Abstract
Since the advent of tyrosine kinase inhibitors, the impact of age on outcome of chronic myeloid leukemia (CML) patients has changed. We therefore analyzed patients from the randomized CML study IV to investigate disease manifestations and outcome in different age groups. One thousand five hundred twenty-four patients with BCR-ABL-positive chronic phase CML were divided into four age groups: (1) 16–29 years, n = 120; (2) 30–44 years, n = 383; (3) 45–59 years, n = 495; and (4) ≥60 years, n = 526. Group 1 (adolescents and young adults (AYAs)) presented with more aggressive disease features (larger spleen size, more frequent symptoms of organomegaly, higher white blood count, higher percentage of peripheral blasts and lower hemoglobin levels) than the other age groups. In addition, a higher rate of patients with BCR-ABL transcript levels >10 % on the international scale (IS) at 3 months was observed. After a median observation time of 67.5 months, no inferior survival and no differences in cytogenetic and molecular remissions or progression rates were observed. We conclude that AYAs show more aggressive features and poor prognostic indicators possibly indicating differences in disease biology. This, however, does not affect outcome.
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Introduction
Chronic myeloid leukemia (CML) appears in all age groups. The incidence increases with age. In western countries, median age at diagnosis is 64 years [1, 2] and around 54 years [3] in clinical studies. Before the introduction of imatinib, older age was a negative prognostic factor, as reflected by the risk stratification scores, Sokal and Euro [4, 5]. After the introduction of imatinib, the outcome of patients with CML has improved, and older age seems to have lost its negative impact [6, 7].
A recent analysis that compares patients less than 65 years with patients older than 65 years treated with frontline imatinib reports no difference in an outcome between these two age groups [8]. Another analysis that compares 15–29-year-old adolescents and young adults (AYAs) with patients older than 29 years with newly diagnosed chronic phase (CP) CML treated with first-line tyrosine kinase inhibitors (TKIs) reports inferior response rates in the younger group [9]. AYAs have been of particular interest in oncology because differences compared to older age have been observed in various neoplasias: In acute lymphoblastic leukemia, different disease features and a better outcome are reported in AYAs in comparison to older patients [10, 11]. A worse prognosis has been reported in breast cancer [12, 13], colorectal cancer [14], and soft tissue sarcomas [15], pointing to different biological features of these cancers in younger age [16].
Few data exist on presentation and outcome of AYAs with CML possibly due to the low incidence of CML in this age group.
The aim of this study was to analyze the impact of age on outcome of CML using patients from the German CML study IV with particular attention to the group of patients younger than 29 years.
Patients and methods
The German CML study IV is a five-arm randomized study which compares 400 mg imatinib, 800 mg imatinib, 400 mg imatinib in combination with interferon alpha (IFN-α), 400 mg imatinib in combination with low-dose cytarabine, and 400 mg imatinib after failure to IFN-α [17].
Newly diagnosed BCR-ABL-positive CP-CML patients diagnosed in participating centers were included. There was no upper age limit. Patients with comorbidities that would preclude study participation or study drug treatment were excluded as well as pregnant or nursing women and patients with secondary malignancy causing reduced life expectancy or requiring therapy.
Patients, 16 years and older, were included. Twenty-nine years was defined as upper cutoff age for AYAs [9, 18–21]. For older patients, the lower cut off at age 60 years was chosen [6, 22]. Age groups, 30–59, were evenly divided into two groups (30–44 and 45–59).
Gender, performance status, risk scores, clinical manifestations, blood count, type of transcripts, and presence of additional chromosomal aberrations (ACAs) [23] were analyzed at the time of diagnosis. Cytogenetic and molecular responses, rates of progression to accelerated phase (AP) and blast crisis (BC), and overall survival (OS) were analyzed throughout the observation time of the study. Patients were analyzed for achieving complete cytogenetic remission (CCR), major molecular remission (MMR), and molecular remission ≤0.01 % on the international scale (MR4), if at least one sample of sufficient quality was available.
For follow-up analyses of CCR, at least 20 marrow cell metaphases were evaluated. Measurements of BCR-ABL and total ABL transcripts were determined by quantitative reverse transcriptase polymerase chain reactions from peripheral blood samples [24–26] and were performed in standardized laboratories [27]. The analysis of molecular endpoints was restricted to patients expressing b2a2 and/or b3a2 transcripts only.
Response definitions, AP, and BC were defined according to ELN criteria and the recent standardized definitions of molecular response [28–30]. All living patients were censored at the time of their last visit. In estimating the cumulative incidences of molecular or cytogenetic remissions, patients were censored at the time they received a second-generation TKI or were transplanted.
OS was calculated from date of diagnosis to death from any cause (whether on or off TKI) or to the latest follow-up date.
Baseline characteristics and hematological parameters were compared with the chi-squared or the Kruskal–Wallis tests. Cumulative incidences were calculated under consideration of competing risks [31, 32] defined by AP, BC, and death. Probabilities of OS were calculated by the Kaplan–Meier method and compared by log-rank test. Comparisons between cumulative incidences were performed by the Gray test [33]. Relative overall survival was calculated dividing the observed survival probabilities by the expected survival probability of the general German population matching age and sex. Level of significance was 0.05. Due to the exploratory character of this work, no adjustment of p values was done. All calculations were performed with the SAS software Version 9.1.3.
The protocol followed the Declaration of Helsinki and was approved by the ethics committee of the Medizinische Fakultät Mannheim der Universität Heidelberg and by local ethics committees of participating centers. Written informed consent was obtained from all patients before they entered the study.
Results
One thousand five hundred fifty-one patients with newly diagnosed BCR-ABL-positive CML in CP were randomized from July 2002 through March 2012. Data entry was closed on May 24, 2012.
One thousand five hundred twenty-four patients at the age of 16 years and older were evaluable for follow-up (Fig. 1). The median age at diagnosis was 52 years. The median observation time was 67.5 (0.1–123.8) months.
Patients were divided into four age groups according to age at diagnosis: group 1, 16–29 years (n = 120, 8 %); group 2, 30–44 years (n = 383, 25 %); group 3, 45–59 years (n = 495, 32 %); and group 4, ≥60 years (n = 526, 35 %). All patients received imatinib as first or second-line treatment in the study except for ten patients who only received IFN. Recruitment to this arm was terminated in 2005 [17]. More patients in group 1 were transplanted (19 %) compared to 12, 7, and 1 % in groups 2, 3, and 4, respectively. The number of patients according to age groups and therapy arm are shown in Table 1.
There was a predominance of male gender in all age groups, but group 1 showed a significantly higher percentage of male patients in comparison to group 4 (67 % for groups 1 and 2 each, 61 % for group 3, and 54 % for group 4, p = 0.011).
Most patients had a Karnofsky index >80 %, but 12 % of patients in group 1 had a Karnofsky index between 50–80 % compared to 9 % in groups 2 and 3 and 16 % in group 4 (Table 2).
Patients in group 1 had the highest proportion of high-risk patients according to Euro and EUTOS scores. By EUTOS score, 18 % of patients in group 1 were high risk in comparison to 16 % (ns), 11 % (p = 0.031), and 8 % (p < 0.002) in groups 2, 3, and 4, respectively.
Group 1 presented with a larger spleen size (median length of 5 cm below the costal margin), more often with symptoms of organomegaly, higher white blood cell counts (WBC), a higher percentage of blasts in the peripheral blood (median of 144 × 109/L), and lower hemoglobin levels (median of 11.1 g/dL). There were no differences in fatigue, weight loss, fever, or other symptoms, in the percentage of eosinophils, basophils, platelets, bone marrow blasts, ACAs, and type of BCR-ABL transcripts at diagnosis between the four groups (Table 2).
No significant differences in cumulative incidences of CCR, MMR, and MR4 were found between group 1 and the other 3 groups (Fig. 2a–c).
The 5-year OS probability of group 1 was 96.7 %, 93.8 % for group 2, 92.5 % for group 3, and 82.9 % for group 4. OS was lower only in group 4 in comparison to the other three age groups (p < 0.001) as observed in the general population [34]. The relative survival (RS) when the general German population was taken into account was 96.9 % in group 1, 94.5, 95.1, and 93.1 % in groups 2–4, respectively [34].
Regarding progression during the observation time, no differences were observed between the age groups. The cumulative incidences of progression at 5 years were 8.7, 7.3, 5.3, and 6.1 % for groups 1 to 4, respectively (Fig. 3).
More patients in group 1 had BCR-ABL IS ≥10 % at 3 months (42 %) than patients above 44 years (26 % for group 3, p = 0.026 and 25 % for group 4, p = 0.018). There was no difference to group 2 (Table 2).
A correlation between a specific cause of death age group and therapy arm was not observed. Causes of death in each group are shown in Table 3.
Discussion
The median age of the 1,524 CML patients of the CML study IV was 52 years with a male preponderance. AYAs represented 8 % of the study population in agreement with reports of CML incidence in AYAs [9, 35].
AYAs in our study presented features of a more aggressive disease, with higher levels of WBC and blasts in the peripheral blood, lower hemoglobin, larger spleen size, and more frequent organomegaly-related symptoms. The larger spleen size is reflected in the EUTOS score in which age is not included as a parameter and is in line with a study of Pemmaraju et al. who report a higher frequency of splenomegaly at diagnosis in 61 AYAs than in 407 older patients [9], and a study of Cortes et al. who report that splenomegaly was more frequent in patients below 60 years than above 60 years [6]. Similar observations have been made in children with CML (increased rates of splenomegaly and leucocytosis) [36–38], supporting our findings that aggressive disease features become less apparent as age increases.
Although a worse outcome was expected in our group of 120 AYAs [9], no differences in cumulative incidence of CCR, MMR, and MR4 were observed in comparison to the other three groups. This is different from the results of Pemmaraju et al. [9] who report significantly lower cytogenetic and molecular responses in AYAs. The two studies however did not find difference in OS. No inferior survival after a median observation time of 5.6 years was observed in our study either. We have observed, however, a greater percentage of younger patients with BCR-ABL transcript levels above 10 % at 3 months in comparison to patients 44 years and older. Transcript levels above 10 % are correlated with an unfavorable prognosis [39, 40] and identify patients that require more frequent monitoring [41].
These findings could suggest different disease biology of CML in younger patients. The identification of distinct age-related genetic and biologic features has been found in various neoplasms: in colon cancer chromosomal instability and a greater tumor invasion is observed in younger patients [42]. In papillary thyroid cancer, different gene expression and advanced disease presentation in AYAs were correlated with better prognosis [43]. In breast cancer, younger women show unique genetic pathways recognized as negative prognostic markers [13]. In acute lymphoblastic leukemia (ALL), distinct biological findings are reported in AYAs, which are generally correlated with poor prognosis: increased incidence of Philadelphia chromosome and intrachromosomal amplification of chromosome 21, increased promoter methylation, and more frequent T cell immunophenotype as well as presence of a mediastinal mass. Due to treatment optimization, ALL outcome is better in AYAs than in adults [10, 11, 44].
In our analysis, we did not detect obvious biological differences. We did not observe differences in transcript type or ACAs nor did others: no differences in transcript type in relation to age were found in 146 pediatric CML patients, including 30 AYAs [36]. Differences in stem cell biology, bone marrow microenvironment, or signaling pathways could exist since many biologic pathways are triggered by BCR-ABL and are successfully inhibited by TKI therapy [45–47] but data to support this in AYAs are still lacking.
Another possible interpretation of the more aggressive features at diagnosis of CML in AYAs could be that younger patients are less frequently transferred to the physician than older ones and only when symptoms are apparent as a consequence of better health and less frequent comorbidities than in older people. As there are no data to support this hypothesis, this remains speculative.
Since the introduction of imatinib, response rates have improved and progression of the disease rarely occurs [48]. Treatment with imatinib explains the high 5-year OS of AYAs in our study (97 %) in comparison to a recently published population-based study in the Netherlands, which started in the pre-imatinib era (1989–2009), in which the 5-year relative survival of AYAs with CML is reported to be 68 % in males and 76 % in females [49].
We conclude that AYAs with CML show features of a more aggressive disease indicating possible biological differences of younger patients that need to be investigated. Also, the higher transcript level at 3 months suggests a worse prognosis of AYAs. Nevertheless, younger patients do well in spite of poorer prognostic indicators.
References
Howlader N, Noone A, Krapcho M, Neyman N, Aminou R, Altekruse S, Kosary C, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner M, Lewis D, Chen H, Feuer E, Cronin K, (Editors) SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations).Bethesda, MD:National Cancer Institute;2012http://seer.cancer.gov/csr/1975_2009_pops09/. Accessed 10 March 2012
Bjorkholm M, Ohm L, Eloranta S, Derolf A, Hultcrantz M, Sjoberg J, Andersson T, Hoglund M, Richter J, Landgren O, Kristinsson SY, Dickman PW (2011) Success story of targeted therapy in chronic myeloid leukemia: a population-based study of patients diagnosed in Sweden from 1973 to 2008. J Clin Oncol 29(18):2514–2520. doi:10.1200/jco.2011.34.7146
Rohrbacher M, Berger U, Hochhaus A, Metzgeroth G, Adam K, Lahaye T, Saussele S, Müller MC, Hasford J, Heimpel H, Hehlmann R (2009) Clinical trials underestimate the age of chronic myeloid leukemia (CML) patients. Incidence and median age of Ph/BCR-ABL-positive CML and other chronic myeloproliferative disorders in a representative area in Germany. Leuk 23(3):602–604. doi:10.1038/leu.2008.245
Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, Tso CY, Braun TJ, Clarkson BD, Cervantes F, Rozman C (1984) Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood 63(4):789–799
Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, Alimena G, Steegmann JL, Ansari H (1998) A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 90(11):850–858
Cortes J, Talpaz M, O’Brien S, Giles F, Rios MB, Shan JQ, Faderl S, Garcia-Manero G, Ferrajoli A, Wierda W, Kantarjian H (2003) Effects of age on prognosis with imatinib mesylate therapy for patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Cancer 98(6):1105–1113. doi:10.1002/cncr.11629
Rosti G, Iacobucci I, Bassi S, Castagnetti F, Amabile M, Cilloni D, Poerio A, Soverini S, Palandri F, Cambrin GR, Iuliano F, Alimena G, Latagliata R, Testoni N, Pane F, Saglio G, Baccarani M, Martinelli G (2007) Impact of age on the outcome of patients with chronic myeloid leukemia in late chronic phase: results of a phase II study of the GIMEMA CML Working Party. Haematol 92(1):101–105. doi:10.3324/haematol.10239
Gugliotta G, Castagnetti F, Palandri F, Breccia M, Intermesoli T, Capucci A, Martino B, Pregno P, Rupoli S, Ferrero D, Gherlinzoni F, Montefusco E, Bocchia M, Tiribelli M, Pierri I, Grifoni F, Marzocchi G, Amabile M, Testoni N, Martinelli G, Alimena G, Pane F, Saglio G, Baccarani M, Rosti G (2011) Frontline imatinib treatment of chronic myeloid leukemia: no impact of age on outcome, a survey by the GIMEMA CML Working Party. Blood 117(21):5591–5599. doi:10.1182/blood-2010-12-324228
Pemmaraju N, Kantarjian H, Shan J, Jabbour E, Quintas-Cardama A, Verstovsek S, Ravandi F, Wierda W, O'Brien S, Cortes J (2012) Analysis of outcomes in adolescents and young adults with chronic myelogenous leukemia treated with upfront tyrosine kinase inhibitor therapy. Haematol Hematol J 97(7):1029–1035. doi:10.3324/haematol.2011.056721
Stock W (2010) Adolescents and young adults with acute lymphoblastic leukemia. ASH Educ Program Book 2010(1):21–29. doi:10.1182/asheducation-2010.1.21
Advani AS (2013) Biology and treatment of acute lymphocytic leukemia in adolescents and young adults. ASCO Educ Book 2013:285–289
Anders CK, Johnson R, Litton J, Phillips M, Bleyer A (2009) Breast cancer before age 40 years. Semin Oncol 36(3):237–249. doi:10.1053/j.seminoncol.2009.03.001
Anders CK, Hsu DS, Broadwater G, Acharya CR, Foekens JA, Zhang Y, Wang Y, Marcom PK, Marks JR, Febbo PG, Nevins JR, Potti A, Blackwell KL (2008) Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression. J Clin Oncol 26(20):3324–3330. doi:10.1200/jco.2007.14.2471
Datta RV, LaQuaglia MP, Paty PB (2000) Genetic and phenotypic correlates of colorectal cancer in young patients. New Eng J Med 342(2):137–138. doi:10.1056/NEJM200001133420216
Prakash S, Sarran L, Socci N, DeMatteo RP, Eisenstat J, Greco AM, Maki RG, Wexler LH, LaQuaglia MP, Besmer P, Antonescu CR (2005) Gastrointestinal stromal tumors in children and young adults—a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature. J Pediatr Hematol Oncol 27(4):179–187. doi:10.1097/01.mph.0000157790.81329.47
Bleyer A, Barr R, Hayes-Lattin B, Thomas D, Ellis C, Anderson B (2008) The distinctive biology of cancer in adolescents and young adults. Nat Rev Cancer 8(4):288–298. doi:10.1038/nrc2349
Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Mueller MC, Pletsch N, Proetel U, Haferlach C, Schlegelberger B, Balleisen L, Haenel M, Pfirrmann M, Krause SW, Nerl C, Pralle H, Gratwohl A, Hossfeld DK, Hasford J, Hochhaus A, Saussele S (2011) Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-alpha in newly diagnosed chronic myeloid leukemia. J Clin Oncol 29(12):1634–1642. doi:10.1200/jco.2010.32.0598
Bleyer WA (2002) Cancer in older adolescents and young adults: epidemiology, diagnosis, treatment, survival, and importance of clinical trials. Med Pediatr Oncol 38(1):1–10. doi:10.1002/mpo.1257
Wein S, Pery S, Zer A (2010) Role of palliative care in adolescent and young adult oncology. J Clin Oncol 28(32):4819–4824. doi:10.1200/jco.2009.22.4543
Ferrari A, Thomas D, Franklin ARK, Hayes-Lattin BM, Mascarin M, van der Graaf W, Albritton KH (2010) Starting an adolescent and young adult program: some success stories and some obstacles to overcome. J Clin Oncol 28(32):4850–4857. doi:10.1200/jco.2009.23.8097
Tonorezos ES, Oeffinger KC (2011) Research challenges in adolescent and young adult cancer survivor research. Cancer 117(10):2295–2300. doi:10.1002/cncr.26058
Latagliata R, Breccia M, Carmosino I et al (2005) Elderly patients with Ph+ chronic myelogenous leukemia (CML): results of imatinib mesylate treatment. Leukemia Research 29(3):287–291. doi:doi:dx.doi.org/10.1016/j.leukres.2004.08.002
Fabarius A, Leitner A, Hochhaus A, Müller MC, Hanfstein B, Haferlach C, Gohring G, Schlegelberger B, Jotterand M, Reiter A, Jung-Munkwitz S, Proetel U, Schwaab J, Hofmann WK, Schubert J, Einsele H, Ho AD, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Lauseker M, Pfirrmann M, Hasford J, Saussele S, Hehlmann R (2011) Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood 118(26):6760–6768. doi:10.1182/blood-2011-08-373902
Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J, Baccarani M, Cortes J, Cross NC, Druker BJ, Gabert J, Grimwade D, Hehlmann R, Kamel-Reid S, Lipton JH, Longtine J, Martinelli G, Saglio G, Soverini S, Stock W, Goldman JM (2006) Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 108(1):28–37. doi:2006-01-0092 [pii]10.1182/blood-2006-01-0092
Emig M, Saussele S, Wittor H, Weisser A, Reiter A, Willer A, Berger U, Hehlmann R, Cross NCP, Hochhaus A (1999) Accurate and rapid analysis of residual disease in patients with CML using specific fluorescent hybridization probes for real time quantitative RT-PCR. Leuk 13(11):1825–1832. doi:10.1038/sj.leu.2401566
Cross NC (2009) Standardisation of molecular monitoring for chronic myeloid leukaemia. Best Pract Res Clin Haematol 22(3):355–365
Muller MC, Cross NCP, Erben P, Schenk T, Hanfstein B, Ernst T, Hehlmann R, Branford S, Saglio G, Hochhaus A (2009) Harmonization of molecular monitoring of CML therapy in Europe. Leuk 23(11):1957–1963. doi:10.1038/leu.2009.168
Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, Cervantes F, Deininger M, Gratwohl A, Guilhot F, Hochhaus A, Horowitz M, Hughes T, Kantarjian H, Larson R, Radich J, Simonsson B, Silver RT, Goldman J, Hehlmann R (2009) Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 27(35):6041–6051. doi:10.1200JCO.2009.25.0779
Cross NCP, White HE, Müller MC, Saglio G, Hochhaus A (2012) Standardized definitions of molecular response in chronic myeloid leukemia. Leuk 26(10):2172–2175
Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, Apperley J, Cervantes F, Cortes J, Deininger M, Gratwohl A, Guilhot F, Horowitz M, Hughes T, Kantarjian H, Larson R, Niederwieser D, Silver R, Hehlmann R (2006) Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 108(6):1809–1820. doi:10.1182/blood-2006-02-005686
Pfirrmann M, Hochhaus A, Lauseker M, Sausele S, Hehlmann R, Hasford J (2011) Recommendations to meet statistical challenges arising from endpoints beyond overall survival in clinical trials on chronic myeloid leukemia. Leukemia 25(9):1433–1438
Gooley T, Leisenring W, Crowley J, Storer BE (1999) Estimation of failure probabilities in the presence of competiting risks:new representations of old estimators. Stat Med 18(6):695–706
Gray RJ (1988) A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16(3):1141–1154. doi:10.1214/aos/1176350951
Statistical Yearbook for the Federal Republic of Germany including "International tables" (2011). Federal Statistical Office, Wiesbaden
Bleyer A OLM, Barr R, Ries LAG (eds): Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival:1975–2000. National Cancer Institute, NIH Pub. No. 06–5767. Bethesda, MD 2006. http://seer.cancer.gov/publications/aya/. Accessed 10 March 2012.
Adler R, Viehmann S, Kuhlisch E, Martiniak Y, Röttgers S, Harbott J, Suttorp M (2009) Correlation of BCR/ABL transcript variants with patients characteristics in childhood chronic myeloid leukemia. Eur J Haematol 82(2):112–118
Millot F, Suttorp M, Guilhot J, Sedlacek P, De Bont ES, Li CK, Kalwak K, Lausen B, Srdjana C, Dresse M-F, Biondi A, Baruchel A (2012) The International Registry for Chronic Myeloid Leukemia (CML) in Children and Adolescents (I-CML-Ped-Study): objectives and preliminary results. ASH Annu Meeting Abstracts 120(21):3741
Millot F, Traore P, Guilhot J, Nelken B, Leblanc T, Leverger G, Plantaz D, Bertrand Y, Bordigoni P, Guilhot F (2005) Clinical and biological features at diagnosis in 40 children with chronic myeloid leukemia. Pediatr 116(1):140–143. doi:10.1542/peds.2004-2473
Hanfstein B, Müller MC, Hehlmann R, Erben P, Lauseker M, Fabarius A, Schnittger S, Haferlach C, Goehring G, Proetel U, Kolb HJ, Krause SW, Hofmann WK, Schubert J, Einsele H, Dengler J, Haenel M, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Branford S, Hughes TP, Spiekermann K, Baerlocher GM, Pfirrmann M, Hasford J, Saussele S, Hochhaus A, Sakk GCMLSG (2012) Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leuk 26(9):2096–2102. doi:10.1038/leu.2012.85
Marin D, Ibrahim AR, Lucas C, Gerrard G, Wang L, Szydlo RM, Clark RE, Apperley JF, Milojkovic D, Bua M, Pavlu J, Paliompeis C, Reid A, Rezvani K, Goldman JM, Foroni L (2012) Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol 30(3):232–238. doi:10.1200/jco.2011.38.6565
Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, Cervantes F, Clark RE, Cortes JE, Guilhot F, Hjorth-Hansen H, Hughes TP, Kantarjian HM, Kim DW, Larson RA, Lipton JH, Mahon FX, Martinelli G, Mayer J, Muller MC, Niederwieser D, Pane F, Radich JP, Rousselot P, Saglio G, Saussele S, Schiffer C, Silver R, Simonsson B, Steegmann JL, Goldman JM, Hehlmann R (2013) European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. doi:10.1182/blood-2013-05-501569
Gryfe R, Kim H, Hsieh ETK, Aronson MD, Holowaty EJ, Bull SB, Redston M, Gallinger S (2000) Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 342(2):69–77. doi:10.1056/nejm200001133420201
Vriens M, Moses W, Weng J et al (2011) Clinical and molecular features of papillary thyroid cancer in adolescents and young adults. Cancer 117(2):259–267
Harrison CJ (2009) Cytogenetics of paediatric and adolescent acute lymphoblastic leukaemia. Br J Haematol 144(2):147–156. doi:10.1111/j.1365-2141.2008.07417.x
Belloc F, Moreau-Gaudry F, Uhalde M, Cazalis L, Jeanneteau M, Lacombe F, Praloran V, Mahon F-X (2007) Imatinib and Nilotinib induce apoptosis of chronic myeloid leukemia cells through a Bim-dependant pathway modulated by cytokines. Cancer Biology & Therapy 6(6):912–919
Zhang B, Li M, McDonald T, Holyoake TL, Moon RT, Campana D, Shultz L, Bhatia R (2013) Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt–β-catenin signaling. Blood 121(10):1824–1838. doi:10.1182/blood-2012-02-412890
Mustjoki S, Richter J, Barbany G, Ehrencrona H, Fioretos T, Gedde-Dahl T, Gjertsen BT, Hovland R, Hernesniemi S, Josefsen D, Koskenvesa P, Dybedal I, Markevarn B, Olofsson T, Olsson-Stromberg U, Rapakko K, Thunberg S, Stenke L, Simonsson B, Porkka K, Hjorth-Hansen H (2013) Impact of malignant stem cell burden on therapy outcome in newly diagnosed chronic myeloid leukemia patients. Leuk 27(7):1520–1526. doi:10.1038/leu.2013.19
Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MW, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson RA (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355(23):2408–2417. doi:10.1056/NEJMoa062867
Aben KKVGC, Van Gils NA, Van der Graaf WT, Zielhuis GA (2012) Cancer in adolescents and young adults (15–29 years): a population-based study in the Netherlands 1989–2009. Acta Oncologica 51(7):922–933. doi:10.3109/0284186X.2012.705891
Acknowledgments
The authors would like to thank Gabriele Bartsch, Uwe Böhm, Elke Matzat, Sabine Dean, Ute Kossak, Barbara Müller, Regina Pleil-Lösch, Nicole Schomber, Andrea Poetsch, Inge Stalljann, and all CML trial participants (see supplemental Appendix in the online article).
Conflict of interest
The CML study IV is supported by the Deutsche Krebshilfe (no. 106642 and 109588), Novartis, Nürnberg, Germany, Kompetenznetz für Akute and Chronische Leukämien (BMBF 01GI0270), José-Carreras Leukämiestiftung (DJCLS H09/01f, H06/04v, H03/01, R05/23), and the European LeukemiaNet (LSHC-CT-2004-503216). The authors declare no conflicts of interest.
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Data presented in part at the ELN Frontiers Meeting, November 9–11, 2012, Istanbul, Turkey
The study is registered at NIH, ClinicalTrials.gov identifier: NCT00055874 (http://clinicaltrials.gov)
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Kalmanti, L., Saussele, S., Lauseker, M. et al. Younger patients with chronic myeloid leukemia do well in spite of poor prognostic indicators: results from the randomized CML study IV. Ann Hematol 93, 71–80 (2014). https://doi.org/10.1007/s00277-013-1937-4
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DOI: https://doi.org/10.1007/s00277-013-1937-4