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

Hughes, Timothy P.; Deininger, Michael W.; Hochhaus, Andreas; Branford, Susan; Radich, Jerald P.; Kaeda, Jaspal; Baccarani, Michele; Cortés, Jorge E.; Cross, Nicholas C. P.; Druker, Brian J.; Gabert, Jean; Grimwade, David; Hehlmann, Rüdiger; Kamel‐Reid, Suzanne; Lipton, Jeffrey H.; Longtine, Janina A.; Martinelli, Giovanni; Saglio, Giuseppe; Soverini, Simona; Stock, Wendy; Goldman, John M.

doi:10.1182/blood-2006-01-0092

Cited by 1,077 publications

(918 citation statements)

References 84 publications

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“…27 An International program is now underway to harmonize the reporting of results according to the international scale in chronic myeloid leukemia. 15,16,28,29 In this regard, our study is reliable in that the measurement of BCR-ABL1 transcripts by RQ-PCR was performed at central laboratory and expressed results according to the concept of both international scale (for p210 BCR-ABL1 ) and log reduction from the standardized pooled baseline (for p190 BCR-ABL1 ) for the first time in Ph-positive ALL.…”

Section: Discussionmentioning

confidence: 91%

“…Major molecular response (MMR) was defined as a ratio of BCR-ABL1 to ABL1 p0.1% on the international scale (for p210 BCR-ABL1 ) or a reduction in BCR-ABL1 transcript level by at least 3-log from the standardized pooled baseline value (for p190 BCR-ABL1 ). 15,16 Complete molecular response (CMR 4.5 , 4.5 log sensitivity) was defined as undetectable levels of BCR-ABL1 transcript. On the basis of MRD quality and its kinetics, we stratified entire patients into four subgroups as follows: (1) early-stable molecular responders (EMRs; patients showing early and persistent MMR or CMR 4.5 by the end of two courses of imatinib-based chemotherapy), (2) late molecular responders (LMRs; patients showing a conversion of MRD levels from no MMR to MMR or CMR 4.5 by the end of two courses of imatinib-based chemotherapy), (3) intermediate molecular responders (IMRs; patients showing late or persistent MRD levels of 40.1 to 1% (for p210 BCR-ABL1 ) oro3-log to 2-log reduction (for p190 BCR-ABL1 ) by the end of two courses of imatinib-based chemotherapy) and (4) poor molecular responders (PMRs; patients showing persistent MRD levels of41% (for p210 BCR-ABL1 ) or o2-log reduction (for p190 BCR-ABL1 ) by the end of two courses of imatinib-based chemotherapy).…”

Section: Mrd Monitoringmentioning

confidence: 99%

“…Moreover, MRD assessment was not performed according to the concept of international scale or log reduction from the standardized pooled baseline. 15,16 From this point of view, we conducted a systemic reevaluation to describe the significance of MRD reduction and its kinetics during a uniform first-line imatinib-based chemotherapy course as a risk factor of SCT outcome by analyzing 95 Ph-positive ALL transplants with a sufficient follow-up duration of 5 years.…”

Section: Introductionmentioning

confidence: 99%

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Impact of minimal residual disease kinetics during imatinib-based treatment on transplantation outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia

et al. 2012

Leukemia

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We conducted a systemic evaluation to describe the effect of minimal residual disease (MRD) kinetics on long-term allogeneic transplantation outcome by analyzing 95 adult transplants with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) who received first-line two courses of imatinib-based chemotherapy (median follow-up 5 years). MRD monitoring was centrally evaluated by real-time quantitative PCR (4.5 log sensitivity). After the first course of imatinib-based chemotherapy, 33 patients (34.7%) achieved at least major molecular response. On the basis of MRD kinetics by the end of two courses of imatinibbased chemotherapy, we stratified entire patients into four subgroups: early-stable molecular responders (EMRs, n ¼ 33), late molecular responders (LMRs, n ¼ 35), intermediate molecular responders (IMRs, n ¼ 9) and poor molecular responders (PMRs, n ¼ 18). Multivariate analysis showed that the most powerful factor affecting long-term transplantation outcome was MRD kinetics. Compared with EMRs, IMRs or PMRs had significantly higher risk of treatment failure in terms of relapse and disease-free survival (DFS). LMRs had a tendency toward a lower DFS. Quantitative monitoring of MRD kinetics during the first-line imatinib-based chemotherapy course is useful in identifying subgroups of Ph-positive ALL transplants at a high risk of relapse.

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Section: Discussionmentioning

confidence: 91%

Section: Mrd Monitoringmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impact of minimal residual disease kinetics during imatinib-based treatment on transplantation outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia

et al. 2012

Leukemia

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“…Resistance to imatinib in CML patients has been related to changes to BCR-ABL-dependent or -independent mechanisms (Quintas-Cardama and Cortes, The most frequent process underlying this mechanism is point mutations to BCR-ABL involving the ATP-binding pocket, which prevent imatinib binding (Hughes et al, 2006;O'Hare et al, 2007). However, other mechanisms have also been implicated including the duplication and amplification of the BCR-ABL (Weisberg and Griffin, 2000;le Coutre et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

et al. 2012

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In chronic myeloid leukemia (CML), the BCR-ABL fusion oncoprotein activates multiple pathways involved in cell survival, growth promotion and disease progression. In this report, we show that the signal transducing adaptor protein-2 (STAP-2) is involved in BCR-ABL activity. We demonstrate that STAP-2 bound to BCR-ABL, and BCR and ABL proteins, depending on the STAP-2 Src homology 2-like domain. BCR-ABL phosphorylates STAP-2 Tyr250 and the phosphorylated STAP-2 in turn up-regulated BCR-ABL phosphorylation, leading to enhanced activation of downstream signaling molecules including ERK, STAT5, BCL-xL and BCL-2. In addition, STAP-2 interacts with BCR-ABL to alter chemokine receptor expression leading to downregulation of CXCR4 and upregulation of CCR7. The interaction between STAP-2 and BCR-ABL plays a crucial role in conferring a growth advantage and resistance to imatinib, a BCR-ABL inhibitor, as well as tumor progression. Notably, mice injected with BCR-ABL/STAP-2-expressing Ba/F3 cells developed lymph node enlargement and hepatosplenomegaly. Moreover, suppression of STAP-2 in K562 CML cells resulted in no tumor formation in mice. Our results demonstrate a critical contribution of STAP-2 in BCR-ABL activity, and suggest that STAP-2 might be an important candidate for drug development for patients with CML. Further, the expression of STAP-2 provides useful information for estimating the characteristics of individual CML clones

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“…1,30,31 When a patient initiates treatment with a tyrosine kinase inhibitor (TKI), bone marrow cytogenetics should be measured every 6 months until a CCyR is achieved and then every 1 to 3 years as long as MMR is stable. BCR-ABL transcript levels should be monitored at least every 3 months and every 3 to 6 months once a CCyR is reached.…”

Section: Imatinib Nilotinib Dasatinibmentioning

confidence: 99%

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Kantarjian

Cortés

Rosée

et al. 2010

Cancer

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Identification of BCR‐ABL as the defining leukemogenic event in chronic myelogenous leukemia (CML) revolutionized the treatment of the disease. Imatinib, a potent BCR‐ABL inhibitor, is the standard of care for the first‐line treatment of patients with chronic‐phase CML because of its high long‐term response rates and favorable tolerability profile compared with previous standard therapies. However, resistance to imatinib develops in 2% to 4% of patients annually. For patients with acquired cytogenetic resistance to standard‐dose imatinib (400 mg daily), imatinib dose escalation (600‐800 mg daily) is an excellent first option for managing patients and achieving cytogenetic responses. However, for patients with primary resistance to imatinib, hematologic disease recurrence, or emergent BCR‐ABL kinase domain mutations, imatinib dose escalation may not be sufficient to control the disease. For these patients, the potent second‐generation tyrosine kinase inhibitors dasatinib and nilotinib are available. Both agents provide effective therapeutic options for patients with imatinib resistance or intolerance. For the current overview, the authors reviewed the data supporting the use of both dasatinib and nilotinib in imatinib‐resistant or imatinib‐intolerant patients, and they have highlighted the future of CML therapy. Overall, the article is intended to offer physicians a comprehensive review of the current literature and to provide data supporting various treatment options for patients with CML throughout the course of imatinib therapy and beyond. Cancer 2010. © 2010 American Cancer Society.

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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

Cited by 1,077 publications

References 84 publications

Impact of minimal residual disease kinetics during imatinib-based treatment on transplantation outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia

Impact of minimal residual disease kinetics during imatinib-based treatment on transplantation outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia

STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

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