Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 5423-5423

Abstract: Introduction. Myelodysplastic Syndrome (MDS) is a disease of the elderly. Apart from IPSS, IPSS-R and WPSS, several indexes incorporating patient comorbidities (such as the MDS CI index- Della Porta et al Haematologica 2011, the HCT-CI index - Sorror et al Blood 2005) and performance status (the GFM index- Itzykson et al Blood 2011) have been used to predict outcome in MDS patients treated with azacytidine (AZA). We sought to investigate the effect of comorbidities on the outcome after AZA in a large group of patients from the MDS registry of the Hellenic MDS Study Group. Methods. The present study has been conducted as a retrospective observational cohort one. It included high-risk MDS and low blast count AML patients treated with AZA from 26 centers in Greece from 2007 to 2018. T-test and ANOVA were used to compare scale variables between two or more groups respectively. Univariate analysis of nominal and scale survival data was performed using Kaplan-Meier survival curves and Cox regression respectively. All variables achieving p 〈 0.05 at univariate analysis were considered eligible for multivariate analysis; the latter was based on Cox regression method. Results. We analyzed 536 consecutive patients. Patient characteristics are depicted in Table 1. The median follow-up period was 27.5±4.8 months. 371 patients received at least four cycles of AZA and 165 patients received less than 4 cycles of AZA. Patients who received ≥4 cycles of AZA did not differ from those who received 〈 4 cycles regarding gender, age, estimated Glomerular Filtration Rate (eGFR), cardiovascular, renal, and tumor comorbidities. Significantly higher IPSS-R and GFM scores at baseline were found in the group of patients receiving 〈 4 cycles of AZA compared to patients who received ≥ 4 cycles of AZA (p=0.042 and 0.05 respectively), while transfusion dependence at baseline occurred more often in patients who received ≥ 4 cycles of AZA (p=0.039). To assess the prognostic significance of risk factors on leukemia free survival (LFS) and overall survival (OS), univariate and multivariate analysis for the whole population was performed, as well as a landmark analysis for patients who were treated with at least 4 cycles of AZA. ECOG performance status and the presence of peripheral blasts were independent prognostic factors for LFS and OS for the whole cohort analysis while response to AZA and the presence of peripheral blasts were independent prognosticators for LFS and OS in the landmark analysis. In addition, prior low dose cytarabine was an independent adverse prognostic factor for LFS in the landmark analysis. As regards comorbidities, neither of MDS-CI, HCT-CI and GFM systems independently predicted LFS or OS in either analysis, but eGFR with a cut-off of 45 ml/min was a strong and independent prognosticator for LFS and OS in both the standard and the landmark analysis. Kaplan-Meier survival curves regarding LFS and OS at AZA initiation and landmark analysis after 4th cycle of AZA in relation with eGFR are shown in Figure 1. Conclusion. This is the first study to demonstrate the importance of eGFR at baseline as a prognostic marker for LFS and OS in high-risk MDS and low-blast AML patients treated with AZA. The role of comorbidities and PS needs to be further evaluated in this patient group. Disclosures Symeonidis: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vassilakopoulos:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; WinMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Panayiotidis:Bayer: Other: Support of clinical trial. Pappa:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Gilead: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kotsianidis:Celgene: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-125806

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

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detail.hit.zdb_id: 80069-7

In: Therapeutic Advances in Hematology, SAGE Publications, Vol. 11 ( 2020-01), p. 204062072096612-

Abstract: 5-azacytidine (5-AZA) improves survival of patients with higher-risk myelodysplastic syndromes (MDSs) and oligoblastic acute myeloid leukemia (AML); however, predictive factors for response and outcome have not been consistently studied. Methods: This study of the Hellenic MDS Study Group included 687 consecutive patients with higher-risk MDS and oligoblastic AML treated with 5-AZA. Results: The International Prognostic Scoring System (IPSS) revised version (IPSS-R), Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 or 1 versus ⩾2) and baseline serum ferritin (SF) levels  〉  520 ng/ml were shown to independently predict response to 5-AZA. In the survival analysis, the IPSS and IPSS-R risk classification systems along with the ECOG PS and SF levels  〉  520 ng/ml proved to be independent prognosticators for overall survival (OS), as well as for leukemia-free survival (LFS). Next, we built new multivariate models for OS and LFS, incorporating only ECOG PS and SF levels besides IPSS or IPSS-R risk classification systems. Thereby, the new modified IPSS and IPSS-R risk classification systems (H-PSS, H-PSS-R) could each discriminate a low, an intermediate and a high-risk patient group regarding OS and LFS. The H-PSS and H-PSS-R proved to be better predictors of OS than their previous counterparts as well as the French prognostic score, while the most powerful OS predictor was the new, H-PSS-R system. Conclusions: ECOG PS and SF levels  〉  520 ng/ml independently predict response to 5-AZA, OS and LFS. Their incorporation in the IPSS and IPSS-R scores enhances these scores’ predictive power in 5-AZA-treated higher-risk MDS and oligoblastic AML patients.

Type of Medium: Online Resource

ISSN: 2040-6207 , 2040-6215

URL: Article

DOI: 10.1177/2040620720966121

Language: English

Publisher: SAGE Publications

Publication Date: 2020

detail.hit.zdb_id: 2585183-4

In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 4776-4776

Abstract: Imatinib has become the treatment of choice for CML. The standard dose (SD) for CP CML is 400 mg daily: results are less favourable in pts at high or intermediate Sokal risk vs low Sokal risk ones. In intermediate Sokal risk, the IRIS trial (Hughes et al NEJM 349:15, 2003 ) reported at 12 mos a complete cytogenetic response (CCgR- 0% Ph-pos) rate of 67% and a major molecular response (MMolR) rate of 45%. Pre-clinical and clinical data suggest that high doses (HD - 800 mg daily) of ima may be more effective. The GIMEMA CML Working party is conducting a phase II, multi-istitutional prospective study (serial n. CML/021) to investigate the effects of imatinib HD in intermediate Sokal risk. Between Jan, 2004 and May, 2005, 25 centers enrolled 82 pts (80 eval); median age 56 yrs (26–79). Pts evaluable at 3,6 and 12 mos are 80, 77 and 65, respectively. The median observation time is 12 mos. At 3 and 6 mos, 83% and 97% of the pts reached a stable CHR. At 6 mos, 86% obtained a CCgR and 53% of CCgR pts a MMolR (Bcr-Abl/Abl × 100 ratio & lt; 0.1%). At 12 mos, the CCgR rate was 90% and the MMolR rate was 57%. One patient progressed to accelerated/blastic phase. The compliance to HD treatment was good: at 3, 6 and 12 mos 55%, 52% and 52% of the pts received a median daily dose of imatinib & gt; 600 mg. Non hematopoietic AEs accounted for the great majority of dose reductions. The results of this trial further indicate that imatinib HD induces higher and more rapid responses in intermediate Sokal risk CML pts in early chronic phase, being superior to the results obtained with SD (IRIS) and in the range of the MD Anderson results (Kantarjian et al Blood 2004 103:2873). A second project is reserved to high Sokal risk CML pts in early CP: a multinational group, within EuropeanLeukemianet CML WP, is conducting a phase III trial (1:1) of imatinib 400 mg vs 800 mg. By July 31, 2005, 141 patients have been enrolled: GIMEMA (88 pts), Nordic CML Study Group (Sweden, Denmark, Norway and Finland) (25 pts), Turkey (25 pts) and Israel (3 pt).

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V108.11.4776.4776

Language: English

Publisher: American Society of Hematology

Publication Date: 2006

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4277-4277

Abstract: Abstract 4277 Background MK-0457 is a pan-aurora kinase inhibitor with demonstrated activity against wild-type and mutated BCR-ABL, including the T315I form, as well as FLT3 and JAK-2. It is a promising molecule for the management of Ph+ leukemias, in which the emergence of mutations in the ABL kinase domain still represents the main mechanism of resistance to TK inhibitors. In CML and ALL patients treated with a 5-day continuous infusion of MK-0457 at doses of 24-40 mg/m2/hr every 14 days, an increased incidence of related adverse events was shown. Aim In our Institution, an innovative Phase I clinical study of sequential and concomitant treatment with Dasatinib, previously administered for three months, and MK-0457 has been conducted. This combined activity suggests that MK-0457, in association with Dasatinib, would suppress the emergence of T315I and other resistant clone, improving upon the response rate for Dasatinib and the durability of response. The trial investigated two schedules of therapy: patients who achieved and maintained a major hematologic response after three months of therapy with Dasatinib (70 mg twice daily) received a 6-hour biweekly infusion of MK-0457 at 64 mg/m2/hr, whereas patients who failed to achieve a major hematologic response received a 5-days continuous infusion of MK-0457 at 10 mg/m2/hr, every 4 weeks. Biologically, the first schedule was demonstrated to suppress the emergence of Dasatinib-resistant clones, through a stronger inhibition of BCR-ABL, whereas the second one was showed to inhibit more potently Aurora Kinase activity. Results Two patients with Ph+ ALL and one patient with CML in myeloid blast crisis, previously unsuccessfully treated with imatinib, were enrolled in the protocol. The first two patients, both in hematologic response after three months of treatment with Dasatinib, subsequently received the 6-hour biweekly schedule, maintaining the haematological response. No haematological toxicity was described. The third patient, enrolled in progression disease, received the 5 days MK-0457 schedule of treatment. His peripheral blood count was consistent with a severe pancytopenia, which required frequent platelets and red blood cells transfusions. His bad clinical performance status was compromised by a severe hemorrhagic pleural effusion, responsible for moderate dyspnoea and severe asthenia. After one cycle of MK-0457, a complete recovery of the pulmonary disease and a complete hematologic response were obtained. Conclusions The sequential and concomitant innovative administration of Dasatinib and MK-0457 represents a promising therapeutic strategy for refractory Ph+ CML and ALL, showing a relevant haematological activity in a limited number of patients. Assessment of the benefit risk profile for this combination remains to be determined. Acknowledgments Supported by: European LeukemiaNet, AIL, AIRC, FIRB 2006, Fondazione del Monte di Bologna e Ravenna, Merck Sharp & Dohme. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.4277.4277

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

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In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-01), p. 2335-2335

Abstract: Resistance to the BCR-ABL inhibitor imatinib mesylate (IM) is often caused by the selection of leukemic clones harboring mutations that destabilize the inactive conformation of BCR-ABL, to which IM preferentially binds, shifting the equilibrium toward the active kinase conformation. Hence the need for second -generation kinase inhibitors with a greater flexibility in binding to different BCR-ABL conformations. The 4-anilino-3 quinolinecarbonitrile SKI-606 is a novel Src and ABL kinase inhibitor. We report here that SKI-606 is a potent and antiproliferative agent when tested in K562 cell line and CD34+ cells from patients with chronic myeloid leukemia (CML) blast crisis. In K562 cells, SKI-606 treatment caused a dose-dependent decrease in cell viability accompanied by accumulation in subG1 phase, an effect not observed in BCR-ABL-negative HL-60 cells. Treatment of K562 with 100 nM SKI-606 for 24 hours caused a complete dephosphorylation of Lyn, Stat5 and Bcl-xl, while AKT and Bad phosphorylation was only diminished. Unexpectedly, the phosphorylation of BCR-ABL was less affected. SKI-606 treatment caused a shift to the subG1 phase also of CD34+ cells isolated from both IM-sensitive and resistant patients, the latter harboring the BCR-ABL mutations F359V, Y253H, E255V and E255K. The inhibitory concentration 50% (IC50) was 100 nM SKI-606 for Y253H, E255V, E255K and 1000nM for F359V. Cytofluorimetric analysis of cells from IM- sensitive CML patients indicated an accumulation in subG1 phase following treatment with SKI-606 alone or in combination with IM. Because the crystal structure of the BCR-ABL kinase domain in complex with SKI-606 has not yet been determined and the mode of binding of this inhibitor is unknown, we first used a molecular docking approach to determine SKI-606 binding mode to wild type (wt) form of the BCR-ABL kinase. We found that the interaction between SKI-606 and BCR-ABL was more stable when the activation loop was in the inactive conformation. Moreover, we found that SKI-606 retained the ability of efficiently binding all the above mentioned BCR-ABL variants, but not the T315I. Finally, we identified six BCR-ABL residues located around SKI-606 that, if mutated, could potentially be able to interfere with the SKI-606/BCR-ABL interaction: the charged residues K271, D381 and H361; the hydrophobic/aliphatic residues V299, A380 and M318. These data help refining the use of SKI-606 for treatment of BCR-ABL positive leukemias.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V108.11.2335.2335

Language: English

Publisher: American Society of Hematology

Publication Date: 2006

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 836-836

Abstract: Dasatinib (BMS-354825) is a second-generation BCR-ABL inhibitor active against several imatinib-insensitive BCR-ABL mutant forms. We have treated in the phase II program with dasatinib a total of forty-five Ph+ pts who were resistant to or intolerant of imatinib. At the time of writing, twenty pts have failed to respond to or relapsed on dasatinib therapy. In order to assess which pre-existent or emerging ABL kinase domain (KD) mutations are challenging for dasatinib clinical efficacy, we retrospectively analyzed ABL KD sequences before the start of treatment and every month thereafter, until dasatinib discontinuation. Mutation monitoring was done by D-HPLC, followed by sequencing in D-HPLC-positive cases. Eight pts had primary resistance to dasatinib (Table 1). In all cases, a T315I or a F317L mutation was already detectable before the onset of treatment or became detectable after one month. The mutations persisted up to the time of disease progression, which occurred at a median of 1.5 months (range, 1–4) from dasatinib start. Twelve pts had acquired resistance to dasatinib (Table 1). Relapse occurred after a median of 7.5 months (range, 3–15) from dasatinib start. Mutation analysis performed before the onset of treatment showed that five of these pts had a wild-type ABL sequence, while the remaining seven pts had evidence of various imatinib-resistant KD mutations (G250E, Y253H, E255K, D276G, M351T). At the time of relapse, however, most of the original mutant clones had disappeared, whereas mutations at residues 315 (T315I or T315A) and/or 317 (F317L or F317I) had invariably emerged in all but one pt. This pt was found to have developed a novel K356R mutation which is now under characterization. Our results indicate that residues 315 and 317 are mutation hotspots in dasatinib-resistant pts, according to the experimental observation that they are both involved in inhibitor binding. They also provide a proof of principle that novel, inhibitor-specific mutant variants (i.e., T315A, F317I, K356R) may be selected, and raise some concerns about the limitations of single-agent treatment in the long term disease control of advanced phase-CML or Ph+ ALL pts. Supported by European LeukemiaNet, AIL, AIRC, FIRB and PRIN projects. Table 1 Pt Disease Mutation(s) before dasatinib start Best HR Best CgR Months on dasatinib Mutation(s) at relapse NE, not evaluated Primary resistance 1 CML/AP WT NR none 4 T315I 2 CML/AP T315I NR NE 1 T315I 3 CML/myBC T315I NR NE 1 T315I 4 CML/myBC F317L NR none 3 F317L 5 CML/lyBC T315I NR NE 1 T315I 6 Ph+ ALL T315I, M351T, L387M NR NE 2 T315I, M351T, L387M 7 Ph+ ALL T315I NR NE 1 T315I 8 Ph+ ALL F359V NR NE 2 T315I Acquired resistance 9 CP WT CHR minor 15 T315I 10 CML/myBC G250E NEL none 8 F317L 11 CML/lyBC Y253H CHR complete 9 CHR T315I 12 CML/lyBC WT CHR complete 4 T315I 13 CML/lyBC E255K CHR none 3 E255K, T315I 14 CML/lyBC D276G CHR complete 7 T315I 15 CML/lyBC WT CHR partial 9 F317L 16 Ph+ ALL E255K CHR NE 4 T315I 17 Ph+ ALL Y253H CHR complete 13 T315A, F317L, D276G 18 Ph+ ALL M351T CHR complete 13 M351T, F317L 19 Ph+ ALL WT CHR complete 6 F317I 20 Ph+ ALL WT CHR complete 4 K356R

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V108.11.836.836

Language: English

Publisher: American Society of Hematology

Publication Date: 2006

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detail.hit.zdb_id: 80069-7

In: Hematological Oncology, Wiley, Vol. 36, No. 1 ( 2018-02), p. 174-181

Abstract: This retrospective study aimed to describe the Hellenic experience on the use of brentuximab vedotin (BV) in relapsed/refractory (R/R) Hodgkin lymphoma (HL) given within its indication. From June 2011 to April 2015, ninety‐five patients with R/R HL, who received BV in 20 centers from Greece, were analyzed. Their median age was 33 years, and 62% were males. Sixty‐seven patients received BV after autologous stem cell transplantation failure, whereas 28 patients were treated with BV without a prior autologous stem cell transplantation, due to advanced age/comorbidities or chemorefractory disease. The median number of prior treatments was 4 and 44% of the patients were refractory to their most recent therapy. The median number of BV cycles was 8 (range, 2‐16), and the median time to best response was the fourth cycle. Fifty‐seven patients achieved an objective response: twenty‐two (23%), a complete response (CR), and 35 patients (37%), a partial, for an overall response rate of 60%. Twelve patients (13%) had stable disease, and the remaining twenty‐six (27%) had progressive disease as their best response. At a median follow‐up of 11.5 months, median progression‐free survival and overall survival were 8 and 26.5 months, respectively. Multivariate analysis showed that chemosensitivity to treatment administered before BV was associated with a significantly increased probability of achieving response to BV ( P  = .005). Bulky disease ( P  = .01) and response to BV ( P   〈 .001) were significant for progression‐free survival, while refractoriness to most recent treatment ( P  = .04), bulky disease ( P  = .005), and B‐symptoms ( P  = .001) were unfavorable factors for overall survival. Among the 22 CRs, 5 remain in CR with no further treatment after BV at a median follow‐up of 13 months. In conclusion, our data indicate that BV is an effective treatment for R/R HL patients even outside clinical trials. Whether BV can cure a fraction of patients remains to be seen.

Type of Medium: Online Resource

ISSN: 0278-0232 , 1099-1069

URL: Issue

URL: Article

DOI: 10.1002/hon.v36.1

DOI: 10.1002/hon.2383

Language: English

Publisher: Wiley

Publication Date: 2018

detail.hit.zdb_id: 2001443-0

In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 322-322

Abstract: Resistance to the Bcr-Abl tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) in patients (pts) with chronic myeloid leukemia (CML) and Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) is often caused by selection of point mutations in the Abl kinase domain (KD) altering residues that are directly or indirectly critical for IM binding. Several novel TKIs are now available for IM-resistant pts. In vitro studies have postulated that each of them is likely to retain its own distinct set of insensitive mutations, including novel inhibitor-specific mutations. To assess how Abl KD sequences evolve under the selective pressure of sequential therapy with one or more novel TKIs, we have monitored the mutation status of 101 IM-resistant pts before and during treatment with up to three consecutive novel TKIs (dasatinib, nilotinib, bosutinib). Forty-seven pts had CML in chronic phase; 54 pts had CML in accelerated/blastic phase (AP/BP) or Ph+ ALL. Overall, presence or emergence of TKI-resistant mutations accounted for 90% of cases of dasatinib, nilotinib or bosutinib failure. At the time of IM failure, 55/101 (54%) pts had KD mutations. After switching to a 2nd TKI (n=101 pts), 21/55 (38%) pts who had mutations at baseline as against 8/46 (17%; p=.02) pts who did not have mutations at baseline subsequently relapsed with newly acquired mutations. Median time to relapse was 8 months (range, 3-18). Cloning showed that these mutations could either be acquired by the pre-existing mutated subclone or arise in an independent one. In addition, 15/55 mutated pts did not respond to the 2nd TKI because of the mutation they were harboring at baseline. After switching to a 3rd TKI (n=20 pts), 11/16 mutated pts as against 0/4 non-mutated pts relapsed with newly acquired mutations. Median time to relapse was 3 months (range, 1–5). Switch to a 4th TKI has so far been attempted in 3 mutated pts, but observation time is still too short. Dasatinib failure was associated with the following mutations: T315I, F317L, V299L, T315A, F317I/S/V. Nilotinib failure was associated with the following mutations: Y253H, E255V, T315I, F359C. Bosutinib failure was associated with the following mutations: E255K, T315I, V299L. More detailed analyses will be presented. In summary, the Bcr-Abl kinase is a moving target and pts already harboring mutations, especially those with CML in AP/BP or with Ph+ ALL, have a higher likelihood of developing further mutations under the selective pressure of novel TKIs. It can be hypothesized that in these pts a higher genetic instability may foster rapid emergence of multiple mutations over time within the same or different Bcr-Abl-positive subclones, which are selected or de-selected depending on the sensitivity profile of the specific TKI employed. In this clinical setting combination therapies would probably be more effective than single-agent treatment for long-term disease control. Supported by European LeukemiaNet, AIL, FIRB, COFIN, Fondazione del Monte di Bologna e Ravenna.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.322.322

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-01), p. 2112-2112

Abstract: Extensive submicroscopic deletions adjacent to the breakpoint on derivative chromosome 9 [der(9)] have been reported in a subset of Chronic Myeloyd Leukemia (CML) patients and have been associated with an adverse outcome with conventional drugs and α-interferon (α-IFN). Huntly et al (Blood.2003; 102.2205–12) reported 275 CML pts who were treated with imatinib in CP, suggesting that der(9) deletions were associated with lower response rates and a shorter time to progression. Different data were reported by Quintas-Cardama et al (Blood.2005; 105:2281–6), who did not find any difference related with der(9) deletions in other 320 patients treated with imatinib. In these 2 studies, some patients began imatinib in early CP (51 and 152, respectively) while many patients (224 and 168, respectively) were treated in late CP. To establish the relationship of der(9) deletions with the response to imatinib in early CP patients, we planned a prospective study involving 3 consecutive multicentric national studies of the GIMEMA (Gruppo Italiano Malattie Ematologiche dell’Adulto) CML Working Party. 421 CML patients in early chronic phase were enrolled between January, 2004 and January, 2006; Fluorescence in situ hybridization (FISH) analysis of bone marrow cells was performed using BCR/ABL extra-signal, D-FISH or dual-color dual-fusion probes. At diagnosis, 52 (12%) of them had der(9) deletion and 369 (88%) had not. The 2 groups, with/without deletions, were comparable (no difference in age, Sokal risk, imatinib dose). Median observation time is 12 months. At 3 months, the CHR rates in with/without deletions patients were 87%/92%. At 6 months, the complete cytogenetic response (0% Ph-pos; CCgR) rates were 80%/80%, with major molecular response (MMolR, defined as a Bcr-Abl/Abl x 100 ratio 〈 0.1%) rates of 52%/51%, respectively. At 12 months, CCgR rates were 89%/86% and MMolR 52%/61%. No difference is significant. We conclude that the presence of der(9) deletions at diagnosis do not constitute a negative factor for response to imatinib: the haematological, cytogenetic and molecular response rates resulted equal between the 2 groups of patients with and without der(9) deletions. This finding is relevant to the long term effect of imatinib treatment, since both the CCgR and the MMolR are important and established indicator of long term survival.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V108.11.2112.2112

Language: English

Publisher: American Society of Hematology

Publication Date: 2006

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In: Blood, American Society of Hematology, Vol. 112, No. 9 ( 2008-11-01), p. 3847-3855

Abstract: Ikaros plays an important role in the control of differentiation and proliferation of all lymphoid lineages. The expression of short isoforms lacking DNA-binding motifs alters the differentiation capacities of hematopoietic progenitors, arresting lineage commitment. We sought to determine whether molecular abnormalities involving the IKZF1 gene were associated with resistance to tyrosine kinase inhibitors (TKIs) in Ph+ acute lymphoblastic leukemia (ALL) patients. Using reverse-transcribed polymerase chain reaction, cloning, and nucleotide sequencing, only the non–DNA-binding Ik6 isoform was detected in 49% of Ph+ ALL patients. Ik6 was predominantly localized to the cytoplasm versus DNA-binding Ik1 or Ik2 isoforms, which showed nuclear localization. There was a strong correlation between nonfunctional Ikaros isoforms and BCR-ABL transcript level. Furthermore, patient-derived leukemia cells expressed oncogenic Ikaros isoforms before TKI treatment, but not during response to TKIs, and predominantly at the time of relapse. In vitro overexpression of Ik6 strongly increased DNA synthesis and inhibited apoptosis in TKI-sensitive cells. Genomic sequence and computational analyses of exon splice junction regions of IKZF1 in Ph+ ALL patients predicted several mutations that may alter alternative splicing. These results establish a previously unknown link between specific molecular defects that involve alternative splicing of the IKZF1 gene and the resistance to TKIs in Ph+ ALL patients.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2007-09-112631

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

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detail.hit.zdb_id: 80069-7