STOP second generation (2G)–tyrosine kinase inhibitor (TKI) is a multicenter observational study designed to evaluate 2G-TKI discontinuation in chronic myeloid leukemia (CML). Patients receiving ...first-line or subsequent dasatinib or nilotinib who stopped therapy after at least 3 years of TKI treatment and in molecular response 4.5 (MR4.5) with undetectable BCR-ABL1 transcripts for the 2 preceding years at least were eligible for inclusion. This interim analysis reports outcomes of 60 patients with a minimum follow-up of 12 months (median 47, range: 12-65). Twenty-six patients (43.3%) experienced a molecular relapse defined as the loss of a major molecular response (MMR). Relapses occurred after a median time of 4 months (range: 1-38). Cumulative incidences of molecular relapse by 12 and 48 months were 35% (95% confidence interval CI, 24.79% to 49.41%) and 44.76% (95% CI, 33.35% to 59.91%), respectively. Treatment-free remission (TFR) rates at 12 and 48 months were 63.33% (95% CI, 51.14% to 75.53%) and 53.57% (95% CI, 40.49% to 66.65%), respectively. In univariate analysis, prior suboptimal response or TKI resistance was the only baseline factor associated with significantly worse outcome. A landmark analysis demonstrated that loss of MR4.5 3 months after stopping TKI was predictive of failure to maintain MMR later on. During the treatment-free phase, no progression toward advanced phase CML occurred, and all relapsing patients regained MMR and MR4.5 after restarting therapy. In conclusion, discontinuation of first-line or subsequent 2G-TKI yields promising TFR rates without safety concerns. Further research is encouraged to better define conditions that will offer patients the highest chance to remain free from 2G-TKI therapy.
•First-line or subsequent dasatinib or nilotinib can be safely stopped in CML patients with deep and long-lasting molecular responses.•A suboptimal response or resistance prior to dasatinib or nilotinib is associated with significantly worse treatment-free remission.
Summary Background Imatinib treatment significantly improves survival in patients with chronic myeloid leukaemia (CML), but little is known about whether treatment can safely be discontinued in the ...long term. We aimed to assess whether imatinib can be discontinued without occurrence of molecular relapse in patients in complete molecular remission (CMR) while on imatinib. Methods In our prospective, multicentre, non-randomised Stop Imatinib (STIM) study, imatinib treatment (of >2 years duration) was discontinued in patients with CML who were aged 18 years and older and in CMR (>5-log reduction in BCR–ABL and ABL levels and undetectable transcripts on quantitative RT-PCR). Patients who had undergone immunomodulatory treatment (apart from interferon α), treatment for other malignancies, or allogeneic haemopoietic stem-cell transplantation were not included. Patients were enrolled at 19 participating institutions in France. In this interim analysis, rate of relapse was assessed by use of RT-PCR for patients with at least 12 months of follow-up. Imatinib was reintroduced in patients who had molecular relapse. This study is registered with ClinicalTrials.gov , number NCT00478985. Findings 100 patients were enrolled between July 9, 2007, and Dec 17, 2009. Median follow-up was 17 months (range 1–30), and 69 patients had at least 12 months follow-up (median 24 months, range 13–30). 42 (61%) of these 69 patients relapsed (40 before 6 months, one patient at month 7, and one at month 19). At 12 months, the probability of persistent CMR for these 69 patients was 41% (95% CI 29–52). All patients who relapsed responded to reintroduction of imatinib: 16 of the 42 patients who relapsed showed decreases in their BCR–ABL levels, and 26 achieved CMR that was sustained after imatinib rechallenge. Interpretation Imatinib can be safely discontinued in patients with a CMR of at least 2 years duration. Imatinib discontinuation in this setting yields promising results for molecular relapse-free survival, raising the possibility that, at least in some patients, CML might be cured with tyrosine kinase inhibitors. Funding French Ministry of Health (Programme Hospitalier de Recherche 2006 grants), Institut National du Cancer (INCA).
Despite persistence of leukemic stem cells, patients with chronic myeloid leukemia who achieve and maintain deep molecular responses may successfully stop the tyrosine kinase inhibitor imatinib. ...However, questions remain unanswered regarding the biological basis of molecular relapse after imatinib cessation. In IMMUNOSTIM, we monitored 51 patients from the French Stop IMatinib trial for peripheral blood T cells and natural killer cells. Molecular relapse-free survival at 24 months was 45.1% (95% CI: 31.44%-58.75%). At the time of imatinib discontinuation, non-relapsing patients had significantly higher numbers of natural killer cells of the cytotoxic CD56
subset than had relapsing patients, while CD56
natural killer cells, T cells and their subsets did not differ significantly. Furthermore, the CD56
natural killer-cell count was an independent prognostic factor of molecular-relapse free survival in a multivariate analysis. However, expression of natural killer-cell activating receptors,
leukemia cell line K562-specific degranulation and cytokine-induced interferon-gamma secretion were decreased in non-relapsing and relapsing patients as compared with healthy individuals. After imatinib cessation, the natural killer-cell count increased significantly and stayed higher in non-relapsing patients than in relapsing patients, while receptor expression and functional properties remained unchanged. Altogether, our results suggest that natural killer cells may play a role in controlling leukemia-initiating cells at the origin of relapse after imatinib cessation, provided that these cells are numerous enough to compensate for their functional defects. Further research will decipher mechanisms underlying functional differences between natural killer cells from patients and healthy individuals and evaluate the potential interest of immunostimulatory approaches in tyrosine kinase inhibitor discontinuation strategies.
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High-risk myelodysplastic syndrome/acute myeloid leukemia patients have a very poor survival after azacitidine failure. Guadecitabine (SGI-110) is a novel subcutaneous hypomethylating agent which ...results in extended decitabine exposure. This multicenter phase II study evaluated the efficacy and safety of guadecitabine in high-risk myelodysplastic syndrome and low blast count acute myeloid leukemia patients refractory or relapsing after azacitidine. We included 56 patients with a median age of 75 years Interquartile Range (IQR) 69-76. Fifty-five patients received at least one cycle of guadecitabine (60 mg/m2/d subcutaneously days 1-5 per 28-day treatment cycles), with a median of 3 cycles (range, 0-27). Eight (14.3%) patients responded, including two complete responses; median response duration was 11.5 months. Having no or few identified somatic mutations was the only factor predicting response (
=0.035). None of the 11 patients with
mutation responded. Median overall survival was 7.1 months, and 17.9 months in responders (3 of whom had overall survival >2 years). In multivariate analysis, IPSS-R (revised International Prognostic Scoring System) score other than very high (
=0.03) primary versus secondary azacitidine failure (
=0.01) and a high rate of demethylation in blood during the first cycle of treatment (
=0.03) were associated with longer survival. Thus, guadecitabine can be effective, sometimes yielding relatively prolonged survival, in a small proportion of high-risk myelodysplastic syndrome/low blast count acute myeloid leukemia patients who failed azacitidine. (Trial registered a
).
Summary
The effectiveness of tyrosine kinase inhibitors (TKIs) has made it possible to consider treatment discontinuation in chronic myeloid leukaemia (CML) patients that achieve an excellent ...response. However, a few of the patients included in the Europe Stop Tyrosine Kinase Inhibitors (EURO‐SKI) trial reported musculoskeletal pain shortly after stopping TKIs, considered as a withdrawal syndrome (WS). To identify factors that may predispose to TKI WS, we analysed the pharmacovigilance declarations for the 6 months after stopping TKIs in a large cohort of CML (n = 427) that combined the French patients included in the STop IMatinib 2 (STIM2; n = 224) and EURO‐SKI (n = 203) trials. Among these patients, 23% (99/427) developed TKI WS after stopping imatinib (77/373; 20·4%), nilotinib (12/29; 41·4%) or dasatinib (10/25; 40%). WS concerned mainly the upper body joints, and required multiple symptomatic treatments in 30% of patients. Univariate and multivariate analyses identified two risk factors: duration of TKI treatment risk ratio (RR) = 1·68 (1·02–2·74) with a 93‐month cut‐off time, and history of osteoarticular symptoms RR = 1·84 (1·04–3·28). These findings confirm that WS is a TKI class effect. CML patients should be carefully screened before treatment initiation to identify pre‐existent osteoarticular symptoms. Moreover, before TKI discontinuation, patients should be informed of the possibility of WS, particularly after a long treatment period.
We have previously described the safety and efficacy of pegylated interferon-α2a therapy in a cohort of 62 patients with myeloproliferative neoplasm-associated myelofibrosis followed in centers ...affiliated to the French Intergroup of Myeloproliferative neoplasms. In this study, we report their long-term outcomes and correlations with mutational patterns of driver and non-driver mutations analyzed by targeted next generation sequencing. The median age at diagnosis was 66 years old, the median follow-up since starting pegylated interferon was 58 months. At the time of analysis, 30 (48.4%) patients were alive including 16 still being treated with pegylated interferon. The median survival of patients with intermediate and high-risk prognostic Lille and dynamic International Prognostic Scoring System scores treated with pegylated interferon was increased in comparison to that of historical cohorts. In addition, overall survival was significantly correlated with the duration of pegylated interferon therapy (70
30 months after 2 years of treatment,
<10
).
allele burden was decreased by more than 50% in 58.8% of patients and two patients even achieved complete molecular response. Next-generation sequencing analyses performed in 49 patients showed that 28 (57.1%) of them carried non-driver mutations. The presence of at least one additional mutation was associated with a reduction of both overall and leukemia-free survival. These findings in a large series of patients with myelofibrosis suggest that pegylated interferon therapy may provide a survival benefit for patients with intermediate- or high-risk Lille and dynamic International Prognostic Scoring System scores. It also reduced the
allele burden in most patients. These results further support the use of pegylated interferon in selected patients with myelofibrosis.
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