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- Hasford, Joerg, et al.
(författare)
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Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment : the EUTOS score
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 118:3, s. 686-692
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Tidskriftsartikel (refereegranskat)abstract
- The outcome of chronic myeloid leukemia (CML) has been profoundly changed by the introduction of tyrosine kinase inhibitors into therapy, but the prognosis of patients with CML is still evaluated using prognostic scores developed in the chemotherapy and interferon era. The present work describes a new prognostic score that is superior to the Sokal and Euro scores both in its prognostic ability and in its simplicity. The predictive power of the score was developed and tested on a group of patients selected from a registry of 2060 patients enrolled in studies of first-line treatment with imatinib-based regimes. The EUTOS score using the percentage of basophils and spleen size best discriminated between high-risk and low-risk groups of patients, with a positive predictive value of not reaching a CCgR of 34%. Five-year progression-free survival was significantly better in the low-than in the high-risk group (90% vs 82%, P = .006). These results were confirmed in the validation sample. The score can be used to identify CML patients with significantly lower probabilities of responding to therapy and survival, thus alerting physicians to those patients who require closer observation and early intervention.
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- Koskenvesa, Perttu, et al.
(författare)
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Imatinib and pegylated IFN-alpha 2b discontinuation in first-line chronic myeloid leukemia patients following a major molecular response
- 2014
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 92:5, s. 413-420
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Previous studies indicate that 40-50% of patients with chronic myeloid leukemia in prolonged complete molecular remission may discontinue imatinib therapy without imminent relapse. The combination of pegylated interferon-alpha (Peg-IFN-alpha 2b) and imatinib may increase the rate of successful discontinuation. Methods In this pilot study, we prospectively stopped imatinib from patients (n=12) who had achieved major molecular response (MMR) after >= 12months of treatment with either imatinib or imatinib+Peg-IFN-alpha 2b. Molecular monitoring was carried out monthly for BCR-ABL1. In addition, analyses of lymphocyte immunophenotype, function, and plasma cytokines were performed. Results In the monotherapy group, 5/6 patients lost MMR within 4months. One patient remains to date in MR4.0 61months after discontinuation. In the combination therapy group, 2/6 patients relapsed within 4months while still receiving Peg-IFN-alpha 2b. Four of six patients were able to discontinue both treatments, but three of these patients relapsed after 3months. One patient is still in sustained MR4.0 at 58months off all treatment. All relapsed patients re-responded to imatinib. The two successfully discontinued patients had either an increased number of NK-cells or functionally active T-cells. Conclusions A higher frequency of relapsed patients in our study in comparison with other studies may be due to the shorter duration of imatinib treatment prior to discontinuation. However, in selected patients with an active immune system, even a short duration of TKI therapy (<2yr) may allow for therapy discontinuation but this needs to be confirmed in larger prospective studies.
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| 7. |
- Kreutzman, Anna, et al.
(författare)
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Killer-cell immunoglobulin-like receptor gene profile predicts good molecular response to dasatinib therapy in chronic myeloid leukemia
- 2012
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Ingår i: Experimental Hematology. - : Elsevier BV. - 1873-2399 .- 0301-472X. ; 40:11, s. 906-913
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Tidskriftsartikel (refereegranskat)abstract
- Tyrosine kinase inhibitors have greatly improved the prognosis of chronic myeloid leukemia (CML). In addition to direct kinase inhibition, their effects can also be mediated through immune modulation, such as expansion of cytotoxic T and natural-killer cells observed during dasatinib therapy. As natural-killer cell and partially CD8(+) T-cell function are regulated by killer immunoglobulin-like receptors (KIRs), we studied whether the KIR gene profile is associated with clinical therapy response in dasatinib-treated CML patients (n = 191). In first-line patients, the absence of the inhibitory KIR2DL5A (p = 0.0489), 2DL5B (p = 0.030), and 2DL5all (p = 0.0272) genes were associated with improved molecular response at the 12-month time point. In addition, the same trend was seen with two activating KIR genes, 2DS1 (p = 0.061) and 2DS2 (p = 0.071). Furthermore, when patients were clustered into two groups by their KIR gene profile, the BCR-ABL1 transcript levels differed significantly between the groups (p = 0.047), showing that patients who lacked several KIR genes had better response. The comparison of first-line and second-line patients did not show any significant differences in either KIR or human leukocyte antigen genotypes. Our results show that immunogenetic factors, such as the KIR gene profile, can play a role in tyrosine kinase inhibitor therapy response. Additional studies are warranted to elucidate the functional significance of KIR genes associated with treatment outcomes. (C) 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.
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- Kreutzman, Anna, et al.
(författare)
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Mono/oligoclonal T and NK cells are common in chronic myeloid leukemia patients at diagnosis and expand during dasatinib therapy
- 2010
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 116:5, s. 772-782
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Tidskriftsartikel (refereegranskat)abstract
- In a proportion of patients with chronic myeloid leukemia (CML) being treated with dasatinib, we recently observed large granular lymphocyte (LGL) expansions carrying clonal T-cell receptor (TCR) gamma/delta gene rearrangements. To assess the prevalence and role of clonal lymphocytes in CML, we collected samples from patients (n = 34) at the time of diagnosis and during imatinib and dasatinib therapies and analyzed lymphocyte clonality with a sensitive polymerase chain reaction-based method of TCR gamma and delta genes. Surprisingly, at CML diagnosis, 15 of 18 patients (83%) had a sizeable clonal, BCR-ABL1 negative lymphocyte population, which was uncommon in healthy persons (1 of 12; 8%). The same clone persisted at low levels in most imatinib-treated patients. In contrast, in a distinct population of dasatinib-treated patients, the diagnostic phase clone markedly expanded, resulting in absolute lymphocytosis in blood. Most patients with LGL expansions (90%) had TCR delta rearrangements, which were uncommon in patients without an LGL expansion (10%). The TCR delta clones were confined to gamma delta(+) T- or natural killer-cell compartments and the TCR gamma clones to CD4(+)/CD8(+) alpha beta(+) fractions. The functional importance of clonal lymphocytes as a part of leukemia immune surveillance and the putative anergy- reversing role of dasatinib require further evaluation. (Blood. 2010; 116(5): 772- 782)
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- Olsson-Strömberg, Ulla, et al.
(författare)
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Molecular monitoring and mutation analysis of patients with advanced phase CML and Ph plus ALL receiving dasatinib
- 2010
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 85:5, s. 399-404
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Tidskriftsartikel (refereegranskat)abstract
- As a result of the excellent responses achieved in chronic phase chronic myeloid leukemia since the introduction of imatinib, sensitive techniques such as reverse transcriptase real-time PCR are warranted to monitor patients receiving tyrosine kinase inhibitors (TKI). Our objective was to determine the value of molecular monitoring Ph-positive leukemias under dasatinib treatment. We used real-time PCR and ABL1 kinase domain sequencing on sequential samples from 11 patients with Philadelphia-positive leukemias who received dasatinib. We were able to detect pre-existing mutations in the kinase domain of BCR-ABL1 in four patients, particularly in patients with high BCR-ABL1 transcript levels. Most mutations disappeared with dasatinib, however, in five patients a clone with T315I appeared during dasatinib treatment. We conclude that sensitive molecular monitoring with real-time PCR for BCR-ABL1 transcripts and mutation screening of the ABL1 kinase domain of patients with Philadelphia-positive leukemias are valuable for patient management, however, mutation findings should be interpreted with caution, as mutant clones not always behave in vivo as predicted by in vitro assays.
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| 14. |
- Simonsson, Bengt, et al.
(författare)
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Combination of pegylated IFN-alpha 2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia
- 2011
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Ingår i: Blood. - Washington D.C. : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 118:12, s. 3228-3235
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Tidskriftsartikel (refereegranskat)abstract
- Biologic and clinical observations suggest that combining imatinib with IFN-alpha may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN-alpha 2b (Peg-IFN-alpha 2b) 50 mu g weekly and imatinib 400 mg daily (n = 56) or to receive imatinib 400 mg daily monotherapy (n = 56). The primary endpoint was the major molecular response (MMR) rate at 12 months after randomization. In both arms, 4 patients (7%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg-IFN-alpha 2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg-IFN-alpha 2b arm (82%) compared with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg-IFN-alpha 2b treatment (andlt; 12-week MMR rate 67%, andgt; 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg-IFN-alpha 2b to imatinib markedly increased the MMR rate at 12 months of therapy. Lower doses of Peg-IFN-alpha 2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent.
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| 15. |
- Simonsson, Bengt, et al.
(författare)
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Interferon alpha for Treatment of Chronic Myeloid Leukemia
- 2011
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Ingår i: Current Drug Targets. - 1389-4501 .- 1873-5592. ; 12:3, s. 420-428
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Forskningsöversikt (refereegranskat)abstract
- Treatment of chronic myeloid leukemia (CML) with interferon-alpha (IFN-alpha) was introduced in the early 1980s. Several clinical trials showed a survival advantage for patients treated with IFN-alpha compared to conventional chemotherapy. Some patients achieved longstanding complete cytogenetic remissions (i.e. > 2 log tumor mass reduction). IFN-alpha was then recommended as first line medical treatment until 2001. The mechanism of this anti-leukemic effect is not clear, although IFN-alpha has many effects of potential relevance on stem cells and immunology. There is no evidence of benefit for high dose (in practice a maximally tolerated dose) compared with lower dose IFN-alpha. When IFN-alpha is combined with other drugs, we advice lower dose IFN to minimize toxicity and increase treatment adherence and duration. IFN-alpha combined with Ara-C moderately improves treatment outcome. Imatinib, a tyrosine kinase inhibitor, is now first line treatment for CML, but two large randomized studies show improved outcome when pegylated IFN-alpha is added to the treatment with imatinib. One explanation for this might be that IFN-alpha, contrary to imatinib, stimulates the quiescent stem cells to proliferate and thereby potentially increases sensitivity to imatinib. Although imatinib and other tyrosine kinase inhibitors are very efficient, they are rarely curative. IFN-alpha could be included in curatively aimed combination treatment protocols and thus still be an important element in CML treatment.
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