Molecular monitoring of BCR-ABL transcripts in patients with chronic myelogenous leukemia: Is high sensitivity of clinical value?

Current Hematologic Malignancy Reports

Volumn 5, Issue 2, 2010, Pages 88-94

  Norkin, Maxim ^a   Schiffer, Charles A ^a  

^a WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Chronic myelogenous leukemia chronic phase; Cytogenetic complete remission; Q PCR monitoring; Tyrosine kinase inhibitors

Indexed keywords

BCR ABL PROTEIN; BOSUTINIB; DASATINIB; IMATINIB; NILOTINIB; PROTEIN TYROSINE KINASE INHIBITOR;

CANCER GROWTH; CHRONIC MYELOID LEUKEMIA; FOLLOW UP; GENE EXPRESSION PROFILING; HUMAN; MINIMAL RESIDUAL DISEASE; OVERALL SURVIVAL; PATIENT MONITORING; PROGRESSION FREE SURVIVAL; REAL TIME POLYMERASE CHAIN REACTION; REVIEW; TREATMENT FAILURE;

FUSION PROTEINS, BCR-ABL; HUMANS; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE; PROTEIN KINASE INHIBITORS; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; SENSITIVITY AND SPECIFICITY; TRANSCRIPTION, GENETIC; TREATMENT OUTCOME;

EID: 77954625371     PISSN: 15588211     EISSN: 1558822X     Source Type: Journal    
DOI: 10.1007/s11899-010-0046-x     Document Type: Review

References (42)

1. O'Brien SG, Guilhot F, Larson RA, et al.: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003, 348:994-1004.
2. Roy L, Guilhot J, Krahnke T, et al.: Survival advantage from imatinib compared with the combination interferon-alpha plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials. Blood 2006, 108:1478-1484.
3. Kantarjian HM, Talpaz M, O'Brien S, et al.: Survival benefit with imatinib mesylate versus interferon-alpha-based regimens in newly diagnosed chronic-phase chronic myelogenous leukemia. Blood 2006, 108:1835-1840.
4. • Cortes JE, Jones D, O'Brien S, et al.: Results of dasatinib therapy in patients with early chronic-phase chronic myeloid leukemia. J Clin Oncol 2009, 28:398-404. This study demonstrated very high rates of response using dasatinib in previously untreated patients with early CP CML: 98% of patients achieved a CCyR and 82% of patients had MMR. Responses occurred rapidly, with 94% of patients achieving CCyR by 6 months.
5. • Cortes JE, Jones D, O'Brien S, et al.: Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol 2009, 28:392-397. This study demonstrated very high rates of response using nilotinib in previously untreated patients with early CP CML: 98% of patients achieved a CCyR and 76% of patients had a MMR. Responses occurred rapidly, with 96% of patients achieving CCyR by 3 months.
6. Deininger M, O'Brien SG, Guilhot F, et al.: International Randomized Study of Interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib [abstract]. Blood (ASH Annual Meeting Abstracts) 2009, 114:abstract 1126.
7. 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.
8. Kaeda J, O'Shea D, Szydlo RM, et al.: Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy. Blood 2006, 107:4171-4176.
9. •• Kantarjian H, Schiffer C, Jones D, et al.: Monitoring the response and course of chronic myeloid leukemia in the modern era of BCR-ABL tyrosine kinase inhibitors: practical advice on the use and interpretation of monitoring methods. Blood 2008, 111:1774-1780. In this review, the authors discuss different approaches for monitoring the response to TKIs and provide practical advice on how to interpret the results of molecular monitoring.
10. Saglio G, Kim DW, Issaragrisil S, et al.: Nilotinib demonstrates superior efficacy compared with imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase: results from the International Randomized Phase III ENESTnd Trial [abstract]. Blood (ASH Annual Meeting Abstracts) 2009, 114: abstract LBA-1.
11. Hughes TP, Hochhaus A, Branford S, et al.: Reduction of BCRABL transcript levels at 6, 12, and 18 months (mo) correlates with long-term outcomes on imatinib (IM) at 72 mo: an analysis from the International Randomized Study of Interferon versus STI571 (IRIS) in patients (pts) with chronic phase chronic myeloid leukemia (CML-CP) [abstract]. Blood (ASH Annual Meeting Abstracts) 2008, 112:abstract 334.
12. • de Lavallade H, Apperley JF, Khorashad JS, et al.: Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 2008, 26:3358-3363. This large, retrospective study evaluates the response to imatinib in 204 patients with newly diagnosed CML, confirming its high efficacy. The authors showed that achievement of CCyR correlated with PFS and OS, but achievement of MMR had no further predictive value.
13. Hughes TP, Kaeda J, Branford S, et al.: Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003, 349:1423-1432.
14. O'Brien SG, Guilhot F, Goldman JM, et al.: International Randomized Study of Interferon versus STI571 (IRIS) 7-year follow-up: sustained survival, low rate of transformation and increased rate of major molecular response (MMR) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CMLCP) treated with imatinib (IM) [abstract]. Blood (ASH Annual Meeting Abstracts) 2008, 112:abstract 186.
15. Sokal JE, Cox EB, Baccarani M, et al.: Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood 1984, 63:789-799.
16. Morgan GJ, Hughes T, Janssen JW, et al.: Polymerase chain reaction for detection of residual leukaemia. Lancet 1989, 1 (8644):928-929.
17. Mensink E, van de Locht A, Schattenberg A, et al.: Quantitation of minimal residual disease in Philadelphia chromosome positive chronic myeloid leukaemia patients using real-time quantitative RT-PCR. Br J Haematol 1998, 102:768-774.
18. Cross NC, Feng L, Chase A, et al.: Competitive polymerase chain reaction to estimate the number of BCR-ABL transcripts in chronic myeloid leukemia patients after bone marrow transplantation. Blood 1993, 82:1929-1936.
19. Hochhaus A, Lin F, Reiter A, et al.: Quantification of residual disease in chronic myelogenous leukemia patients on interferon-alpha therapy by competitive polymerase chain reaction. Blood 1996, 87:1549-1555.
20. Gabert J, Beillard E, van der Velden VH, et al.: Standardization and quality control studies of 'real-time' quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia-a Europe Against Cancer program. Leukemia 2003, 17:2318-2357.
21. •• Branford S, Fletcher L, Cross NC, et al.: Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials. Blood 2008, 112:3330-3338. These authors attempted to improve the reproducibility of BCR-ABL transcript measurements by RT-PCR among different laboratories by introducing an international scale (IS) based on laboratoryspecific conversion factors calculated by comparisons performed with patient samples against a reference method. The introduction of the IS enhanced the accuracy of comparing molecular response rates between clinical trials using measurements by different laboratories.
22. Robertson JS: International standardization of gene amplification technology. Biologicals 1998, 26:111-113.
23. Cross NC, Hughes TP, Hochhaus A, Goldman JM: International standardisation of quantitative real-time RT-PCR for BCR-ABL. Leuk Res 2008, 32:505-506.
24. Hughes T, Deininger M, Hochhaus A, et al.: 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 2006, 108:28-37.
25. Cortes J, Talpaz M, O'Brien S, et al.:Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate. Clin Cancer Res 2005, 11:3425-3432. (Pubitemid 40627896)
26. Iacobucci I, Saglio G, Rosti G, et al.: Achieving a major molecular response at the time of a complete cytogenetic response (CCgR) predicts a better duration of CCgR in imatinib-treated chronic myeloid leukemia patients. Clin Cancer Res 2006, 12:3037-3042.
27. • Marin D,Milojkovic D, Olavarria E, et al.: European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood 2008, 112:4437-4444. Outcomes for 224 patients with CML in CP treated at a single institution were followed for a median of 46.1 months to validate treatment response recommendations generated by the European Leukemia- Net. In general, the LeukemiaNet criteria had useful predictive value, but the authors advised combining the categories "failure" and "suboptimal response."
28. • Kantarjian H, O'Brien S, Shan J, et al.: Cytogenetic and molecular responses and outcome in chronic myelogenous leukemia: need for new response definitions? Cancer 2008, 112:837-845. The significance of different response criteria for 276 patients with CML receiving imatinib therapy was evaluated. The achievement of durable CCyR and MMR (continuously for ≥12 months) was associated with longer PFS but showed no overall survival advantage.
29. Branford S, Rudzki Z, Harper A, et al.: Imatinib produces significantly superior molecular responses compared to interferon alfa plus cytarabine in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Leukemia 2003, 17:2401-2409.
30. Press RD, Galderisi C, Yang R, et al.: A half-log increase in BCR-ABL RNA predicts a higher risk of relapse in patients with chronic myeloid leukemia with an imatinib-induced complete cytogenetic response. Clin Cancer Res 2007, 13:6136-6143.
31. Press RD, Willis SG, Laudadio J, et al.: Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib. Blood 2009, 114:2598-2605.
32. 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.
33. Stock W, Westbrook CA, Peterson B, et al.: Value of molecular monitoring during the treatment of chronic myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 1997, 15:26-36.
34. Radich JP, Dai H, Mao M, et al.: Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A 2006, 103:2794-2799.
35. •• Oehler VG, Yeung KY, Choi YE, et al.: The derivation of diagnostic markers of chronic myeloid leukemia progression from microarray data. Blood 2009, 114:3292-3298. These authors identified and validated a six-gene signature that discriminated early CP CML from late CP, AP, and BC CML. This may be a particularly useful tool if it can identify patients in CP with a high likelihood of progression. No such discrimination is possible with currently existing clinical, pathologic, or molecular methods.
36. Stanek E, Aubert RE, Sanders C, et al.: Inadequate BCR-ABL monitoring in imatinib-treated patients with chronic myelogenous leukemia [abstract]. J Clin Oncol (Meeting Abstracts) 2009, 27: abstract 7077.
37. Branford S, Seymour JF, Grigg A, et al.: BCR-ABL messenger RNA levels continue to decline in patients with chronic phase chronic myeloid leukemia treated with imatinib for more than 5 years and approximately half of all first-line treated patients have stable undetectable BCR-ABL using strict sensitivity criteria. Clin Cancer Res 2007, 13:7080-7085.
38. Holtz MS, Bhatia R: Effect of imatinib mesylate on chronic myelogenous leukemia hematopoietic progenitor cells. Leuk Lymphoma 2004, 45:237-245.
39. Chu S, Xu H, Shah NP, et al.: Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood 2005, 105:2093-2098.
40. Morley A: Quantifying leukemia. N Engl J Med 1998, 339:627-629.
41. • Rousselot P, Huguet F, Rea D, et al.: Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood 2007, 109:58-60. This is the first study addressing the possibility of imatinib discontinuation in CML patients with undetectable residual disease for more than 2 years. Twelve patients were included and six patients had a molecular relapse. Molecular response was re-established upon re-introduction of imatinib. Six other patients (50%) continued to have an undetectable level of BCR-ABL transcript after a median follow-up of 18 months.
42. Mahon FX, Rea D, Guilhot F, et al.: Discontinuation of imatinib therapy after achieving a molecular response in chronic myeloid leukemia patients. Blood (ASH Annual Meeting Abstracts) 2009, 114:abstract 859.