Treatment-free Remission Rate Research Articles

Duration of Major Molecular Response and Discontinuation in Deep Molecular Response (MR4.5) Were Associated with Longer Treatment-Free Survival after Imatinib Discontinuation - Results from Two Prospective Brazilian Trials

Several trials have demonstrated the feasibility of discontinuation of tyrosine kinase inhibitors (TKI) treatment in chronic myeloid leukemia (CML) patients (pts) with deep molecular response. Aims: to report the results of two Brazilian imatinib (IM) discontinuation trials and to evaluate factors impacting in treatment-free remission (TFR) and treatment-free survival (TFS) after IM discontinuation. Methods:Between September 2016 and January 2019, 60 CML pts were included in two ongoing phase II, single arm, prospective Brazilian discontinuation trials: Pilot Study of Discontinuation in Patients With Chronic Myeloid Leukemia With Deep Molecular Response - Evaluation of Pioglitazone in Treatment-free Remission (TFR) (EDI-PIO UNICAMP)(NCT02852486)and Imatinib Discontinuation in Patients With Chronic Myeloid Leukemia Chronic Phase With Sustained MR4log(USP) (NCT03239886). Inclusion criteria: age >18 years, chronic phase, minimum of 3 years of IM therapy, deep molecular response for ≥ 2 years (confirmed by 4 tests in the last 2 years, defined as MR4.0 in USP trial and MR4.5 in EDI-PIO). Patients participating in EDI-PIO trial used pioglitazone 30 mg/day plus IM for 3 months before IM discontinuation (n=30). After discontinuation, pts were monitored by quantitative RQ-PCR monthly in the first year, every 2 months in the second year and every 3 months in the third year. Criteria for IM re-initiation: loss of MMR (in one test), loss of cytogenetic response, loss of hematologic response, disease progression or confirmed loss of MR4.0 (this criteria used only in EDI-PIO trial). TFR was calculated from the date of discontinuation until first event (loss of MMR; IM reintroduction; death any cause or last follow-up); TFS was calculated from the date of IM discontinuation until reintroduction or last follow-up (censoring deaths not related to CML). Adverse events after IM discontinuation were reported according to CTCAE. Results:Data cut-off for analysis was February 2019. In the 1stanalysis 48 pts who discontinued IM in MR4.5 were analyzed. Patient's characteristics from EDIPIO (n=30) and USP (n=18) trials were: 57% vs. 67% male, median age of 55 (29-77) and 56 (33-95) years (29-95) at discontinuation; 16% and 33% had used previously Interferon; median duration of IM treatment of 10 (3-16) vs. 10 (5-15) years; median duration of MMR 95 (30-149) vs. 93 (57-130) months; MR4.0 was 90 (26-135) vs. 89 (30-123) months; and MR4.5 was 76 (23-135) vs. 75 (30-102) months; none variable had statistical difference.One patient died in MMR due to cardiac failure. TFR was 61% (95% CI 47-75) at 20 months. Sixteen (33%) out 48 re-initiated IM (2 with confirmed loss of MR4.0 and 14 with loss of MMR) in a median time of 20 (1-26) months. All relapsed pts recovered MMR after IM reintroduction, in a median time of 2 months (0-4). There was no transformation to advanced phases. No serious adverse events were reported during pioglitazone treatment. In the Cox regression the duration of MMR was associated with a longer TFR HR: 0.96 (beta-) (CI 95%:0.94-0.99, P= 0.006). Gender, age at diagnosis, age at discontinuation, treatment with pioglitazone, Sokal and EUTOS scores, BCR-ABL transcripts type, duration of IM therapy, duration of MR4.0 and MR4.5 and previous use of Interferon did not affect TFR.In the second analysis all 60 pts were included. TFS was 56% and was higher in pts who discontinued IM in sustained MR4.5 vs. MR4.0 (63% vs. 33%, P=0.04)(Figure). The independent factors for TFR in the multivariate analysis by Cox-regression were the duration of MMR [HR: 0.97 (beta-), 95%CI: 0.95-0.98, P=0.001] and intermediate/high risk Sokal [HR 3.14 95%CI: 1.08-9.11, P= 0.035]. Twenty-four out of 60 pts (40%) re-initiated IM (2 with confirmed loss of MR4.0 and 22 with loss of MMR).Adverse events occurred in 38 (63%) pts, 30% attributed to withdrawal syndrome. Some pts presented more than one event. Grade 1-2: arthralgia or muscular pain (17), hyperglycemia (4), hypertriglyceridemia (2), polycythemia (2), hypertension (3), and others (11). Four pts had grade 3-4 event: arthralgia (1), death for cardiac failure (1), abortion and hypertriglyceridemia (1). Conclusions:both trials demonstrated the feasibility and safety of IM discontinuation in pts in sustained deep molecular response. The duration of MMR was associated with a higher TFR and TFS rate. Imatinib discontinuation was more successful in pts in stable MR4.5. Figure Disclosures Pagnano: Pint Pharma: Consultancy; Abbvie: Consultancy; Sandoz: Consultancy. Delamain:Novartis: Honoraria.

The Combination of Nilotinib + Pegylated IFN Alpha 2a Provides Somewhat Higher Cumulative Incidence Rates of MR4.5 at M36 Versus Nilotinib Alone in Newly Diagnosed CP CML Patients. Updated Results of the Petals Phase III National Study.

The Combination of Nilotinib + Pegylated IFN Alpha 2a Provides Somewhat Higher Cumulative Incidence Rates of MR4.5 at M36 Versus Nilotinib Alone in Newly Diagnosed CP CML Patients. Updated Results of the Petals Phase III National Study.

Analyses of Predictors of Durable Treatment-Free Remission in Patients with Chronic Myeloid Leukemia in Chronic Phase Following Frontline or Second-Line Nilotinib

Analyses of Predictors of Durable Treatment-Free Remission in Patients with Chronic Myeloid Leukemia in Chronic Phase Following Frontline or Second-Line Nilotinib

Prognostication of Molecular Relapses after Dasatinib or Nilotinib Discontinuation in Chronic Myeloid Leukemia (CML): A FI-LMC STOP 2G-TKI Study Update

Rea: Incyte Biosciences: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nicolini:Sun Pharma Ltd: Consultancy; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Etienne:Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Guerci:INCYTE: Consultancy, Honoraria. Legros:Pfizer: Honoraria, Research Funding; BMS: Honoraria; Novartis: Honoraria; Incyte Biosciences: Honoraria, Research Funding. Coiteux:Pfizer: Honoraria; BMS: Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Mahon:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau.

283P - Effect of study-level factors on treatment-free remission rate in patients with chronic myeloid leukemia: A systematic review and meta-analysis

BackgroundAs most assessments for treatment-free remission (TFR) in patients with chronic myeloid leukemia are recommended to be conducted as prospective trials, we conducted a systematic review and meta-analysis to investigate which study-level factors affected the TFR rate. MethodsThe MEDLINE, Embase, and Cochrane databases were systematically searched from inception to July 2018. A random effect model was used to estimate the overall mean TFR rate, subgroup differences, and regression coefficients with continuous variables. ResultsOverall, 12 tyrosine kinase inhibitor (TKI) stopping studies comprising 1,699 chronic myeloid leukemia patients were included in the analyses. The overall mean TFR rate at 24 months after entering TFR phase was 55% (95% confidence interval [CI], 0.51–0.58). Trials with molecular criteria of MR4.5 or better for stopping TKI reported higher TFR rates than those of MR4.0 (57.2% vs. 50.5%). Trials with eligible criteria for at least 24 months of deep molecular response (DMR) duration demonstrated higher TFR rates than those for 18 or 12 months (60.2% vs. 49.9%). ConclusionsIt is expected that TKI stopping trials with sufficient duration of DMR and molecular criteria of MR4.5 or better could secure approximately 60% of the TFR rate at 24 months after stopping TKI. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Effect of study-level factors on treatment-free remission rate in patients with chronic myeloid leukemia: a systematic review and meta-analysis.

As it is recommended that most assessments for treatment-free remission (TFR) in patients with chronic myeloid leukemia be conducted as prospective trials, we conducted a systematic review and meta-analysis to investigate which study-level factors affected the TFR rate. The MEDLINE, Embase, and Cochrane databases were systematically searched from inception to July 2018. A random effect model was used to estimate the overall mean TFR rate, subgroup differences, and regression coefficients with continuous variables. Overall, 12 tyrosine kinase inhibitor (TKI) stopping studies comprising 1699 chronic myeloid leukemia patients were included in this analysis. The overall mean TFR rate at 24months after entering TFR phase was 55% [95% confidence interval (CI) 0.51-0.58]. Trials with molecular criteria of MR4.5 or better for stopping TKI reported higher TFR rates than those of MR4.0 (57.2% vs. 50.5%). Trials with eligible criteria for at least 24months of deep molecular response (DMR) duration demonstrated higher TFR rates than those for 18 or 12months (60.2% vs. 49.9%). Our results suggest that TKI stopping trials with sufficient duration of DMR and molecular criteria of MR4.5 or better may account for approximately 60% of the TFR rate at 24months after stopping TKI.

Consolidation Treatment With Ponatinib 15 mg on Treatment Free-Remission Rate in Patients With Chronic Myeloid Leukemia

Consolidation Treatment With Ponatinib 15 mg on Treatment Free-Remission Rate in Patients With Chronic Myeloid Leukemia

PF407 TREATMENT‐FREE REMISSION IN PATIENTS WITH CHRONIC MYELOGENOUS LEUKEMIA FOLLOWING FIRST‐LINE DASATINIB, 1ST DADI/IMIDAS4

Background:The main treatment goal for patients with chronic phase chronic myelogenous leukemia (CML‐CP) is discontinuation of tyrosine kinase inhibitor (TKI) therapy. In the previous DAsatinib Discontinuation (DADI) trial, we showed that 44.4% of CML patients treated with second‐line or subsequent dasatinib could stop dasatinib safely if they sustained DMR (0.01% ≥ IS)for a minimum of 1 year. No study has examined treatment free remission (TFR) in a large cohort after discontinuation of first‐line dasatinib treatment.Aims:We report the the results of a phase II trial designed to investigate TFR after dasatinib discontinuation in CML patients who sustained DMR for at least 1 year after treatment with first‐line dasatinib (the 1st DADI / IMIDAS4 trial).Methods:In this trial, we enrolled patients with CML‐CP at 23 Japanese centers. Patients with CML‐CP with DMR and more than 24 months of first‐line dasatinib were enrolled. Patients with sustained DMR during the 1‐year dasatinib consolidation phase were eligible into the TFR phase. Molecular responses were assessed every 3 months during the consolidation phase and every month during the TFR phase by real‐time quantitative polymerase chain reaction.The primary end point was TFR at 6 months, and the secondary end point was TFR at 12 months. Molecular relapse was defined as loss of DMR at two consecutive times points or loss of major molecular response (MMR; 0.1% ≥ IS); in these cases, the patient was re‐administered dasatinib at the previously effective dose. Analysis of natural killer (NK) and T‐cell profiles was performed to identify the factors responsible for molecular relapse throughout the preregistration period of the study.Results:Patients (n = 68) diagnosed with CML‐CP and achieving DMR after receiving first‐line dasatinib treatment for at least 24 months, were eligible for the 1‐year consolidation phase. Nine patientswere excluded from the discontinuation phase.Fifty‐ nine patients were enrolled into the TFR phase of the study. The median age was 63 (31–94). Forty‐three patients had low Sokal risk scores and 16 patients had high or intermediate scores. The median duration of DMR and total time dasatinib treatment were 23.3 (11.1–56.2) months and 40.2 (35.1–111) months, respectively. The median dose of dasatinib during DMR and the total dose from initiation of treatment were 21,840 (3,600–38,700) mg and 67,100 (5,350–332,480) mg, respectively. Thirty‐three patients sustained TFR for a median follow‐up of 23.3 months (11.7 –31.0 months). Both overall probability of TFR at 6 and 12 months was 55.9% (95% CI, 44.6–70.1, Figure). The duration of first‐line dasatinib treatment (≥40 months or <40 months; P = 0.72) did not correlate with the TFR rate, which had been thought to correlate with duration of TKI treatment. Overall, 26 patients experienced loss of DMR within 6 months; all received dasatinib at the previously effective dose, resulting in rapid achievement of MMR (24 of the 26 patients achieved DMR). Univariate and multivariate analyses revealed that low CD4/CD8 ratio was a significant favorable prognostic factor [Hazard ratio, 0.33 (0.14–0.79; P = 0.012), meanwhile, NK cell counts did not affect TFR.Summary/Conclusion:The TFR rate of 55.9% (the present study used very stringent criteria for molecular relapse) is a clinically important outcome with the shortest treatment time among previous TKI discontinuation studies. T cell‐mediated immune responses have a greater impact on TFR in CML than NK cell‐mediated immune responses. This trial was registered as number UMIN000011099.image

PS1172 DDPCR AT THE TIME OF TKI DISCONTINUATION IN CHRONIC PHASE CHRONIC MYELOID PATIENTS IS PREDICTIVE OF TREATMENT‐FREE REMISSION OUTCOME

Background:Only few prognostic factors ‐ the median duration of treatment or of deep molecular response (DMR) ‐ have so far been associated to a positive outcome after TKI discontinuation in chronic myeloid leukemia (CML) patients. Thus, the identification of candidates that may impact on this primary treatment endpoint remains elusive. Digital droplet PCR (ddPCR) is an accurate molecular tool that could prove advantageous for the quantification of the BCR‐ABL1 fusion transcript copy number compared to classic RQ‐PCR and could help in better identify patients candidate for TKI discontinuation.Aims:To evaluate the predictive role of ddPCR in CML patients in sustained DMR tested at the time of TKI treatment discontinuation.Methods:We studied 50 RNA samples of CML patients who discontinued treatment while in RQ‐PCR undetectable DMR (MR4–4.5) according to IS for more than 2 years. The ddPCR assay was performed in triplicate using the Biorad‐QX200 platform. To test the BCR‐ABL fusion transcript and ABL control gene, we used the same primers and probes used in the standard RQ‐PCR reaction. Each reaction mixture was partitioned into approximately 20,000 droplets and then amplified. Cycled droplets were read in the QX200 droplet‐reader and analysis of the ddPCR data was performed using the QuantaSoft analysis software (Biorad Laboratories GmbH, Munich, Germany). We collected the clinical follow‐up data from the patients’ medical history and correlated them with ddPCR positivity or negativity at the time of discontinuation using the Wilcoxon signed‐rank test.Results:Fifty patients discontinued treatment in DMR after a median duration of response of 2.5 years (range 1.5–7.2). The median age was 59 years (range 32–87.4), 33 were female. According to the Sokal risk at baseline, 25 patients were classified as low risk, 21 as intermediate and 4 as high risk. Forty‐two patients received front‐line imatinib and 8 were treated with second generation TKIs. The median duration of treatment before discontinuation was 11.9 years (range 3.3–17.9). At the time of discontinuation, 28 patients (56%) were ddPCR‐negative and 24 of them (86%) remained in treatment‐free remission (TFR), while 4 patients (14%) relapsed after a median time of 5.5 months (range 4.0–27.0). Twenty‐two patients (44%) were ddPCR positive at the time of discontinuation: 12 of them (55%) remained in TFR after a median time of observation of 13.2 months, while 10 patients (45%) relapsed after a median of 3.5 months (range 1.0–16.0). The difference in TFR rate between the two groups is statistically significant (p = 0.026, Figure 1). We compared the characteristics of ddPCR‐negative versus ddPCR‐positive patients and failed to detect differences in the type of transcript (p = 0.155), Sokal risk score (p = 0.684), previous IFN treatment (p = 0.70), type of TKI received (p = 0.250), median duration of TKI treatment (10.9 years in positive versus 13.1 years in negative patients, p = 0.639) and median duration of DMR (2.4 years in positive versus 2.8 years in negative patients, p = 0.134).Summary/Conclusion:These results suggest that by ddPCR it is possible to predict the TFR outcome of CML patients in DMR (MR4–4.5) at the time of TKI discontinuation. This method, compared to RQ‐PCR, appears to be superior in terms of quantification of low levels of residual disease in patients who have already achieved a DMR and may successfully identify candidates to treatment discontinuation.image

Treatment-free remission (TFR) following frontline (1L) nilotinib (NIL) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): 192-week data from the ENESTfreedom study.

7013 Background: In ENESTfreedom (NCT01784068), which evaluated TFR following 1L NIL in CML-CP pts, 51.6% remained in TFR 48 wks after stopping treatment (primary endpoint) and durability of TFR was demonstrated at 144 wks. Data from longer follow-up (192 wks) evaluating maintenance of TFR are reported. Methods: Pts with MR4.5 ( BCR-ABL1IS ≤0.0032%) and ≥2y of 1L NIL entered a 1y consolidation; pts with sustained deep molecular response (MR) were eligible for TFR. NIL was resumed after loss of major MR (MMR; BCR-ABL1IS ≤0.1%). At the latest data cut-off (Sep 17 2018), all pts had completed ≥192 wks of TFR, resumed NIL, or discontinued the study. Results: By the data cut-off, of 190 pts entering TFR, 87 were ongoing, 91 had resumed NIL, and 12 had permanently discontinued. The TFR rate at 192 wks was 44.2% (84/190, 95% CI: 37.0–51.6%). Of 89 pts with successful TFR at 144 wks, 5 were not assessable for TFR at 192 wks as 2 had discontinued by 192 wks due to pt/physician decision, and 3 with MR4.5 previously did not have 192 wk PCR data. Of 91 pts who resumed NIL, 90 (98.9%) regained MMR and 84 (92.3%) regained MR4.5. 75/90 and 73/84 pts, respectively, had stable MMR and MR4.5 at 48 wks later. There were no cases of disease progression or new deaths. 10 deaths were reported in the 144-wk analysis, none due to CML. The 192-wk treatment-free survival rate was 48.7% (95% CI 41.4–55.6%). Of 89 pts remaining in TFR for > 144 wks (including 87 pts for > 192 wks), all-grade AE rates during consolidation and each subsequent 48 wk period of TFR were 84.3%, 77.5%, 70.8%, 48.3%, and 52.8%, respectively. All-grade musculoskeletal pain AE rates were 15.7%, 40.4%, 9.0%, 3.4% and 3.4%, respectively; cardiovascular event rates were low across these periods. Among pts who resumed NIL, most common AEs were nasopharyngitis (18.7%) and pruritus, fatigue, and increased lipase (14.3% each); the majority of AEs were grade 1/2. Conclusions: Results continue to support the long-term durability and safety of TFR at 192 wks after stopping 1L NIL; overall AE rates declined during the TFR phase and musculoskeletal pain AEs were transient. Pts should continue to be regularly monitored during TFR. Clinical trial information: NCT01784068.

ENESTop 192-week results: Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after stopping second-line (2L) nilotinib (NIL).

7005 Background: In the ENESTop study (NCT01698905) of TFR in pts with CML-CP who achieved a sustained deep molecular response (MR) with 2L NIL, 57.9% remained in TFR 48 wks after stopping NIL (primary endpoint). Analyses at 144 wks showed durability of TFR. Data from longer follow-up (192 wks) evaluating the maintenance of TFR are reported. Methods: Pts treated with ≥2 y NIL after > 4 wks imatinib (≥3 y total) and achieving MR4.5 ( BCR-ABL1IS ≤0.0032%) on NIL were eligible. After a 1 y consolidation, pts with no confirmed loss of MR4.5 could attempt TFR. NIL was resumed upon loss of major MR ( BCR-ABL1IS ≤0.1%) or confirmed loss of MR4 ( BCR-ABL1IS ≤0.01%). At the data cut-off (Sep 24 2018), all pts had completed ≥192 wks of TFR, resumed NIL, or discontinued the study. Results: By the data cut-off, of 126 pts entering TFR, 56 were ongoing, 59 had resumed NIL, and 11 had discontinued. TFR rate at 192 wks was 46.0% (58/126; 95% CI, 37.1–55.1%); all but 1 of the 58 pts were in MR4.5. Only 1/61 pts in TFR at 144 wks lost response by 192 wks (confirmed loss of MR4); another 2 pts discontinued due to serious AE (polycythemia vera) and pt/guardian decision, respectively. Of 59 pts who resumed NIL, 56 (94.9%) and 55 (93.2%) regained MR4 and MR4.5, respectively. 40/56 pts (71.4%) who regained MR4 had stable MR4 at 96 wks (12 discontinued < 96 wks, and 4 remained on study with < 96 wks, after regaining MR4); 37/55 pts (67.3%) who regained MR4.5 had stable MR4.5 at 96 wks (12 discontinued < 96 wks, and 6 remained on study with < 96 wks, after regaining MR4.5). There were no disease progressions, deaths due to CML, or new deaths since the 144-wk analysis. The 192 wk treatment-free survival rate was 50.3% (95% CI, 41.2–58.7%). Of 62 pts who remained in TFR for > 144 wks, 11.3%, 53.2%, 21.0%, 14.5% and 3.2% had musculoskeletal pain AEs during consolidation and each subsequent 48 wk period of TFR. Among 59 pts who resumed NIL, most common AEs were hypertension (20.3%) and arthralgia (13.6%); the majority of AEs were grade 1/2. Conclusions: Results demonstrate long-term durability and safety of TFR following 2L NIL, with no disease progressions or CML-related deaths, and musculoskeletal pain AEs were transient. Clinical trial information: NCT01698905.

Clinical analysis on outcomes in patients with chronic myeloid leukemia in chronic phase after tyrosine kinase inhibitors discontinuation and their influencing factors

Objective To explore the clinical outcomes and their influencing factors of tyrosine kinase inhibitors (TKI) discontinuation in patients with chronic myeloid leukemia in chronic phase (CML-CP). Methods From January 1999 to April 2018, a total of 16 patients with CML-CP who underwent routine outpatient follow-up in Department of Hematology, West China Hospital of Sichuan University, and discontinued TKI for more than 6 months were selected as subjects. Among them, there were 6 male patients and 10 females; the median age at diagnosis was 39.5 years (24.8-53.8 years). The median age at time of TKI discontinuation was 45.5 years old (30.3-69.0 years old). According to whether molecular recurrence occurred during the follow-up period after TKI discontinuation, the patients were divided into recurrent group (n=5) and non-recurrent group (n=11). The clinical data of patients with TKI before and after discontinuation were collected by retrospective method. The causes of TKI discontinuation, treatment-free remission (TFR) status after TKI discontinuation and its possible influencing factors were analyzed. In this study, composition ratio of gender, stage of CML, and TKI discontinuation causes were compared between the two groups using Fisher′s exact test. The Mann-Whitney U test was used to compare the non-normal distribution measurement data, such as duration of TKI treatment, time from TKI treatment to major molecular response (MMR)/deep molecular response (DMR), time of MMR/DMR maintenance. The TFR rate at 6 and 12 months after TKI discontinuation in patients was calculated by Kaplan-Meier method. The procedure followed in this study was in line with the revised Helsinki Declaration of the World Medical Association in 2013. Results ① Among all the 16 patients with CML-CP, causes of TKI discontinuation included TKI-related adverse reactions (n=5), patients′ expectancy (n=5), pregnancy/planned pregnancy (n=4), financial burden (n=1), and combined solid tumor (n=1). The median time of TKI treatment in 16 patients with CML-CP was 53.0 months (34.0-156.0 months). Among them, 15 patients achieved DMR before TKI discontinuation and 1 patient only obtained MMR. The median time to achieve DMR before TKI discontinuation was 39.0 months (10.0-144.0 months). ② The median follow-up time of 16 patients with CML-CP after TKI discontinuation was 17.0 months (7.0-75.0 months). At the end of follow-up, 11 patients had no molecular recurrence, and the median time of TFR was 12.0 months (2.0-75.0 months). TFR rates at 6 and 12 months after TKI discontinuation were 68.8% and 61.9%, respectively. Molecular recurrence occurred in 5 patients. The median recurrence time was 4.0 months (2.0-5.0 months) after TKI discontinuation, and the BCR-ABLIS level was 0.14%-0.88% at the time of recurrence. Among the 5 patients with molecular recurrence, 4 patients restarted TKI at 3, 4, 6 and 8 months after relapse, obtained MMR after 2, 3, 4, and 5 months of restarting TKI, obtained molecular response (MR)4.5 after 2, 3, 7 and 8 months of restarting TKI, respectively. ③ In this study, 5 patients with molecular recurrence occurred within 6 months after TKI discontinuation. The composition ratio of gender, stage of CML, causes of TKI discontinuation, previous treatment of interferon-α, TKI type, as well as duration of TKI treatment, time of initiation of TKI treatment to MMR/DMR, time of MMR/DMR maintenance, age at TKI discontinuation between two groups were compared. And the differences were not statistically significant (P>0.05). ④ Among 16 patients with CML-CP, 2 patients developed TKI withdrawal syndrome, which was characterized by systemic bone pain or myalgia. Conclusions Patients with CML-CP who receive long-term TKI and maintain continuous DMR, long-term TFR can be obtained in about 50% patients, but long-term MR should be monitored after TKI discontinuation. The above-mentioned influencing factors that may affect the clinical outcomes of TKI discontinuation were not statistically different between the recurrent group and the non-recurrent group, which may be related to small sample size of this study. Key words: Leukemia, myeloid; Leukemia, myeloid, chronic-phase; Leukemia, myelogenous, chronic, BCR-ABL positive; Prognosis; Tyrosine kinase inhibitor; Treatment discontinuation; Treatment free remission

The proportion of different BCR-ABL1 transcript types in chronic myeloid leukemia. An international overview.

There are different BCR-ABL1 fusion genes that are translated into proteins that are different from each other, yet all leukemogenic, causing chronic myeloid leukemia (CML) or acute lymphoblastic leukemia. Their frequency has never been systematically investigated. In a series of 45503 newly diagnosed CML patients reported from 45 countries, it was found that the proportion of e13a2 (also known as b2a2) and of e14a2 (also known as b3a2), including the cases co-expressing e14a2 and e13a2, was 37.9% and 62.1%, respectively. The proportion of these two transcripts was correlated with gender, e13a2 being more frequent in males (39.2%) than in females (36.2%), was correlated with age, decreasing from 39.6% in children and adolescents down to 31.6% in patients ≥ 80 years old, and was not constant worldwide. Other, rare transcripts were reported in 666/34561 patients (1.93%). The proportion of rare transcripts was associatedwith gender (2.27% in females and 1.69% in males) and with age (from 1.79% in children and adolescents up to 3.84% in patients ≥ 80 years old). These data show that the differences in proportion are not by chance. This is important, as the transcript type is a variable that is suspected to be of prognostic importance for response to treatment, outcome of treatment, and rate of treatment-free remission.

Outcomes of unplanned tyrosine kinase inhibitor discontinuation in patients with chronic myeloid leukemia: retrospective analysis of real-world experience in a single institution

ABSTRACTObjectives: To explore real-world prognoses for tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML) patients and the associated reasons for TKI discontinuation.Methods: We investigated, using the medical records of 85 consecutive CML patients who received TKIs between December 2001 and August 2016 at our hospital, reasons for discontinuation, duration of TKI treatment before discontinuation, molecular response (MR) status at TKI discontinuation, treatment-free remission (TFR) duration, and overall survival after TKI discontinuation.Results: TKI therapy was discontinued in 21 patients. The median treatment duration before discontinuation was 68.3 months. The response statuses at discontinuation were MR4 (n = 2), MR4.5 (n = 4), and ≥MR5 (n = 15). The reasons were pleural effusion (n = 5); requests for prolonged deep molecular response (DMR) (n = 4); ischemic heart disease, anemia, and economic problems (each, n = 3); renal dysfunction (n = 2); and hyperkalemia, diarrhea, dementia, asthma, and desire to get pregnant, (each, n = 1). All patients were alive with median follow-up period of 32.1 months. TFR was maintained in 14 patients, and the 2-year TFR proportion was 66.7%. Seven patients restarted TKI therapy and achieved MR4 within median of 3 months. The duration of TKI administration before discontinuation (≥ 70 months) was favored longer TFR durations.Conclusion: TKI was safely discontinued in clinical practice and yielded TFR rates similar to those observed in previous clinical trials, regardless of reason. Achievement of TFR significantly impacts patients’ quality of life and should be considered in clinical practice.

Impact of Treatment Free Remission (TFR) with Nilotinib in 2nd Line for Chronic Myeloid Leukemia on Savings That May Fund All BCR-ABL Tests in the Brazilian Public Healthcare System during and after Nilotinib Treatment

Objectives: To estimate the savings and opportunity costs of nilotinib considering treatment free remission after 2nd line treatment of chronic myeloid leukemia (CML) with Nilotinib to fund BCR-ABL molecular test under the Brazilian public healthcare system (SUS) perspectiveMaterials and methods: A budget impact analysis was developed to estimate the savings for the public health system with TFR eligible patients. ENESTop (Mahon FX et al., 2018), an ongoing, single-arm, phase 2 study is the first trial specifically evaluating treatment-free remission (TFR; ie, stopping tyrosine kinase inhibitor [TKI] treatment without a loss of response) in patients with chronic myeloid leukemia in chronic phase (CML-CP) who achieved a sustained deep molecular response after switching from imatinib to nilotinib. In this trial, patients using nilotinib, who had 4.5 log molecular response after at least 24 months of Nilotinib treatment after switching from imatinib, entered into 12 months of consolidation phase and if they maintain MR 4.5 log response (77%), treatment was discontinued as planned in study protocol (57.9% TFR rate at 48 weeks - primary endpoint).A systematic review of the literature was developed over the efficacy of the use of nilotinib in 2nd line for patients diagnosed with CML. Efficacy data used to input the economic model is informed in a published randomized controlled clinical trial (ENESTcmr trial, Hughes TP et al., 2015), a 48 month, open-label, randomized, phase 3 study designed to investigate whether patients with complete cytogenetic response but persistent minimal residual disease on long-term imatinib ( ≥ 2 years prior imatinib) could achieve MR 4.5 log response by switching from imatinib to Nilotinib 400 mg BID. In this study, 33%, 42%, 46% and 52% of patients achieved 4.5 log molecular response by 12, 24, 36 and 48 months of nilotinib treatment after switching from imatinib. The total annual cost in 2017 with nilotinib was extracted from an official Brazilian database (http://paineldeprecos.planejamento.gov.br).Results: Considering that MR 4.5 log response patients will start consolidation in the first year, the economic impact will reduce in BRL 7,2M in the second year year, reaching a saving of BRL 11,4M in the fifth year. The total accumulated saving for the Brazilian public system (SUS) in 5-years was over BRL 38,1M. We also evaluated the necessary investments on BCR-ABL monitoring tests for all CML patients in the public market, as this test is not reimbursed by Brazilian public healthcare system (SUS). We estimated a budget impact of BRL 4.5M per year considering an average of 2 monitoring tests per patient, thus in 5 years an investment of 22,5M in BCR-ABL would be necessary.Discussion: The deep molecular response (MR 4.5 log) in may lead to patient discontinuation in those patients achieving 4.5 log molecular response after at least 24 months of nilotinib treatment and maintaining this response after 12 months. Furthermore, the possibility of TFR with nilotinib will save resources in health sytems allowing to invest in other needs. As demonstrated in this study, savings generated by nilotinib in 2nd line considering the possibility of TFR could allow the incorporation of BCR-ABL test for all CML patients in the public health system (SUS), which is essential in the current management of CML.Conclusion: Nilotinib in 2nd line treatment may generate savings for the public healthcare system (SUS) that could fund the BCR-ABL test for all CML patients. DisclosuresVivona:Novartis: Employment. Leite:Novartis: Employment. Matsuo:Novartis: Employment. Teich:Novartis: Consultancy.

Dose Reduction of First and Second Generation TKIs Is Effective in the Maintenance of Major Molecular Response and May Predict Successful Tfr in CML Patients

Introduction: As patients (pts) diagnosed with chronic myeloid leukaemia (CML) in CP are predicted to have a life expectancy comparable to that of the normal population, clinical concern has focused on the burden of long-term side effects and quality of life. Stopping tyrosine kinase inhibitor (TKI) is possible in a selected group of pts, resulting in a 50% chance of treatment free remission (TFR). Limited data, however, are available on the outcome of TKI dose reduction (DR) in maintaining molecular responses.Methods: We retrospectively analysed the outcome of TKI DR in pts in ≥MR3 treated at our centre from Jan 2000 until May 2015. We defined different low dose groups (LDG), according to the actual TKI dose: for imatinib (IM), 300mg and 200mg; for dasatinib (DAS), 70-80mg, 50mg, 40mg and 20mg; for nilotinib (NIL), 400-450mg, 300mg or ≤200mg; and for bosutinib (BOS), 300mg, 200mg and <200mg.Given the ‘real life’ setting, pts may have received either 1) multiple DRs of the same TKI or 2) different TKIs at different low doses. For scenario 1): we analysed the dose that maintained ≥MR3 and was used for the longest period of time. In case of loss of molecular response on a lower dose level, the next dose was considered a further ‘case’ and the patient was analysed more than once. In scenario 2) the patient was analysed once for each TKI received at low dose. MR3 and MR4 were defined conventionally. The molecular recurrence free survival (MRFS) was estimated by Kaplan-Meier.Results: We included 232 pts (IM=83 pts, cases=85; DAS=75, cases=79; NIL=72, cases=73; BOS=32, cases=33), of whom 8 pts were included in two different LDG on the same TKI (because of loss of response on the lower dose: imatinib n=2, dasatinib n=4, nilotinib n=1, bosutinib n=1). 22 and 4 pts received 2 low dose (LD) TKIs and 3 LD TKIs respectively. The total number of cases was 270. Reasons for DR included any degree of adverse event deemed significant by the clinician or pre-emptive DR at the time of introduction of a subsequent TKI due to intolerance to the previous TKI. All IM pts were treated first line, whereas the majority of pts (n=159, 88.8%) received their current 2GTKI as ≥ 2 line. Median follow-up on LD TKI was 25.3 months (1.9-175). Patient characteristics by TKI are shown in Tables 1-4.The 2-year MRFS were: IM, 88.4% (95% CI, 87.7-89.1%), and 92.7% and 77.2% for LDG1 and LDG2 respectively; DAS 92.8% (95% CI, 92.2-93.4%); and 100%, 96.2%, 92.3% and 85.6% for LDG1, LDG2, LDG3 and LDG4 respectively; NIL 93.4% (95% CI, 92.6-94.1%); and 93.3%, 88.9% and 100% for LDG1, LDG2 and LDG3, respectively; BOS 91.7% (95% CI, 90-93%); and 100% for LDG1 and LDG2 and 75% for LDG3 (Figure 1 a,b,c and d).One patient on NIL required DR for grade 3 liver toxicity, progressed to blast crisis after losing MR3 on 300mg daily and died post allo-SCT. One patient, who had achieved only CHR on IM, developed a T315I mutation on 50mg DAS second line while in MR3, having lost MR4, and was changed to ponatinib. One patient on DAS died of an unrelated brain tumour.In each TKI cohort, 59/83 pts (71%) remained on LD IM, 51/75 (68%) pts on LD DAS, 35/72 (48.6%) pts on LD NIL and 30/32 (93.7%) pts on LD BOS. 55 pts stopped LD TKI while in sustained MR4 or greater (IM n=21/83 [25.3%], DAS n=12/75 [16%], NIL n=20/72 [27.8%], BOS n=2/30 [6.6%]) with a 2-year probability of TFR of 79.4% (95% CI, 78.3-80.5%) (compared to 50% at 2 years in EURO-SKI), with a median observation time of 28 months (5-83.7) in non-relapsing pts. TFR in the different cohorts were 85.7%, 62.3%, 80% and 100% for IM, DAS, NIL and BOS respectively.Conclusion: For selected pts in ≥MR3 lowering the TKI dose can improve the tolerability of TKI therapy without impacting responses. The higher rate of TFR observed in our pts than in published stopping studies probably reflects cohorts of pts already shown to maintain deep responses on lower than standard doses of TKI, and mirrors the results of the UK NIHR Destiny study. [Display omitted] DisclosuresApperley:Incyte: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Milojkovic:Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau.

The e13a2 BCR-ABL1 Transcript Is Associated with Higher Rates of Molecular Recurrence after Treatment-Free Remission Attempts: Retrospective Analysis of the Adelaide Cohort

The e13a2 BCR-ABL1 Transcript Is Associated with Higher Rates of Molecular Recurrence after Treatment-Free Remission Attempts: Retrospective Analysis of the Adelaide Cohort

Second Attempt of TKI Discontinuation with Dasatinib for Treatment-Free Remission after Failing First Attempt with Imatinib: Treatment-Free Remission Accomplished By Dasatinib (TRAD) Trial

Introduction: A Canadian tyrosine kinase inhibitor (TKI) discontinuation trial is ongoing to determine if using dasatinib (DA) can lead to a successful treatment-free remission (TFR) after failing a first attempt of TKI discontinuation after imatinib (IM) treatment. The preliminary result indicate : 1) The 6-month molecular relapse-free survival (mRFS) rate is estimated as 58.0%; 2) DA re-treatment is feasible and safe, with achievement of excellent rates of MMR and MR4. We report here the preliminary analysis of the TFR rate at 6 months after DA discontinuation for the second TFR attempt. Methods and materials: This prospective clinical trial (BMS CA180-543, Clinicaltrial.gov NCT#02268370) has 3 phases: 1) IM discontinuation phase, 2) DA rechallenge phase, 3) DA discontinuation phase. Molecular relapse is defined as an increase in BCR-ABL transcript level MR4 for a 2nd TFR attempt. The null hypothesis was a TFR2 rate of 17.5% while the alternative hypothesis was a TFR2 rate of 35.0% and the study was designed to reject our null hypothesis if > 28% of patients remain in TFR after DA discontinuation. Results: As of Jun 15, 2018, 53 (40.4%) of 131 enrolled patients experienced molecular relapse after IM discontinuation with a mRFS rate of 58.0% at 12 months (95% CI, 42.1-71.0%). Of the 53 patients who lost response, 51 patients received DA. The incidence of MMR, MR4 and MR4.5 at 3 months was 97.7%, 89.9%, and 84.6%, respectively. 25/ 51 patients receiving DA attained MR4.5 for 12 months or longer and discontinued it for a 2nd TFR attempt (TFR2). 21/25 (84.0%) of these patients lost molecular response at a median of 3.7 months after DA discontinuation. The estimated TFR2 rate after DA discontinuation was 21.5±8.5% at 6 months (95% CI [7.9-39.5%], Fig 1A). Thus we cannot reject our null hypothesis based on this result. For risk factor analysis for maintaining TFR2, the variables analysed included Sokal risk score, IM duration, MR4/MR4.5 duration, monthly doubling time after IM discontinuation, time to molecular relapse after IM discontinuation, molecular relapse pattern after IM discontinuation (MMR loss vs MR4 loss), and BCR-ABL1 qPCR value prior to DA discontinuation. 1) Time to molecular relapse after IM discontinuation correlates with TFR2 (p 2) Molecular relapse pattern after IM discontinuation correlates with TFR2. The group who had loss of MMR after IM discontinuation lost molecular response faster after DA discontinuation (n=19; median 3.0 months) compared to those with two consecutive losses of MR4(n=6; 6.43 months; p=0.0435, HR 2.991; Fig 3B). 3) The group with 5.5 log reduction or deeper in BCR-ABL1 qPCR transcripts prior to DA discontinuation (n=19) showed a TFR2 rate of 28.7% at 6 months (median TFR2 duration of 4.04 months) versus 0% in the group with qPCR transcript level between 4.5 and 5.4 log reduction (n=6, median TFR2 duration of 2.89 months; p=0.017; Fig 3C). We did not identify any other risk factor for molecular relapse after DA discontinuation . The expansion kinetics of the leukemic clone after DA discontinuation is similar to that after IM discontinuation. Conclusion: These preliminary results suggest that rechallenge with DA after failing a first IM discontinuation attempt for TFR is well tolerated and effective as most cases rapidly regained at least MR4. However, more strict criteria should be considered for TFR2 attempt, including achievement of a 5.5 log reduction or deeper in BCR-ABL1 qPCR levels prior to the 2nd TKI discontinuation attempt, and a MR4 duration of more than 12 months. Disclosures Kim:Pfizer: Consultancy; Paladin: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Busque:BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Savoie:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Bence-Bruckler:Lundbeck: Membership on an entity9s Board of Directors or advisory committees. Delage:BMS: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity9s Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Pfizer: Research Funding; Roche: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees. Liew:Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees; BMS: Membership on an entity9s Board of Directors or advisory committees. Laneuville:BMS: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Paladin: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Lipton:Bristol-Myers Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Leber:Novartis Canada: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity9s Board of Directors or advisory committees.

Feasibility of treatment discontinuation in chronic myeloid leukemia in clinical practice: results from a nationwide series of 236 patients

Over half of chronic myeloid leukemia (CML) patients in deep molecular response do not lose the major molecular response (MMR) after stopping treatment with tyrosine kinase inhibitors (TKI). This strategy is safe in clinical trials, but its applicability in the real-life setting remains unsettled. We describe the outcomes after TKI discontinuation in a nationwide series of 236 CML patients. Median follow-up from treatment discontinuation was 21.5 months and 5 patients died from CML-unrelated causes. TKI therapy was reinitiated due to MMR loss (n = 52), increase ≥ 1 log in BCR-ABL transcript level without losing MMR (n = 12), patient preference (n = 2), and withdrawal syndrome (n = 1). Treatment-free remission rate at 4 years was 64% (95% confidence interval, CI: 55%–72%). Cumulative incidence of molecular recurrence at 3 years was 33% (95% CI: 26%–38%). TKI treatment for < 5 years and MR4.5 duration shorter than 4 years were both associated with higher incidence of molecular recurrence. No patient had disease progression. Response status at last control was: MR4.5 (n = 196), MR4 (n = 15), MMR (n = 14), complete cytogenetic response (n = 10), and other (n = 1). A significant increase in Hb and cholesterol levels was observed after imatinib withdrawal. Our results demonstrate that TKI treatment discontinuation is feasible in real-life clinical practice.

Long-term treatment-free remission (TFR) following frontline (1L) nilotinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): ENESTfreedom 144-wk results.

7063Background: ENESTfreedom (NCT01784068) is a phase 2 study evaluating TFR following 1L nilotinib in newly diagnosed CML-CP pts. We previously reported 48- and 96-wk TFR rates of 51.6% and 48.9%....