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In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1399-1399

Abstract: Abstract 1399 Introduction: Massively parallel pyrosequencing in picoliter-sized wells is an innovative technique and allows highly-sensitive deep-sequencing to detect molecular aberrations. As an international consortium we had investigated previously the robustness, precision, and reproducibility of 454 amplicon next-generation sequencing (NGS) across 10 laboratories from 8 countries (Kohlmann et al., Leukemia, 2011;25:1840–8). Aims: In Phase II of the study we now established distinct working groups for various hematological malignancies, i.e. acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphatic leukemia (CLL), chronic myelogenous leukemia (CML), myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPN). 26 laboratories from 13 countries are currently part of the research consortium. Each working group selected gene targets and developed amplicons of interest to be studied in various hematological malignancies by deep-sequencing (454 Life Sciences, Branford, CT). Results: In total, 74 genes were identified by the study centers to be of interest for mutational screenings in the respective scientific working groups. Overall, 1146 primer sequences resulting in 573 amplicons were designed and tested. Where appropriate, individual genes were combined into panels and validated designs were set up as standardized preconfigured oligonucleotide primer plates. So far, in AML 679 cases had been screened for CEBPA mutations. RUNX1 mutations were analyzed in 864 cases applying the deep-sequencing read counts to study the stability of such mutations at relapse and the utility of this marker to detect minimal residual disease. Analyses on DNMT3A (n=126) and BCOR (n=83) were focused to perform landscape analyses and to investigate the prognostic utility of these markers. Additionally, this working group is focusing on TET2, ASXL1, and TP53 (n=195) analyses. A novel prognostic model is being developed allowing to stratify AML into prognostic subgroups based on molecular markers only. In ALL, 236 pediatric and adult cases have been screened for TP53 mutations both at diagnosis and relapse of ALL. Pediatric and adult leukemia expert labs developed content to study the mutation incidence of other B and T lineage markers such as IKZF1, JAK2, IL7R, PAX5, LEF1, CRLF2, PHF6, WT1, JAK1, PTEN, AKT1, IL7R; NOTCH1, or FBXW7. Interestingly, the molecular landscape of CLL is changing rapidly. As such, a separate working group focused on analyses including NOTCH1, SF3B3, MYD88, XPO1, FBXW7 and BIRC3. 541 cases were screened already to investigate the range of mutational burden of NOTCH1 mutations for their prognostic relevance in a large unselected cohort of adult CLL. In MDS, RUNX1 mutation analyses were performed in 898 cases. Further, the prognostic relevance of TP53 mutations in MDS with isolated deletions of chromosome 5q was studied in a cohort including 105 MDS 5q- cases. Additional content was developed targeting genes of the cellular splicing component, e.g. SF3B1, SRSF2, SF1, U2AF1, ZRSR2. In BCR-ABL-negative MPN, 10 genes of interest (JAK2, MPL, EZH2, IDH1, IDH2, TET2, CBL, IKZF1, SH2B3, ASXL1) have been analyzed in a cohort of 170 cases searching for novel somatic mutations addressing their relevance for disease progression and leukemia transformation. Moreover, an assay was developed and applied to 10 CMML cases allowing the simultaneous analysis of 25 leukemia-associated target genes in a single sequencing using just 20 ng of starting DNA. A group of laboratories focused on ultra-deep sequencing analyses of the BCR-ABL tyrosine kinase domain. Analyses were performed so far on 106 cases to study the dynamics of expansion of mutated clones under various tyrosine kinase inhibitors. Conclusion: A comprehensive molecular characterization of hematological malignancies today requires high diagnostic sensitivity and specificity. As part of the IRON-II study, a network of laboratories studied a variety of hematological diseases applying standardized amplicon-based deep-sequencing assays. Distinct working groups have been forged to address scientific questions and in total 4013 cases had been analyzed thus far. Disclosures: Kohlmann: Roche Diagnostics: Honoraria; MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership; Roche Diagnostics: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.1399.1399

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 3281-3281

Abstract: Chronic myeloproliferative disorders (CMPD) associated with rearrangements of the ‘platelet-derived growth factor receptor A’ (PDGFRA) at chromosome 4q12 are excellent candidates for targeted therapy with imatinib. To date, two fusion genes involving PDGFRA have been described: FIP1L1-PDGFRA and BCR-PDGFRA. Here we report a female patient who presented in advanced phase of an atypical myeloproliferative disease. Routine cytogenetic analysis revealed an ins(9;4)(q34;q21q31). Although no break was visible at 4q12, FISH analysis with flanking BAC probes indicated that PDGFRA was disrupted. To identify the partner gene we employed 5′-RACE PCR, exploiting the fact that all known PDGFRA fusions involve exon 12 of this gene. The resulting PCR-products consisted of 5′-sequences derived from CDK5RAP2 (CDK5 regulatory subunit associated protein 2) located on 9q33 and 3′-sequences derived from PDGFRA. CDK5RAP2 encodes a protein that is believed to be involved in centrosomal regulation. FISH analysis confirmed the co-localization of 5′ CDK5RAP2 and 3′ PDGFRA sequences. RT-PCR confirmed the in-frame mRNA fusion between exon 13 of CDK5RAP2, a 40-bp insert which was partially derived from PDGFRA intron 11 and a truncated PDGFRA exon 12. No reciprocal fusion transcript could be amplified by RT-PCR. The predicted CDK5RAP2-PDGFRA protein consists of 1003 amino acids and retains both tyrosine kinase domains of PDGFRA and several potential dimerisation domains of CDK5RAP2 suggesting a mechanism of tyrosine kinase activation similar to BCR-ABL. Treatment with 400 mg imatinib was initiated and the patient achieved a complete cytogenetic and molecular remission. However, hematological response was only partial with residual blasts repeatedly detectable in the blood and marrow. The patient rapidly developed acute leukemia while still remaining in complete cytogenetic and molecular remission suggesting the outgrowth of a second imatinib-resistant leukemic clone. These findings and the fact that the ins(9;4) was only seen in 24% of metaphases at diagnosis suggests that CDK5RAP2-PDGFRA may have been a secondary abnormality. In summary, we have identified a third fusion gene involving PDGFRA, underlining the fundamental role of activated tyrosine kinases in CMPD’s and their possible response to targeted therapy with imatinib.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V106.11.3281.3281

Language: English

Publisher: American Society of Hematology

Publication Date: 2005

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 611-611

Abstract: In chronic myeloid leukemia (CML), clonal chromosome aberrations in metaphases not carrying a t(9;22)(q34;q11) have been described during treatment with tyrosine kinase inhibitors (TKIs), so-called Philadelphia-negative (Ph-) clones. The most frequent abnormalities in these Ph- clones reported are -7, +8 and -Y. This pattern of cytogenetic aberrations is comparable to alterations found in MDS. In the majority of patients no clear evidence of a secondary hematologic malignancy is observed. However, few cases especially with -7 were reported to evolve to MDS or even AML. Aim 1) Analyze whether TKI-treated CML patients who developed Ph- clones also harbour molecular mutations. 2) Evaluate whether these mutations were already present at diagnosis of CML. Patients and Methods We selected 42 patients (pts) treated with TKIs (Imatinib: n=27, Nilotinib: n=2, and 13 pts who were treated with 2 or 3 different TKIs) who developed Ph- clones. Median time from start of therapy to analysis was 3.2 years (range 8.9 months-13.5 years). 23 cases were male and 19 female; median age was 63.3 years (range: 34.1-83.9 years). Cytogenetics in pts with Ph- clones were as follows: +8 sole (n=18), -Y (n=7), -7 sole (n=2), +9 (n=2), an 10 cases with various abnormalities. Additional three cases had two different clones: 1) -7 and +8; 2) +8 and +Y, 3) -Y and +Y. Median clone size was 37.5% (range 10-100%) of all metaphases. BCR-ABL1 levels at the time point of analysis were between 0 and 4.5 (median: 0.019) according to international scale. All cases were analyzed with a pan-myeloid gene panel of 29 genes: ASXL1, BCOR, BRAF, CBL, DNMT3A, ETV6, EZH2, FLT3 (TKD), IDH1, IDH2, JAK2, KIT, KRAS, MLL-PTD, NOTCH1, NPM1, NRAS, PRPF40B, PTPN11, RUNX1, SF1, SF3A1, SF3B1, SRSF2, TET2, TP53, U2AF1, U2AF2 and ZRSR2. Either complete coding genes or hotspots were first amplified by a microdroplet-based assay (RainDance, Lexington, MA) and subsequently sequenced with a MiSeq instrument (Illumina, San Diego, CA). RUNX1 was sequenced on the 454 Life Sciences NGS platform and the MLL-PTD was analyzed by quantitative real time PCR. Median coverage per amplicon was 2215 reads (range 100-24,716). The lower limit of detection was set at a cut-off of 1.5%. Results In total, in 13/42 pts (31.0%) one (n=9) or two (n=4) of the analyzed genes were mutated. Median mutation load was 15% (range: 3-50%). In detail, mutations in the following genes were detected: ASXL1 (n=5), DNMT3A (n=4), NRAS (n=2) and each one in BCOR, CBL, MLL-PTD, RUNX1, TET2 and ZRSR2. 4 pts had combinations of: 2 ASXL1mut, 2 NRASmut, BCORmut and RUNX1mut, or ASXL1mut with MLL-PTD, respectively. Subsequently, the mutations were tracked as far as serially collected samples were available (12 pts with a total of 125 samples, range: 3-20 samples/pt) from earlier or later time points. In 6 cases it clearly could be shown that the mutations were not present at diagnosis and arose 5 months, 7 months, 14 months, 15 months, 5 years, and 7 years after start of TKI therapy, respectively. In all these cases the mutation loads increased in parallel to decreasing BCR-ABL1 levels. In one of these cases one mutation was found 3 years and a second 11 years after start of therapy. Importantly, in three of these cases the molecular mutations were detectable before the cytogenetic aberration in the Ph- clone. In six further cases mutations were present with similar levels in several samples but due to lack of samples from initial diagnosis no estimation of the time to their occurrence was possible. In one of these cases the BCR-ABL1 load increased again during therapy and the DNMT3A mutation decreased showing that the BCR-ABL+ clone and the DNMT3Amut clone were competitive clones. Conclusions 1) For the first time we show that more than 30% of CML patients treated with TKI who develop Ph- clones as defined by cytogenetic abnormalities, also harbour molecular mutations. 2) For most of the cases it was shown that these mutations arose during treatment. 3) In some cases the molecular mutations were detectable before the cytogenetic aberrations. This may be regarded as further proof of the malignant character of these Ph- clones. However, none of the analyzed cases, so far, developed a secondary disease, i.e. MDS or AML, thus the relevance of these findings is still unclear and needs further attention. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kuznia:MLL Munich Leukemia Laboratory: Employment. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Nadarajah:MLL Munich Leukemia Laboratory: Employment. Jeromin:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Roller:MLL Munich Leukemia Laboratory: Employment. Albuquerque:MLL Munich Leukemia Laboratory: Employment. Weissmann:MLL Munich Leukemia Laboratory: Employment. Eder:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership; Novartis: Research Funding. Hochhaus:Novartis: Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.611.611

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: British Journal of Haematology, Wiley, Vol. 152, No. 6 ( 2011-03), p. 713-720

Type of Medium: Online Resource

ISSN: 0007-1048

URL: Issue

URL: Article

DOI: 10.1111/bjh.2011.152.issue-6

DOI: 10.1111/j.1365-2141.2010.08472.x

Language: English

Publisher: Wiley

Publication Date: 2011

detail.hit.zdb_id: 1475751-5

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4983-4983

Abstract: Abstract 4983 Chromosomal or molecular aberrations in eosinophilia-associated myeloproliferative neoplasms (Eos-MPN) often involve receptor (e.g. PDGFRA at 4q12, PDGFRB at 5q31, FGFR1 at 8p11) or intracellular (e.g. ABL1 at 9q34, JAK2 at 9p24) tyrosine kinases (TK). Fusion genes with rearrangement of PDGFRA or PDGFRB are known to be associated with rapid and durable complete hematological and clinical remission on treatment with imatinib; many of these cases also achieve complete molecular remission (undetectable fusion gene transcripts by nested reverse transcriptase polymerase chain reaction, RT-PCR). The most common fusion genes in Eos-MPN are FIP1L1-PDGFRA caused by a cytogenetically invisible interstitial deletion on 4q12, and ETV6-PDGFRB as consequence of a reciprocal translocation t(5;12)(q31-33;p13). Due to restricted availability of molecular diagnostic tools, a substantial proportion of Eos-MPN patients with t(5;12) are treated with imatinib based on karyotype but without confirmation of the underlying fusion gene by fluorescence-in-situ-hybridization (FISH) or RT-PCR. We report here on three patients (male, n=2; female, n=1) (median age 58 years, range 38-71) with Eos-MPN (median absolute eosinophil numbers in peripheral blood 8,100/μL, range 2,300-62,000) in chronic (n=2) or secondary acute myeloid leukemia (AML)/blast phase (n=1). Cytogenetic analysis revealed a t(5;12) (n=2) or a complex karyotype with involvement of chromosome arms 5q and 12p (n=1). Despite the fact that the clinical and hematological phenotype was resembling ETV6-PDGFRB positive disease (e.g. leukocytosis, eosinophilia, hypercellular marrow, splenomegaly), all three cases tested negative for ETV6-PDGFRB. A fourth patient with t(5;12)(q31;p13) but negative for ETV6-PDGFRB had identical clinical characteristics except basophilia of 7% without eosinophilia. Further molecular analyses revealed an ETV6-ACSL6 fusion gene in all four patients. Two patients received imatinib (400 mg/d) without knowledge of the molecular status and two patients were treated with sorafenib (400-800 mg/d) due to its multitargeted activity towards signal transduction molecules. No responses were observed to imatinib or sorafenib. Two male patients received an allogeneic stem cell transplantation (SCT) from a related or a matched unrelated donor, respectively. The first patient died on day +67 due to relapse of secondary AML/blast phase while the second patient died on day +64 due to transplant related complications. After failure to imatinib, the female patient with secondary AML/blast crisis only received supportive care because of comorbidity and died 7 months after diagnosis due to cytopenia-related complications. The remaining chronic phase male patient is alive 5 months after diagnosis. In addition to patients known from the literature (n=6), primary AML or rapid progression to secondary AML/blast phase has been observed in 7 of overall 10 patients with t(5;12) and an ETV6-ACSL6 fusion gene indicating a potentially aggressive clinical course. Consistent with the lack of involvement of a TK, the disease is primarily resistant to currently available TK-inhibitors and allogeneic SCT should be considered in eligible patients. In conclusion, treatment with TK-inhibitors in patients with myeloproliferative neoplasms and a t(5;12) should only be initiated if involvement of PDGFRB is confirmed by FISH or PCR analysis. Disclosures Haferlach: MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.4983.4983

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 743-743

Abstract: Amplicon deep-sequencing using second-generation sequencing technology is an innovative molecular diagnostic technique and enables a highly-sensitive detection of mutations. As an international consortium we had investigated previously the robustness, precision, and reproducibility of 454 amplicon next-generation sequencing (NGS) across 10 laboratories from 8 countries (Leukemia, 2011;25:1840-8). Aims In Phase II of the study, we established distinct working groups for various hematological malignancies, i.e. acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and multiple myeloma. Currently, 27 laboratories from 13 countries are part of this research consortium. In total, 74 gene targets were selected by the working groups and amplicons were developed for a NGS deep-sequencing assay (454 Life Sciences, Branford, CT). A data analysis pipeline was developed to standardize mutation interpretation both for accessing raw data (Roche Amplicon Variant Analyzer, 454 Life Sciences) and variant interpretation (Sequence Pilot, JSI Medical Systems, Kippenheim, Germany). Results We will report on the design, standardization, quality control aspects, landscape of mutations, as well as the prognostic and predictive utility of this assay in a cohort of 8,867 cases. Overall, 1,146 primer sequences were designed and tested. In detail, for example in AML, 924 cases had been screened for CEBPA mutations. RUNX1 mutations were analyzed in 1,888 cases applying the deep-sequencing read counts to study the stability of such mutations at relapse and their utility as a biomarker to detect residual disease. Analyses of DNMT3A (n=1,041) were focused to perform landscape investigations and to address the prognostic relevance. Additionally, this working group is focusing on TET2, ASXL1, and TP53 analyses. A novel prognostic model is being developed allowing stratification of AML into prognostic subgroups based on molecular markers only. In ALL, 1,124 pediatric and adult cases have been screened, including 763 assays for TP53 mutations both at diagnosis and relapse of ALL. Pediatric and adult leukemia expert labs developed additional content to study the mutation incidence of other B and T lineage markers such as IKZF1, JAK2, IL7R, PAX5, EP300, LEF1, CRLF2, PHF6, WT1, JAK1, PTEN, AKT1, IL7R, NOTCH1, CREBBP, or FBXW7. Further, the molecular landscape of CLL is changing rapidly. As such, a separate working group focused on analyses including NOTCH1, SF3B1, MYD88, XPO1, FBXW7 and BIRC3. Currently, 922 cases were screened to investigate the range of mutational burden of NOTCH1 mutations for their prognostic relevance. In MDS, RUNX1 mutation analyses were performed in 977 cases. The prognostic relevance of TP53 mutations in MDS was assessed in additional 327 cases, including isolated deletions of chromosome 5q. Next, content was developed targeting genes of the cellular splicing component, e.g. SF3B1, SRSF2, U2AF1, and ZRSR2. In BCR-ABL1-negative MPN, nine genes of interest (JAK2, MPL, TET2, CBL, KRAS, EZH2, IDH1, IDH2, ASXL1) have been analyzed in a cohort of 155 primary myelofibrosis cases searching for novel somatic mutations and addressing their relevance for disease progression and leukemia transformation. Moreover, an assay was developed and applied to CMML cases allowing the simultaneous analysis of 25 leukemia-associated target genes in a single sequencing run using just 20 ng of starting DNA. Finally, nine laboratories are studying CML, applying ultra-deep sequencing of the BCR-ABL1 tyrosine kinase domain. Analyses were performed on 615 cases investigating the dynamics of expansion of mutated clones under various tyrosine kinase inhibitor therapies. Conclusion Molecular characterization of hematological malignancies today requires high diagnostic sensitivity and specificity. As part of the IRON-II study, a network of laboratories analyzed a variety of disease entities applying amplicon-based NGS assays. Importantly, the consortium not only standardized assay design for disease-specific panels, but also achieved consensus on a common data analysis pipeline for mutation interpretation. Distinct working groups have been forged to address scientific tasks and in total 8,867 cases had been analyzed thus far. Disclosures: Kohlmann: Roche Diagnostics: Honoraria; MLL Munich Leukemia Laboratory: Employment. Martinelli:Roche Diagnostics: Research Support Other. Alikian:Roche Diagnostics: Research Support Other. Auber:Roche Diagnostics: Research Support Other. Belickova:Roche Diagnostics: Research Support Other. Bronzini:Roche Diagnostics: Research Support Other. Cazzaniga:Roche Diagnostics: Research Support Other. Chiaretti:Roche Diagnostics: Research Support Other. Ernst:Roche Diagnostics: Research Support Other. Fuellgrabe:Roche Diagnostics: Research Support Other. Gabriel:Roche Diagnostics: Research Support Other. Hernandez:Roche Diagnostics: Research Support Other. Jansen:Roche Diagnostics: Research Support Other. Iacobucci:Roche Diagnostics: Research Support Other. Lion:Roche Diagnostics: Research Support Other. Lode:Roche Diagnostics: Research Support Other. Martinez-Lopez:Roche Diagnostics: Research Support Other. Mills:Roche Diagnostics: Research Support Other. Mossner:Roche Diagnostics: Research Support Other. Machova Polakova:Roche Diagnostics: Research Support Other. Porret:Roche Diagnostics: Research Support Other. Pospisilova:Roche Diagnostics: Research Support Other. Preudhomme:Roche Diagnostics: Research Support Other. Sayitoglu:Roche Diagnostics: Research Support Other. Soverini:Roche Diagnostics: Research Support Other. Spinelli:Roche Diagnostics: Research Support Other. Thiede:Roche Diagnostics: Research Support Other. Vandenberghe:Roche Diagnostics: Research Support Other. Yeoh:Roche Diagnostics: Research Support Other. Hochhaus:Roche Diagnostics: Research Support Other. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership; Roche Diagnostics: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.743.743

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Laboratoriumsmedizin, Walter de Gruyter GmbH, Vol. 36, No. 6 ( 2012-01-01)

Abstract: Die chronische myeloische Leukämie ist eine neoplastische Erkrankung der Hämatopoese, charakterisiert durch die BCR-ABL1-Fusion. Zur Behandlung neu diagnostizierter Patienten sind drei selektive Tyrosinkinase-Inhibitoren zugelassen. Zur Beurteilung der Residualerkrankung ist eine frühe und engmaschige molekulargenetische Verlaufskontrolle unumgänglich. Sie ermöglicht eine frühe Prognoseeinschätzung sowie ein frühes Erkennen eines Rezidives bzw. einer Therapieresistenz. Eine Harmonisierung der Nachweismethode und des Laborberichts ist wichtig für die Beurteilung des Therapieverlaufs. Eine rasche Befundübermittlung motiviert den Patienten zur Therapietreue. In dieser Stellungnahme diskutiert eine deutsche Expertengruppe Harmonisierungsempfehlungen zur Nachweismethode und zum Laborbericht.

Type of Medium: Online Resource

ISSN: 1439-0477 , 0342-3026

URL: Article

DOI: 10.1515/labmed-2012-0022

Language: Unknown

Publisher: Walter de Gruyter GmbH

Publication Date: 2012

detail.hit.zdb_id: 2081704-6

detail.hit.zdb_id: 2909042-8

SSG: 15,3

In: Leukemia, Springer Science and Business Media LLC

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-024-02327-2

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2024

detail.hit.zdb_id: 2008023-2

In: American Journal of Hematology, Wiley, Vol. 95, No. 7 ( 2020-07), p. 824-833

Abstract: We report on 18 patients with myeloid neoplasms and associated tyrosine kinase (TK) fusion genes on treatment with the TK inhibitors (TKI) ruxolitinib ( PCM1‐JAK2 , n = 8; BCR‐JAK2 , n = 1) and imatinib, nilotinib or dasatinib ( ETV6‐ABL1 , n = 9). On ruxolitinib (median 24 months, range 2‐36 months), a complete hematologic response (CHR) and complete cytogenetic response (CCR) was achieved by five of nine and two of nine patients, respectively. However, ruxolitinib was stopped in eight of nine patients because of primary resistance (n = 3), progression (n = 3) or planned allogeneic stem cell transplantation (allo SCT, n = 2). At a median of 36 months (range 4‐78 months) from diagnosis, five of nine patients are alive: four of six patients after allo SCT and one patient who remains on ruxolitinib. In ETV6‐ABL1 positive patients, a durable CHR was achieved by four of nine patients (imatinib with one of five, nilotinib with two of three, dasatinib with one of one). Because of inadequate efficacy (lack of hematological and/or cytogenetic/molecular response), six of nine patients (imatinib, n = 5; nilotinib, n = 1) were switched to nilotinib or dasatinib. At a median of 23 months (range 3‐60 months) from diagnosis, five of nine patients are in CCR or complete molecular response (nilotinib, n = 2; dasatinib, n = 2; allo SCT, n = 1) while two of nine patients have died. We conclude that (a) responses on ruxolitinib may only be transient in the majority of JAK2 fusion gene positive patients with allo SCT being an important early treatment option, and (b) nilotinib or dasatinib may be more effective than imatinib to induce durable complete remissions in ETV6‐ABL1 positive patients.

Type of Medium: Online Resource

ISSN: 0361-8609 , 1096-8652

URL: Issue

URL: Article

DOI: 10.1002/ajh.v95.7

DOI: 10.1002/ajh.25825

Language: English

Publisher: Wiley

Publication Date: 2020

detail.hit.zdb_id: 1492749-4

In: Blood Advances, American Society of Hematology, Vol. 4, No. 3 ( 2020-02-11), p. 440-443

Abstract: FIP1L1-PDGFRA–positive myeloid/lymphoid neoplasms with eosinophilia (MLN-eo) are exquisitely sensitive to imatinib. Almost all patients achieve a complete molecular remission (CMR) by nested reverse transcription polymerase chain reaction, which can be maintained with low-dose imatinib (eg, 3 × 100 mg/wk). Because imatinib can be safely stopped in a substantial proportion of patients with BCR-ABL1–positive CML, we sought to analyze the clinical and molecular follow-up of 12 FIP1L1-PDGFRA–positive patients with MLN-eo in chronic phase who discontinued imatinib after achievement of a CMR. Median time of treatment and median time of CMR before imatinib discontinuation (last dose at 3 × 100 mg/wk, n = 8; or 100 mg/d, n = 4) were 80 (range, 43-175) and 66 (range, 37-174) months, respectively. A molecular relapse was observed in 4 patients after 10, 22 (n = 2), and 24 months. A second CMR was achieved in 3 patients after 3, 4, and 21 months. Eight patients (62%) are in ongoing CMR (median, 17 months; range, 3-71 months). Molecular relapse-free survival was 91% at 12 months and 65% at 24 months. No significant differences (eg, dose and duration of imatinib treatment or duration of CMR before imatinib discontinuation) were identified between patients with and without molecular relapse. Our data demonstrate that imatinib can be safely stopped in FIP1L1-PDGFRA–positive MLN-eo because of a high treatment-free remission at 12 and 24 months and because most patients achieve a rapid second CMR after restart of imatinib.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2019001111

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 2876449-3