Publications by authors named "Jeanette Lundin"

29 Publications

  • Page 1 of 1

Risk-adapted bendamustine + rituximab is a tolerable treatment alternative for elderly patients with chronic lymphocytic leukaemia: a regional real-world report on 141 consecutive Swedish patients.

Br J Haematol 2020 11 10;191(3):426-432. Epub 2020 Aug 10.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Bendamustine + rituximab (BR) is the current first-line standard-of-care for chronic lymphocytic leukaemia (CLL) in fit patients aged 66-70 years, whereas chlorambucil + CD20 antibody is recommended in older patients with co-morbidities. This retrospective real-world study investigated whether risk-adapted BR was safe and effective in elderly patients. All 141 CLL patients in the Stockholm region (diagnosed from 2007 to 2016, identified from regional registries) who had received BR as first (n = 84) or later line (n = 57) were analysed. Median age was 72 years, 49% had Binet stage C, 40% had Cumulative Illness Rating Scale (CIRS) score ≥ 6, 20% Eastern Cooperative Oncology Group (ECOG) score 2. None had del(17p). Only 15% of patients aged ≥80 years received full-dose bendamustine and 65% of them postponed rituximab until cycle 2. Corresponding numbers in patients 73-79 years were 21% and 36% and in <73 years, 63% and 33%. Overall response rate was 83% (first line) and 67% (later line) (P < 0·022) equally distributed between age subsets. ECOG, immunoglobulin heavy chain variable region (IGHV) mutational status and cytogenetics, but not treatment line and age, were significant factors on progression-free survival (PFS) in multivariate analysis. Infections and neutropenia/thrombocytopenia (≥grade 3) were similar across age subgroups. In summary, BR was well tolerated even in patients ≥80 years, with similar efficacy and safety as in less old patients, provided that carefully adapted dosing was applied.
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http://dx.doi.org/10.1111/bjh.17032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689859PMC
November 2020

Calcein release assay as a method for monitoring serum complement activity during monoclonal antibody therapy in patients with B-cell malignancies.

J Immunol Methods 2020 01 17;476:112675. Epub 2019 Oct 17.

Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Dębinki 1 street, 80-211 Gdańsk, Poland. Electronic address:

Monoclonal antibodies ofatumumab (anti-CD20) and alemtuzumab (anti-CD52) which are approved for usage in patients with chronic lymphocytic leukemia (CLL), efficiently activate the classical complement pathway. However complement is an exhaustible component and high doses of its activators may deplete complement-dependent cytotoxicity (CDC) potential, thus reducing the effect of repeated mAb dosing. Widely used method to measure CDC activity of patients' serum is hemolytic assay (CH50) on sheep erythrocytes. Despite its simplicity, such CH50 assay may not reflect pivotal interactions between patient serum and human complement inhibitors on the surface of target cells. We propose calcein release assay performed on tumor cells similar to those targeted by therapeutic antibodies as an alternative method. We analyzed serum samples collected from 12 patients participating in the clinical study, receiving s.c. 30 mg alemtuzumab three times per week combined with i.v. ofatumumab at an initial dose of 300 mg in week 3 further escalated to 2000 mg every other week. All serum samples were measured by hemolytic assay on sheep erythrocytes as well as using calcein release assay on CD20-positive Raji cells. Our data show that results obtained from both assays are related to each other at the level of the whole group (n = 96 samples, Spearman r = 0.504, p < .001) but may substantially differ when analyzing individual patients. Furthermore, by using CDC assay on Raji cells, we found that in the presented clinical study CDC serum potential was not significantly affected when measured before consecutive administrations in most of the patients.
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http://dx.doi.org/10.1016/j.jim.2019.112675DOI Listing
January 2020

Ibrutinib induces rapid down-regulation of inflammatory markers and altered transcription of chronic lymphocytic leukaemia-related genes in blood and lymph nodes.

Br J Haematol 2018 10 20;183(2):212-224. Epub 2018 Aug 20.

Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.

In chronic lymphocytic leukaemia (CLL) patients, treatment with the Bruton tyrosine kinase inhibitor ibrutinib induces a rapid shift of tumour cells from lymph nodes (LN) to peripheral blood (PB). Here, we characterized in depth the dynamics of ibrutinib-induced inflammatory, transcriptional and cellular changes in different compartments immediately after treatment initiation in seven relapsed/refractory CLL patients. Serial PB and LN samples were taken before start and during the first 29 days of treatment. Changes in plasma inflammation-related biomarkers, CLL cell RNA expression, B-cell activation and migration markers expression, and PB mononuclear cell populations were assessed. A significant reduction of 10 plasma inflammation markers, the majority of which were chemokines and not CLL-derived, was observed within hours, and was paralleled by very early increase of CD19 circulating cells. At the RNA level, significant and continuous changes in transcription factors and signalling molecules linked to B-cell receptor signalling and CLL biology was observed in both PB and LN CLL cells already after 2 days of treatment. In conclusion, ibrutinib seems to instantly shut off an ongoing inflammatory response and interfere with diverse sensitive pathways in the LN.
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http://dx.doi.org/10.1111/bjh.15516DOI Listing
October 2018

Phase I-II study of lenalidomide and alemtuzumab in refractory chronic lymphocytic leukemia (CLL): effects on T cells and immune checkpoints.

Cancer Immunol Immunother 2017 01 4;66(1):91-102. Epub 2016 Nov 4.

Department of Hematology, Karolinska University Hospital Solna, 171 76, Stockholm, Sweden.

This phase I-II study explored safety, immunomodulatory and clinical effects of lenalidomide (weeks 1-16) and alemtuzumab (weeks 5-16) in 23 patients with refractory chronic lymphocytic leukemia. Most patients had Rai stage III/IV disease and were heavily pretreated (median 4 prior therapies), and 61% had del(17p)/del(11q). Eleven of 19 evaluable patients (58%) responded, with a median response duration of 12 months (1-29+); time to progression was short in non-responders. Lenalidomide had a narrow therapeutic dose range, 2.5 mg/day was not efficient, and maximum tolerated dose was 5 mg/day. Grade 3-4 neutropenia and thrombocytopenia occurred in 84 and 55%, 30% had febrile neutropenia, and CMV-reactivation requiring valganciclovir occurred in 30% of patients. The frequency of proliferating (Ki67) CD8 T cells was increased at week 4, with further increase in both the CD4 and CD8 subsets (p < 0.01 and <0.05), which was accompanied by significant upregulation of HLA-DR after addition of alemtuzumab. Antigen-experienced cells increased at week 4 as the frequency of effector memory cells increased in the CD8 subset (p < 0.003), while effector cells decreased in both the CD8 and CD4 subsets (p < 0.0001 and p < 0.01). The Th1/Th2 balance was unchanged at week 4 but shifted toward a Th2 profile after combination therapy. At end of treatment, the frequency of Th17 and regulatory T cells was reduced (p < 0.01), naïve T cells decreased, and effector memory T cells increased (p < 0.05 and p < 0.01). Granzyme B T cells increased at 30-week follow-up (p < 0.05). PD-1 expression was unaffected. In conclusion, low-dose lenalidomide and alemtuzumab induced major perturbations of T cells, including increased proliferative activity and cytotoxic potential.
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http://dx.doi.org/10.1007/s00262-016-1922-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5222940PMC
January 2017

Real-world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: data from 95 consecutive patients treated in a compassionate use program. A study from the Swedish Chronic Lymphocytic Leukemia Group.

Haematologica 2016 12 19;101(12):1573-1580. Epub 2016 May 19.

Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.

Ibrutinib, a Bruton's tyrosine kinase inhibitor is approved for relapsed/refractory and del(17p)/TP53 mutated chronic lymphocytic leukemia. Discrepancies between clinical trials and routine health-care are commonly observed in oncology. Herein we report real-world results for 95 poor prognosis Swedish patients treated with ibrutinib in a compassionate use program. Ninety-five consecutive patients (93 chronic lymphocytic leukemia, 2 small lymphocytic leukemia) were included in the study between May 2014 and May 2015. The median age was 69 years. 63% had del(17p)/TP53 mutation, 65% had Rai stage III/IV, 28% had lymphadenopathy ≥10cm. Patients received ibrutinib 420 mg once daily until progression. At a median follow-up of 10.2 months, the overall response rate was 84% (consistent among subgroups) and 77% remained progression-free. Progression-free survival and overall survival were significantly shorter in patients with del(17p)/TP53 mutation (P=0.017 and P=0.027, log-rank test); no other factor was significant in Cox proportional regression hazards model. Ibrutinib was well tolerated. Hematomas occurred in 46% of patients without any major bleeding. Seven patients had Richter's transformation. This real-world analysis on consecutive chronic lymphocytic leukemia patients from a well-defined geographical region shows the efficacy and safety of ibrutinib to be similar to that of pivotal trials. Yet, del(17p)/TP53 mutation remains a therapeutic challenge. Since not more than half of our patients would have qualified for the pivotal ibrutinib trial (RESONATE), our study emphasizes that real-world results should be carefully considered in future with regards to new agents and new indications in chronic lymphocytic leukemia.
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http://dx.doi.org/10.3324/haematol.2016.144576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479603PMC
December 2016

Outcomes of patients with fludarabine-refractory chronic lymphocytic leukemia: a population-based study from a well-defined geographic region.

Leuk Lymphoma 2014 Aug 4;55(8):1774-80. Epub 2014 Feb 4.

Departments of Hematology and Oncology, Karolinska University Hospital , Stockholm , Sweden.

Patients with fludarabine-refractory (FR) chronic lymphocytic leukemia (CLL) receive novel agents in pivotal, non-randomised phase-2 trials. Understanding outcome of FR-CLL in health-care may provide important contextual information. Records from 1301 patients (Stockholm-Cancer-Registry 1991-2010) identified 92 FR-patients; bulky lymph-nodes (BFR-group), double-refractory (DR-group), or Others'-group for outcome-analysis. Median age was 69 years 67% had Rai-stage III/IV with median 3 prior therapies. Overall response-rate was 20%; significantly lower in BFR (8%, p = 0.01) and DR (20%, p = 0.01) than in 'Others' (31%). Time-to-treatment-failure (months) was significantly longer in 'Others' (9.2) than in BFR/DR (5.3/4.4) (p < 0.01) and significantly longer (p < 0.05) in antibody-treated patients (9.1) compared to other regimens (5.2). Early-death occurred in 5%, ≥ grade III-infections in 20%. Median overall-survival (OS) was 18 months; 29 in BFR vs. 13 in DR (p = 0.054). Male sex was the only prognostic factor on OS (p = 0.01, HR 2.2, multivariate-Cox-regression). Our results, without external referrals, facilitate interpretation of non-randomised trials/novel drugs in advanced-stage-CLL.
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http://dx.doi.org/10.3109/10428194.2013.827786DOI Listing
August 2014

The tyrosine kinase receptor ROR1 is constitutively phosphorylated in chronic lymphocytic leukemia (CLL) cells.

PLoS One 2013 24;8(10):e78339. Epub 2013 Oct 24.

Department of Oncology-Pathology, Immune and Gene therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna and Karolinska Institute, Stockholm, Sweden.

Phosphorylation of receptor tyrosine kinases (RTKs) has a key role in cellular functions contributing to the malignant phenotype of tumor cells. We and others have previously demonstrated that RTK ROR1 is overexpressed in chronic lymphocytic leukemia (CLL). Silencing siRNA downregulated ROR1 and induced apoptosis of CLL cells. In the present study we analysed ROR1 isoforms and the phosphorylation pattern in CLL cells (n=38) applying western blot and flow-cytometry using anti-ROR1 antibodies and an anti-phospho-ROR1 antibody against the TK domain. Two major ROR1 bands with the size of 105 and 130 kDa respectively were identified, presumably representing unglycosylated (immature) and glycosylated (mature) ROR1 respectively as well as a 260 kDa band which may represent dimerized ROR1. A ROR1 band of 64 kDa that may correspond to a C-terminal fragment was also noted, present only in the nucleus. The 105 kDa ROR1 isoform was more frequently expressed in non-progressive as compared to progressive CLL patients (p=0.03). The 64, 105, 130 and 260 kDa bands were constitutively phosphorylated both at tyrosine and serine residues. Phosphorylation intensity of the mature (130 kDa) isoform was significantly higher in progressive than in non-progressive disease (p<0.001). Incubation of CLL cells with a mouse anti-ROR1 KNG or an anti-ROR1 CRD mAb respectively induced dephosphorylation of ROR1 before entering apoptosis. In conclusion CLL cells expressed different isoforms of ROR1 which were constitutively phosphorylated. The mature, phosphorylated ROR1 isoform was associated with a progressive disease stage. Targeting ROR1 by mAbs induced specific dephosphorylation and leukemic cell death. ROR1 might be an interesting therapeutic target.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078339PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3813472PMC
February 2015

Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia.

Haematologica 2011 Aug 5;96(8):1161-9. Epub 2011 May 5.

Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

Background: High-resolution genomic microarrays enable simultaneous detection of copy-number aberrations such as the known recurrent aberrations in chronic lymphocytic leukemia [del(11q), del(13q), del(17p) and trisomy 12], and copy-number neutral loss of heterozygosity. Moreover, comparison of genomic profiles from sequential patients' samples allows detection of clonal evolution.

Design And Methods: We screened samples from 369 patients with newly diagnosed chronic lymphocytic leukemia from a population-based cohort using 250K single nucleotide polymorphism-arrays. Clonal evolution was evaluated in 59 follow-up samples obtained after 5-9 years.

Results: At diagnosis, copy-number aberrations were identified in 90% of patients; 70% carried known recurrent alterations, including del(13q) (55%), trisomy 12 (10.5%), del(11q) (10%), and del(17p) (4%). Additional recurrent aberrations were detected on chromosomes 2 (1.9%), 4 (1.4%), 8 (1.6%) and 14 (1.6%). Thirteen patients (3.5%) displayed recurrent copy-number neutral loss of heterozygosity on 13q, of whom 11 had concurrent homozygous del(13q). Genomic complexity and large 13q deletions correlated with inferior outcome, while the former was linked to poor-prognostic aberrations. In the follow-up study, clonal evolution developed in 8/24 (33%) patients with unmutated IGHV, and in 4/25 (16%) IGHV-mutated and treated patients. In contrast, untreated patients with mutated IGHV (n=10) did not acquire additional aberrations. The most common secondary event, del(13q), was detected in 6/12 (50%) of all patients with acquired alterations. Interestingly, aberrations on, for example, chromosome 6q, 8p, 9p and 10q developed exclusively in patients with unmutated IGHV.

Conclusions: Whole-genome screening revealed a high frequency of genomic aberrations in newly diagnosed chronic lymphocytic leukemia. Clonal evolution was associated with other markers of aggressive disease and commonly included the known recurrent aberrations.
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http://dx.doi.org/10.3324/haematol.2010.039768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148910PMC
August 2011

Tumor burden status evaluated by computed tomography scan is of prognostic importance in patients with chronic lymphocytic leukemia.

Med Oncol 2010 Sep 25;27(3):820-5. Epub 2009 Aug 25.

Department of Hematology, Karolinska University Hospital Solna, 171 76, Stockholm, Sweden.

It has been discussed if computed tomography (CT) scan is necessary to perform or not, to provide prognostic information in patients with chronic lymphocytic leukemia. In the current National Institute Chronic lymphocytic leukemia Working Group (NCI-WG) guidelines, CT scan is not recommended outside clinical trials but states that further trials are warranted. Computed tomography scan of lymphadenopathy and/or splenomegaly was detected in totally 74 patients, leading to a modified Rai stage in 9 (12%) patients (from stage I to II). Using CT, 19 patients fulfilled the GELF high tumor burden criteria and/or one bulky node > or =7 cm. CT showed splenomegaly in totally 54 (73%) patients, of which 22 (41%) cases had not had been detected during clinical examination. According to the NCI response criteria for chronic lymphocytic leukemia (CLL), 15 (22%) patients showed a CR and 43 (62%) a PR, while when including CT findings, 12 (17%) fulfilled criteria for CR and 41 (59%) for PR. Patients with a high lymphadenopathy tumor burden according to the GELF criteria at the time of initiation of first-line therapy had a shorter time from response to next therapy or death, 12 months compared with 35 months for patients with less advanced lymphadenopathy (P = 0.002). There was also a trend for a shorter overall survival in the high tumor burden group, 58 months compared to 75 months (P = 0.098). Massive splenomegaly was related to a shorter therapy-free as well as overall survival. In our opinion, clinical examination is not sufficient for evaluation of abdominal lymphnodes and spleen in patients with therapy requiring CLL.
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http://dx.doi.org/10.1007/s12032-009-9292-yDOI Listing
September 2010

Lack of association between the MDM2 promoter polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia.

Leuk Res 2010 Mar 1;34(3):335-9. Epub 2009 Jul 1.

Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.

The 309T>G polymorphism in the promoter region of the MDM2 gene, known as SNP309, has recently been suggested as an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL) although this has been questioned. To investigate this further, we analyzed the MDM2 SNP309 genotypes in 418 CLL patients and correlated the results with established CLL prognostic factors, time to treatment and overall survival. In this Swedish cohort, no association existed between any particular MDM2 SNP309 genotype, overall survival and time to treatment. Furthermore, no correlation was shown between the MDM2 SNP309 genotypes and Binet stage, IGHV mutational status and recurrent genomic aberrations. In summary, this study argues against the use of the MDM2 SNP309 as a prognostic marker in CLL.
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http://dx.doi.org/10.1016/j.leukres.2009.06.006DOI Listing
March 2010

Alemtuzumab to treat refractory autoimmune hemolytic anemia or thrombocytopenia in chronic lymphocytic leukemia.

Curr Hematol Malig Rep 2009 Jan;4(1):47-53

Department of Hematology, Karolinska University Hospital Solna, SE-171 76, Stockholm, Sweden.

Autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP) are recognized complications of chronic lymphocytic leukemia (CLL) that can be life-threatening if not managed appropriately. Conventional therapies for these autoimmune disorders, such as corticosteroids, splenectomy, and immunosuppressive agents, may not induce complete resolution in all patients, and relapses are common. In recent years, monoclonal antibodies such as alemtuzumab and rituximab, already used successfully for the management of lymphoproliferative disorders, have been shown to be effective in the treatment of a range of autoimmune disorders. The potent antitumor activity of alemtuzumab, in combination with its profound immunosuppressive activity, prompted investigation of its use in patients with severe CLL-related AIHA and ITP. Results from a range of reports confirm the efficacy of alemtuzumab for the treatment of severe, CLL-related autoimmune cytopenias that have failed to respond to conventional therapies and may even be rituximab-refractory.
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http://dx.doi.org/10.1007/s11899-009-0007-4DOI Listing
January 2009

Phase II study of subcutaneous alemtuzumab without dose escalation in patients with advanced-stage, relapsed chronic lymphocytic leukaemia.

Br J Haematol 2009 Jan 30;144(1):78-85. Epub 2008 Oct 30.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

This phase II study (n = 20) aimed to evaluate type, severity and duration of side-effects and efficacy following subcutaneous (SC) alemtuzumab, without dose-escalation, in advanced-stage relapsed chronic lymphocytic leukaemia (CLL) patients. Alemtuzumab 30 and 3 mg was administered SC simultaneously day 1, followed by 30 mg three times per week. Injection-site-reactions were recorded every 6-24 h until resolved using National Cancer Institute criteria and a new skin toxicity subscale. The first doses of 30 mg and 3 mg produced injection-site-reactions (all but one were grade 1/2) in 13/20 and 9/20 patients, respectively. The second dose (on day 3) resulted in skin-reactions in 10/20 patients and the third, fourth, fifth and sixth injections produced reactions in 6/20, 1/20, 2/20 and 0/20 patients, respectively. Mild "flu-like" symptoms occurred during week 1 in 10/20 patients. All side-effects had subsided by the sixth dose. 15/20 patients (75%) responded (12 partial responses, three complete responses) with a median time-to-treatment-failure of 20 months. Symptomatic cytomegalovirus-reactivation occurred in 6/20 patients. Two deaths occurred: one bacterial pneumonia and one adenovirus-infection. The present study showed how to assess cutaneous-toxicity in detail and that 30 mg alemtuzumab SC administered upfront was well tolerated. Optimized alemtuzumab therapy in properly selected patients may result in high efficacy even in advanced CLL. Our results need to be confirmed in extended studies.
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http://dx.doi.org/10.1111/j.1365-2141.2008.07451.xDOI Listing
January 2009

Performance of calibration standards for antigen quantitation with flow cytometry in chronic lymphocytic leukemia.

Cytometry B Clin Cytom 2007 Nov;72(6):450-7

Department of Oncology (Radiumhemmet), Karolinska University Hospital, Stockholm, Sweden.

Background: The fluorescence intensities of CD3, CD4 on T cells and CD20, CD22 molecules on B cells were quantitatively measured on lymphocytes from chronic lymphocytic leukemia (CLL) patients and healthy donors.

Methods: The performance of three different types of microbeads was compared, i.e. Quantum molecules of equivalent soluble fluorochrome (Q-MESF), Quantum simply cellular (QSC), and QuantiBRITE (QB). As all PE-conjugates had a F/P ratio of 1:1, the MESF units represented also the antibody binding capacity (ABC).

Results: The ABCs of CD4 and CD20 antigens estimated with QSC (ABC(QSC)) were higher than those assigned with QB (ABC(QB)) with an average difference 49%. Higher numbers of antigenic sites were obtained with Q-MESF than with QSC for CD20 antigen. On the contrary, CD4 antigenic sites numbers estimated with QSC were higher than those estimated with Q-MESF. ABC values estimated with Quantum MESF PE (ABC(Q-MESF)) were approximately 15% higher than ABC(QSC), whereas ABC(Q-MESF) was approximately 49% higher than ABC(QB). Statistically significant correlations were found between the values obtained using various standards. The present study is the first to report down-regulation of CD3 antigen on T cells from patients with CLL.

Conclusions: This study emphasizes the relevance of quantitative measurement of fluorescence intensity by flow cytometry as a standardized approach to measure and interpret the expression of some CLL markers and reduce variability of results obtained at different sites in multi-center clinical studies.
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http://dx.doi.org/10.1002/cyto.b.20359DOI Listing
November 2007

Reconstitution of the T-cell repertoire following treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with B-cell chronic lymphocytic leukaemia.

Br J Haematol 2006 Nov 22;135(4):475-85. Epub 2006 Sep 22.

Immune and Gene Therapy Laboratory, Department of Oncology and Pathology, Cancer Centre Karolinska (CCK), Karolinska Institutet, Stockholm, Sweden.

In this pilot study, T-cell receptor B-variable (TCR-BV) gene usage in CD4 and CD8 T cells was assessed, by real-time polymerase chain reaction, as well as complementarity-determining region 3 (CDR3)-length polymorphism, before and after therapy in five patients with B-cell chronic lymphocytic leukaemia who received alemtuzumab (anti-CD52 monoclonal antibody) as first-line therapy. A decline in expression of most BV family genes in both CD4 and CD8 T cells was observed after alemtuzumab treatment, which was followed by a gradual increase in most BV families during long-term follow-up. After treatment, CDR3-length polymorphism showed an even more restricted pattern in CD4 T cells compared with pretreatment, with a shift towards a monoclonal/oligoclonal pattern. The clonally restricted pattern was significantly reduced in CD4 (P < 0.01) but not in CD8 T cells. This was followed by a gradual increase in the number of peaks within the CDR3 region of the different TCR-BV families, i.e. a polyclonal repertoire, during long-term follow-up. A restricted CDR3 pattern became even more restricted after treatment, but normalised during unmaintained follow-up. These results indicate that perturbations in the T-cell alterations following alemtuzumab are complex and include not only changes in CD4/CD8 T-cell numbers but also a highly restricted T-cell repertoire especially in CD4 T cells.
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http://dx.doi.org/10.1111/j.1365-2141.2006.06324.xDOI Listing
November 2006

Signaling molecules and cytokine production in T cells of patients with B-cell chronic lymphocytic leukemia: long-term effects of fludarabine and alemtuzumab treatment.

Leuk Lymphoma 2006 Jul;47(7):1229-38

Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Stockholm, Sweden.

Fludarabine and alemtuzumab are routinely used for treatment of B-cell chronic lymphocytic leukemia (B-CLL). The present study aimed to compare the expression of signaling molecules and cytokine production by T cells of B-CLL patients in long-term unmaintained remission/plateau phase following fludarabine or alemtuzumab treatment with that of indolent/untreated B-CLL patients and healthy donors. The frequency and intensity of TCR-CD3zeta chain, p56lck, p59fyn, ZAP-70, PI3-kinase and interferon (IFN)-gamma/interleukin (IL)-4 production in CD4 and CD8 T cells was examined by flow cytometry. T-cell function was assessed by stimulation with purified protein derivative (PPD) and phytohemagglutinin (PHA). Despite a reduction in number, the expression of IFN-gamma/IL-4 in T-cells in patients was significantly higher than in healthy donors. The intensity of most signaling molecules in treated patients was relatively unaffected vs. healthy donors but lower than untreated-indolent patients. However, the total number of T cells which expressed each of the signaling molecules was decreased in patients, with no difference between fludarabine- and alemtuzumab-treated patients. The T-cell response to PHA but not PPD was reduced in treated patients. The results suggest that, despite some alterations in signaling molecules and a reduction in T-cell number, overall T-cell functions may be relatively well preserved long-term after treatment with fludarabine and alemtuzumab.
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http://dx.doi.org/10.1080/10428190600565503DOI Listing
July 2006

Strategies in the management of alemtuzumab-related side effects.

Semin Oncol 2006 Apr;33(2 Suppl 5):S29-35

Department of Oncology and Hematology, Karolinska University Hospital, Stockholm, Sweden.

B-cell chronic lymphocytic leukemia has traditionally been treated with alkylating agents and purine analogues. The introduction of alemtuzumab, a CD52 monoclonal antibody with significant clinical activity in chemotherapy refractory B-cell chronic lymphocytic leukemia, is accompanied by a side effect profile different from that resulting from chemotherapy. The intravenous administration of alemtuzumab is usually accompanied by transient infusion-related side effects manifesting primarily as flu-like symptoms. These reactions can be reduced by use of corticosteroid prophylaxis, and will subside gradually during continued treatment. Alternatively, administration of alemtuzumab subcutaneously may markedly reduce the occurrence of general side effects but results in limited transient local skin reactions in most patients. Neutropenia (grade 4) may occur in approximately 20% of patients, but is usually transient and/or responds promptly to colony stimulating factor therapy; episodes of febrile neutropenia are infrequent. The major side effect of alemtuzumab is T-cell depletion, leading to an increased risk of infection, in particular reactivation of cytomegalovirus. This event typically occurs 3 to 8 weeks after initiation of therapy, coinciding with the T-cell nadir. With vigilance and early detection, these infections are usually manageable and do not cause organ failure. Preliminary data indicate that other infections following alemtuzumab therapy do not seem to occur at a frequency that is higher than expected, probably because of the general prophylactic use of cotrimoxazole (trimethoprim and sulfamethoxazole) and valacyclovir in combination with clinical tumor regressions. The overall safety profile of alemtuzumab appears to be beneficial in relation to disease severity and prognosis in patients with fludarabine-refractory B-cell chronic lymphocytic leukemia.
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http://dx.doi.org/10.1053/j.seminoncol.2006.01.027DOI Listing
April 2006

Alemtuzumab therapy for severe autoimmune hemolysis in a patient with B-cell chronic lymphocytic leukemia.

Med Oncol 2006 ;23(1):137-9

Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.

B-cell chronic lymphocytic leukemia (B-CLL) is the most common cause of autoimmune hemolytic anemia (AIHA), and a subgroup of these patients who develop both these conditions fail to respond to corticosteroids, cytotoxic drugs, splenectomy, and iv immunoglobulins. Alemtuzumab is a humanized anti-CD52 monoclonal antibody that is an effective therapy for B-CLL, mycosis fungoides, and T-cell prolymphocytic leukemia. Here we present a case report of a 78-yr-old woman with B-CLL and progressive life-threatening AIHA with hemoglobin count 5.5 g/dL following fludarabine treatment, who was treated successfully with alemtuzumab. The anemia was completely reversed and hemoglobin count remains at 14 g/dL after 15 mo of unmaintained follow-up. No infectious complications were noted during or after alemtuzumab therapy. We conclude that alemtuzumab may be indicated for the treatment of AIHA in B-CLL patients who have failed other treatments.
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http://dx.doi.org/10.1385/MO:23:3DOI Listing
June 2006

Advances in the use of monoclonal antibodies in the therapy of chronic lymphocytic leukemia.

Semin Hematol 2004 Jul;41(3):234-45

Departments of Hematology/Oncology, Karolinska University Hospital, Stockholm, Sweden.

Monoclonal antibody (moAb)-based therapies are evolving as an integrated component in the treatment of chronic lymphocytic leukemia (CLL). Advantages such as different mechanisms of action (compared with those of chemotherapy), no or minimal stem cell toxicity, as well as the absence of hair loss and delayed nausea may result in a rapidly increasing usage of these agents in different phases of the disease. The combination of moAbs with chemotheraputic agents has shown promising results in early studies as well as their role in the eradication of minimal residual disease (MRD). The availability of an increasing number of new moAbs together with a better understanding of their effector function will hopefully lead to improved therapeutic outcomes for patients with CLL and related disorders.
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http://dx.doi.org/10.1053/j.seminhematol.2004.05.005DOI Listing
July 2004

Therapy for mycosis fungoides.

Curr Treat Options Oncol 2004 Jun;5(3):203-14

Department of Hematology and Oncology, Karolinska Hospital, SE-171 76 Stockholm, Sweden.

Treatment of mycosis fungoides (MF) is indicated to reduce symptoms, improve clinical appearance, prevent secondary complications, and prevent progression of disease, all of which may have an impact on survival. Treatment of MF includes topical and systemic therapies, which can be administered alone or in combination. Psoralen and ultraviolet A radiation is effective in early-stage MF, inducing complete remissions in most patients. Psoralen and ultraviolet A radiation may also be combined with low doses of interferon (IFN)-alpha to treat stage I/II disease. However, early aggressive therapy with radiation and chemotherapy does not improve the prognosis. Local radiotherapy or total skin electron beam irradiation has been used with success to control advanced skin disease. Extracorporeal photopheresis may also be used successfully, but it is not generally available. Once the disease becomes refractory to topical therapy, IFN-alpha single-agent or combination chemotherapy may be administered, but the duration of response is often less than 1 year and ultimately all patients will relapse and become refractory. Among chemotherapeutic agents, pentostatin, gemcitabine, and liposomal doxorubicin seem to be particularly effective. Response rates after combined modality therapy with total skin electron beam irradiation and chemotherapy/IFN-alpha appear similar to response rates of chemotherapy alone. Therefore, there is a great need for the further development of novel emerging treatment modalities, such as retinoids (ie, bexarotene) and immunotherapeutic agents (ie, cytokines, tumor vaccines, and monoclonal antibodies), all of which appear to have significant therapeutic potential in patients with MF. Biologically based therapies may reduce the need for genotoxic therapies, such as cytostatics and radiotherapy.
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http://dx.doi.org/10.1007/s11864-004-0012-8DOI Listing
June 2004

Blood concentrations of alemtuzumab and antiglobulin responses in patients with chronic lymphocytic leukemia following intravenous or subcutaneous routes of administration.

Blood 2004 Aug 15;104(4):948-55. Epub 2004 Apr 15.

Therapeutic Antibody Centre, Old Road, Headington, Oxford, OX3 7JT, United Kingdom.

Alemtuzumab is a humanized anti-CD52 antibody licensed for refractory B-cell chronic lymphocytic leukemia (B-CLL), when given intravenously at 30 mg thrice weekly. However, the intravenous route is associated with infusion-related reactions and is inconvenient. We measured blood concentrations in 30 relapsed patients treated with intravenous alemtuzumab and in 20 patients from a previously untreated group who received similar doses subcutaneously. Highest trough samples in the intravenous group were less than 0.5 microg/mL to 18.3 microg/mL (mean 5.4 microg/mL). The cumulative dose required to reach 1.0 microg/mL was 13 mg to 316 mg (mean 90 mg). Higher blood concentrations correlated with the achievement of better clinical responses and minimal residual disease. The highest measured concentrations in the subcutaneous group were similar (0.6 microg/mL to 24.8 microg/mL, mean 5.4 microg/mL). However, the cumulative dose to reach 1.0 microg/mL was higher: 146 mg to 1106 mg (mean 551 mg). No antiglobulin responses were detected in 30 patients given intravenous alemtuzumab whereas 2 of 32 patients given subcutaneous alemtuzumab made substantial anti-idiotype responses. Thus, subcutaneous alemtuzumab achieved concentrations similar to those for intravenous alemtuzumab, although with slightly higher cumulative doses. Subcutaneous alemtuzumab is more convenient and better tolerated but may be associated with some patients forming anti-alemtuzumab antibodies, particularly those patients who were previously untreated.
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http://dx.doi.org/10.1182/blood-2004-02-0593DOI Listing
August 2004

A pilot study of alemtuzumab (anti-CD52 monoclonal antibody) therapy for patients with relapsed or chemotherapy-refractory peripheral T-cell lymphomas.

Blood 2004 Apr 30;103(8):2920-4. Epub 2003 Dec 30.

Department of Oncology, Uppsala University Hospital, Uppsala, Sweden.

Patients with peripheral T-cell lymphomas (PTLs) have an extremely poor prognosis when relapsed or refractory to conventional chemotherapy. We have studied alemtuzumab, a humanized anti-CD52 monoclonal antibody, as therapy for patients with heavily pretreated and refractory PTL. Fourteen patients entered the study. All had clinical stage III or IV disease. Patients received a rapidly escalating dosage of alemtuzumab during the first week and, thereafter, 30 mg intravenously 3 times per week for a maximum of 12 weeks. Trimethoprim/sulphamethoxazole and valaciclovir prophylaxis was given to all patients. The overall response rate was 36% (5 of 14). Three patients achieved a complete remission (CR) and 2 patients a partial remission. The durations of the CRs were 2, 6, and 12 months, respectively. Toxicity included cytomegalovirus reactivation in 6 patients, which was successfully treated with ganciclovir or foscarnet; pulmonary aspergillosis in 2 patients; and pancytopenia in 4 patients. Epstein-Barr virus-related hemophagocytosis was observed in 2 patients. Five patients died of causes related to the treatment, in combination with advanced disease. We conclude that alemtuzumab is active when used in patients with advanced, heavily pretreated PTL, although it is associated with significant hematologic toxicity and infectious complications. Further studies are warranted in younger patients and patients with less advanced disease.
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http://dx.doi.org/10.1182/blood-2003-10-3389DOI Listing
April 2004

Phase II study of cyclophosphamide, interferon-alpha and betamethasone (CIB) as induction therapy for patients 60-75 years of age with multiple myeloma stages II and III.

Hematol J 2003 ;4(4):248-52

Department of Hematology, Karolinska Hospital, Stockholm, Sweden.

Cyclophosphamide, interferon-alpha and betamethasone are all effective agents for the treatment of multiple myeloma (MM) with different mechanisms of action. The clinical effect of a combination of cyclophosphamide 725 mg/m(2) i.v. days 1 and 3, interferon-alpha 7 x 10(6) IE/m(2) s.c./day, days 1-4 and betamethasone 30 mg orally days 1-4 (CIB) was studied in patients aged 60-75 years with previously untreated MM stages II and III. Granulocyte-macrophage colony-stimulating factor (GM-CSF) 5 microg/kg/day s.c. was administered to all patients from day 5 until the day the granulocyte count exceeded 1.0 x 10(9)/l. CIB was repeated every fourth week. Interferon-alpha 3 x 10(6) IE s.c. t.i.w. was given as maintenance therapy in responding patients.A total of 28 patients (median age: 67 years) entered the study. In all, 12 patients had stage II and 16 had stage III MM. A total of 22 patients (79%) showed an objective response, including five complete remissions (CR) and 17 partial remissions (PR). All seven patients with Bence-Jones MM responded (five CR and two PR). The median response duration time was 14 months (range 5-38+). CIB was relatively well tolerated although febrile neutropenia or septicaemia occurred in 5% of the cycles and a dose-reduction of cyclophosphamide due to grade IV neutropenia was performed in 11% of the patients.CIB seems to be an effective regimen for remission induction in MM patients aged up to 75 years as an alternative to VAD (vincristine, doxorubicin, dexamethasone) if a regimen with intensity higher than that of oral melphalan/prednisone is warranted.
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http://dx.doi.org/10.1038/sj.thj.6200301DOI Listing
April 2004

Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome.

Blood 2003 Jun 23;101(11):4267-72. Epub 2003 Jan 23.

Department of Hematology/Oncology, Karolinska Hospital, Stockholm, Sweden.

This phase 2 study evaluated the safety and efficacy of alemtuzumab in 22 patients with advanced mycosis fungoides/Sézary syndrome (MF/SS). Most patients had stage III or IV disease, reduced performance status, and severe itching. The overall response (OR) rate was 55%, with 32% of patients in complete remission (CR) and 23% in partial remission (PR). Sézary cells were cleared from the blood in 6 of 7 (86%) patients, and CR in lymph nodes was observed in 6 of 11 (55%) patients. The effect was better on erythroderma (OR, 69%) than on plaque or skin tumors (OR, 40%) and in patients who had received 1 to 2 previous regimens (OR, 80%) than in those who had received 3 or more prior regimens (OR, 33%). Itching, self-assessed on a 0 to 10 visual analog scale, was reduced from a median of 8 before treatment to 2 at end of therapy. Median time to treatment failure was 12 months (range, 5-32+ months). Cytomegalovirus (CMV) reactivation (causing fever without pneumonitis and responding to ganciclovir) occurred in 4 (18%) patients. Six additional patients had suspect or manifest infection (fever of unknown origin, 3; generalized herpes simplex, 1; fatal aspergillosis, 1). One patient had fatal Mycobacterium pneumonia at 10+ months. All serious infectious adverse events (except CMV) occurred in patients who had received 3 or more prior regimens. Progression of squamous cell skin carcinoma was noted in 1 patient. Alemtuzumab shows promising clinical activity and an acceptable safety profile in patients with advanced MF/SS, particularly in patients with erythroderma and severe itching and those who were not heavily pretreated.
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http://dx.doi.org/10.1182/blood-2002-09-2802DOI Listing
June 2003

Fatal adenovirus infection during alemtuzumab (anti-CD52 monoclonal antibody) treatment of a patient with fludarabine-refractory B-cell chronic lymphocytic leukemia.

Med Oncol 2002 ;19(4):277-80

Department of Hematology and Oncology, Karolinska Hospital, Stockholm, Sweden.

Alemtuzumab (Campath-1H) is a humanized CD52 monoclonal antibody that targets normal as well as malignant B- and T-lymphocytes. Alemtuzumab has significant antitumor activity in chronic lymphocytic leukemia (B-CLL) but also induces immunosuppression. We describe a case of fatal adenovirus infection in a heavily pretreated patient with fludarabine-refractory B-CLL receiving alemtuzumab therapy, drawing attention to the fact that also viruses other than cytomegalovirus (CMV) and herpes simplex (HSV) need to be considered in B-CLL patients with fever of unknown origin while on alemtuzumab treatment.
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http://dx.doi.org/10.1385/MO:19:4:277DOI Listing
April 2003

Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL).

Blood 2002 Aug;100(3):768-73

Department of Hematology, Karolinska Hospital, and Huddinge University Hospital, Stockholm, Sweden.

This phase II study determined the efficacy and safety of alemtuzumab, a humanized anti-CD52 monoclonal antibody, delivered subcutaneously as first-line therapy, over a prolonged treatment period of 18 weeks in 41 patients with symptomatic B-cell chronic lymphocytic leukemia (B-CLL). Injections were administered subcutaneously 3 times per week, from week 2 to 3 onward. An overall response rate (OR) of 87% (95% CI, 76%-98%; complete remission [CR], 19%; partial remission [PR], 68%) was achieved in 38 evaluable patients (81% of intent-to-treat population). CLL cells were cleared from blood in 95% patients in a median time of 21 days. CR or nodular PR in the bone marrow was achieved in 66% of the patients and most patients achieved this after 18 weeks of treatment. An 87% OR (29% CR) was achieved in the lymph nodes. The median time to treatment failure has not yet been reached (18+ months; range, 8-44+ months). Transient injection site skin reactions were seen in 90% of patients. Rigor, rash, nausea, dyspnea, and hypotension were rare or absent. Transient grade IV neutropenia developed in 21% of the patients. Infections were rare, but 10% patients developed cytomegalovirus (CMV) reactivation. These patients rapidly responded to intravenous ganciclovir. One patient, allergic to cotrimoxazole prophylaxis, developed Pneumocystis carinii pneumonia. Alemtuzumab is highly effective as first-line treatment in patients with B-CLL. Prolonged treatment is important for maximal bone marrow response. Subcutaneous administration induced very few "first-dose" flulike symptoms and may reduce health care costs in comparison with the intravenous infusions.
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http://dx.doi.org/10.1182/blood-2002-01-0159DOI Listing
August 2002