Second-Generation Tyrosine Kinase Inhibitor Discontinuation in Chronic Myeloid Leukemia Patients with Stable Deep Molecular Response: A Systematic Review and a Meta-Analysis

The treatment with 2nd-generation tyrosine kinase inhibitors (2G-TKIs), namely, dasatinib and nilotinib, has been reported to have faster and deeper responses in newly diagnosed chronic phase-chronic myeloid leukemia (CP-CML) patients as compared with imatinab. A number of studies on the discontinuation of 2G-TKIs have been conducted and recently published. A meta-analysis was conducted in this study to assess the rate of treatment-free remission (TFR) rate as well as the long-term safety of 2G-TKI discontinuation in CML patients with stable deep molecular response (DMR). 517 patients were recruited in 5 single-armed, prospective cohort studies. The overall weighted mean TFR rate at the follow-up of 12 months reached 57% (95% CI 51-64%; I 2 = 56.4 %). The weighted mean TFR rate at the 24-month follow-up was 53% (95% CI 47-60%; I 2 = 47.1 %). The loss of TFR was primarily concentrated in the first 12 months. 96.5% of patients, having restarted TKI therapy after a molecular relapse, achieved major molecular response (MMR) rapidly. There were four deaths at the two-year follow-up. As suggested from the results of the final study, 2G-TKI discontinuation in CML patients with stable DMR was reported to be feasible. Relapsed patients were retreated with 2G-TKI, and over 95% of patients could reach MMR. Almost no deaths occurred due to adverse events in two years after discontinuation, and more than half of the patients could maintain a TFR.

TKI discontinuation in CML: how do we make more patients eligible? How do we increase the chances of a successful treatment-free remission?

Treatment-free remission (TFR) is a new and significant goal of chronic myeloid leukemia management. TFR should be considered for patients in stable deep molecular response (DMR) after careful discussion in the shared decision-making process. Second-generation tyrosine kinase inhibitors (TKIs) improve the speed of response and the incidence of DMR. Treatment may be changed to a more active TKI to improve the depth of response in selected patients who have not reached DMR. Stem cell persistence is associated with active immune surveillance and activation of BCR-ABL1-independent pathways, eg, STAT3, JAK1/2, and BCL2. Ongoing studies aim to prove the efficacy of maintenance therapies targeting these pathways after TKI discontinuation.

Treatment Free Survival (TFS) in Patients (pts) with Chronic Myeloid Leukemia (CML) Carrying Atypical BCR-ABL1 Fusion Transcripts: The French CML Group (Fi-LMC) Experience

Aims Life expectancy of CML pts optimally responding to tyrosine kinase inhibitors (TKI) is close to that of the general population and recently, TFR has been acknowledged as a new goal of CML management. TKI discontinuation in the view of TFR requires the achievement of deep and long-lasting molecular responses (MR). The gold standard BCR-ABL mRNA quantification technology and MR definitions rely on internationally standardized (IS) RT-qPCR but atypical transcripts located outside the Major-BCR region, harbored by 1-2% of pts, cannot be expressed on the IS scale. Thus, most trials and clinical practice recommendations prevent such pts from attempting TFR. The Fi-LMC group retrospectively collected real-life observations to assess TFR likelihood in this rare population. Methods Data from CML pts with precise characterization of atypical transcripts in whom any line TKI was stopped for any reason but after at least 2 years of undetectable molecular residual disease (UMRD) by individualized non-standardized RT-qPCR were collected. RT-qPCR sensitivity varied depending on transcript type and local molecular biology laboratory. TFS was estimated by the Kaplan-Meier method. Relapse was analyzed using the cumulative incidence function, relapse being as UMRD loss at any time and any level during follow-up (FU). Results Our series comprised 16 adult CP CML pts with atypical BCR-ABL fusions including 12 males (75%). Median age at CML diagnosis was 56 years (range: 21-75) and that at TKI discontinuation was 67 years [range: 29-82]. Sokal score was low, intermediate and high in 7, 8 and 1 pts, respectively. ELTS score was low and intermediate in 10 and 4 pts, respectively and unknown in 2. Most pts expressed e19a2 (n=6) followed by e6a2 (n=4), b3a3 (n=3), b2a3 (n=2) and e8a2 (n=1). Seven pts discontinued imatinib, 4 stopped dasatinib, 4 nilotinib and 1 bosutinib. Number of lines of therapy was 2 in 8 pts, 1 in 5 pts and 3 in 3 pts. Median TKI treatment duration before discontinuation was 64 months (range: 31-218) and median duration of UMRD was 41 months (range: 21-168). The median FU after TKI discontinuation was 68 months (range: 3-149). Five pts experienced relapse leading to TKI resumption. Four relapses occurred within 3-6 months and included 2 loss of hematologic response in CP, 1 loss of hematologic response in accelerated phase CML and 1 molecular recurrence with BCR-ABL transcripts up to 1.5%. One relapse occurred at 49 months and consisted in loss of a complete cytogenetic response. These 5 pts resumed TKI and regained UMRD within 6 months, including 1 pt who died in UMRD from non-CML-related cause at the age of 82 years and 1 pt who rapidly failed a 2 nd TKI discontinuation attempt. In 1 additional pt, BCR-ABL transcripts became detectable intermittently with maximum transcript level of 0.15% and TKI was not resumed. The median FU of pts who remained treatment-free was 68 months (range: 8-149). Overall, the 5-year cumulative incidence of relapse regardless of whether TKI was resumed was 41.6% (95% confidence interval: 21.9%-78.7%) (Figure 1). The 5-year TFS rate was 65.2% (95% confidence interval: 40.3%-90.2%) (Figure 2). Conclusions Our observational study of TKI discontinuation in CML pts with atypical BCR-ABL transcripts is the largest reported so far. While effort must be made for proper assessment of deep MR, preliminary results suggest that TFS pattern might favorably compare with that obtained in pts with Major-type BCR-ABL transcripts. However, relapses may be more aggressive and caution is required in order to avoid loss of hematologic responses and progression. Whether the type of atypical fusion gene influences TKI discontinuation outcome, as well as other potential prognostic factors, need to be determined in a larger series. Figure 1 Figure 1. Disclosures Charbonnier: Novartis: Speakers Bureau; Incyte: Speakers Bureau. Rea: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Etienne: Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; BMS: Honoraria.

Highly Sensitive Droplet Digital PCR to Identify CML Patients with a High Probability of Achieving Treatment-Free Remission

Introduction: Treatment Free Remission (TFR) is the ultimate goal of therapy for most CML patients. Despite adopting consensus eligibility criteria of a sustained deep molecular response and more than 4 years of TKI therapy, the relapse rate after TKI cessation is still around 50%. More sensitive detection of residual leukaemia has the potential to improve our capacity to predict TFR outcomes for individual patients. Aim: To correlate droplet digital PCR (ddPCR) assay results with TFR outcome, especially in the setting of undetectable levels measured by qRT-PCR. Method: ddPCR was performed on blood samples from 51 TFR-eligible CML patients at the time of TKI cessation. 5 µg RNA per sample was used in 8 wells/sample using the BioRad QXDx BCR-ABL %IS kit on QX200 ddPCR system which yielded BCR-ABL1% (IS) directly. All these patients achieved MR4.5 that was sustained for ≥ 2 years. Results: 100% of patient were in MR4.5 via qRT-PCR at the time of stopping. 61% of the 51 patients evaluated relapsed within 12 months. Median duration of TKI therapy for the whole group was 5.8 years (range 2.2- 14 years). 20 patients achieved TFR success with a median follow up of 24 months (TFR group; sustained BCR-ABL1 <0.1% (IS) after TKI discontinuation for ≥12 months), while 31 patients relapsed (Relapse group; BCR-ABL1 >0.1% (IS) after stopping; median time of relapse 3 months, range 1-10 months). A ROC curve analysis correlated TFR outcome with ddPCR results, with BCR-ABL1 level ≥0.003% via ddPCR at the time of stopping identified as an optimal cut-off. Kaplan-Meier analysis showed that 89% of the patients with ddPCR ≥0.003 relapsed after TKI cessation, whereas the ddPCR <0.003 demonstrated a significantly reduced relapse rate to 54% (p=0.01, Figure 1A). In addition, the TFR group (median BCR-ABL1 0.00065%) demonstrated approximately two-fold lower levels of BCR-ABL1transcript level compared to the relapse group (median 0.0012%). Interestingly, 7/31 (23%) of the relapsed group had undetectable BCR-ABL1 transcript even with the current highly sensitive method, while this undetectable level was only observed in 35% of the TFR group. We next assessed other known predictors of TFR success relative to ddPCR results in a Cox proportional hazard model. We have previously demonstrated that the BCR-ABL1 halving time after commencing therapy is highly predictive of TFR. At a univariate level, transcript type (e13a2 versus e14a2, p=0.01), BCR-ABL1 halving time (p>0.0001), and mRNA quantitation by ddPCR ≥ 0.003% (p=0.02) were all significantly associated with clinical outcome. Other variables including gender, age, ELTS score, Sokal score, MR4.5 duration and TKI duration were not associated with clinical outcome in this cohort (Figure 1B). In the multivariate analyses (Figure 1C), ddPCR remained an independent predictor after adjusting for ELTS, TKI duration and MR4.5 duration. Interestingly, ddPCR was not an independent predictor after adjusting for BCR-ABL1 transcript type or halving time. Conclusion: QXDx ddPCR assay is a promising tool for molecular residual disease monitoring in CML, especially when the BCR-ABL1 is undetectable by conventional method. The CML patients with levels of detectable BCR-ABL1 ≥0.003% measured by ddPCR have a significantly higher probability of relapse compared to patients with lower levels of the transcript. The ≥0.003% BCR-ABL1 level cut-off value could be a potential tool to aid decision-making when attempting TKI discontinuation in CML. However, even though a measurable level of BCR-ABL1 above 0.003% via ddPCR identified patients at high risk of relapse after a TFR attempt, it does not rule out the possibility of TFR; and a negative ddPCR result does not exclude the risk of molecular relapse. ddPCR may be most useful where other TFR predictive factors including BCR-ABL1 transcript type and halving time are not available. In-kind support was received from Bio-Rad for this study. Figure 1 Figure 1. Disclosures Branford: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cepheid: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hughes: Novartis: Honoraria, Research Funding; Incyte: Honoraria; BMS: Honoraria, Research Funding. Yeung: BMS: Honoraria, Research Funding; Amgen: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria.

Risk of Progression in Chronic Phase - Chronic Myeloid Leukemia (CML) Patients Eligible for Tyrosine Kinase Inhibitor Discontinuation (TFR-PRO study): Preliminary Results

Background. Over 50% of CP-CML patients will achieve a deep molecular response (DMR) at some point during treatment with Tyrosine Kinase Inhibitors (TKI), where DMR is defined as BCR-ABL1 transcript levels lower than 1/10000 (or MR4). Treatment discontinuation (TD) in CP-CML patients with stable DMR is successful in approximately half of cases, with a relapse free survival (RFS) of 48-61% at 3 years. TD is considered safe, since MMR is achieved in almost all cases when TKI re-initiation is required. As such, treatment-free remission (TFR) is now usually attempted outside of clinical trials and is part of many CML guidelines. The progression to accelerated phase/blast crisis (AP/BC) after TD was considered virtually impossible for a long time. However, recent reports document at least six cases of disease progression after TD, some of which were fatal. These observations raise concerns about the safety of TD, since now the practice can no longer be considered completely immune from the risk of disease progression, an occurrence that drastically changes the patient situation and perspective when it develops. To best counsel patients and more safely apply TD, a precise quantification of the risk of progression in this setting is needed. Study Design and Methods The TFR-PRO project monitor CML patients in long term treatment and with stable DMR, followed at 28 centers in 4 different countries (Canada, Italy, Germany, Spain). Each center is expected to enroll approximately 100 patients. The following variables were measured: time adjusted rates (TAR) of molecular relapse (loss of MR3) and of progression to AP/BC; progression free and overall survival. Primary Objective To quantify the risk of progression to AP/BP, expressed as TAR, after TKI discontinuation in CML patients who undergo a first or subsequent TKI discontinuation attempt. This value will be compared to that obtained in a similar population of patients with the same characteristics who do not discontinue TKI treatment. A flexible statistical approach will allow to attribute patients to the two groups according to their decision about TKI discontinuation and to the loss of MR3. Patients eligibility includes a history of at least 3 years of TKI treatment and at least 18 months of continuous DMR. Results The study opened on July 24 th,2020. Twelve centers are presently active with 303 eligible patients registered, for a total of 1614 person years available for analysis. Median follow up is 4.99 years (range 0.39-15.00 years), median age at diagnosis is 50.4 years and 47.9% patients are female. Sokal score (available in 147 patients) is low in 44.90%, intermediate in 32.65% and high in 22.45%. A total of 116 patients (38.28%) attempted TD at some point; 10 patients (3.30%) attempted TD twice. Loss of MR3 occurreded in 44/116 (37.93%) patients after TD for a TAR of 15.69/100 person years, (95% confidence interval (CI) [11.68-21.09]), but also in patients who did not attempt TD (21/187, or 11.23%), TAR: 1.83/100 person years, 95%CI [1.19-2.81], p<0.0001. No patient progressed to AP/BC and therefore the TAR of progression is 0% with an upper value of 95%CI of 1.07/100 person years for patients who attempted TD, and with an upper value of 95%CI of 0.26/100 person years for patients who did not attempt TD. Conclusions These preliminary results obtained in a real world scenario indicate that approximately 40% of eligible patients attempt TD. The loss of MR3 after TD seem to happen less frequently (38%) than previously reported. Patients who discontinue treatment have a significantly higher risk of losingMR3 than those who continue treatment, and the risk of progression to AP/BC is lower than 1.07/100 person years. More patients need to be enrolled in this study in order to better estimate this latter number. Disclosures Assouline: Gilead: Speakers Bureau; Jewish General Hospital, Montreal, Quebec: Current Employment; Johnson&Johnson: Current equity holder in publicly-traded company; Novartis: Honoraria, Research Funding; Eli Lilly: Research Funding; Roche/Genentech: Research Funding; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Amgen: Current equity holder in publicly-traded company, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Abruzzese: Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Elena: CELGENE: Other: funding for meeting participation; PFIZER: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees. Saussele: Roche: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Gambacorti-Passerini: Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy.

Half: A Prospective Multi-Centre Phase II Clinical Trial Evaluating the Efficacy and Safety of Tyrosine Kinase Inhibitors' Discontinuation after Two-Step Dose Reduction in Patients with Chronic Myeloid Leukemia in Deep Molecular Remission

Background. Treatment-free remission (TFR) has become a new treatment goal for chronic myeloid leukemia (CML) patients. However, usually abrupt tyrosine kinase inhibitors (TKIs) therapy discontinuation has been successful only in about half of eligible patients and it can cause burdening TKI withdrawal syndrome (TWS) in about 30% of them. Moreover, any robust clinical or biological factor predictive for successful TFR has not been identified yet. On top of that, sustainable deep molecular response (DMR) as the main prerequisite for TKI discontinuation attempt is achieved only in 20-40% of patients. The majority of CML patients, therefore, need to be treated with the effective and well-tolerated drug for a long time or even life-long. Study design and methods. With the recognition of all these aspects, we designed a nationwide prospective investigator-initiated phase II clinical trial HALF (ClinicalTrials.gov NCT04147533) in order to evaluate efficacy and safety of TKI discontinuation after previous two-step dose reduction in patients with CML in DMR (Fig. 1). Step-wise TKI dose reduction, i.e. half of the standard during the first 6 months after study entry, and the same dose given alternatively (every other day) during the next 6 months, was derived from pharmacokinetics and experimental data as well as from clinical trials' results. We assume that the step-wise and eventually meaningful TKI dose reduction enables a higher rate of patients achieving successful TFR with less pronounce TWS, or even would represent a more reasonable and safer alternative to the complete and sudden TKI interruption. This unique nationwide academic project has been facilitated by hematological patients care centralization in the Czech Republic. A primary study objective is to evaluate the proportion of patients in major molecular response (MMR) at 6 and 12 months and in TFR at 18, 24, and 36 months after the study enrollment, respectively, and molecular recurrence-free survival at all mentioned time points as well. Main secondary and exploratory objectives are: to evaluate the proportion of patients loosing MMR and in whom MMR and MR4.0 would be re-achieved after TKI re-introduction, time to MMR and MR4.0 re-achievement, FFS, PFS, OS, TWS, and QoL assessment, predictive factors for successful TFR identification, quantification of BCR-ABL1 using digital droplet PCR at both the DNA and mRNA levels, immunological profiling, BCR-ABL1 kinetics mathematical modeling, assessment of TKI pharmacokinetics, clonal hematopoiesis and pharmaco-economics. Results. The study was launched in December 2019; however, due to the COVID-19 outbreak, patients' recruitment started on June 16, 2020. Here, characteristics of the first 74 patients included in the study until April 2021 are presented. There were 37 males and 37 females, with median age at the time of diagnosis of 53 years (range, 23-74) and at the time of the study entry of 67 years (range, 35-86). A median time of CML disease, TKI treatment, and DMR duration before the study initiation was as follows: 9.9 years (range, 4.4-22.5), 9.8 years (range, 4.2-20.2), and 7.3 years (range, 3.2-18.3), respectively. The ELTS score was low, intermediate, high and unknown in 62.2%, 21.6%, 13.5%, and 2.7% of patients, respectively. At the time of study entry, 58 patients (79.5%) were treated with imatinib, 10 (13.7%) with nilotinib, and 5 (6.8%) with dasatinib, respectively, whereas in 63 patients (86.3%) it was in the first line of therapy. With almost half of patients (48.6%), the TKI dose was already reduced at the time of study entry. With 10 (13.5%) patients, interferon-α treatment preceded TKI administration. At the time of this abstract preparation, on July 26, 2021, altogether 102 patients (from planned 150) have been enrolled in the study; 48 of them (47.1%) have already moved to the second de-escalation phase and 9 (8.8%) patients to the TFR phase. There were 2 cases of confirmed MMR loss (both in month 8 after the study entry) and no patient experienced symptoms resembling TWS. Conclusions. Despite the COVID-19 pandemic, the HALF study was successfully launched and initiated in the majority of centers, with 102 already included patients and continuing intensive enrolment. Based on our very preliminary results, the step-wise dose reduction seems to be an effective and safe approach. More included patients, longer follow-up and further analyses are needed in order to reach all set up objectives. Figure 1 Figure 1. Disclosures Žácková: Angelini: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Faber: Angelini: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Novartis: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Pfizer: Other: conference fees; TERUMO: Other: conference fees. Bělohlávková: Novartis: Consultancy; BMS/Celgene: Consultancy. Horňák: Angelini: Honoraria. Svobodník: Roche: Speakers Bureau; Janssen-Cilag: Speakers Bureau. Machová Poláková: Incyte: Consultancy; Angelini: Consultancy; Novartis: Research Funding. Mayer: Principia: Research Funding.

Treatment Free Remission in Patients with Chronic Phase CML: A Single Center Experience

Introduction: Treatment-free remission (TFR) is an emerging treatment goal in chronic phase chronic myeloid leukemia (CP-CML). The NCCN guidelines suggest patients must meet the following criteria in order to be eligible for an attempt at TKI discontinuation: use of a TKI for at least 3 years with no history of TKI resistance who have maintained a deep molecular response (MR4 - BCR-ABL IS ≤0.01%) for at least 2 years. The aim of this study was to identify predictors of long-term TFR in CP-CML patients who discontinue TKI therapy at our institution. Methods: We retrospectively identified all CP-CML patients who had discontinued TKIs after meeting TKI discontinuation criteria at Moffitt Cancer Center. Patient charts were reviewed to collect data on demographics, disease characteristics, and outcomes. TFR was calculated from date of TKI discontinuation to date of molecular recurrence (defined as loss of MMR (BCR-ABL IS ≥0.1%) or date of last follow up). Statistical analysis was performed utilizing Kaplan-Meier curves and log rank (Mantel-Cox) test. Results: A total of 102 patients met TKI discontinuation criteria and stopped treatment to attempt TFR. The median age at diagnosis was 53.5 years (19-83 years). The median age at TKI discontinuation was 61 years (28-92 years). Fifty (49.5%) patients were male. Four patients (3.9%) had previously received interferon α. At a median follow up of 29 months, the TFR rate was 56.8%, with molecular recurrence occurring in 44 patients. 93 patients had a follow up of at least 6 months. Of the 44 patients with molecular recurrence, 37 (84%) recurred within 6 months and 41 (93%) within 12 months of TKI cessation. The rate of TFR at 12 months and 24 months was 58% (95% CI: 48-68%) and 53% (95% CI: 43-64%), respectively [Figure 1]. Baseline characteristics along with univariate analysis of the 102 patients included in the study are shown in Table 1. Age, BMI at discontinuation, gender, Sokol risk index, last TKI prior to discontinuation, lines of therapy, or duration on TKI prior to discontinuation did not significantly affect rates of TFR. Patients with sustained MR4.5 (BCR-ABL IS <0.0032%) for 2 years prior to discontinuation showed a trend toward higher probability of TFR at 12 months compared to those in MR4 (62% vs 49%; p=0.055). Median time to regain MMR after restarting treatment in patients with molecular recurrence was 90 days (range 28-443 days). 32 patients (31%) developed TKI withdrawal syndrome with symptoms including headache, arthralgia, myalgia and fatigue. Conclusions: At our center, 102 CP-CML patients qualified for TKI cessation. The rate of TFR at 12 months was 58% which is consistent with published data from numerous TKI discontinuation clinical trials. We were unable to identify any factors that were predictive of successful TFR, however those patients with a deeper molecular response (MR 4.5) at the time of TKI cessation trended towards higher rates of TFR at 12 months, suggesting that the depth of response is important for achieving prolonged TFR. Identifying methods to further deepen molecular response in CP-CML patients may ultimately lead to higher rates of TFR in the future. Figure 1 Figure 1. Disclosures Nodzon: Takeda: Consultancy. Komrokji: Jazz: Consultancy, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acceleron: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Consultancy. Sallman: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Incyte: Speakers Bureau; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Padron: Blueprint: Honoraria; Incyte: Research Funding; Stemline: Honoraria; Taiho: Honoraria; Kura: Research Funding; BMS: Research Funding. Kuykendall: BluePrint Medicines: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria, Speakers Bureau; CTI Biopharma: Honoraria; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; PharmaEssentia: Honoraria. Lancet: Jazz: Consultancy; Astellas: Consultancy; Agios: Consultancy; Millenium Pharma/Takeda: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; BerGenBio: Consultancy; AbbVie: Consultancy. Pinilla Ibarz: Sellas: Other: ), patents/royalties/other intellectual property; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory; MEI, Sunesis: Research Funding. Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Treatment-Free Remission in Chronic Myeloid Leukemia and New Approaches by Targeting Leukemia Stem Cells

The therapeutic landscape for chronic myeloid leukemia (CML) has improved significantly with the approval of tyrosine kinase inhibitors (TKIs) for therapeutic use. Most patients with optimal responses to TKIs can have a normal life expectancy. Treatment-free remission (TFR) after discontinuing TKI has increasingly become a new goal for CML treatment. However, TKI only “control“ CML, and relapse after discontinuation has become a key factor hindering patient access to attempt TFR. In this study, we reviewed studies on TKI discontinuation, including both first and second-generation TKI. We also reviewed predictors of relapse, new monitoring methods, and strategies targeting leukemic stem cells.

Continued Discontinuation of TKI Treatment in Medullary Thyroid Carcinoma – Lessons From Individual Cases With Long-Term Follow-Up

BackgroundThe tyrosine kinase inhibitors (TKI) vandetanib and cabozantinib are approved as targeted therapies in advanced medullary thyroid carcinoma (MTC) with symptoms or high tumour burden. Only recently, toxicity in long-time TKI usage was analysed. However, little is known about the impact of TKI discontinuation on MTC disease course after longer-term therapy. Here, we report our experience in a series of 7 MTC patients with vandetanib treatment of up to 87 months followed by discontinuation for concerns of toxicity or due to side-effects. The discontinuation of TKI therapy is a relevant clinical scenario. To our knowledge we present the largest single center series on an important aspect of TKI management.MethodsRetrospective analysis of MTC patients with continued discontinuation of vandetanib treatment in a tertiary referral endocrine tumour centre. Analysis included a review of patients’ records for TKI indication, and treatment response as well indications for continued TKI discontinuation and follow-up by clinical assessment, calcitonin and CEA doubling times as well as imaging (ultrasound, CT).ResultsSeven MTC patients [6 sporadic MTC, 1 Multiple Endocrine Neplasie Type 2a (MEN2a)] with previous vandetanib treatment (median: 41 months; range 7-87 months) and continued TKI discontinuation were identified out of 161 analysed MTC files. TKI treatment was initiated due to high tumour burden and symptoms or RECIST (Response Evaluation Criteria In Solid Tumors) progression in all patients. Two patients (29%) remained stable after discontinuation of vandetanib until now (follow-up of 47 and 61 months). Both patients had been on TKI therapy for 73 and 58 months. Five patients (71%) developed progressive disease after TKI discontinuation. In 2 patients, vandetanib was restarted after 45 and 52 months resulting again in disease control. One patient was enrolled in a new RET kinase inhibitor trial after 45 months of vandetanib discontinuation. Two patients declined restart of treatment due to mental health issues leading to discontinuation of vandetanib in the first place (after 7 and 38 months of treatment) and both patients died of rapidly progressive disease. At time points of tumour progression, calcitonin-doubling time (CDT) was < 2 years in all patients.ConclusionThis case series suggests that discontinuation of long-term vandetanib treatment with documented stable disease does not automatically result in rapid disease progression but may be followed by prolonged “TKI free” stable disease in individual patients. Analysis of calcitonin and CDT during discontinuation is indicated as it will unmask tumour progression earlier than imaging. Restart with the same TKI is possible in case of progression.

Case Report: Multi-Omics Analysis and CAR-T Treatment of a Chronic Myeloid Leukemia Blast Crisis Case 5 Years After the Discontinuation of TKI

Most relapsed chronic myeloid leukemia (CML) patients after tyrosine kinase inhibitor (TKI) discontinuation are in a chronic phase and could achieve remission through restarting the TKI treatment. Here we reported a case of sudden lymphoid blast crisis after 67 months of TKI discontinuation and depicted the patient by DNA and RNA sequencing to investigate intrinsic molecular features. The mutations of TGFBR2 and PCNT and the dysregulations of TGF-β and other pathways might accelerate the B cell transformation, which may serve as a blast crisis risk indicator of CML. Single-cell transcriptome data revealed that several clusters of immature B cells and late pro-B cells presented clone evolution during the treatment. After failing multiple lines of TKIs, conditioning chemotherapies and chimeric antigen receptor T cells (CAR-T) targeting CD19 and CD22 were performed to achieve remission. In conclusion, we report the first case of a CML patient with sudden lymphoid blast crisis after a long treatment-free remission and additional gene abnormalities other than BCR-ABL1 might participate in the progression, which need to be closely monitored, and CAR-T could be a solution to the chemoresistant progression.