage and a median follow-up of 4 years, was completed with data from the compulsory cancer and population registries. Among 506 treated and untreated patients aged 70-79 years with AML (non-APL), there was a direct correlation between the RI rate in each health region (range 36-76%) and the two-year overall survival, with no censored observations (6-21%) (chi-squared for trend=11.3, P<0.001; r2=0.86, P<0.02, nonparametric). A 1-month landmark analysis showed significantly better survival in regions with higher RI rates (P=0.003). Differences could not be explained by demographics, and was found in both de novo and secondary leukemias. The 5-year survival of the overall population aged 70-79 years was similar between the regions. Survival of 70-79-year-old AML patients is better in regions where more elderly patients are judged eligible for remission induction.


Subject(s)
Attitude of Health Personnel , Leukemia, Myeloid/drug therapy , Patient Selection , Acute Disease , Adolescent , Adult , Age Distribution , Age Factors , Aged , Aged, 80 and over , Follow-Up Studies , Humans , Leukemia, Myeloid/mortality , Middle Aged , Registries , Remission Induction , Survival Rate , Sweden/epidemiology , Treatment Outcome
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