Loss of Major Molecular Response As a Trigger for Restarting Tyrosine Kinase Inhibitor Therapy in Patients With Chronic-Phase Chronic Myelogenous Leukemia Who Have Stopped Imatinib After Durable Undetectable Disease

Rousselot, Philippe; Charbonnier, Aude; Cony‐Makhoul, Pascale; Agapé, Philippe; Nicolini, Franck E.; Varet, Bruno; Gardembas, Martine; Étienne, Gabriel; Réa, Delphine; Roy, Lydia; Escoffre‐Barbe, Martine; Guerci‐Bresler, Agnès; Tulliez, Michel; Prost, Stéphane; Spentchian, Marc; Cayuela, Jean Michel; Reiffers, Josy; Chomel, Jean‐Claude; Turhan, Ali G.; Guilhot, Joëlle; Guilhot, François; Mahon, François‐Xavier

doi:10.1200/jco.2012.48.5797

Cited by 362 publications

(439 citation statements)

References 13 publications

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“…In the ISAV study 48% of patients relapsed, with an overall risk of relapse at 36 months of 52%. The fact that imatinib can be interrupted was already demonstrated in other trials such as the STIM and the TWISTER studies [16][17][18]22,23]. The relapse of approximately 50% of patients after 2 years of FUP is now a consistent figure across several studies, including patients treated with second generation TKIs [24].…”

Section: Discussionmentioning

confidence: 92%

“…Despite this indication, several interruption studies showed that it is possible to safely interrupt imatinib treatment without experiencing progression of disease [13][14][15]. The STIM trial, the largest interruption study so far, showed that approximately 40% of patients maintained CMR [16,17]. The majority of the relapses (58%) occurred in the first 6 months after imatinib interruption.…”

Section: Introductionmentioning

confidence: 99%

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Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study

et al. 2015

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Imatinib is effective for the treatment of chronic myeloid leukemia (CML). However even undetectable BCR-ABL1 by Q-RT-PCR does not equate to eradication of the disease. Digital-PCR (dPCR), able to detect 1 BCR-ABL1 positive cell out of 10 7 , has been recently developed. The ISAV study is a multicentre trial aimed at validating dPCR to predict relapses after imatinib discontinuation in CML patients with undetectable Q-RT-PCR. CML patients under imatinib therapy since more than 2 years and with undetectable PCR for at least 18 months were eligible. Patients were monitored by standard Q-RT-PCR for 36 months. Patients losing molecular remission (two consecutive positive Q-RT-PCR with at least 1 BCR-ABL1/ABL1 value above 0.1%) resumed imatinib. The study enrolled 112 patients, with a median follow-up of 21.6 months. Fifty-two of the 108 evaluable patients (48.1%), relapsed; 73.1% relapsed in the first 9 months but 14 late relapses were observed between 10 and 22 months. Among the 56 not-relapsed patients, 40 (37.0% of total) regained Q-RT-PCR positivity but never lost MMR. dPCR results showed a significant negative predictive value ratio of 1.115 [95% CI: 1.013-1.227]. An inverse relationship between patients age and risk of relapse was evident: 95% of patients <45 years relapsed versus 42% in the class 45 to <65 years and 33% of patients 65 years [P(v 2 ) < 0.0001]. Relapse rates ranged between 100% (<45 years, dPCR1) and 36% (>45 years, dPCR-). Imatinib can be safely discontinued in the setting of continued PCR negativity; age and dPCR results can predict relapse.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study

et al. 2015

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“…It has also been noted in this study and others that patients with low level positivity for BCR-ABL transcripts may be able to remain off therapy with only close monitoring. This was recently addressed systematically by French investigators, where it appeared safe and effective to only resume patients on TKI therapy if their transcript level became >0.1% (i.e., loss of MMR) [75].…”

Section: Treatment Duration and Discontinuationmentioning

confidence: 99%

Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management

2014

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Disease overview: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1–2 cases per 100,000 adults, and accounts for ∼15% of newly diagnosed cases of leukemia in adults. Diagnosis: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR‐ABL fusion oncogene, which in turn translates into a Bcr‐Abl oncoprotein. Frontline therapy: Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and dasatinib have been approved by the US Food and Drug Administration for the first‐line treatment of patients with newly diagnosed CML in chronic phase (CML‐CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses; their impact on long‐term survival remains to be determined. Salvage therapy: For patients who fail frontline therapy, second‐line options include second and third generation TKIs. Although second and third generation TKIs are potent and specific BCR‐ABL TKIs, they exhibit unique pharmacological profiles and response patterns relative to different patient characteristics, such as patients comorbidities, disease stage, and BCR‐ABL mutational status. Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib. Allogeneic transplantation remains an important therapeutic option for CML‐CP who have failed at least 2 TKIs, and for all patients in advanced phase disease. Am. J. Hematol. 89:547–556, 2014. © 2014 Wiley Periodicals, Inc.

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“…For example, early case reports of TFR using lower thresholds for cessation-such as major cytogenetic response, CCyR, or MMR-demonstrated high rates of molecular and/or cytogenetic relapse, with nearly all patients relapsing following TKI cessation [47][48][49]. In studies of patients achieving deeper molecular responses, relapse in TFR was less frequent, occurring in approximately one-half to two-thirds of patients following frontline imatinib cessation [28,45,50,51]. The particular level of deeper molecular response required for successful TFR following TKI therapy is not yet known.…”

Section: Clinical Tfr Studies With Imatinibmentioning

confidence: 99%

“…The particular level of deeper molecular response required for successful TFR following TKI therapy is not yet known. Factors that are potentially predictive of relapse in TFR (e.g., time to BCR-ABL1 negativity, sex, Sokal risk score, duration of imatinib treatment prior to TFR) have been evaluated in several studies but without consistent results [28,51,52].…”

Section: Clinical Tfr Studies With Imatinibmentioning

confidence: 99%

Molecular monitoring to improve outcomes in patients with chronic myeloid leukemia in chronic phase: Importance of achieving treatment‐free remission

Erba

2015

American J Hematol

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Imatinib was the first BCR-ABL1 tyrosine kinase inhibitor (TKI) developed for the treatment of patients with chronic myeloid leukemia (CML); subsequently, the introduction of more potent BCR-ABL1 TKIs has raised expectations regarding the speed and depth of response. This review discusses how molecular monitoring is being used as an integral part of the treatment regimen to achieve improved outcomes in patients with CML. The long-term prognostic implications of achieving early molecular response to TKI therapy and the feasibility of maintaining treatment-free remission will also be discussed in light of current clinical data.

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Loss of Major Molecular Response As a Trigger for Restarting Tyrosine Kinase Inhibitor Therapy in Patients With Chronic-Phase Chronic Myelogenous Leukemia Who Have Stopped Imatinib After Durable Undetectable Disease

Abstract: Loss of MMR is a practical and safe criterion for restarting therapy in patients with CML with prolonged CMR.

Cited by 362 publications

References 13 publications

Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study

Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study

Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management

Molecular monitoring to improve outcomes in patients with chronic myeloid leukemia in chronic phase: Importance of achieving treatment‐free remission

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