Assessment ofBCR-ABL1Transcript Levels at 3 Months Is the Only Requirement for Predicting Outcome for Patients With Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors

PurposeWe studied BCR-ABL1 transcript levels in patients with chronic myeloid leukemia in chronic phase (CML-CP) at 3, 6, and 12 months after starting imatinib to identify molecular milestones that would predict for overall survival (OS) and other outcomes more reliably than serial marrow cytogenetics.Patients and MethodsWe analyzed 282 patients with CML-CP who received imatinib 400 mg/d as first-line therapy followed by dasatinib or nilotinib if treatment with imatinib failed. We used a receiver operating characteristic curve to identify the cutoffs in transcript levels at 3, 6, and 12 months that would best predict patient outcome. We validated our findings in an independent cohort of 95 patients treated elsewhere.ResultsPatients with transcript levels of more than 9.84% (n = 68) at 3 months had significantly lower 8-year probabilities of OS (56.9% v 93.3%; P < .001), progression-free survival, cumulative incidence of complete cytogenetic response, and complete molecular response than those with higher transcript levels. Similarly, transcript levels of more than 1.67% (n = 87) at 6 months and more than 0.53% (n = 93) at 12 months identified high-risk patients. However, transcript levels at 3 months were the most strongly predictive for the various outcomes. When we compared OS for the groups defined molecularly at 6 and 12 months with the usual cytogenetic milestones, categorization by transcript numbers was the only independent predictor for OS (relative risk, 0.207; P < .001 and relative risk, 0.158; P < .001, respectively).ConclusionA single measurement of BCR-ABL1 transcripts performed at 3 months is the best way to identify patients destined to fare poorly, thereby allowing early clinical intervention.

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Chronic myeloid leukemia (CML) with P190BCR-ABL: analysis of characteristics, outcomes, and prognostic significance

Blood ◽

10.1182/blood-2009-02-204693 ◽

2009 ◽

Vol 114 (11) ◽

pp. 2232-2235 ◽

Cited By ~ 89

Author(s):

Dushyant Verma ◽

Hagop M. Kantarjian ◽

Dan Jones ◽

Rajyalakshmi Luthra ◽

Gautam Borthakur ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Prognostic Significance ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Blast Phase ◽

Complete Hematologic Response ◽

Risk Patients

Abstract The most common BCR-ABL transcripts in chronic myeloid leukemia (CML) are e13a2(b2a2) and e14a2(b3a2). Other transcripts such as e1a2 are rare and their outcome with tyrosine kinase inhibitors (TKI) therapy is undefined. We analyzed 1292 CML patients and identified 14 with only e1a2 transcripts, 9 in chronic phase (CP), 1 in accelerated phase (AP), and 4 in blast phase (BP). Of the CP, 4 achieved complete hematologic response (CHR); 2, complete cytogenetic response (CCyR); 2, partial cytogenetic response (PCyR), and 1 did not respond to imatinib. Five patients progressed to myeloid BP (3), lymphoid BP (1), or AP (1). The AP patient received various TKIs sequentially and achieved only CHR. BP patients received hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, adriamycin, dexamethasone) plus imatinib/dasatinib or idarubicin plus cytarabine (Ara-C); 2 did not respond, 1 had CCyR, and 1 short-lasting complete molecular response (CMR). Overall, cytogenetic responses lasted 3 to 18 months; only 2 achieved major molecular response (MMR) on TKI. P190BCR-ABL CML is rare and is associated with an inferior outcome to therapy with TKI. These patients need to be identified as high-risk patients.

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Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: when is this a safe option to consider?

Hematology ◽

10.1182/asheducation-2013.1.184 ◽

2013 ◽

Vol 2013 (1) ◽

pp. 184-188 ◽

Cited By ~ 6

Author(s):

Kendra Sweet ◽

Vivian Oehler

Keyword(s):

Chronic Myeloid Leukemia ◽

Imatinib Mesylate ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Deep Level ◽

Chronic Phase ◽

Cytogenetic Response ◽

Response To Therapy ◽

Molecular Response ◽

Rt Pcr

Abstract Mrs G is a 54-year-old woman with a diagnosis of chronic-phase chronic myeloid leukemia dating back 8 years. She had a low-risk Sokal score at diagnosis and was started on imatinib mesylate at 400 mg orally daily within one month of her diagnosis. Her 3-month evaluation revealed a molecular response measured by quantitative RT-PCR of 1.2% by the International Scale. Within 6 months of therapy, she achieved a complete cytogenetic response, and by 18 months, her BCR-ABL1 transcript levels were undetectable using a quantitative RT-PCR assay with a sensitivity of ≥ 4.5 logs. She has maintained this deep level of response for the past 6.5 years. Despite her excellent response to therapy, she continues to complain of fatigue, intermittent nausea, and weight gain. She is asking to discontinue imatinib mesylate and is not interested in second-line therapy. Is this a safe and reasonable option for this patient?

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Prognostic Significance of hOCT1 and ABCG2 Expression in Chronic Myeloid Leukemia Patients Treated with Imatinib

Blood ◽

10.1182/blood.v112.11.5033.5033 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5033-5033

Author(s):

Yeo-Kyeoung Kim ◽

Hee-Nam Kim ◽

Ri Yu ◽

Il-Kwon Lee ◽

Jae-Sook Ahn ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Statistical Significance ◽

Prognostic Significance ◽

Chronic Phase ◽

Progression Free Survival ◽

Organic Cation Transporter ◽

Cytogenetic Response ◽

Molecular Response ◽

Mrna Levels

Abstract Background: Imatinib mesylate is a substrate for both the drug influx transporter human Organic Cation Transporter 1 (hOCT1; SLCA22) and the efflux transporter ATP-binding cassette transporters (ABCG2; BCRP). The correlation between the expression of these two transporters of imatinib and the clinical outcome of imatinib in chronic myeloid leukemia (CML) patients remain clarified. Methods: hOCT-1 and ABCG2 mRNA levels were determined by performing real-time polymerase chain reaction assays on 83 BM samples obtained at initial diagnosis from the patients with chronic phase CML treated with imatinib (started at 400mg/day). Results: Of patients with higher hOCT-1 mRNA expression than median value (≥ 34.53 a.u.) at diagnosis, 59.5% achieved complete cytogenetic response (CCyR) at 6 months, whereas of patients with no more than a median hOCT-1 expression, 33.3% could achieve CCyR at 6 months (p=0.035). Furthermore, patients with low hOCT-1 showed higher rate of suboptimal response [failed to achieve complete hematologic response (CHR) by 3 months, major cytogenetic response (MCyR) by 6 months, CCyR by 12 months, and major molecular response (MMR) by 18 months] than those with high hOCT-1 expression (55.9% vs. 33.3%. p=0.048). There was no statistical significance in progression-free survival (PFS) or overall survival (OS) according to the hOCT-1 expression levels. Patients with low ABCG2 expression (< 13.53 a.u.) showed higher MMR rate at 18 months (57.1% vs. 35.5 %, p=0.09) and longer PFS (3 yr PFS, 87.2% vs. 64.1%, p=0.07) than those with high ABCG2 expression but there was no statistical significance. The time to achieving MMR was significantly shorter in patients with low ABCG2 expression than in those with high ABCG2 expression (6.9 ± 2.1 ms vs. 12.2 ± 4.2 ms, p=0.09). The patients with high hOCT-1 expression showed shorter time to achieving MMR, but there was no statistical significance (8.1 ± 1.9 vs. 10.5 ± 1.7, p=0.50). Conclusions: This study demonstrates that pretreatment assay of hOCT-1 and ABCG2 expression may help us to identify the treatment outcome in the CML patients treated with imatinib.

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Restrospective Multicenter Study Evaluating Efficacy and Safety of Dasatinib and Nilotinib in Patients with Imatinib-Resistant or –intolerant Chronic Myeloid Leukemia in Chronic Phase: Korean CML Working Party

Blood ◽

10.1182/blood.v120.21.1691.1691 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1691-1691

Author(s):

Jeong-Ok Lee ◽

Inho Kim ◽

Joo-Seop Chung ◽

Yeo-Kyeoung Kim ◽

Ho-Young Yhim ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Progression Free Survival ◽

Cytogenetic Response ◽

Molecular Response ◽

Efficacy And Safety ◽

Event Free Survival ◽

Free Survival ◽

Imatinib Resistant

Abstract Abstract 1691 Dasatinib and nilotinib have been founded to be effective and well-tolerated in patients who develop resistance or intolerance to imatinib. Not enough data are currently available to recommend one over the other as the preferred second-line therapy based on efficacy data. Therefore we planned a multicenter retrospective study to analyze the efficacy and safety of dasatinib and nilotinib in patients with imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase. In this Korean multicenter study, 126 patients imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase were treated with dasatinib (n=76) or nilotinib (n=50) The purpose of this study was to compare rates of cytogenetic and molecular response rate, event-free survival (EFS), progression-free survival (PFS) and overall survival (OS), and toxicities of nilotinib and dasatinib treatment of imatinib-resistant or –intolerant chronic myeloid leukemia in chronic phase. PFS was defined as the time from the start of treatment to the earliest date of any of following event: loss of complete hematologic response (CHR), loss of major cytogenetic response (MCyR), progression to accelerated phase (AP) or blastic phase (BP), discontinuation due to treatment failure as assessed by the clinician, and death from any cause on therapy. Event was defined by any one of the following: loss of CHR, loss of MCyR, progression to AP or BP, discontinuation due to treatment failure as assessed by the clinician, treatment discontinuation due to toxicity, and death from any cause on therapy. For dasatinib and nilotinib group, median ages (51 years old vs. 53), median durations of CML (23.7 months vs. 19.8 ) before receiving dasatinib or nilotinib and duration of prior imatinib treatment (21.7 months vs 17.7) were comparable. Nilotinib group had a higher proportion of intermediate and high sokal scores at the time of diagnosis than dasatinib group (41.5 vs 29.3% (high), 41.5% vs 32.5%(intermediate), 17.1% vs 37.9(low), p= 0.04). After median follow-up durations of 20.2 months of dasatinib group and 25.3 months of nilotinib group, the rates of major molecular response were 50.0% for dasatinib group and 59.6% for nilotinib group (p=NS) and the rates of MCyR (complete and partial cytogenetic response) were 78.4% for dasatinib group and 74.5% for nilotinib group (p=NS). The estimated EFS at 24 months was 67% and 48% in dasatinib and nilotinib group, respectively. (p<0.05). The estimated PFS at 24 months was 85% and 56% in dasatinib and nilotinib group, respectively. (p<0.05) Overall survival rates were comparable in both treatment groups (24-months OS; dasatinib 91%, nilotinib 94%; p=0.65). Both were generally well tolerated. Hematologic toxicities were more frequent among patients receiving dasatinib. 10 patients (13%) had pleural effusion in dasatinib; 9 events were grade 1 or 2. Elevated liver enzyme were more frequent among patients receiving dasatinib. In conclusion, In this study population, nilotinib and dasatinib showed similar cytogenetic and molecular response rates and survival. Toxicity profiles of two drugs were different and both drugs showed tolerable toxicities. In terms of event-free survival and progression-free survival, dasatinib was superior to nilotinib, but caution is warranted in interpretation because baseline characteristics including hematologic and cytogenetic response at the time of start with dasatinib and nilotinib and sokal scores at the time of diagnosis were different. Disclosures: No relevant conflicts of interest to declare.

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Imatinib for Newly Diagnosed Patients With Chronic Myeloid Leukemia: Incidence of Sustained Responses in an Intention-to-Treat Analysis

Journal of Clinical Oncology ◽

10.1200/jco.2007.15.8154 ◽

2008 ◽

Vol 26 (20) ◽

pp. 3358-3363 ◽

Cited By ~ 387

Author(s):

Hugues de Lavallade ◽

Jane F. Apperley ◽

Jamshid S. Khorashad ◽

Dragana Milojkovic ◽

Alistair G. Reid ◽

...

Keyword(s):

Overall Survival ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Progression Free Survival ◽

Cytogenetic Response ◽

Kinase Domain ◽

Molecular Response ◽

Imatinib Treatment ◽

Newly Diagnosed

Purpose Imatinib is remarkably effective in treating newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase (CP). To date, most of the available data come from a single multicenter study in which some of the patients were censored for diverse reasons. Here, we report our experience in treating patients at a single institution in a setting where all events were recorded. Patients and Methods A total of 204 consecutive adult patients with newly diagnosed CML in CP received imatinib from June 2000 until August 2006. Response (hematologic, cytogenetic, and molecular), progression-free survival (PFS) and survival were evaluated. Results At 5 years, cumulative incidences of complete cytogenetic response (CCyR) and major molecular response (MMR) were 82.7% and 50.1%, respectively. Estimated overall survival and PFS were 83.2% and 82.7%, respectively. By 5 years, 25% of patients had discontinued imatinib treatment because of an unsatisfactory response and/or toxicity. The 5-year probability of remaining in major cytogenetic response while still receiving imatinib was 62.7%. Patients achieving a CCyR at 1 year had a better PFS and overall survival than those failing to reach CCyR, but achieving a MMR conferred no further advantage. The identification of a kinase domain mutation was the only factor predicting for loss of CCyR. Conclusion Imatinib is highly effective in most patients with CML-CP; patients who respond are likely to live substantially longer than those treated with earlier therapies. Achieving CCyR correlated with PFS and overall survival, but achieving MMR had no further predictive value. However, approximately one third of patients still need better therapy.

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The achievement of an early complete cytogenetic response is a major determinant for outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors

Blood ◽

10.1182/blood-2011-04-348110 ◽

2011 ◽

Vol 118 (17) ◽

pp. 4541-4546 ◽

Cited By ~ 95

Author(s):

Elias Jabbour ◽

Hagop Kantarjian ◽

Susan O'Brien ◽

Jenny Shan ◽

Alfonso Quintas-Cardama ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Chronic Phase ◽

Cytogenetic Response ◽

Major Determinant ◽

Molecular Response ◽

Complete Cytogenetic Response

Abstract We analyzed the association between achievement of early complete cytogenetic response (CCyR) and event-free survival (EFS) and overall survival (OS) in patients with newly diagnosed chronic myeloid leukemia in chronic phase treated with imatinib 400 mg (n = 73), or imatinib 800 mg daily (n = 208), or second- generation tyrosine kinase inhibitors (n = 154). The overall CCyR rates were 87%, 91%, and 96%, respectively (P = .06); and major molecular response (MMR) rates were 77%, 87%, and 89%, respectively (P = .05). Their 3-year EFS rates were 85%, 92%, and 97% (P = .01), and OS rates were 93%, 97%, and 100% (P = .18), respectively. By landmark analysis, patients with 3-, 6-, and 12-month CCyR had significantly better outcome: 3-year EFS rates of 98%, 97%, and 98% and OS rates of 99%, 99%, and 99%, respectively, compared with 83%, 72%, and 67% and 95%, 90%, and 94%, in patients who did not achieve a CCyR. Among patients achieving CCyR at 12 months, the depth of molecular response was not associated with differences in OS or EFS. In conclusion, second tyrosine kinase inhibitors induced higher rates of CCyR and MMR than imatinib. The achievement of early CCyR remains a major determinant of chronic myeloid leukemia outcome regardless of whether MMR is achieved or not.

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Meta-Analysis of Gastrointestinal Adverse Events from Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia

Cancers ◽

10.3390/cancers13071643 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1643

Author(s):

Prahathishree Mohanavelu ◽

Mira Mutnick ◽

Nidhi Mehra ◽

Brandon White ◽

Sparsh Kudrimoti ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Meta Analysis ◽

Chronic Phase ◽

Molecular Response ◽

Gastrointestinal Adverse Events

Tyrosine kinase inhibitors (TKIs) are the frontline therapy for BCR-ABL (Ph+) chronic myeloid leukemia (CML). A systematic meta-analysis of 43 peer-reviewed studies with 10,769 CML patients compared the incidence of gastrointestinal adverse events (GI AEs) in a large heterogeneous CML population as a function of TKI type. Incidence and severity of nausea, vomiting, and diarrhea were assessed for imatinib, dasatinib, bosutinib, and nilotinib. Examination of combined TKI average GI AE incidence found diarrhea most prevalent (22.5%), followed by nausea (20.6%), and vomiting (12.9%). Other TKI GI AEs included constipation (9.2%), abdominal pain (7.6%), gastrointestinal hemorrhage (3.5%), and pancreatitis (2.2%). Mean GI AE incidence was significantly different between TKIs (p < 0.001): bosutinib (52.9%), imatinib (24.2%), dasatinib (20.4%), and nilotinib (9.1%). Diarrhea was the most prevalent GI AE with bosutinib (79.2%) and dasatinib (28.1%), whereas nausea was most prevalent with imatinib (33.0%) and nilotinib (13.2%). Incidence of grade 3 or 4 severe GI AEs was ≤3% except severe diarrhea with bosutinib (9.5%). Unsupervised clustering revealed treatment efficacy measured by the complete cytogenetic response, major molecular response, and overall survival is driven most by disease severity, not TKI type. For patients with chronic phase CML without resistance, optimal TKI selection should consider TKI AE profile, comorbidities, and lifestyle.

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Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure

Blood ◽

10.1182/blood-2011-11-390120 ◽

2012 ◽

Vol 119 (15) ◽

pp. 3403-3412 ◽

Cited By ~ 191

Author(s):

H. Jean Khoury ◽

Jorge E. Cortes ◽

Hagop M. Kantarjian ◽

Carlo Gambacorti-Passerini ◽

Michele Baccarani ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Phase 1 ◽

Chronic Phase ◽

Progression Free Survival ◽

Cytogenetic Response ◽

Abl Tyrosine Kinase ◽

Kaplan Meier

Bosutinib, a dual Src/Abl tyrosine kinase inhibitor (TKI), has shown potent activity against chronic myeloid leukemia (CML). This phase 1/2 study evaluated the efficacy and safety of once-daily bosutinib 500 mg in leukemia patients after resistance/intolerance to imatinib. The current analysis included 118 patients with chronic-phase CML who had been pretreated with imatinib followed by dasatinib and/or nilotinib, with a median follow-up of 28.5 months. In this subpopulation, major cytogenetic response was attained by 32% of patients; complete cytogenetic response was attained by 24%, including in one of 3 patients treated with 3 prior TKIs. Complete hematologic response was achieved/maintained in 73% of patients. On-treatment transformation to accelerated/blast phase occurred in 5 patients. At 2 years, Kaplan-Meier–estimated progression-free survival was 73% and estimated overall survival was 83%. Responses were seen across Bcr-Abl mutations, including those associated with dasatinib and nilotinib resistance, except T315I. Bosutinib had an acceptable safety profile; treatment-emergent adverse events were primarily manageable grade 1/2 gastrointestinal events and rash. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (8%) and rash (4%). Bosutinib may offer a new treatment option for patients with chronic-phase CML after treatment with multiple TKIs. This trial was registered at www.clinicaltrials.gov as NCT00261846.

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The Role of Monitoring the Bcr-Abl Transcript Levels in the Management of Patients with Chronic Myeloid Leukemia

Acta Medica Marisiensis ◽

10.2478/amma-2013-0015 ◽

2013 ◽

Vol 59 (2) ◽

pp. 71-74

Author(s):

Aliz-Beáta Tunyogi ◽

I Benedek ◽

Judit Beáta Köpeczi ◽

Erzsébet Benedek ◽

Enikő Kakucs ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Blast Crisis ◽

Chronic Gvhd ◽

Molecular Response ◽

Imatinib Treatment ◽

Molecular Monitoring ◽

Hematopoietic Stem ◽

Transcript Levels

Abstract Introduction: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder; the molecular hallmark of the disease is the BCR-ABL gene rearrangement, which usually occurs as the result of a reciprocal translocation between chromosomes 9 and 22. Tyrosine kinase inhibitors (TKI) were the first drugs that targeted the constitutively active BCR-ABL kinase and it have become the standard frontline therapy for CML. Monitoring the treatment of CML patients with detection of bcr-abl transcript levels with real time qualitative polymerase chain reaction (RQ-PCR) is essential in evaluating the therapeutic response. Material and method: At the Clinical Hematology and BMT Unit Tîrgu Mureș, between 2008-2011, we performed the molecular monitoring of bcr-abl transcript levels with RQ-PCR in 16 patients diagnosed with CML. Results: We have 11 patients on imatinib treatment who achieved major molecular response. One patient lost the complete molecular response after 5 years of treatment. Two patients in blast crisis underwent allogeneic hematopoietic stem cell transplantation from identical sibling donors. The first patient is in complete molecular remission after 4 years of the transplant with mild chronic GVHD. The other patient had an early relapse with treatment refractory disease and died from evolution of the disease. Three patients with advanced phases of the disease present increasing transcript levels. We performed the dose escalation, and for two of them the switch to the second generation of TKI. Conclusions: Regular molecular monitoring of individual patients with CML is clearly desirable. It allows for a reassessment of the therapeutic strategy in cases of rising levels of BCR-ABL as an early indication of loss of response.

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A Retrospective Analysis about Frequency of Monitoring in Italian Chronic Myeloid Leukemia Patients after Discontinuation

Journal of Clinical Medicine ◽

10.3390/jcm9113692 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3692

Author(s):

Matteo Dragani ◽

Giovanna Rege Cambrin ◽

Paola Berchialla ◽

Irene Dogliotti ◽

Gianantonio Rosti ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Molecular Response ◽

Molecular Monitoring ◽

Delay In Diagnosis ◽

Number Of Patients

Successful discontinuation of tyrosine kinase inhibitors has been achieved in patients with chronic-phase chronic myeloid leukemia (CML). Careful molecular monitoring after discontinuation warrants safe and prompt resumption of therapy. We retrospectively evaluated how molecular monitoring has been conducted in Italy in a cohort of patients who discontinued tyrosine kinase inhibitor (TKI) treatment per clinical practice. The outcome of these patients has recently been reported—281 chronic-phase CML patients were included in this subanalysis. Median follow-up since discontinuation was 2 years. Overall, 2203 analyses were performed, 17.9% in the first three months and 38.4% in the first six months. Eighty-six patients lost major molecular response (MMR) in a mean time of 5.7 months—65 pts (75.6%) during the first six months. We evaluated the number of patients who would experience a delay in diagnosis of MMR loss if a three-month monitoring schedule was adopted. In the first 6 months, 19 pts (29.2%) would have a one-month delay, 26 (40%) a 2-month delay. Very few patients would experience a delay in the following months. A less intense frequency of monitoring, particularly after the first 6 months off treatment, would not have affected the success of treatment-free remission (TFR) nor put patients at risk of progression.

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