Depth of molecular remission on tyrosine kinase inhibitor (TKI) treatment is of rising importance for chronic myeloid leukemia (CML) patients (pts) with regard to possible treatment discontinuation ...and competing TKIs available to improve molecular response. At present, it is unknown which level of deep molecular response is necessary for optimal prognosis and for successfully stopping therapy. The aim of this work is both to evaluate the technical feasibility of molecular monitoring at the mentioned level and to search for factors allowing to predict MR5.0 in pts on imatinib (IM)-based treatment.
Real-time quantitative PCR on mRNA BCR-ABL transcripts in addition to total ABL transcripts as internal control has been performed on a LightCycler platform in 1,442 pts within the randomized CML-Study IV and adapted according to the International Scale (IS). In order to qualify for MR5.0 the BCR-ABLIS expression should meet one of the following criteria: a positive result ≤0.001% or a negative result with a minimum sample quality of 100,000 ABL copies (Cross et al., Leukemia 2012). Calculating cumulative incidences of remission or progression, the competing risks progression and/or death before possible progression were considered. Cox models were estimated for the multivariate analysis.
In 1,198 of the 1,442 molecularly examined pts at least one sample fulfilled the sensitivity criteria for a MR5.0 (8,266 of 24,101 samples, 34.3%). Cumulative incidence of MR5.0 was 51% at 8 years. The median time to MR5.0 according to randomized treatment arms differed as follows: IM 800mg 79.7 months (mos), IM 400mg 95.0 mos, IM 400mg + IFNα 98.0 mos, IM 400mg + AraC 103.3 mos, IM 400mg after IFN failure 112.9 mos. A Cox model examining the different treatment arms compared to IM 400mg revealed a significantly higher chance for MR5.0 in the IM 800mg arm (HR 1.305, 95% CI 1.003-1.698, p=0.048). Baseline factors like thrombocytosis >450/nl were associated with better responses (HR 1.701 compared to <450/nl, 95% CI 1.405-2.059, p<0.001) and higher leukocyte counts >100/nl (HR 0.503 compared to <50/nl, 95% CI 0.400-0.632, p<0.001) and 50-100/nl (HR 0.746 compared to <50/nl, 95% CI 0.591-0.942, p=0.014) with unfavorable responses. Other upfront factors like age, gender, blasts, eosinophils, hemoglobin, and EUTOS score did not significantly influence the probability for MR5.0. Taken all treatment arms together, our analyses have shown that the chance of achieving a MR5.0 by 8 years was considerably reduced if the pts had a BCR-ABLIS >10% at 3 mos (40.2% vs 58.0%), >1% at 6 mos (40.3% vs 68.7%), >0.1% at 12 mos (37.7% vs 72.0%), and >0.1% at 24 mos (21.5% vs 60.5%).
This evaluation of a large randomized trial reveals feasibility of MR5.0 detection in the majority of pts underlining the benefits of standardized molecular monitoring on the IS with optimized highly sensitive technologies. Baseline low leukocyte count, high thrombocyte count and high dose IM treatment are predictors of future MR5.0. Further, early molecular landmarks qualify for excellent outcome giving hope to a rising number of pts to successfully discontinue treatment and avoid possible side effects or comorbidities.
Müller:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Hehlmann:BMS: Consultancy, Research Funding; Novartis: Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Saussele:Novartis: Honoraria, Research Funding, Travel Other; BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria.
Early assessment of BCR-ABL transcript levels at 3 months allows the prediction of survival and may serve as a trigger for treatment intensification in CML patients with slow response to imatinib. ...The exact decline of BCR-ABL transcript levels within the first 3 months of treatment is defined by the ratio BCR-ABL transcripts at 3 months to BCR-ABL transcripts at baseline. This ratio might better reflect the individual biology of disease and its susceptibility to tyrosine kinase inhibition.
A total of 408 chronic phase CML patients (pts) with baseline and 3 month blood samples available in one single laboratory were investigated. Pts with pre-treatment before first blood sampling were excluded (imatinib with or without hydroxyurea, n=58; hydroxyurea only, n=49). A total of 301 evaluable pts (median age 52 years, range 18-85, 41% female) were treated with an imatinib-based therapy within the CML-Study IV. Median follow-up was 4.8 years. Transcript levels of BCR-ABL, total ABL, and beta-glucuronidase (GUS) were determined by quantitative RT-PCR. Exploratory landmark analyses were performed with regard to overall and progression-free survival (OS, PFS) to evaluate the prognostic significance of (i) BCR-ABL/GUS before treatment, (ii) the individual reduction of transcripts given by (BCR-ABL/GUS at 3 months) / (BCR-ABL/GUS before treatment), and (iii) the 3-month 10% BCR-ABLIS landmark.
The median BCR-ABL/GUS ratio was 15.5% at diagnosis (0.06-107) and 0.63% at 3 months (0-84) reflecting a decline to the 0.04-fold (1.4 log reduction).
i) No prognostic cut-off could be identified for BCR-ABL/GUS before treatment.
ii) A reduction to the 0.35-fold of the initial BCR-ABL transcript level at diagnosis (0.46 log reduction) was identified as best cut-off according to a hazard ratio of 5.6 (95%-CI 2.3-13.4, p<0.001 for PFS). Using this cut-off a high-risk group of 48 pts (16% of pts, 5-year PFS and OS: 77% and 83%) was separated from a good-risk group of 253 pts (84% of pts, 5-year PFS and OS: 96% and 98%).
iii) As a comparison we investigated the 10% BCR-ABLIS landmark at 3 months with a hazard ratio of 2.4 (95%-CI 1.0-5.8, p=0.06 for PFS). With this landmark a high-risk group of 67 pts (22% of pts, 5-year PFS and OS: 87% and 90%) was separated from a good-risk group of 234 pts (78% of pts, 5-year PFS and OS: 95% and 97%).
A two-group risk stratification according to the individual reduction of BCR-ABL transcripts to the 0.35-fold of pre-treatment levels yields a superior separation of risk groups with a 5-year difference of 19% for PFS and 15% for OS. This predictive marker might identify patients at risk more precisely than 3-month 10% BCR-ABLIS.
Hehlmann:BMS: Consultancy, Research Funding; Novartis: Research Funding. Saussele:Novartis: Honoraria, Research Funding, Travel Other; BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; ARIAD: Consultancy, Honoraria; Pfizer: Consultancy. Müller:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding.
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?
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.
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.
Table 1Overview of cytogenetic analysis of BC ptsTotal BC ptsPts with BC cytogeneticsMajor route ACA n (%)Minor route ACA n (%)t(9;22)(q34;q11) or t(v;22) without ACA n (%)BU1152117 (81)1 (5)3 (14)HU1173116 (52)7 (23)8 (26)IFN1595621 (38)6 (11)29 (52)IM734927 (55)13 (27)9 (18)total464157812749
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
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.
In acute leukemias, specific cytogenetic aberrations frequently correlate with myeloid or lymphoid phenotype of blasts and influence risk stratification. In chronic myeloid leukemia (CML) blast ...crisis (BC) it is not clear whether myeloid or lymphoid phenotype of blasts could be distinguished by specific chromosomal aberrations and have prognostic value. At diagnosis of CML, major route additional cytogenetic aberrations (ACA) like +8, i(17)(q10), +19, +der(22)t(9;22)(q34;q11) and minor route ACA like -X, del(1)(q21), del(5)(q11q14), +10,-21, resulting in an unbalanced karyotype have been described to adversely affect outcome. Patients with minor route ACA (for example 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)) resulting in a balanced karyotype did not show differences in overall survival and progression free survival compared to patients with the standard translocation, a variant translocation or the loss of the Y chromosome. Aim of this study was to analyze the impact of the phenotype (myeloid or lymphoid) on time to BC and on cytogenetic pattern.
73 out of 1524 evaluable patients (4.8%) randomized until March 2012 to the German CML-Study IV (a 5-arm trial to optimize imatinib therapy) progressed to BC. Cytogenetic data of 23 out of 32 patients with myeloid BC and 14 out of 21 patients with lymphoid BC were available. In 15 patients, cytogenetic analysis were missing whereas 2 and 3 patients had megakaryoblastic and mixed phenotype, respectively and were not considered in this analysis. Karyotypes of lymphoid and myeloid BC were divided in major route and minor route ACA and balanced and unbalanced karyotypes. Categorical covariates were compared with Fisher's exact test, while continuous covariates were compared with the Mann-Whitney-Wilcoxon test. Survival probabilities after BC were compared using the log-rank test.
Out of 23 patients with myeloid BC, 14 (61%) had major route unbalanced ACA (n=10) or minor route unbalanced ACA (n=4), 4 had minor route balanced ACA and 5 patients had the translocation t(9;22)(q34;q11) or a variant translocation t(v;22) without ACA.13 out of 14 (93%) patients with lymphoid BC had major route unbalanced (n=10) or minor route unbalanced ACA (n=3) and 1 had the standard translocation t(9;22)(q34;q11) only. Between myeloid and lymphoid BC, the difference in the distribution of unbalanced ACA was apparent, but not statistically significant (p=0.06). The most frequently observed major route ACA was trisomy 8 in both groups (7 vs. 6), +der (22)t(9;22)(q34;q11) was more frequently found in myeloid than lymphoid BC (6 vs. 2), +19 was found in both phenotypes (3 vs. 3) whereas an isochromosome i(17)(q10) and an isoderivative chromosome ider(22)t(9;22)(q34;q11) were less frequent and found only in myeloid BC (1 for each vs 0 for each aberration). In lymphoid BC, 5 of 14 patients (36%) had ACA which involved chromosome 7 (del(7)(q22) and -7) whereas in myeloid BC only 2 patients (9%) had -7 (p=0.08). The balanced karyotype with a translocation t(3;21)(q26;q22) and the translocation t(9;11)(p22;q23) described in acute myeloid leukemia was observed in 3 patients with myeloid CML (2 and 1, respectively) and in none with lymphoid phenotype. No differences were observed in time to BC for patients with lymphoid vs. myeloid BC (p=0.31, median time: 409 vs. 453 days) and survival after onset of BC (p=0.9, median time: 544 vs. 284 days).
The proportion of unbalanced karyotypes was higher in lymphoid than in myeloid BC. In lymphoid BC alterations of chromosome 7 were more often present whereas +der(22)t(9;22)(q34;q11) was observed more frequently in myeloid BC. The reciprocal translocations t(3;21)(q26;q22) and t(9;11)(p22;q23) described in acute myeloid leukemias were only observed in myeloid BC. However these cytogenetic differences do not seem to alter the course of BC.
Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hehlmann:Novartis: Research Funding; BMS: Consultancy, Research Funding. Hochhaus:Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Travel Other. Müller:Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding; Ariad: Honoraria. Saussele:Pfizer: Honoraria; BMS: Honoraria, Research Funding, Travel, Travel Other; Novartis: Honoraria, Research Funding, Travel Other.
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Five-year overall survival (OS) of chronic myeloid leukemia (CML) patients treated with imatinib exceeds 90%. With many tyrosine kinase inhibitors (TKI) available as treatment options for CML, the ...influence of TKI therapy on OS is difficult to define. Comorbidities can complicate randomized trials. Their influence on OS in CML has not been studied so far.
We sought to evaluate the influence of comorbidities at diagnosis of CML on remission rates and OS of patients with Philadelphia and/or BCR-ABL positive chronic-phase CML. The CML-Study IV, a randomized five-arm trial designed to optimize imatinib therapy alone or in combination, used very few exclusion criteria as compared to other studies which typically excluded patients with severe illnesses.
The age-adjusted Charlson Comorbidity Index (CCI) is the most extensively studied comorbidity index (Charlson ME et al., 1987) and has been validated for long-term studies. The score weighs a) the severity of comorbidities (e.g. one point is allocated to myocardial infarction and diabetes, two points to non-active malignancies) and b) the age of patients (with one point for each decade above 40 years). The CCI at diagnosis was calculated for each randomized patient. For the analyses, patients were grouped into CCI 2, 3-4, 5-6, and ≥7. Performance status was measured by the Karnofsky Score (KS) and patients were grouped into 50-80, >80-<100, and 100. Correlation analyses were performed by the chi-square test. Survival probabilities were calculated by Kaplan-Meier curves. Calculating cumulative incidences, the competing risks progression and/or death were considered. Cox models were estimated for the multivariate analysis to analyse the prognostic influence of the candidate factors age, sex, leukocytes, hemoglobin, EUTOS score, KS, and CCI on OS.
1551 patients were randomized from 2002 to 2012, 1524 patients were evaluable. Median follow-up time was 67.5 months. Additional to CML, 521 index comorbidities were reported in 1519 patients resulting in the following CCI groups: i) CCI 2: 589 patients, ii) CCI 3 or 4: 599 patients, iii) CCI 5 or 6: 229 patients, and iv) CCI ≥ 7: 102 patients. Median value of the CCI was 3 (range: 2-12). The distribution of the CCI groups was not different between treatment arms. Most common comorbidities were diabetes (n=106), non-active cancer (n=102), chronic pulmonary disease (n=74), renal insufficiency (n=47), myocardial infarction (n=38), cerebrovascular disease (n=29), congestive heart failure (n=28), and peripheral vascular disease (n=28).
Between patients with CCI 2, 3-4, 5-6, and ≥7 no significant differences in remission rates were found neither for time to complete cytogenetic remission (CCR) nor for time to major molecular remission (MMR). Median times to CCR were 12.9, 12.6, 13.7, and 13.1 months and to MMR 17.5, 15.9, 16.5, and 18.1 months, respectively. No differences were observed between the CCI groups for the cumulative incidences of progression. As expected, significant differences in OS according to CCI at diagnosis were observed (s. Fig. 1, p<0.001). Probabilities of OS at 8 years for patients with CCI 2, 3-4, 5-6, and ≥7 were 93.6%, 89.4%, 78.7%, and 45.2%.
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We found a correlation between CCI and KS (p<0.001). In multivariate analysis CCI (p<0.001), KS (p=0.022), and EUTOS Score (p=0.012) were significant predictors of OS. Hazard ratios for the CCI group 3-4, 5-6, >7 (each vs. 2), were 1.695 (95%-confidence interval, CI 1.066-2.695), 3.231 (CI 1.942-5.376) and 6.495 (CI 3.817-11.111), respectively. Separating the CCI into an age-related part and a comorbidity-related part, the comorbidity-related part was still an important risk factor (Wald test, p=0.002).
Comorbidities of CML-patients do not seem to have an impact on the success of imatinib treatment. In CML-Study IV, even patients with a considerable comorbidity benefitted from imatinib as the chances to achieve MMR and CCR did not differ from those of healthier CML-patients. Our data also indicate that OS alone is not any more an appropriate measure for the effectiveness of a specific treatment for CML, as TKI have reduced the CML-related lethality to too low levels. Adjusting for comorbidity is essential for a valid comparison and interpretation of OS observed with different TKIs in CML-patients.
Saussele:Pfizer: Honoraria; BMS: Honoraria, Research Funding, Travel, Travel Other; Novartis: Honoraria, Research Funding, Travel Other. Hehlmann:BMS: Consultancy, Research Funding; Novartis: Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Müller:Ariad: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau.
The outcome of elderly patients with chronic myeloid leukemia (CML) treated with imatinib has been studied in several trials. However, there are no reports on the effects of different imatinib ...dosages in older vs. younger CML patients.
To evaluate the efficacy of imatinib in the elderly, we analyzed data from the German CML-Study IV, a randomized 5-arm trial designed to optimize imatinib therapy alone or in combination. There was no upper age limit for inclusion. Patients with BCR-ABL positive CML in chronic phase randomized to imatinib 400 mg/d (IM400) or imatinib 800 mg/d (IM800) were compared, stratified according to median age at diagnosis in western populations ≥ 65 years vs. < 65 years, regarding effectively administered imatinib dose, time to hematologic, cytogenetic and molecular remissions, adverse events (AEs), rates of progression to accelerated phase (AP) and blast crisis (BC), survival, and causes of death. The full 800 mg dose was given after a 6 weeks run-in period with imatinib 400 mg/d to avoid excessive cytopenias. The dose could then be reduced according to tolerability for maximum patients' compliance.
From July 2002 through March 2012, 1,551 patients were randomized, 828 of these to IM400 or IM800. Median age of these patients was 52 years (IM400: 53 years; IM800: 51 years). 784 patients were evaluable for follow-up (IM400: 382; IM800: 402). 193 patients were ≥ 65 years, 591 < 65 years. 110 patients (29%) on IM400 and 83 (21%) on IM800 were ≥ 65 years. Median observation time on IM400 was 63.0 months in the elderly and 67.6 months in the younger group, on IM800 50.9 months in the elderly and 50.1 months in the younger group. The median dose per day was lower for elderly patients on IM800 (421 mg/d for patients ≥ 65 years vs. 556 mg/d for patients < 65 years), with the highest median dose in the first year (466mg/d for patients ≥ 65 years vs. 630mg/d for patients < 65 years). The median dose for patients on IM400 was 400 mg/d for both age groups. There was no difference between age groups in achieving a complete hematologic remission or a complete cytogenetic remission, neither if IM400 and IM800 were combined, nor in an analysis according to treatment groups. Elderly patients on IM400 achieved major molecular remission (MMR) and deep molecular remission (MR4) significantly later than younger patients (18.1 vs. 15.9 months, p=0.013; 54.4 vs. 33.3 months, p=0.012, respectively) whereas no difference was detected for patients on IM800 (11.9 vs. 10.5 months; 24.2 vs. 26.1 months, respectively). Imatinib was well tolerated in elderly patients with only few WHO grade 3-4 AEs being more frequent in the elderly than in younger patients (dermatologic AEs on IM400: 5.4 vs. 0.4%; infections on IM800: 8.3 vs. 2.5%). There were no significant differences between age groups in probabilities of progression to AP or BC neither if IM400 and IM800 were combined, nor in an analysis according to treatment groups. Five-year age-adjusted relative survival for elderly patients was comparable to that of younger patients.
We could demonstrate that elderly patients achieved molecular remissions significantly later when treated with standard dose imatinib but not when treated with higher imatinib dosages. As the safety profile of IM800 in senior patients was favorable too we conclude, that the optimal dose for elderly patients could be higher than 400 mg/d.
Müller:Ariad: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:Pfizer: Consultancy; ARIAD: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Travel Other. Hehlmann:BMS: Consultancy, Research Funding; Novartis: Research Funding. Saussele:BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria; Novartis: Honoraria, Research Funding, Travel Other.
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.
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.
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.
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.
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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.
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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.
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.
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.
Abstract 913
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.
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.
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).
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.
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.
Abstract 3746
The increase of overall survival in chronic myeloid leukemia (CML) requires closer long-term observation in the face of a potential carcinogenicity of tyrosine kinase inhibitors (TKIs). ...Preclinical studies with imatinib in rats showed neoplastic changes in kidneys, urinary bladder, urethra, preputial and clitoral glands, small intestine, parathyroid glands, adrenal glands, and nonglandular stomach. Two epidemiologic studies on patients with chronic myeloproliferative neoplasms (CMPN) and CML (Frederiksen H et al., Blood 2011; Rebora P et al., Am J Epidemiol 2010) found an increased risk of secondary malignancies compared with the general population independent of treatment. In contrast, in a recent analysis of patients with CML and CMPN treated with TKI (Verma D et al., Blood 2011) a decreased risk of secondary malignancies was reported.
To further elucidate the risk of TKI treated CML patients for the development of secondary malignancies we analysed data of the CML study IV, a randomized 5-arm trial (imatinib 400 mg vs. imatinib 800 mg vs. imatinib 400 mg in combination with interferon alpha vs. imatinib 400 mg in combination with AraC vs. imatinib 400 mg after interferon failure).
From February 2002 to April 2012, 1551 CML patients in chronic phase were randomized, 1525 were evaluable. Inclusion criteria allowed the history of primary cancer if the disease was in stable remission. Forty-nine malignancies were reported in 43 patients before the diagnosis of CML. If relapses occurred within 5 years after diagnosis of primary cancer they were not considered for further analysis. Median follow-up was 67.5 months. Age-standardized incidence rates were calculated from the age-specific rates using the European standard population (1976).
In total, 67 secondary malignancies in 64 patients were found in CML patients treated with TKI (n=61) and interferon alpha only (n=3). Twelve of these patients developed neoplasms after diagnosis of a primary cancer before diagnosis of CML, 5 patients with metastases or recurrence of the first malignancy (range of diagnosis 5–19 years after primary cancer). Median time to secondary malignancy was 2.5 years (range 0.1–8.3 years). The types of neoplasms were: prostate (n=9), colorectal (n=6), lung (n=6), non Hodgkin’s lymphoma (NHL; n=7), malignant melanoma (n=5), skin tumors (basalioma n=4 and squamous cell carcinoma n=1), breast (n=5), pancreas (n=4), kidney (n=4), chronic lymphocytic leukemia (n=3), head and neck (n=2), biliary (n=2), sarcoma (n=2), and esophagus, stomach, liver, vulva, uterus, brain, cancer of unknown origin (each n=1). With these numbers the age-standardized incidence rates of secondary malignancies in CML patients were calculated: 534 cases per 100,000 for men (confidence interval 350;718), and 582 for women (confidence interval 349;817). The incidence rates of the general population in Germany were 450 and 350 cases, respectively (“Krebs in Deutschland 2007/2008”, 8th ed., Robert Koch Institute, 2012). The incidence rate of NHLs was higher for CML patients than for the general population but this is not significant.
In our cohort, the incidence rate of secondary neoplasms in CML patients was slightly increased compared to the general population. The most common secondary malignancies in CML patients under treatment were cancers of the skin, prostate, colon, lung and NHL. Since the occurrence of secondary neoplasia increases over time, long-term follow-up of CML patients is warranted.
Müller:Novartis, BMS: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis, BMS, MSD, Ariad, Pfizer: Consultancy Other, Honoraria, Research Funding. Hehlmann:Novartis: Research Funding.
Abstract 67
Dose optimized imatinib (IM) at doses of 400– 800mg has been shown to induce faster and deeper cytogenetic and molecular – responses than standard IM (400mg/day). Since complete molecular ...remission (CMR 4.5) identifies a subgroup of patients who may stay in remission even after discontinuation of treatment, it was of interest to analyse whether CMR 4.5 is reached faster with dose optimized IM and whether CMR 4.5 correlates with survival.
CMR 4 and CMR 4.5 are defined as ≤ 0.01% BCR-ABL IS or ≥ 4. log reduction and ≤ 0.0032% BCR-ABL IS or ≥ 4.5 log reduction, respectively, from IRIS baseline as determined by real-time PCR. CML-Study IV is a five arm randomized study of IM 400 mg vs IM 400 mg + IFN vs. IM 400 mg + Ara C vs. IM after IFN failure vs. IM 800 mg. In the IM 800 arm, a 6 weeks run in period at IM 400 mg was followed by a dose increase to 800 mg and then by a dose reduction according to tolerability. Grade 3 or 4 adverse effects (AE) were to be avoided. From July 2002 to March 2012 a total of 1551 patients with newly diagnosed chronic phase CML were randomized of whom 1525 were evaluable. Median age was 52 years, 88% were EUTOS low risk, 12% high risk, 36% were Euro score low risk, 52% intermediate and 12% high risk, 38% were Sokal low risk, 38% intermediate and 24% high risk. 113 patients were transplanted, 246 received 2nd generation TKI. 152 patients have died, 90 of CML or unknown reasons, 62 of not directly CML-related causes.
After a median observation time of 67,5 months 6 years OS was 88.2% and PFS 85.6%. CCR, MMR, CMR 4 and CMR 4,5 were achieved significantly faster with dose optimized IM (400 – 800 mg). No significant differences in remission rates were observed between IM 400 mg and the combination arms IM 400 mg + IFN and IM 400 mg + Ara C, whereas IM after IFN failure thus far yielded significantly slower response rates. After 4 years CCR rates were for IM 400, IM 400 + IFN, IM 400 + Ara C, IM 400 after IFN, and IM 800, 80%, 75%, 73%, 59% and 80%, respectively, MMR rates 84%, 77%, 82%, 61% and 88%, CMR 4 rates 57%, 55%, 55%, 40% and 65%, and CMR 4.5 rates 40%,42%, 42%, 28% and 52%, respectively. CMR 4 was reached after a median of 27 months with IM 800 and 41.5 months with IM 400. CMR 4.5 was reached after a median of 41.5 months with IM 800 and 63 months with IM 400. EUTOS low risk patients reached all remissions faster than EUTOS high risk patients. The differences of CMR 4 rates between IM 800 and IM 400 at 3 years were 13% and at 4 years 8%, and of CMR 4.5 rates at 3 years 10% and at 4 years 13%. Grade 3 and 4 AE were not different between IM 400 and dose optimized IM 800.
Independent of treatment approach, CMR 4 and more clearly CMR 4.5 at 3 years predicted better OS and PFS, if compared with patients without CMR 4 or CMR 4.5, respectively. CMR 4 and 4.5 were stable. After a median duration of CMR 4 of 3.7 years only 4 of 792 patients with CMR 4 have progressed. Life expectancy with CMR 4 and 4.5 was identical to that of the age matched population.
We conclude that dose optimized IM induces CMR 4.5 faster than IM 400 and that CMR 4 and CMR 4.5 at 3 years are associated with a survival advantage. Dose optimized IM may provide an improved therapeutic basis for unmaintained treatment discontinuation in patients with CML.
Hehlmann:Novartis: Research Funding. Müller:Novartis, BMS: Consultancy, Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Hochhaus:Novartis, BMS, MSD, Ariad, Pfizer: Consultancy Other, Honoraria, Research Funding.
