CC BY
9Citation: Cellular Therapy and Transplantation, Vol. 1, No. 2, 2 December 2008, p. 86-92 doi: 10.3205/ctt-2008-en-000015.01
© The Authors. This article is provided under the following license: Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 Germany, http://creativecommons.org/licenses/by-nc-nd/3.0/de/deed.en
Submitted: 29 September 2008, accepted: 10 October 2008, published: 2 December 2008
Integration of Leukemia Research in Europe: The Paradigm CML1
R. Hehlmann, S. Saußele
III. Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Str. 7-11, 68305 Mannheim, Germany
Correspondence: Rüdiger Hehlmann, Medizinische Fakultät Mannheim, Universität Heidelberg, D-68305 Mannheim, Germany; Tel.: +49 6213834450, Fax:+ 49 6213834239, E-mail: ruediger.hehlmann@med3.ma.uni-heidelberg.de
'Presented at the 2nd Raissa Gorbatschewa Memorial Symposium in St. Petersburg, Russia, on 20.09.2008
Summary
Leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good.
Keywords: European LeukemiaNet, European integration, chronic myeloid leukemia
Introduction
One of the main challenges of current leukemia research is the rarity of leukemias. The incidence of the various leukemias per 100,000 population/year range between around 1 (ALL) and 3-4 (CLL). The challenge is met by collaboration within cooperative groups and networks. Integration of leukemia research in Europe has been achieved to a high degree by cooperation at the level of national leukemia study groups, notably CML study groups, and by networking on national and European levels. The German CML Study Group (founded in 1982) was one of the cofounders of the European Investigators on CML Group (EI-CML), which was
initiated by S. Tura, Bologna, in 1992. Fig. 1 shows the distribution of national CML study groups in Europe. On a German level, the German CML Study Group, together with other German leukemia study groups, started the German Competence Network "Akute und chronische Leukämien" (KNL) in 1997, which was funded by the German Ministry for Education and Research in 1999. The KNL, which combines all leukemia study groups in one country and the EI-CML, which combines all European groups cooperatingon one leukemia, started the European LeukemiaNet (ELN) in 2002. This has been funded by the European Commission (EC) as a Network of Excellence (NoE) from 2004 onwards. Fig. 2 shows a flow diagram of the integration of leukemia research in Europe.
The groups forming the ELN all have convincing records in promoting leukemia research and improving survival for patients with leukemia. An example is the German CML Study Group, with its 600 participants in about 300 centers (Fig. 3). The group has conducted 5 major randomized studies over the past 25 years, which has improved survival of CML patients in Germany significantly from a median survival time of 3-4 years in 1983 to an expected median of about 25 years in 2008. Fig. 4 shows the improvement of survival in the trials of the German CML Study Group up to the present time. The current 5-year-survival of 93% in CML Study IV is better than that reported by any other study group.
The ELN, representing a collaboration of European leukemia study groups and their interdisciplinary partner groups, currently
comprises 147 centers in 28 countries (Fig. 5), and involves about 1,000 physicians and scientists. The participating leukemia study groups are caring for some 10,000 leukemia patients across Europe. Cooperation is amongst 95 national leukemia study groups and 102 interdisciplinary partner groups as depicted in Figs. 6 and 7.
The goals of the ELN are to strengthen scientific and technological excellence in research and treatment of leukemias, promote clinical trials, prepare guidelines, and spread excellence. The success of the European approach in improving research and patient outcome is well illustrated by the paradigm chronic myeloid leukemia (CML).
95 national study groups
European Networks CML AML ALL CLL MDS CMPD
Austria • • • • • •
Belgium * • • • •
Croatia •
Cyprus •
Czech Republic • • • •
Denmark • • • • •
Finland • •
France • • * • • • •
Germany • • • • • •
Hungary • •
Ireland •
Israel • • •
Italy • • • • • • •
Luxembourg • •
Netherlands • • • • • •
Norway •
Poland • • • •
Romania • • •
Russia • •
Serbia •
Spain ■ • • • • • • ■
Sweden • • • • • ■
Switzerland • • • •
Turkey • •
UK • • • • • •
European EI-CML EORTC EORTC ERIC EBMT ECLAP
consortia EBMT EORTC European ET
102 interdisciplinary partner groups
Platform for interdisciplinary specialities Diagnostics Cytogenetics MRD Gene profiling SCT Supportive Care Infections Registry Guidelines
Austria • • • • • •
Belarus • •
Belqijm • • • • • •
Croatia •
Czech Republic • • •
Denmark • • •
Finland • • • •
France • • • • • • • •
Germany • • • • • • • •
Greece •
Hunqary •
Israel • •
Italy • • • • • • • •
Lithuania •
Netherlands • • • • • * • •
Poland • • •
Russia • •
Spain • • • • * » *
Sweden • • • • • • • •
Switzerland • • • • * • •
Turkey • • • • •
UK • ■ ■ ■ ■ • • •
European consortia EGIL EORTC EBMT CLWP EBMT ESH EHA
Paradigm CML
1847: Term "Leukämie" coined 1960: Philadelphia chromosome discovered 1985: Fusion gene BCR-ABL detected 1990: BCR-ABL induces leukemia in mice 1998: BCR-ABL TK inhibitor imatinib in phase I 2008: Median survival (expected) 25 years
The term "leukemia" was coined in 1847 [1] to describe patients with what was later recognized to be CML. The name was later given to the whole group of leukemias. CML became the first neoplastic disease regularly associated with a chromosomal aberration, the Philadelphia-translocation (1960) [2]. CML also became the first neoplastic disease in which the molecular pathogenesis was elucidated. In 1985, the fusion gene BCR-ABL coding for a BCR-ABL fusion tyrosine kinase (TK) was detected, [3] and in 1990 it was shown that BCR-ABL can induce leukemia
in mice4 [4,5] This finding prompted experiments to inhibit BCR-ABL TK via specific inhibitors [6]. In 1998, a phase I trial with the TK inhibitor imatinib was started. The outcome was striking. Even patients with advanced disease achieved cytogenetic remissions [7]- This success was achieved by the cooperation of academic research with drug development by the pharmaceutical industry. The development of a "targeted" therapy for CML would not have been possible without close cooperation among all players in the field (trial groups, groups in cytogenetic and molecular research, pharmaceutical industry, etc.)
The molecular elucidation of CML pathogenesis relied heavily on earlier research with retroviruses and oncogenes. In this research an acute leukemia-inducing murine retrovirus, termed Abelson Virus, was found to contain a 5.6 kb long cellular RNA-sequence which, due to its oncogenic potential, was termed an "ABL oncogene". In the human genome, ABL is located on chromosome 9, from whence part of it is translocated to chromosome 22 in exchange
for a larger piece of chromosome 22 called the "breakpoint cluster region" (BCR), which is in turn translocated to chromosome 9 adjacent to the remaining ABL sequences. According to the locations of the breakpoint and the size of the resulting fusion proteins, 3 sizes of proteins can be identified: a p210 BCR-ABL protein, which is regularly associated with CML; a p190 BCR-ABL protein, which is predominantly found in ALL; and a p230 BCR-ABL protein, which is found in a rare form of CML called "chronic neutrophilic leukemia" or CNL. The BCR-ABL proteins with the locations of the TKs are depicted in Fig. 8. Due to these
findings, CML became the first neoplastic disease in which elucidation of pathogenesis led to a rationally designed therapy targeted at the cause of the disease. The 6-year-survival rate with imatinib in the so-called "IRIS trial", a randomized comparison of imatinib with the former standard therapy interferon (IFN), currently stands at 88%, with a complete cytogenetic remission rate of 82% [8]. The development of survival in CML in various trials during the years 1979-2008 is depicted in Fig. 9. Imatinib has been shown to be superior to IFN, and the survival rate with imatinib is better than with any other therapy.
BCR-ABL tyrosine kinases
IBB I I
SH3SH2SH1
Coiled- Ser-thr- DBL-like RAC GAP coil motif kinase
Binding sites (nucleus, ONA, actin)
p190 kd (e1a2)
p210 kd (b2a2,
b3a2) ^
p230 kd (e19a2)
CML: Survival 1979-2007
Median survival: 2.5 years
to
Schilling, Crowley 1979
tmann et al., 2007
Years after diagnosis
Med. surv. (Ph+): 3.9 years
o »40 eo in mo t2D w m «o Months Cervantes, Razman 1982
Perspective 2008
6 year survival 88%
CML-related deaths
(Including 3% afler BMT. 4% nort-CML related)
12 24 36 48 60 72 S4 Months Since Randomization
Hochhaus et al, ASH 2007
The problem with current imatinib therapy is that—due to various reasons—within 6 years about 37% of patients do not respond satisfactorily or at all to imatinib, or are suspended from treatment. This is in part due to resistance mutations
[9], but also to disease evolution or adverse effects. Therefore various treatment optimization trials were started to improve imatinib therapy either by combination with other agents such as IFN or araC, or by increasing the imatinib dosage. One of these studies, the German 5-arm randomized CML Study IV (GEIST), started in 2002 and has currently recruited more than 1200 patients (Fig. 10). With a survival rate of 94% in the primary imatinib arms, it is more successful than in any other current study. After 36 months, rates of major cytogenetic responses in the primary imatinib arms are close to 90%, of complete cytogenetic remissions more than 85%, and of major molecular remissions around 79%.
Once blast crisis (BC) develops, prognosis remains poor. Median survival of 605 patients with BC in the German CML Studies I, II, III and IIIA (recruitment 1983-2003) is 4 months (Fig. 11). Only 21 patients remain alive; 15 of them after transplantation.
One study of the German CML Study Group (CML-Study III) has evaluated the role of stem cell transplantation by randomized comparison with best available drug treatment
[10]. After a median observation time of more than 8 years with an observation time up to 11 years, a significant survival advantage for best available drug treatment was determined (Fig. 12). It is concluded that drug treatment now should be first line therapy for CML. Stem cell transplantation remains an important second line option and may be given first line on an individual basis.
Various second line TK inhibitors are currently in various phases of evaluation. Dasatinib, which is 325 times more potent than imatinib, has been shown to have an 18-month-survival outcome of 96% in imatinib resistant or intolerant patients [11,12]. In the chronic phase, 100 mg dasatinib once a day has been shown to be equally effective and less toxic than 2x70 mg. Dasatinib has remarkable activity in BC with a 2-year-survival of 38% in myeloid and 26% in lymphoid BC. A relevant property of dasatinib is its ability to pass the blood/ brain barrier [13]. Nilotinib is about 30 times more potent than imatinib, and also has good activity in blast crisis with a 12-month-survival rate of 42% [14].
In conclusion, dasatinib and nilotinib have hematologic and cytogenetic efficacy in imatinib resistant and intolerant CML in all phases, and are active against all BCR-ABL TK-mutations except T315I. Main toxicities are cytopenias and pleural effusions (dasatinib). After dasatinib and nilotinib treatment new resistance mutations have been observed. For mutation I255V/K both drugs are not sufficiently efficacious at the standard dose, and a dose increase is recommended. In F317L, nilotinib is efficacious, in Y253H dasatinib. Agents in clinical studies include dasatinib and nilotinib in randomized evaluation for first line therapy; bosutinib, INNO406, histone deacetylase inhibitors, aurora kinase inhibitors and others, alone or in combination with other agents, in phase I and II and more in preclinical evaluation.
Fig.
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CML-Study IV: Survival
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....... Primary IFN
5 year survival 91%: n=122
6 12 18 24 30 36 42 48 54 60
Months after diagnosis
66 72
A major goal of the ELN is the development of guidelines for diagnosis and treatment in leukemias. CML management recommendations were published in 2006 [15], APL guidelines in 2008 [16], an update for CML is planned for 2009, and AML guidelines are in preparation. The current CML recommendations are summarized in the algorithm in Fig. 13 [17]. In case of intolerance, toxicity or pregnancy IFN is recommended, in case of imatinib failure or resistance, 2nd generation TK inhibitors or allo-SCT. In the case of suboptimal response patients should be observed closely, and an increase of imatinib dosage should be attempted. If the treatment effect is less than expected
or the toxicity unusually high, compliance should be checked, interactions with other drugs or food considered and the imatinib blood levels determined.
Challenges remaining and requiring new modes of cooperation concern geographic variations and demographics, quality controlled outcome of CML for international comparability, the availability of standardized diagnostics Europe-wide and globally, the role of TK inhibitor trough levels for response and outcome, and the provision of continued information and communication to all players in the field. In order to address these topics, a
EUTOS for CML
European Treatment and Outcome Stuc/v Goals:
• European CML registry
• Molecular monitoring
• Pharmacological monitoring Fig. 14 * Spread of Excellence
public-private partnership between the CML members of ELN and Novartis Oncology Europe has been initiated: the European Treatment and Outcome Study (EUTOS) for CML (Fig. 14). The goals of this cooperation are expansion of the European CML registry, standardized molecular monitoring on an international basis, pharmacological monitoring and the spread of excellence. The contract was signed between the University of Heidelberg as legal representative of the ELN and Novartis in June 2007.
In summary, leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good.
References
1. Virchow R. Weißes Blut (Leukämie). Archiv für path Anat. 1847;1:563.
2. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science. 1960;132:1497-1501.
3. Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 1985;315:550-554.
4. Daley GQ, van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990;247:824-830.
5. Heisterkamp N, Jenster G, ten Hoeve J et al. Acute leukaemia in bcr/abl transgenic mice. Nature. 1990;344:251-253.
6. Druker BJ, Tamura S, Buchdunger E et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Medic. 1996;2:561-566.
7. Druker BJ, Talpaz M, Resta DJ et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031-1037.
8. Druker BJ, Guilhot F, O'Brien SG et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.
9. Hochhaus A, La Rosee P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia. 2004;18:1321-1331.
10. Hehlmann R, Berger U, Pfirrmann M et al. Drug treatment is superior to allografting as first line therapy in chronic myeloid leukemia. Blood. 2007;109:4686-4692.
11. Talpaz M, Shah NP, Kantarjian H et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531-2541.
12. Hochhaus A, Baccarani M, Deininger M et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous
leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008;22:1200-1206.
13. Porkka K, Koskenvesa P, Lundan T et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood. 2008;112:1005-1012.
14. Kantarjian H, Giles F, Wunderle L et al. Nilotinib (AMN107), a novel, highly active, selective BCR-ABL tyrosine kinase inhibitor in patients with Philadelphia-Chromosome (Ph) positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) who are resistant to imatinib mesylate therapy. N Engl J Med. 2006;2542-2551.
15. Baccarani M, Saglio G, Goldman J et al. Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809-1820.
16. Sanz MA, Grimwade D, Tallman MS et al. Guidelines on the management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2008;prepublished online September 23,2008.
17. Hehlmann R, Hochhaus A, Baccarani M. Chronic myeloid leukaemia. Lancet. 2007;370:342-350.
© The Authors. This article is provided under the following license: Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 Germany, http://creativecommons.org/licenses/by-nc-nd/3.0/de/deed.en
Ссылка: Клеточная терапия и трансплантация, том 1, номер 2, 2 декабря 2008, с. 92
doi: 10.3205/ctt-2008-ru-000015.02
Интеграция исследований в области лейкозов в Европе: парадигма хронического миелолейкоза
Хельман Р., Саусселе С.
Резюме
В обзорной статье рассматриваются проблемы в исследовании хронического миелолейкоза (ХМЛ). В частности, ввиду низкой частоты лейкозов в населении, необходима интеграция исследований в Европе путем создания кооперативных групп и исследовательских сетей. Так, Германская группа по изучению ХМЛ, основанная в 1982 г., была в числе основателей Европейской группы по ХМЛ, впоследствии (с 2002 г.) образовалась европейская LeukemiaNet (ELN) под эгидой Европейской комиссии. В Германии в исследованиях по ХМЛ объединены 600 участников из 300 центров. Германская группа провела за 25 лет 5 крупных рандомизированных исследований, причем средняя выживаемость возросла с 3-4 лет в 1983 г. до 25 лет в 2008 г.
Европейская сеть по изучению лейкозов сейчас объединяет 147 центров в 28 странах, включая около 1000 врачей и ученых, под наблюдением находятся около 10000 больных ХМЛ.
Особый акцент делается на изучении ХМЛ, которое было наиболее эффективным в рамках ELN. Из истории исследования ХМЛ следует, что он был первой формой лейкоза с известной специфической мутацией (bcr/abl), и с 1998 г. были начаты клинические испытания иматиниба - ингибитора тирозин киназы, давшие прекрасные результаты. Это был первый опыт «нацеленной» терапии лейкоза с
учетом дефектного гена bcr/abl. В исследовании IRIS было показано клиническое преимущество от лечения иматинибом по сравнению с альфа-интерфероном.
Новые проблемы связаны с постепенным развитием резистентности к иматинибу у части больных (не менее 37% случаев), в силу развития мутаций гена-мишени или эволюции заболевания, а иногда - из-за побочных эффектов терапии. Поэтому дальнейшие работы связаны с комбинированным лечением (совместно с интерфероном или Ара-С) или повышением дозы иматиниба, примером которых является программа GEIST (с 2002 г.), причем полная цитогенетическая ремиссия достигается более чем в 85% случаев.
Основным вопросом является тактика лечения ХМЛ в фазе бластного криза, где продолжительность жизни пока невелика. Предприняты исследования по лечению этих больных путем трансплантации стволовых клеток, по сравнению с наилучшим доступным терапевтическим методом. При длительном наблюдении (8-11 лет) было показано значительное преимущество от применения второго (терапевтического) способа по критериям выживаемости. Поэтому лекарственное лечение было рекомендовано в качестве терапии первой линии при ХМЛ. Трансплантация стволовых клеток остается важной тактикой второй линии и может назначаться в качестве средства первой линии на индивидуальной основе.
Кроме того, на испытаниях в настоящее время находятся препараты-ингибиторы тирозин-киназы второго поколения, как, например, дазатиниб, весьма эффективный у больных, ХМЛ, резистентных к иметинибу, будучи при этом менее токсичным препаратом, эффективным для использования в бластном кризе ХМЛ, способным к проникновению через гемато-энцефалический барьер. Другой препарат, нилотиниб, более чем в 30 раз мощнее иматиниба и также является эффективным при бластном кризе заболевания.
Итак, дазатиниб и нилотиниб эффективны по гематологическим и цитогенетическим критериям в иматиниб-резистентных случаях ХМЛ во всех фазах заболевания и активны при всех мутациях BCR-ABL TK, кроме T315I. Основные токсические реакции состоят в цитопении и плевральной эффузии (дазатиниб). Однако после терапии этими препаратами возникают новые мутации (I255V/K, F317L, Y253H), которые заставляют переходить на лечение другим препаратом. В настоящее время ряд других препаратов проходит клинические испытания, в том числе бозутиниб, ингибиторы гистон-деацетилазы и Аурора-киназы.
Кроме того, сеть ELN разрабатывает правила и руководства по диагностике и лечению. Проблемы состоят в географических различиях демографических особенностей контроля качества диагностики исходов заболевания, сравнимости между государствами, оптимизации контактов между участниками программ. В связи с этим началось частно-общественное партнерство между ELN и фирмой Новартис Онколоджи в рамках программы EUTOS по лечению ХМЛ, с целью стандартизации мониторинга результатов, совершенствования молекулярной диагностики.
Ключевые слова: Европейская Сеть по изучению лейкозов, европейская интеграция, хронический миелоидный лейкоз, ингибиторы тирозинкиназы
