Abstract
We examined safety and efficacy of STI-571 in 24 bcr/abl-positive patients with CML post PBSCT. At start of STI-571 therapy, nine patients presented in blast crisis (BC) or in accelerated phase (AP), and 15 in chronic phase (CP). Patients were evaluated for hematologic, cytogenetic and molecular response, survival and toxicity. In general, STI-571 was well tolerated in this heavily pretreated group of patients with a non-hematologic and hematologic toxicity profile similar to that observed in a previous phase I trial at comparable doses. Five of nine patients with CML in transformation (AP, BC) were evaluable for hematologic response. Two of five patients had transient reductions in WBC and blasts, and three patients achieved a sustained hematologic response (>4 weeks). Cytogenetic analysis in these patients revealed numerical and/or structural responses. In CML chronic phase, STI-571 induced complete hematologic responses in all patients and major cytogenetic responses in 61% of patients with a complete cytogenetic response rate of 46%. This report indicates that STI-571 is a safe and effective drug in heavily pretreated patients. No apparent additional side-effects were noted in this patient cohort. The high rate of complete hematologic and complete cytogenetic responses in CP patients is remarkable, as intensive treatment approaches plus IFN-alpha failed to be efficient in achieving long-term stabilization of CML in this patient cohort.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Goldman JM, Druker BJ . Chronic myeloid leukemia: current treatment options Blood 2001 98: 2039–2042
Silver RT, Woolf SH, Hehlmann R, Appelbaum FR, Anderson J, Bennett C, Goldman JM, Guilhot F, Kantarjian HM, Lichtin AE, Talpaz M, Tura S . An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemias: developed for the American Society of Hematology Blood 1999 94: 1517–1536
Hehlmann R, Hochhaus A, Berger U, Reiter A . Current trends in the management of chronic myelogenous leukemia Ann Hematol 2000 79: 345–354
Italian Cooperative Study Group on CML. IFN-alpha2a as compared with conventional chemotherapy for the treatment of CML N Engl J Med 1994 330: 820–825
Chronic Myeloid Leukemia Triallists’ Collaborative Group. Interferon alpha versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials J Natl Cancer Inst 1997 89: 1616–1620
McGlave PB, De Fabritiis P, Deisseroth A, Goldman J, Barett M, Reiffers J, Simonsson B, Carella A, Aeppli D . Autologous transplants for chronic myelogenous leukaemia: results Lancet 1994 343: 486–488
Deisseroth AB, Zu Z, Claxton D, Hanania EG, Fu S, Ellerson D, Goldberg L, Thomas M, Janicek K, Anderson WF, Hester J, Korbling M, Durett A, Moen R, Berenson R, Heimfeld S, Hamer J, Clavert L, Tibbits P, Talpaz M, Kantarjian H, Champlin R, Reading C . Genetic marking shows that Ph+ cells present in autologous transplants of chronic myelogenous leukemia (CML) contribute to relapse after autologous bone marrow transplantation in CML Blood 1994 83: 3068–3076
Rowley JD . A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence and Giemsa staining Nature 1973 243: 290–293
Sawyers CL . Chronic myeloid leukaemia N Engl J Med 1999 340: 1330–1340
Shtivelman E, Lifshitz B, Gale RP, Roe BA, Canaani E . Alternative splicing of RNAs transcribed from the human abl gene and from the BCR/ABL fused gene Cell 1986 27: 277–284
Ben-Neriah Y, Daley GQ, Mes-Masson AM, Witte ON, Baltimore D . The chronic myelogenous leukemia-specific P210 protein is the product of the bcr/abl hybrid gene Science 1986 233: 212–214
Heisterkamp N, Jenster G, tenHoeve J, Zovich D, Pattengale PK, Groffen J . Acute leukemia in bcr/abl transgenic mice Nature 1990 344: 251–253
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
Kelliher MA, McLaughlin J, Witte ON, Rosenberg N . Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL Proc Natl Acad Sci USA 1990 87: 6649–6653
Elefanty AG, Hariharan IK, Cory S . Bcr/abl, the hallmark of chronic myelogenous leukemia in man, induces multiple hematopoietic neoplasms in mice EMBO J 1990 9: 1069–1078
Kindler T, Meyer RG, Fischer T . BCR-ABL as a target for novel therapeutic interventions Exp Opin Ther Targets 2002 6: 85–101
Buchdunger E, Zimmermann J, Mett H, Meyer T, Muller M, Druker BJ, Lydon NB . Inhibition of the Abl protein-tyrosin kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative Cancer Res 1996 56: 100–104
Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB . Effects of a selective inhibitor of the ABL tyrosine kinase on the growth of BCR-ABL positive cells Nat Med 1996 2: 561–566
Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J . Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase Science 2000 289: 1938–1942
Druker BJ, Talpaz M, Resta D, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL . 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
Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M . Activity of a specific inhibitor of the bcr-abl tyrosine kinase in the blast crisis of CML and ALL with the Philadelphia chromosome N Engl J Med 2001 344: 1038–1042
Sawyers CL, Hochhaus A, Silver RT, Goldman JM, Miller C, Ottmann OG, Schiffer CA, Talpaz M, Guilhot F, Niederwieser D, Fischer T, O'Brien SG, Stone R, Corneo G, Russell N, Reiffers J, Shea T, Chapuis B, Coutre S, Tura S, Morra E, Larsen R, Saven A, Peschel C, Gratwohl A, Mandelli F, Ben-Am M, Gathmann I, Capdeville R, Paquette RL, Druker B . Glivec™ (imatinib mesylate) induces hematologic and cytogenetic responses in patients with CML in myeloid blast crisis: results of a phase II study Blood 2002 99: 3530–3539
Talpaz M, Silver RT, Druker B, Goldman JM, Gambacorti-Passerini C, Guilhot F, Schiffer CA, Fischer T, Deininger MW, Lennard AL, Hochhaus A, Ottmann OG, Gratwohl A, Baccarani M, Stone R, Tura S, Mahon FX, Fernandes-Reese S, Gathmann I, Capdeville R, Kantarjian HM, Sawyers CL . Glivec™ (imatinib mesylate) induces durable hematologic and cytogenetic responses in patients with accelerated phase CML: results of a phase II study Blood 2002 99: 1928–1937
Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta D, Capdeville R, Zoellner U, Talpaz M, Druker B . Glivec (imatinib mesylate) induces hematologic and cytogenetic responses in the majority of patients with chronic myeloid leukemia in chronic phase: results of a phase II study N Engl J Med 2002 346: 645–652
Hess G, Reifenrath C, Friedrich-Freksa A, Beyer V, Naumann S, Schuch B, Huber C, Fischer T, Decker HJ . Autologous transplantation of in vivo purged PBSC in CML: comparison of FISH, cytogenetics, and PCR detection of Philadelphia chromosome in leukapheresis products Cancer Genet Cytogenet 2000 117: 1–8
Cross NC, Melo JV, Feng L, Goldman JM . An optimized multiplex polymerase chain reaction (PCR) for detection of BCR-ABL fusion mRNAs in haematological disorders Leukemia 1994 8: 186–189
Emig M, Saussele S, Wittor H, Weisser A, Reiter A, Willer A, Berger U, Hehlmann R, Cross NC, Hochhaus A . Accurate and rapid analysis of residual disease in patients with CML using specific fluorescent hybridization probes for real time quantitative RT-PCR Leukemia 1999 13: 1825–1832
Fischer T, Neubauer A, Mohm J, Huhn D, Busemann C, Link H, Arseniev L, Bussing B, Novotny J, Ganser A, Duyster J, Bunjes D, Westermeier T, Flohr T, Despres D, Gamm H, Decker J, Derigs G, Aulitzky W, Huber C . Outcome of peripheral blood stem cell mobilization in advanced phases of CML is dependent on the type of chemotherapy applied Ann Hematol 1998 77: 21–26
Fischer T, Neubauer A, Mohm J, Huhn D, Busemann C, Link H, Arseniev L, Bussing B, Novotny J, Ganser A, Duyster J, Bunjes D, Kreiter S, Aulitzky W, Hehlmann R, Huber C . Chemotherapy-induced mobilization of karyotypically normal PBSC for autografting in CML Bone Marrow Transplant 1998 21: 1029–1036
Deininger MW, Goldman JM, Lydon N, Melo JV . The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells Blood 1997 90: 3691–3698
Hochhaus A, Reiter A, Saussele S, Reichert A, Emig M, Kaeda J, Schultheis B, Berger U, Shepherd PC, Allan NC, Hehlmann R, Goldman JM, Cross NC . Molecular heterogeneity in complete cytogenetic responders after interferon alpha therapy for chronic myeloid leukemia: low levels of minimal residual disease are associated with continuing remission Blood 2000 95: 62–66
Fang G, Naekyung Kim C, Perkins CL, Ramadevi N, Winton E, Wittmann S, Bhalla KN . CCGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to antileukemic drugs Blood 2000 96: 2246–2253
Thiesing TJ, Ohno-Jones S, Kolibaba KS, Druker BJ . Efficacy of STI-571, an ABL tyrosine kinase inhibitor, in conjunction with other antileukemic agents against BCR-ABL-positive cells Blood 2000 96: 3195–3199
Acknowledgements
This work was supported by Deutsche José Carreras Leukämie-Stiftung eV and a research grant from Novartis Pharmaceuticals.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Fischer, T., Reifenrath, C., Hess, G. et al. Safety and efficacy of STI-571 (imatinib mesylate) in patients with bcr/abl-positive chronic myelogenous leukemia (CML) after autologous peripheral blood stem cell transplantation (PBSCT). Leukemia 16, 1220–1228 (2002). https://doi.org/10.1038/sj.leu.2402565
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2402565
Keywords
This article is cited by
-
The chimeric ubiquitin ligase SH2-U-box inhibits the growth of imatinib-sensitive and resistant CML by targeting the native and T315I-mutant BCR-ABL
Scientific Reports (2016)
-
Long-term follow-up of patients with chronic myeloid leukemia having received autologous stem cell transplantation
Annals of Hematology (2011)
-
Allo-hematopoietic cell transplantation for Ph chromosome-positive ALL: impact of imatinib on relapse and survival
Bone Marrow Transplantation (2009)
-
Imatinib use either pre- or post-allogeneic hematopoietic cell transplantation (allo-HCT) does not increase cardiac toxicity in chronic myelogenous leukemia patients
Bone Marrow Transplantation (2009)
-
Update on practical aspects of the treatment of chronic myeloid leukemia with imatinib mesylate
Current Hematologic Malignancy Reports (2006)