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In: Blood, American Society of Hematology, Vol. 119, No. 12 ( 2012-03-22), p. 2965-2966

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2012-01-405373

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

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detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 28, No. 8 ( 2010-03-10), p. 1429-1435

Abstract: Imatinib induces sustained remissions in patients with chronic myelogenous leukemia (CML), but fails to eradicate CML stem cells. This is of major concern regarding the issues of cure, long-term imatinib tolerability, and imatinib resistance. We therefore asked whether interferon alfa-2a (IFN) alone could maintain molecular remissions achieved by a prior combination therapy with imatinib and IFN. Patients and Methods Imatinib therapy was stopped in 20 patients who had concomitantly been pretreated with imatinib and IFN for a median of 2.4 years (range, 0.2 to 4.8 years) and 2.5 years (range, 0.2 to 4.9 years), respectively. After imatinib discontinuation, remission status was monitored monthly by quantitative analysis of the peripheral-blood BCR-ABL mRNA levels using real-time polymerase chain reaction. Proteinase-3 expression and proteinase-3–specific cytotoxic T cells (CTLs) were longitudinally measured to assess putative markers of IFN response. Results With a median time of 2.4 years after imatinib withdrawal (range, 0.5 to 4.0 years), 15 (75%) of 20 patients remained in remission. The number of patients in complete molecular remission increased under IFN from two patients at baseline to five patients after 2 years. Relapses occurred in five patients within 0.4 years (range, 0.2 to 0.8 years), but patients underwent rescue treatment with imatinib, re-establishing molecular remission. IFN therapy was associated with an increase in the expression of leukemia-associated antigen proteinase 3 and induction of proteinase-3–specific CTLs. Conclusion Treatment with IFN enables discontinuation of imatinib in most patients after prior imatinib/IFN combination therapy and may result in improved molecular response. Induction of a proteinase-3–specific CTL response by IFN may contribute to this effect.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2009.25.5075

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2010

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 782-782

Abstract: Abstract 782 Introduction: Current evidence indicates that acquired genetic instability in chronic myeloid leukemia (CML) as a consequence of the t(9;22)(q34;q11) and the resulting BCR-ABL fusion causes the continuous acquisition of additional chromosomal aberrations (ACA) and mutations and thereby progression to accelerated phase and blast crisis (BC). Around 10 –12% of patients in chronic phase (CP) CML have ACA already at diagnosis. During the course of the disease this number rises to 80% in BC. Acquisition of ACA during treatment is considered as a poor prognostic indicator, whereas the impact of ACA at diagnosis is controversial. Patients and methods: Clinical and cytogenetic data of 1151 out of 1311 patients with Philadelphia and BCR-ABL positive CP CML randomized until 2009 to the German CML-Study IV were investigated in a prospective study. There were 459 females (40%) and 692 males (60%). Median age was 53 years (range, 16–88). All patients were treated with imatinib alone or in combination with interferon alpha or araC. The impact of ACA at diagnosis on time to complete cytogenetic and major molecular remission (CCR, MMR) and progression-free and overall survival (PFS, OS) was investigated. Written informed consent was obtained from all patients prior to entering the study. Results: At diagnosis 1003/1151 patients (87%) had the standard t(9;22)(q34;q11) only and 69 patients (6.0%) had a variant t(v;22). In 60 of 69 patients with t(v;22), only one further chromosome was involved in the translocation, in 7 patients two, and in 2 patients three further chromosomes were involved. Seventy-nine patients (6.9%) had ACA. Of these, 38 patients (3.3%) lacked the Y chromosome (-Y) and 41 patients (3.6%) had ACA except -Y. Sixteen of the 41 patients had major-route ACA (+8, i(17)(q10), +der(22)t(9;22)(q34;q11), ider(22)(q10)t(9;22)(q34;q11)) and 25 minor-route ACA [e.g. t(3;12), t(4;6), t(2;16), t(1;21)]. In patients with major-route ACA, trisomy 8 was the most frequent additional alteration (n=9). +der(22)t(9;22)(q34;q11) was observed in six patients, isochromosome (17)(q10) in five patients and ider(22)(q10)t(9;22)(q34;11) in three patients. After a median observation time of 5.3 years for patients with t(9;22), t(v;22), -Y, minor- and major-route ACA median times to CCR were 1.01, 0.95, 0.98, 1.49 and 1.51 years, to MMR 1.40, 1.58, 1.65, 2.49 and 〉 7 years, 5-year PFS 90%, 81%, 88%, 96% and 50% and 5-year OS 92%, 87%, 91%, 96% and 53%, respectively. In patients with major-route ACA times to CCR and MMR were longer. PFS and OS were shorter (p 〈 0.001) than with standard t(9;22)(q34;q11). Loss of Y chromosome had no influence on time to CCR or MMR, PFS and OS. Conclusion: We conclude that the prognostic impact of additional cytogenetic findings at diagnosis of CML is heterogeneous and consideration of their types may be important. Major-route ACA identify a small group of patients with significantly poorer prognosis as compared to all other patients requiring early and more intensive intervention such as stem cell transplantation. Disclosures: Hochhaus: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kneba:Hoffmann La Roche: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.782.782

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 119, No. 2 ( 2012-01-12), p. 530-539

Abstract: BCR-ABL overexpression and stem cell quiescence supposedly contribute to the failure of imatinib mesylate (IM) to eradicate chronic myeloid leukemia (CML). However, BCR-ABL expression levels of persisting precursors and the impact of long-term IM therapy on the clearance of CML from primitive and mature bone marrow compartments are unclear. Here, we have shown that the number of BCR-ABL–positive precursors decreases significantly in all bone marrow compartments during major molecular remission (MMR). More importantly, we were able to demonstrate substantially lower BCR-ABL expression levels in persisting MMR colony-forming units (CFUs) compared with CML CFUs from diagnosis. Critically, lower BCR-ABL levels may indeed cause IM insensitivity, because primary murine bone marrow cells engineered to express low amounts of BCR-ABL were substantially less sensitive to IM than BCR-ABL–overexpressing cells. BCR-ABL overexpression in turn catalyzed the de novo development of point mutations to a greater extent than chemical mutagenesis. Thus, MMR is characterized by the persistence of CML clones with low BCR-ABL expression that may explain their insensitivity to IM and their low propensity to develop IM resistance through kinase point mutations. These findings may have implications for future treatment strategies of residual disease in CML.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2010-08-303495

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. 118, No. 26 ( 2011-12-22), p. 6760-6768

Abstract: The prognostic relevance of additional cytogenetic findings at diagnosis of chronic myeloid leukemia (CML) is unclear. The impact of additional cytogenetic findings at diagnosis on time to complete cytogenetic (CCR) and major molecular remission (MMR) and progression-free (PFS) and overall survival (OS) was analyzed using data from 1151 Philadelphia chromosome–positive (Ph+) CML patients randomized to the German CML Study IV. At diagnosis, 1003 of 1151 patients (87%) had standard t(9;22)(q34;q11) only, 69 patients (6.0%) had variant t(v;22), and 79 (6.9%) additional cytogenetic aberrations (ACAs). Of these, 38 patients (3.3%) lacked the Y chromosome (−Y) and 41 patients (3.6%) had ACAs except −Y; 16 of these (1.4%) were major route (second Philadelphia [Ph] chromosome, trisomy 8, isochromosome 17q, or trisomy 19) and 25 minor route (all other) ACAs. After a median observation time of 5.3 years for patients with t(9;22), t(v;22), −Y, minor- and major-route ACAs, the 5-year PFS was 90%, 81%, 88%, 96%, and 50%, and the 5-year OS was 92%, 87%, 91%, 96%, and 53%, respectively. In patients with major-route ACAs, the times to CCR and MMR were longer and PFS and OS were shorter (P 〈 .001) than in patients with standard t(9;22). We conclude that major-route ACAs at diagnosis are associated with a negative impact on survival and signify progression to the accelerated phase and blast crisis.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2011-08-373902

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 2840-2840

Abstract: Abstract 2840 Background: Pomalidomide in a single arm phase-I/II study and one randomized four arm phase-II study in primary myelofibrosis (MF) and post-polycythemia vera/essential thrombocythemia (post-PV/ET) MF showed efficacy in particular with respect to improvement in anemia. To date, pomalidomide has been evaluated in MF at two dose levels, 0.5mg and 2.0 mg/day. Aims: To evaluate clinical efficacy of pomalidomide alone and in combination with prednisolone (PRED) in patients with primary or post-PV/ET MF and cytopenia. Methods: The main inclusion criteria for primary or post-PV/ET MF patients were red blood cell (RBC)-transfusion-dependence or hemoglobin 〈 10 g/dl, and/or thrombocytopenia 〈 50/nl and/or neutropenia 〈 1.0/nl; patients 〉 =50 years were eligible. Treatment consisted of pomalidomide (POM) 2mg/day; prednisone (PRED) 30mg/day was added in patients who did not respond (≤ stable disease) within three months of therapy. The primary endpoint was response assessed by IWG criteria and extended by the criterion red blood cell transfusion-independence (Gale RP et al., Leuk Res. 2011). Concurrent hydroxyurea in patients with proliferative disease and aspirin 100 mg/d in patients with platelets between 50/nl and 1000/nl were administered. The statistical design of the study was based on the Simon optimal two-stage design. Here we report on the first stage of the study. Median follow-up according to the method of Korn was 18 months. Results: Thirty-eight patients were treated with POM 2 mg/d, the median age was 71 years (range 51–83), 34% were female. Twenty-seven had primary and 11 post-PV/ET MF. Disease stage at study-entry according to the DIPSS was high-risk in 13 (34%), intermediate-2 risk in 22 (58%) and intermediate-1 risk in 3 (8%). Incidence of high-risk cytogenetics, JAK2 V617F mutation and MPL W515L mutation were 29% (10/34), 55% (21/38) and 18% (7/38), respectively. Twenty-seven patients (71%) were RBC-transfusion- and 7 (18%) platelet-transfusion dependent. Median duration of treatment with POM was 11.4 months with 5 patients continue on treatment 24+ months. PRED was added after 3 months in 19 of 28 eligible patients. POM dose-reduction (n=8, 1mg/d; n=2, 0.5mg/d) was performed after a median time of 34 days (range 3–308 days) due to fatigue (n=2), thrombo- and/or neutropenia (n=7), rash (n=1). Seven patients with high risk characteristics (n=6 RBC-transfusion dependent, n=4 high risk cytogenetics) experienced transformation into blast phase (BP), the actuarial probability of transformation to BP measured from diagnosis was 6.0% (SE 4.1%) at 2 years and 22.4% (SE 8.4%) at 5 years. Response was observed in 14 patients (37%) after a median time of 4.8 months (n=1 complete remission, n=5 clinical improvement-platelets, n=3 clinical improvement-erythrocytes, n=5 red cell transfusion-independence); 8 responders received concomitant PRED and responded after a median of three months (range 0.8–11.7 months) of the addition of PRED. In 5 of 14 responders POM dose was reduced due to toxicity, notably before response occurred. Responses were observed within the first 3 months (n=4), between month 4 to 6 (n=4) and beyond month 6 (n=6) with the latest response seen at 12.7 months. There was no correlation between response and JAK2/MPL mutation status or cytogenetics. Basophilia defined as greater than 50% increase in absolute basophil count at month 3 was in trend associated with response (p=0.06). Conclusions: POM with or without PRED in patients with different risk groups of patients with primary and post-PV/ ET MF was effective with a response rate of 37%. Based on results of this first cohort the protocol was amended; i) POM dose has been adjusted to 0.5 mg/d, ii) up-front randomization of PRED at month 4 or month 7 in patients without response but stable disease to single agent POM was introduced. Disclosures: Schlenk: Celgene: Research Funding. Off Label Use: Pomalidomide is so far not approved for the treatment of primary and secondary myelofibrosis.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.2840.2840

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

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In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4012-4012

Abstract: Tyrosine kinase inhibitors (TKI) have changed the natural course of CML. Their efficacy leads to normal life expectancy in the vast majority of patients. With the advent of 2nd generation TKI and the now available choice of drugs, safety issues have gained interest. We have used the randomized CML-Study IV for a long-term safety evaluation of imatinib. Study and Patients CML-Study IV comprises 1551 patients randomized to 5 treatment arms with 3 imatinib-based combinations and 2 different imatinib-dose schedules. 1501 patients have received imatinib and were evaluable. Median age at diagnosis was 53 years, 88% were EUTOS low risk. At the last evaluation (04/11/2013) 1003 patients still received imatinib, 164 had died, 275 were switched to a 2nd generation TKI, 106 were transplanted. The longest observation time was 11.5 years, the median observation time was 6.5 years, with a 10-year survival probability of 84 %. The median time to imatinib discontinuation has not been reached after 10.2 years. 80 patients are under observation for more than 10 years, 18 of these have discontinued imatinib. Out of the 1501 patients that had received imatinib, 1375 patients received imatinib as first-line treatment and had a sufficient documentation of treatment. Methods AE were reported at each follow-up visit. The CTC AE list of the NCI was used for coding of AE and severity grading. Additionally, for detection of hematologic AE lab results were screened for deviations from reference ranges. The AE were analyzed according to the “as treated” principle, using Kaplan-Meier curves (virtually no competing risks, almost all patients died after end of imatinib treatment). Only the first event of the respective type was considered. All analyses started at the first day of imatinib treatment and were censored when the patient discontinued imatinib, received another treatment or died. To assess the differences between men and women, Cox models were estimated. Results In 1137 out of 1375 patients (83%) non-hematologic AE (5160 singular events) were reported during imatinib treatment (all grades), in 322 grade 3/4 AE (23%) (645 singular events). At 3 years, probability of a non-hematologic AE (any grade) was already 76% (95%-CI: 73-79%), at 6 years 85% (95%-CI: 82-88%) and at 8 years 91% (Fig.1). The probability of grade 3/4 non-haematologic AE was 38% (95%-CI: 34-42%) at 6 years and 43% (CI: 37-48%) at 8 years. 156 patients reported hematologic grade 3/4 AE (187 singular events).The probability of hematologic grade 3/4 AE was 17% at 6 years (95%-CI: 15-21%) with most events observed during the first year of treatment (probability after one year 10.5%). The most frequently reported non-hematologic AE (all grades, any time) were gastrointestinal (6-year-probability 52%, 95%-CI: 48-56%), fluid overload or edema (6y-prob. 45%, 95%-CI: 40-49%), rash (6y-prob. 32%, 95%-CI: 28-36%), myalgia or arthralgia (6y-prob. 30%, 95%-CI: 27-34%), fatigue (6y-prob. 26%, 95%-CI: 22-29%), flu-like symptoms (6y-prob. 22%, 95%-CI: 19-26%), infections (6y-prob. 24%, 95%-CI: 20-28%) and neurological symptoms (6y-prob. 26%, 95%-CI: 22-29%). AE probability profiles over time have been generated for each AE (Figs. 2-3). For women the risk for non-hematologic events was increased 1.35-fold (95% CI: 1.18-1.55) for all grades (Figs. 1-3) and 1.13-fold (95% CI: 0.91-1.41) for grade 3/4, and 1.26-fold (95% CI: 0.91-1.71) for grade 3/4 hematologic AE. In 5 patients peripheral arterial occlusive disease grade 2 or 3 was reported, but none could be clearly assigned to imatinib (vascular risk profile of one patient incompletely reported). A definite association between any AE and death was not found. Conclusion As AE by definition may or may not be considered related to the medical treatment an exact assessment of the safety of imatinib is difficult. Most AE were recorded during the first three years with decreasing frequency later on. The increased AE risk in women was mostly grade 1/2 and is commonly seen also in other treatment areas. Given that no imatinib-related death was recorded and that grade 3/4 AE could typically be properly treated we consider imatinib as a safe, comparably well tolerated TKI even after prolonged treatment. After 10 years imatinib continues to be an excellent choice for the treatment of CML in most patients. Disclosures: Hehlmann: Novartis: Research Funding; BMS: Consultancy, Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Müller:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding; Ariad: Honoraria. Saussele:Novartis: Honoraria, Research Funding, Travel Other; BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.4012.4012

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2737-2737

Abstract: The impact of the type of therapy on cytogenetic evolution in chronic myeloid leukemia (CML) regarding the occurrence of additional cytogenetic aberrations (ACA) at the time point of blast crisis (BC) may be critical. The aim of this analysis was to elucidate whether patients (pts) treated with imatinib (IM) had ACA less frequently than pts treated with BU and other therapies used prior to IM as hydroxyurea (HU) and interferon alpha (IFN). We comparatively analyze the BC karyotype of CML pts treated in consecutive trials of the German CML Study Group (Studies I, II and IV) to answer the following question: Does CML therapy influence the occurrence or even induce ACA or do these alterations rather reflect the natural history and the biology of the disease and are independent of therapy? Materials and methods Cytogenetic data of 157 pts with Philadelphia chromosome and BCR-ABL positive CML in BC were analyzed from a total of 2,380 pts randomized to CML study I (BU vs. HU vs. IFN, recruitment 1983 – 1991), CML study II (IFN + HU vs. HU, recruitment 1991 – 1994), and CML study IV (IM 400 mg vs. IM 800 mg vs. IM 400 mg +IFN vs. IM 400 mg + AraC vs. IM 400 mg after IFN failure recruitment 2002 – 2012). Cytogenetic analysis was reported according to ISCN 2005. ACA were divided into major route (+8, i(17)(q10), +19, +der(22)t(9;22)(q34;q11)) and minor route alterations (reciprocal translocations other than the t(9;22)(q34;q11), e.g. t(1;21), t(2;16), t(3;12), t(4;6), t(5;8), t(15;20) (Fabarius et al., Blood 2011). Confirmatory testing of pairwise comparisons of therapies with regard to their frequency of major ACAs was performed using two-sided chi-square test. To keep the level of significance at 0.05 despite multiple testing, a priori hypotheses were hierarchically ordered: First, frequency of major route ACA of pts on IM was compared with that on BU, then, with HU and with IFN. Next, the comparisons of IFN vs. BU and IFN vs. HU were planned. Cumulative incidences were estimated under consideration of death before BC as a competing risk. Results 115 of 188 pts randomized to BU (CML study I), 117 of 194 pts randomized to HU (CML study I only) and 159 of 360 randomized to IFN-based therapy (CML studies I+II) progressed to BC. Eight-year cumulative incidence probability of BC was 0.63 [95%-confidence interval (CI): 0.56; 0.69], 0.60 [95%-CI: 0.53; 0.66] , and 0.49 [95%-CI: 0.43; 0.54] in pts randomized to BU, HU, and IFN-based therapy, respectively and 0.06 [95%-CI: 0.04; 0.07] in pts on IM (CML-study IV). Three-year survival probabilities after BC were 0.009 [95%-CI: 0.001; 0.043] with BU, 0.017 [95%-CI: 0.003; 0.055] with HU, 0.013 [95%-CI: 0.003; 0.042] with IFN, and 0.252 [95%-CI: 0.157; 0.368] with IM. Cytogenetic data at BC with banding analysis were available from 21 pts on BU, 31 on HU, 56 on IFN and 49 on IM. 81% of pts treated with BU, 52% with HU, 38% with IFN and 55% with IM showed major route ACA. All other pts had minor route ACA or translocation t(9;22)(q34;q11) and variant translocation (t(v;22)) without ACA (Table 1). The difference in major route ACA between BU and IM was significant (p = 0.04, two-sided chi-square test). There was no statistically significant difference in ACA between pts on HU and IFN in comparison to IM. According to the testing order, further comparative testing was not possible. However, the differences of induction of major route ACA between HU and BU and IFN and BU were even more pronounced than the difference between IM and BU. The most frequently observed major route ACA was trisomy 8 in all studies and therapy arms. Conclusions The type of cytogenetic aberrations in CML BC after different therapies is comparable. The characteristic major route ACA after various therapies points to a CML BC-related chromosomal pattern rather than a therapy-induced effect. Pts treated with IM showed a significantly lower rate of major route ACA than BU. IM not only reduces the frequency of BC and increases survival probabilities but appears to moderately change the biology of BC as compared to BU Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hehlmann:BMS: Consultancy, Research Funding; Novartis: Research Funding. Hochhaus:Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Travel Other. Müller:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding; Ariad: Honoraria. Kolb:Pierre Fabre, Therakos: Honoraria; Kolb Consulting UG: Consultancy, Equity Ownership. Saussele:BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria; Novartis: Honoraria, Research Funding, Travel Other.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.2737.2737

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 913-913

Abstract: Abstract 913 Introduction: Acquired genetic instability in chronic myeloid leukemia (CML) as a consequence of the translocation t(9;22)(q34;q11) and the resulting BCR-ABL fusion causes the continuous acquisition of additional chromosomal aberrations and mutations and thereby progression to accelerated phase (AP) and blast crisis (BC). At least 10% of patients in chronic phase (CP) CML show additional alterations at diagnosis. This proportion rises during the course of the disease up to 80% in BC. Acquisition of chromosomal changes during treatment is considered as a poor prognostic indicator, whereas the impact of chromosomal aberrations at diagnosis depends on their type. Patients with major route additional chromosomal alterations (major ACA: +8, i(17)(q10), +19, +der(22)t(9;22)(q34;q11) have a worse outcome whereas patients with minor route ACA show no difference in overall survival (OS) and progression-free survival (PFS) compared to patients with the standard translocation, a variant translocation or the loss of the Y chromosome (Fabarius et al., Blood 2011). However, the impact of balanced vs. unbalanced (gains or losses of chromosomes or chromosomal material) karyotypes at diagnosis on prognosis of CML is not clear yet. Patients and methods: Clinical and cytogenetic data of 1346 evaluable out of 1544 patients with Philadelphia and BCR-ABL positive CP CML randomized until December 2011 to the German CML-Study IV, a randomized 5-arm trial to optimize imatinib therapy by combination, or dose escalation and stem cell transplantation were investigated. There were 540 females (40%) and 806 males (60%). Median age was 53 years (range, 16–88). The impact of additional cytogenetic aberrations in combination with an unbalanced or balanced karyotype at diagnosis on time to complete cytogenetic and major molecular remission (CCR, MMR), PFS and OS was investigated. Results: At diagnosis 1174/1346 patients (87%) had the standard t(9;22)(q34;q11) only and 75 patients (6%) had a variant t(v;22). In 64 of 75 patients with t(v;22), only one further chromosome was involved in the translocation; In 8 patients two, in 2 patients three, and in one patient four further chromosomes were involved. Ninety seven patients (7%) had additional cytogenetic aberrations. Of these, 44 patients (3%) lacked the Y chromosome (-Y) and 53 patients (4%) had major or minor ACA. Thirty six of the 53 patients (2.7%) had an unbalanced karyotype (including all patients with major route ACA and patients with other unbalanced alterations like -X, del(1)(q21), del(5)(q11q14), +10, t(15;17)(p10;p10), -21), and 17 (1.3%) a balanced karyotype with reciprocal translocations [e.g. t(1;21); t(2;16); t(3;12); t(4;6); t(5;8); t(15;20)]. After a median observation time of 5.6 years for patients with t(9;22), t(v;22), -Y, balanced and unbalanced karyotype with ACA median times to CCR were 1.05, 1.05, 1.03, 2.58 and 1.51 years, to MMR 1.31, 1.51, 1.65, 2.97 and 2.07 years. Time to CCR and MMR was longer in patients with balanced karyotypes (data statistically not significant). 5-year PFS was 89%, 78%, 87%, 94% and 69% and 5-year OS 91%, 87%, 89%, 100% and 73%, respectively. In CML patients with unbalanced karyotype PFS (p 〈 0.001) and OS (p 〈 0.001) were shorter than in patients with standard translocation (or balanced karyotype; p 〈 0.04 and p 〈 0.07, respectively). Conclusion: We conclude that the prognostic impact of additional cytogenetic alterations at diagnosis of CML is heterogeneous and consideration of their types may be important. Not only patients with major route ACA at diagnosis of CML but also patients with unbalanced karyotypes identify a group of patients with shorter PFS and OS as compared to all other patients. Therefore, different therapeutic options such as intensive therapy with the most potent tyrosine kinase inhibitors or stem cell transplantation are required. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Equity Ownership. Hochhaus:Novartis, BMS, MSD, Ariad, Pfizer: Consultancy Other, Honoraria, Research Funding. Müller:Novartis, BMS: Consultancy, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.913.913

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. 124, No. 21 ( 2014-12-06), p. 155-155

Abstract: Background: In the current ELN recommendations (Baccarani et al., Blood 2013) the optimal time point to achieve major molecular remission (MMR) is defined at 12 months after diagnosis of CML. MMR is not a failure criterion at any time point leading to uncertainties when to change therapy in CML patients not reaching MMR after 12 months. Aims: We sought to evaluate a failure time point for MMR using data of the CML-Study IV, a randomized five-arm trial designed to optimize imatinib therapy alone or in combination. In addition the optimal time-point to achieve a MMR should be evaluated. Methods: Patients with valid molecular analysis on MR4 level were divided randomly into a learning (LS) and a validation sample (VS). For the LS, MR2 (defined as BCR-ABL 〈 1% which corresponds to complete cytogenetic remission (Lauseker et al. 2014)), MMR and deep molecular remission levels (MR4 or deeper) monthly landmarks were defined between one and five years after diagnosis. A patient was considered to be in MR2, MMR or MR4 from the first diagnosis of the corresponding remission level and could only change to a higher level of response. Patients were censored after SCT. The best prediction time was found via dynamic prediction by landmarking (van Houwelingen, Scand J Stat 2007). For the failure time point analysis, for each of the resulting 48 landmarks, a Cox model was used to define the time to progression with age and EUTOS score as additional prognostic factors. Additionally, the regression coefficients of the model of one landmark were converted to hazard ratios (HR) and treated as dependent on the HRs of the other landmarks, using a cubic smoothing function (see Fig 1). The minimum of this function was considered to be the optimal landmark point for the prediction of progression-free survival (PFS). For the calculated time point, landmark analysis for probability of PFS (defined as appearance of accelerated phase, blast crisis or death) was performed in the VS. For the evaluation of the optimal time point of achieving a MMR the same analysis was done from 0.25 to 5 years to define the time to MR4 or deeper. Results: 1551 patients were randomized from 2002 to 2012, 1358 had a valid molecular analysis on the MR4 level. 114 patients in the imatinib after IFN arm and 16 patients with missing EUTOS score were excluded. Of the 1228 evaluable patients two thirds were randomly allocated to the LS (n=818) and one third to the VS (n=410). Percentage of patients of the LS in MR2, MMR and MR4 or deeper at one year was 28%, 29% and 14%, and at 5 years 5%, 21% and 71%, respectively. Monthly time points in between were also calculated. 44 patients of the LS reached MMR on second generation tyrosine kinase inhibitors.. The minimum of the cubic function of the HRs was found for MMR at 2.34 years with a HR of 0.25 (compared to patients without any remission) and 0.75 compared to those in MR2. For MR4 or deeper no exact time point could be calculated (see Fig. 1), although it was shown that the risk of progression was slightly lower for MR4 than for MMR. Since the time interval for molecular evaluation in the study is 3 months, the validation was done with 2.25 instead of 2.34 years. 364 of the 410 of the VS were still at risk at this time point and evaluable. A significant PFS advantage for patients in MMR could be demonstrated (p=0.018). At 8 years, the probability of PFS for patients in MMR was 90.8% (confidence interval 87.0-93.7%) vs. 80.5% (confidence interval 70.2-88.6%) for patients not in MMR (see Fig 2). For the optimal MMR analysis no singular time point could be calculated as the earlier a MMR was reached the higher was the chance to achieve a MR4. Conclusions: In this model, an optimal time point to predict PFS in patients with MMR was defined at 2.25 years after diagnosis and could be validated as significant. Nevertheless, patients being in MMR had a lower risk of progression than patients not being in MMR on any other time point as well. With this model we can give hints when to define MMR as failure and a change in therapy should be considered. Despite this we should keep in mind that the earlier MMR was achieved the higher was the chance to achieve deep molecular response later during therapy. Figure 1 Cubic smoothing function of the HR to predict PFS with confidence intervals Figure 1. Cubic smoothing function of the HR to predict PFS with confidence intervals Figure 2 Landmark analysis at 2.25 years for PFS of the VS Figure 2. Landmark analysis at 2.25 years for PFS of the VS Disclosures Saussele: Novartis: Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria, Travel, Travel Other. Hehlmann:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Hanfstein:Novartis: Research Funding; Bristol-Myers Squibb: Honoraria. Neubauer:MedUpdate: Honoraria, Speakers Bureau. Kneba:Novartis: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pfirrmann:Novartis: Consultancy; Bristol-Myers Squibb: Honoraria. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Müller:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.155.155

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

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