Correlations between Mutations in Cancer-Related Genes, Therapy Responses and Outcomes of the 3 rd Generation Tyrosine Kinase-Inhibitor (TKI) in Persons with Chronic Myeloid Leukemia Failing Prior TKI-Therapy

Abstract Background Most, but not everyone with chronic myeloid leukaemia (CML) responds to imatinib or 2 nd-generation tyrosine kinase-inhibitors (TKIs). Mutations in cancer-related genes and in other than ABL1 may explain variable responses and outcomes to the 3 rd-generation TKIs including ponatinib and olverembatinib. Aim Interrogate correlations between mutations in cancer-related genes and therapy responses and outcomes to 3 rd-generation TKIs. Methods We used deep targeted sequencing for cancer-related mutations and Sanger sequencing for BCR::ABL1 on DNA samples from 167 subjects with CML failing to the prior imatinib and/or 2 nd-generation TKI-therapy and just before receiving a 3 rd-generation TKI. Gene ontology (GO) analysis was used to evaluate functional enrichment in GO terms among mutated genes. Optimal cut-offs for variant allele frequencies (VAFs) of the common mutations were determined by analyzing receiver-operator characteristic (ROC) curves. A Cox multi-variable regression model was used to identify correlations between mutations in cancer-related genes and therapy responses and outcomes of 3 rd-generation TKI-therapy. Results 167 subjects in chronic phase (n = 125) and accelerated phase (n = 42) received ponatinib (n = 28) or olverembatinib (n = 139) therapy. 27 subjects were exposed to imatinib; 79, a 2 nd-generation TKI; 61, imatinib and a 2 nd generation TKI. 142 (85%) subjects had ABL1 mutations including ABL1T315I (n = 116) or others (n = 26). 163 subjects had other cancer-related mutations which were evaluated in epigenetic regulators (n = 150), transcription factors (n = 84), cell signaling (n = 42), tumor suppressors (n = 39), protein kinases (n = 27), chromatin modification (n = 9) and DNA damage repair (n = 3) related-genes according to functional enrichment. The top 10 mutations were ASXL1 (n = 115), RUNX1 (n = 12), KMT2D (n = 12), PHF6 (n = 8), KMT2C (n = 8), IKZF1 (n = 8), STAT5A (n = 8), DNMT3A (n = 7), TET2 (n = 6) and BCOR (n = 6). 20 subjects had high-risk additional chromosomal abnormalities (ACAs). Frequency of BCR::ABL1 mutations was inversely- (p < 0.001) and of cancer-related mutations directly-related (p = 0.009) to increasing exposure to prior TKI therapies. These relationships were especially so for mutations in KMT2C (p = 0.06), DNMT3A (p = 0.09), KDM6A (p = 0.06) and TNFAIP3 (p = 0.08). BCR::ABL1 (82% vs. 95%, p = 0.03), RUNX1 (5% vs. 14%, p = 0.04), KMT2C (3% vs. 10%, p = 0.08) and IKZF1 (3% vs. 10%, p = 0.10) were more common in accelerated phase. With a median follow-up of 34 months (interquartile range [IQR], 12-40 months), 95 and 71 subjects achieved a complete cytogenetic response (CCyR) and major molecular response (MMR). 18 subjects transformed to accelerated (n = 8) or blast (n = 10) phases, 16 died of disease progression (n = 12) or other causes (n = 4). 3-year cumulative incidences of CCyR and MMRwere 65% (95% Confidence Interval [CI], 58, 71%) and 52% (43, 61%). 3-year probabilities of progression-free survival (PFS) and survival were 88% (81, 92%) and 91% (85, 95%). Mutations in tumor suppressor genes were more common in subjects not achieving a CCyR (27% vs. 19%, p = 0.01). In multi-variable analyses ASXL1 mutation with a VAF ≥ 17% and a PHF6 mutation were significantly associated with lower cumulative incidences of CCyR (p < 0.001 and p = 0.032) and MMR (p < 0.001 and p = 0.04). Moreover, subjects with BCR-ABL1T315I mutation had significantly higher cumulative incidences of CCyR (p = 0.07) and MMR (p = 0.04) than those with no BCR-ABL1 mutation and other BCR-ABL1 non-T315I mutation. Increasing age, more Ph 1-chromosome-positive cells, the best prior therapy-response < partial cytogenetic response (PCyR) and more TKI-therapies were associated with poor responses. STAT5A mutation was significantly associated with worse PFS (p = 0.002) and survival (p < 0.001), RUNX1 mutation (p = 0.006), high-risk ACAs (p = 0.07) and accelerated phase (p = 0.002) with worse PFS and increasing age (p = 0.05) and comorbidity(ies) (p = 0.05) with wosre survival. Conclusions ASXL1 mutations with a VAF ≥ 17% and PHF6 mutations were associated with poor responses of the 3 rd-generation TKI-therapy. STAT5A and RUNX1 mutations and high-risk ACAs were also associated with worse outcomes in persons receiving a 3 rd-generation TKI. These data should help physicians select people to receive 3 rd-generation TKIs. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Nilotinib therapy in an imatinib intolerant chronic myeloid leukemia patient with pulmonary severe hypertension

Clinical Management Issues ◽

10.7175/cmi.v4i2s.1072 ◽

2015 ◽

Vol 4 (2S) ◽

pp. 17-20

Author(s):

Mario Annunziata

Keyword(s):

Side Effects ◽

Tyrosine Kinase ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Chronic Myeloid Leukemia Patient ◽

Cytogenetic Response ◽

Myelogenous Leukemia ◽

Molecular Response ◽

Cutaneous Rash

Imatinib mesylate is a tyrosine kinase inhibitor that has significant efficacy in the treatment of chronic myelogenous leukemia. In general, hematologic and extrahematologic side effects of imatinib therapy are mild to moderate, with the large majority of patients tolerating prolonged periods of therapy. However, a minority of patients are completely intolerant of therapy, while others are able to remain on therapy despite significant side effects. Here, we describe a chronic phase CML patient with pulmonary arterial hypertension, mechanical hearth valve, who experienced extrahematologic adverse event (persistent grade III cutaneous rash, despite two discontinuations of imatinib and using of steroid). Necessitating switch to one of new tyrosine kinase inhibitors, nilotinib, has resulted in complete cytogenetic response and major molecular response, after 3 and 6 months, respectively. No cross-intolerance with imatinib was observed during nilotinib therapy. Besides, this clinical case suggests that warfarin and nilotinib can be used concurrently without the risk of increased anticoagulant effect.

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Determinants of Choice of Front-Line Tyrosine Kinase Inhibitor for Chronic Phase CML: A Study from the "Registro Italiano LMC & Campus CML"

Blood ◽

10.1182/blood-2020-135972 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 35-36

Author(s):

Mario Tiribelli ◽

Roberto Latagliata ◽

Massimo Breccia ◽

Isabella Capodanno ◽

Maria Cristina Miggiano ◽

...

Keyword(s):

High Risk ◽

Tyrosine Kinase ◽

Research Funding ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Multivariable Analysis ◽

Chronic Phase ◽

Front Line ◽

Line Therapy ◽

Concomitant Medications

Introduction : therapy of chronic phase (CP) chronic myeloid leukemia (CML) is based on tyrosine kinase inhibitors (TKIs) in virtually all patients. Three TKIs are approved for first-line therapy in Italy: imatinib and two second-generation (2G) TKIs, dasatinib and nilotinib. Choice of the front-line TKI is based on a combined evaluation of patient's and disease characteristics, age, risk, comorbidities and concomitant medications. Treating physician's preference and, in some cases, economic considerations, particularly after the advent of generic imatinib, may play a role in TKI selection. However, to date, few data are available on TKI use in a whole nation and on the possible drivers of treatment choice. Aim of the present work was to analyse the use of front-line TKI therapy in a large, unselected cohort of Italian CP-CML patients, correlating patient's features to drug choice. Methods: in the framework of the national Campus CML program, we retrospectively evaluated 1422 patients with CP-CML diagnosed from 2012 and 2019 in 21 haematologic Centres, mostly in academic and/or tertiary hospitals, widespread through the entire Italian territory and treated frontline with imatinib, dasatinib or nilotinib. Results: median age at diagnosis was 59.9 years [interquartile range (IQR) 47.1 - 71.7], with 317 (22.3%) patients under 45 years, 552 (38.8%) between 45 and 65 years and 553 (38.9%) older than 65 years; 821 (57.7%) patients were males. Among 1364 evaluable patients, CML risk according to Sokal score was low in 540 (39.6%), intermediate in 610 (44.7%) and high in 214 (15.7%) patients respectively; the number at low, intermediate or high risk according to the novel ELTS score among 1325 evaluable patients was 759 (57.3%), 402 (30.3%) and 164 (12.4%) respectively. Considering comorbidities, 1003 (70.6%) patients had at least one active disease at the time of CML diagnosis, the most common being hypertension (n=547, 38.5%), previous neoplasms (n=185, 13.0%), diabetes (n=150, 10.6%), chronic bronchopulmonary diseases (n=114, 8.0%), acute myocardial infarction (n=95, 6.7%), previous stroke (n=36, 2.5%) and other vascular diseases (n=98, 6.9%). Among 1335 evaluable patients, 813 (60.9%) were taking at least one concomitant medication, with 280 (21.0%) taking 3-5 drugs and 140 (10.5%) taking 6+ drugs at time of TKI start. As to the frontline therapy, 794 (55.8%) received imatinib and 628 (44.2%) were treated with 2G-TKIs, (226 dasatinib and 402 nilotinib) respectively. According to age, 2G-TKIs were chosen for majority of patients aged <45 (69.1%) while imatinib was used in 76.9% of patients over 65 (p<0.001). There was a predominance of imatinib use across all Sokal (51.1% in low, 61.3% in intermediate and 51.4% in high) and ELTS (50.3% in low, 60.4% in intermediate and 66.5%) risk categories. We observed a prevalent use of 2G-TKIs in patients presenting with higher WBC counts (55.1% if WBC >100,000/mm3 vs 38.2% if WBC <100,000/mm3; p<0.001), lower Hb (53.8% if Hb <10 g/dl vs 41.9 if Hb >10 g/dl; p=0.001) and bigger spleen (65.1% if spleen >5 cm vs 44.8% if spleen 1-5 cm vs 37.3% if spleen not palpable; p<0.001). There was a decreasing use of 2G-TKIs with higher number of concomitant drugs: 64.4% for 0, 47.7% for 1-2, 27.0% for 3-5 and 13.6% for >5 drugs, respectively (p<0.001). Concordantly, there was a significant higher use of imatinib in patients with hypertension (69.8%), diabetes (70.0%), COPD (73.7%), previous neoplasms (73.0%), AMI (86.3%) or stroke (97.2%) history (p<0.001 for all conditions). Lastly, we observed a wider use of imatinib (61.1%) in patients diagnosed in years 2018-19, compared to those of the period 2012-17 (53.7%; p=0.01). In multivariable analysis, factors correlated with imatinib use were age > 45 years, intermediate or high Sokal risk, presence of some comorbidities (2nd neoplasia and stroke) and number of concomitant medications. Conclusions: preliminary results of this observational study on almost 1500 patients show that around 55% of newly diagnosed Italian CP-CML patients receive imatinib as front-line therapy, and that the use of 2G-TKI is prevalent in the younger patients and in those with no concomitant clinical conditions. The counterintuitive finding of imatinib prevalence as frontline treatment in high risk patients might be explained by the older age of these patients. Introduction of the generic formulation in 2018 seems to have fostered the use of imatinib. Figure Disclosures Breccia: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria. Cavazzini:Pfize: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Saglio:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Roche: Research Funding.

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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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Characteristics and outcome of chronic myeloid leukemia patients with F317L BCR-ABL kinase domain mutation after therapy with tyrosine kinase inhibitors

Blood ◽

10.1182/blood-2008-04-149948 ◽

2008 ◽

Vol 112 (13) ◽

pp. 4839-4842 ◽

Cited By ~ 52

Author(s):

Elias Jabbour ◽

Hagop M. Kantarjian ◽

Dan Jones ◽

Neeli Reddy ◽

Susan O'Brien ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Cytogenetic Response ◽

Kinase Domain ◽

Disease Stage ◽

Kinase Domain Mutation

Abstract Mutations in codon 317 after treatment with imatinib and dasatinib have been reported. We reviewed patients with chronic myeloid leukemia and mutations after tyrosine kinase inhibitor (TKI) therapy. F317L was detected in 20, including 12/99 (12%) with mutation after imatinib failure, and 8/16 (50%) after dasatinib (P = .001). Median follow-up from mutation detection was 25 months. At the time of F317L, 8 patients were in chronic phase (CP), 6 in accelerated phase, and 6 in blast phase. There was no difference in characteristics between patients with or without F317L mutations, or with no mutations. A complete cytogenetic response was acheived in 3 of 6 patients treated with nilotinib, 2 of 2 with imatinib, and 0 of 3 with dasatinib. Survival of patients with F317L was similar to those with other mutations (P = .45). Patients in CP had better outcome, with a 2-year survival of 75%. F317L mutation is resistant to dasatinib but sensitive to other TKIs. The prognosis is dependent mostly on the disease stage.

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Prognostic Significance of the Lost of a Major Molecular Response In Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia (Ph+CML).

Blood ◽

10.1182/blood.v116.21.3435.3435 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3435-3435

Author(s):

J. Valentin García-Gutiérrez ◽

Pilar Herrera ◽

Marta Jimenez-Rolando ◽

María Tenorio ◽

María Calbacho ◽

...

Keyword(s):

Kinase Inhibitors ◽

Conflicts Of Interest ◽

Residual Disease ◽

Prognostic Significance ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Cytogenetic Response ◽

Myelogenous Leukemia ◽

Molecular Response ◽

Major Molecular Response

Abstract Abstract 3435 Background: Albeit of well-known, dramatic improvements, there remain some questions to be solved around Ph+CML in treatment with tyrosine kinase inhibitors (TKI). Among these, the significance of the amount of minimal residual disease (MRD) measured by RT-PCR. For instance, loss of a so-called major molecular response (MMR) is claimed to be a Òsuboptimal responseÓ and following the ELN recommendations, a change in treatment should be considered in these patients. Aims: To evaluate the relevance of a loss of MMR in patients with complete cytogenetic response (CCR). Study Group and Methods: We have analized 81 patients treated with imatinib for CML in chronic phase with a median follow up of 66 months. 36 patients started imatinib after interferon failure and 45 as front line therapy. Major Molecular Response (MMR; BCR-ABL/ABL ratio<0.1% IS) at any time was achieved by 63 patients. Results: 22 patients (34%) lost MMR (documented al least twice). The risk of losing MMR was higher in late MMR (>18 months) compared with those cases whose MMR came much earlier (<18 months): 70% vs 18% (p=. 000). We have found no correlation among the lost of MMR and classical prognostic factors (Sokal-Index, mutations at the TK domain or imatinib plasma levels). Of these 22 patients, 7 (32 %) recovered MMR later with no therapy changes, 8 (36%) experienced fluctuations in the BCR-ABL transcript-levels without losing CCR, 4 (19%) did not attain a MMR but remained in stable CRR, and 3 (13%) lost CCR. These regained MMR after being treated on second generation TKI. The results show how the stability of the early MMR is greater than late MMR (table1). Conclusions: In our experience, one third of the patients who lost MMR recovered it later on the same treatment. And only 13% went on to treatment failure. Perhaps some similar cases (after first losing MMR) should be closely monitored before a change in treatment. Also of note is, of course regarding only our experience, that the risk of a loss of MMR seems to be maximal in patients who achieve a late MMR. Disclosures: No relevant conflicts of interest to declare.

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Clarithromycin Targeting Autophagy Potentiates Tyrosine Kinase Inhibitor-Induced Cell Death in Resistant Chronic Myeloid Leukemia (CML) Patients

Blood ◽

10.1182/blood.v118.21.4450.4450 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4450-4450

Author(s):

A. M. Carella ◽

Gioacchino Catania ◽

G. Beltrami ◽

G. Pica

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

De Novo ◽

Conflicts Of Interest ◽

Blast Crisis ◽

Cytogenetic Response ◽

Ifn Alpha

Abstract Abstract 4450 M-TOR is a key regulator of autophagy. Rapamycin and clarithromycin (structurally similar to rapamycin), have been demonstrated to have in vitro activity in blocking autophagy. In four patients with advanced CML, remarkable response to the combination of clarithromycin and a tyrosine kinase inhibitor was observed. Here we present the results achieved by the combination. A 43-year-old woman was diagnosed with high-risk Sokal CML in February 2000. She was treated with IFN-alpha and imatinib (400 mg/day) with persistence of 100% Ph-positive metaphases. In March 2006, WBC was no longer controlled and she was treated with nilotinib. Complete hematologic response (CHR) was achieved by the end of April 2006, but there was no cytogenetic response (CyR). She was given dasatinib (70 mg b.i.d.) without complete cytogenetic response (CCyR) and after 7 months the bcr-abl/abl ratio was 6.1% in March 2011. At that time, the patient had an infection (otits/pharyngitis) sensitive to clarithromycin, which was added to dasatinib at a dose of 500 mg b.i.d. April 2011 there was a surprising reduction in the transcript to 0.5%. As of June 2011, the value was 0.05%, and the patient continues to receive clarithromycin (500 mg/day) and dasatinib (100 mg/day). Nowadays (August 1), the patient is in CHR, CCyR and major molecular remission (MMR) (bcr-abl/abl ratio 0.001%). The patient stopped clarithromycin and he is continuing on dasatinib. A 53-year-old man was diagnosed with de novo lymphoid blast crisis CML in August 2010; bcr-abl/abl ratio was 95.2%. He had a sibling donor. In October 2010 bcr-abl/abl ratio was reduced to 0.2% after chemo + imatinib. In November 2010, bcr-abl/abl ratio was 22% and he was treated with dasatinib (70 mg b.i.d.) with WBC control and a small reduction of bcr-abl/abl ratio (18% in February 2011). Soon thereafter, he underwent allogeneic transplant. Two months after transplant (May 2011) the disease progressed and bcr-abl/abl value had increased to 47%. He was restarted on dasatinib (100 mg/day) but the transcript increased in 4 weeks to 143%. Because of our previous experience, we added clarithromycin to dasatinib on June 2, 2011. Two weeks later, bcr-abl/abl value was reduced to 3.2%, and to 1.5% after another week. We stopped clarithromycin and three weeks later under dasatinib alone the transcript increased to 20%. From one week we added newly clarithromycin to dasatinib. A 68 year old man was diagnosed with CML in October 1999. A CCyR was achieved after autografting and soon after IFN-alpha was given as maintenance. In October 2000 the patient relapsed. A second CCyR was achieved in December 2001 after imatinib (400 mg/day), which lasted for six years. In October 2006 bcr-abl/abl ratio was 4.5%. He was treated with dasatinib (70 mg. b.i.d.) with WBC control but with no CyR. In March 2011, bcr-abl/abl ratio was 42.5%. Nilotinib (600 mg. b.i.d.) was begun with no change in bcr-abl/abl ratio after 2 months. In June 2011, clarithromycin (500 mg. b.i.d.) was added; 3 weeks later, the bcr-abl/abl ratio had decreased to 17% and two weeks later (July 13, 2011) to 4%. On July 28, bcr-abl/abl is 0,00022%. A 70 year old woman was diagnosed with CML in November 1998. She was treated with IFN-alpha but only partial CyR was achieved. In January 2001, 100% Ph-positive metaphases were found in BM. She was begun on imatinib (400 mg/day) but the karyotype did not change. In May 2005 she was started on nilotinib (600 mg/daily) since bcr-abl/abl ratio was 26.5%. Blood counts were controlled but there was no change in cytogenetics. In August 2010 WBC increased to 100×103/l. Dasatinib (70 mg. b.i.d.) was begun. Because blood count control was inadequate, hydroxyurea was added. In December 2010, bcr-abl/abl ratio had increased to 140%, and E255V mutation was found. In May 2011, clarithromycin (500 mg. b.i.d.) was added. In 2 weeks, the WBC had decreased from 76×103/l to 10×103/l and bcr-abl/abl ratio was 30% (June 4, 2011). One month later (July 4, 2011) bcr-abl/abl ratio was 3% and the mutation was no longer found in bone marrow. In the last evaluation (July 13, 2011) bcr-abl/abl ratio was 0.00096%. The patient stopped clarithromycin and she is on dasatinib alone. In conclusion, no patients have gone off study for toxicity. In no case we observed grade 3–4 myelosuppression. The remarkable responses obtained in these 4 patients support the hypothesis that inhibition of autophagy may make CML cells sensitive to killing by tyrosine kinase inhibitors. Disclosures: No relevant conflicts of interest to declare.

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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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Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: when and for whom?

Haematologica ◽

10.3324/haematol.2019.242891 ◽

2020 ◽

Vol 105 (12) ◽

pp. 2738-2745

Author(s):

Ehab Atallah ◽

Charles A. Schiffer

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Quantitative Polymerase Chain Reaction ◽

Chronic Phase ◽

Molecular Response ◽

Remission Criteria ◽

Treatment Free Remission

Treatment discontinuation is considered one of the main goals of therapy for patients with chronic myeloid leukemia. Several criteria are felt to be necessary to consider discontinuation, while others may predict a better chance of achieving treatment-free remission. Criteria for discontinuation include patients in chronic phase chronic myeloid leukemia, a minimum duration of tyrosine kinase inhibitor therapy of 3 years, sustained deep molecular response for at least 2 years and a molecular response of at least MR4. In addition, proper education of the patient on the need for more frequent monitoring, possible side effects related to stopping and having a reliable real-time quantitative polymerase chain reaction laboratory are paramount to the safety and success of treatment-free remission. Realistically though, a maximum of only 20-30% of newly diagnosed patients will be able to achieve a successful treatment-free remission. In this article we will review for whom and when a trial of discontinuation should be considered.

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Management of Adverse Events Associated With Tyrosine Kinase Inhibitor Use in Adult Patients With Chronic Myeloid Leukemia in Chronic Phase: An Advanced Practice Perspective

Journal of the Advanced Practitioner in Oncology ◽

10.6004/jadpro.2021.12.5.7 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Stephanie Bauer, RN, MSN, BC-FNP ◽

Holly Comer, MSN, APRN ◽

Brooke Ramsey, RN, MSN, ANP-BC ◽

Katy Thomas, RN, MSN, ANP-C

Keyword(s):

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Response To Therapy ◽

Molecular Response ◽

Life Management

The tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, nilotinib, bosutinib, and ponatinib have drastically improved the life expectancies of patients with chronic myeloid leukemia in chronic phase (CML-CP). While survival outcomes are comparable across first-line TKIs, each TKI has a unique toxicity profile that should be considered before starting or managing any treatment. Furthermore, the safety and tolerability of TKIs are particularly important in CML-CP, as the majority of patients remain on treatment for several years or for life. Management of adverse events (AEs) is critical to ensure adherence to treatment and to maintain efficacy and quality of life; management should also be considered in the context of the patient’s molecular response to therapy to avoid switching TKIs unnecessarily. We present case studies examining pleural effusion occurring with bosutinib and dasatinib, cardiovascular events associated with nilotinib and ponatinib, and myelosuppression, which is common across all TKIs. We discuss the management of these AEs based on international guidelines and present our collective experience for advanced practitioners to consider.

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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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