High-risk additional chromosomal abnormalities at low blast counts herald death by CML
Authors: Hehlmann Rüdiger , Voskanyan Astghik , Lauseker Michael , Pfirrmann Markus , Kalmanti Lida , Rinaldetti Sebastien , Kohlbrenner Katharina , Haferlach Claudia , Schlegelberger Brigitte , Fabarius Alice , Seifarth Wolfgang , Spieß Birgit , Wuchter Patrick , Krause Stefan , Kolb Hans-Jochem , Neubauer Andreas , Hossfeld Dieter K. , Nerl Christoph , Gratwohl Alois , Baerlocher Gabriela M. , Burchert Andreas , Brümmendorf Tim H. , Hasford Jörg , Hochhaus Andreas , Saußele Susanne , Baccarani Michele ,   for the SAKK and the German CML Study Group, von Weikersthal L. Fischer , Hahn M. , Schlimok G. , Reichert D. , Janssen J. , Martens U. , Majunke P. , Reichert Peter , Neben K. , Korsten S. , Scholz Ch. , Oldenkott B. , Heßling J. , Kingreen D. , Sperling C. , Schelenz C. , Blau I. , Urmersbach A. , Ludwig W. , Le Coutre P. , Arnold R. , de Wit M. , Pezzutto A. , Schäfer E. , Schroers R. , Lochter A. , Behringer D. , Ko Y. , Weidenhöfer S. , Verbeek W. , Brossart P. , Trenn G. , Pommerien W. , Krauter J. , Doering G. , Munzinger H. , Diekmann C. , Hertenstein B. , Stier S. , Möller-Faßbender F. , Hänel M. , Zöller T. , Lamberti C. , Koch B. , Henzel A. , Wagner S. , Schmalenbach A. , Hoffknecht M. , Ehninger G. , Kiani A. , Illmer T. , Aul C. , Flaßhove M. , Henneke F. , Simon M. , Müller L. , Becker H. , Janz R. , Eckart M. J. , Fuchs R. , Schlegel F. , Wattad M. , Rudolph R. , Beelen D. W. , Lindemann A. , Linck D. , Wassman  , Jäger E. , Al-Batran S. , Reiber T. , Waller C. F. , Hoeffkes H. , Schulz L. , Tajrobehkar K. , Mittermüller J. , Pralle H. , Runde V. , Hoyer A. , Tessen H. , Trümper L. , Schmidt C. , Sieber M. , Eschenburg H. , Depenbusch R. , Rösel S. , Lindemann H. W. , Wolf H. , Spohn C. , Moeller R. , Hossfeld D. , Zander A. , Schafhausen P. , Köster H. , Hollburg W. , Schmitz N. , Dürk H. , Hemeier M. , Grote-Metke A. , Weischer H. , Bechtel B. , Balleisen L. , Sosada M. , Ho A. , Petersen V. , Dengler J. , Bildat S. , Hahn L. , Dietzfelbinger H. , Gröschel W. , Bartholomäus A. , Freier W. , Sievers B. , Pfreundschuh I.-M. , Herrmann T. , Fauser A. , Menzel J. , Kemmerling M. , Hansen R. , Link H. , Schatz M. , Bentz M. , Prümmer O. , Kneba M. , Heymanns J. , Schmitz S. , Scheid C. , Lollert A. , Neise M. , Planker M. , Stauch M. , Schröder M. , Kempf B. , Vehling-Kaiser U. , Kremers S. , Köchling G. , Müller L. , Hartmann F. , Neuhaus T. , Fetscher S. , Kämpfe D. , Heil G. , Uppenkamp M. , Goldmann B. , Huber T. Fischer , Hieber U. , Plöger C. , Griesshammer M. , Lange C. , Göttler B. , Lunscken C. , Schiel X. , Scheidegger C. , Stötzer O. , Hitz H. , Schick H. , Völkl S. , Spiekermann K. , Berdel W. , Hebart H. , Ladda E. , Schmidt P. , Burkhardt U. , Hentschke S. , Falge C. , Reschke D. , Köhne C. A. , Müller-Naendrup C. , Sauer M. , Frühauf S. , Ranft K. , Dencausse Y. , Sandritter B. , Baake G. , Hofknecht M. , Dengler R. , Edinger M. , Schenk M. , Wehmeier A. , Weidelich H.-P. , Pihusch R. , Stahlhut K. , Baldus M. , Matzdorff A. , Geer T. , Schanz S. , Käfer G. , Gassmann W. , Priebe-Richter C. , Demandt M. , Springer G. , Fiechtner H. , Denzlinger C. , Schleicher J. , Assman D. , Gaeckler R. , Adam G. , Waladkhani A. , Rendenbach B. , Forstbauer H. , Kanz L. , Jacki S. , Stegelmann F. , Kalhori N. , Nusch A. , Langer W. , Müller F. , Brettner S. , Uebelmesser B. , Kamp T. , Schadeck-Gressel C. , Josten K. , Klein O. , Schwerdtfeger R. , Baurmann H. , Strotkötter H. , Fett W. , Raghavachar A. , Maintz C. , Goebler M. C. , Schlag R. , Elsel W. , Wernli M. , Heim D. , Wuillemin W. , Hess U. , Gmür J. , Mayer J. 
Published: May 2020

Blast crisis is one of the remaining challenges in chronic myeloid leukemia (CML). Whether additional chromosomal abnormalities (ACAs) enable an earlier recognition of imminent blastic proliferation and a timelier change of treatment is unknown. One thousand five hundred and ten imatinib-treated patients with Philadelphia-chromosome-positive (Ph+) CML randomized in CML-study IV were analyzed for ACA/Ph+ and blast increase. By impact on survival, ACAs were grouped into high risk (+8, +Ph, i(17q), +17, +19, +21, 3q26.2, 11q23, −7/7q abnormalities; complex) and low risk (all other). The presence of high- and low-risk ACAs was linked to six cohorts with different blast levels (1%, 5%, 10%, 15%, 20%, and 30%) in a Cox model. One hundred and twenty-three patients displayed ACA/Ph+ (8.1%), 91 were high risk. At low blast levels (1–15%), high-risk ACA showed an increased hazard to die compared to no ACA (ratios: 3.65 in blood; 6.12 in marrow) in contrast to low-risk ACA. No effect was observed at blast levels of 20–30%. Sixty-three patients with high-risk ACA (69%) died (n = 37) or were alive after progression or progression-related transplantation (n = 26). High-risk ACA at low blast counts identify end-phase CML earlier than current diagnostic systems. Mortality was lower with earlier treatment. Cytogenetic monitoring is indicated when signs of progression surface or response to therapy is unsatisfactory.