Loss Of Major Molecular Response Research Articles

1098P - Incidence of imatinib resistance in chronic myeloid leukemia (CML) patients: Experience from resource poor center of eastern India

BackgroundThe management of Chronic Myeloid Leukemia (CML) has undergone a paradigm shift with advent of the tyrosine kinase inhibitor (TKI), namely imatinib. Despite a high remission rate, a significant proportion of patients showed resistance and/or intolerance to imatinib therapy, be it primary or secondary. However, the scenario of resistance along with the prevalence and clinical route of CML in the Eastern part of India remains elusive. To observe the incidence of resistance to TKI after years of therapy, we performed a study in a tertiary cancer care centre, serving patients from Eastern Indian states as well as neighbor countries like Bangladesh and Bhutan. Based on the CML cases registered at the centre for the last 13 years, we performed a longitudinal assessment of the disease history and molecular management to portray the incidence of imatinib resistance in CML patients.Table: 1098PTable: 1098PNo. of registered CML cases (2005-2017)Median period of Imatinib treatmentNo. of patients showing Loss of MMR (BCR-ABL >1.0%)No. of patients undergoing BCR-ABL KD mutation testing (% affordability)No. of patients showing BCR-ABL KD mutationPatients with Imatinib failure but no detectable BCR-ABL KD mutation98626 months10120 (20%)11 (55% of resistant pool)9 (45% of resistant pool) MethodsThe methods in schematic are described below: No. of CML cases with disease history ↓ Patients showing loss of Major Molecular Response (MMR), detected by Real-Time quantitative PCR ↓ Mutation analysis in BCR-ABL kinase domain (KD) (by Sanger sequencing) ↓ Calculation of type and incidence of KD mutation ↓ The survival analyses performed by Kaplan-Meier analysis. ResultsThe results are presented in tabular form as below:.After years of therapy, KD mutations are seen in 55% of imatinib-resistant patients. The survival analysis showed significant difference between treatment-sensitive and –resistant pools. ConclusionsThe incidence of imatinib resistance has been increasingly detected in Eastern-Indian region after long term therapy with imatinib. However, the full scenario could not be depicted due to resource constraints. More numbers of patients are to be tested to achieve robust evidence. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

PF409 DURABILITY AND IMPACT ON QUALITY OF LIFE OF TREATMENT‐FREE REMISSION (TFR) IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) AFTER STOPPING FRONTLINE (1L) NILOTINIB: ENESTFREEDOM 192‐WK RESULTS

Background:ENESTfreedom (NCT01784068) is a single‐arm, open‐label, phase 2 study evaluating TFR in patients with CML in chronic phase who achieved a sustained deep molecular response (DMR) with 1L nilotinib. In the primary analysis, 51.6% of patients remained in TFR 48 wks after stopping nilotinib. Analyses at 144 wks showed durability of TFR.Aims:To assess longer‐term maintenance and safety of TFR after 192 wks of follow‐up.Methods:Eligible patients had been treated with ≥2 y of 1L nilotinib and achieved MR4.5 (BCR‐ABL1 IS ≤0.0032%). After 1 y of consolidation treatment, patients with sustained DMR could attempt TFR. Nilotinib was resumed upon loss of major molecular response (MMR; BCR‐ABL1 IS ≤0.1%). As of 17 Sep 2018 (data cut‐off), all patients had either completed ≥192 wks of TFR, resumed nilotinib, or discontinued the study.Results:Of 190 patients who had entered TFR, 87 remained in TFR, 91 had resumed nilotinib and 12 had discontinued the study by the data cut‐off. At 192 wks, the TFR rate was 44.2% (84/190, 95% CI: 37.0–51.6%). Of patients in TFR at 144 wks, 5/89 were not evaluable for TFR at 192 wks as 2 had discontinued by 192 wks due to patient/physician decision, and 3 who were previously in MR4.5 did not have 192‐wk PCR data. A total of 90/91 (98.9%) and 84/91 (92.3%) patients who resumed nilotinib regained MMR and MR4.5, respectively. At 48 wks after regaining MMR or MR4.5, 75/90 and 73/84 patients, respectively, had stable responses. There were no disease progressions or deaths due to CML. A total of 10 deaths were reported in the 144‐wk analysis, with no new deaths reported subsequently. The treatment‐free survival rate at 192 wks was 48.7% (95% CI 41.4–55.6%; Figure). Rates of all‐grade AEs were 84.3% during consolidation and 77.5%, 70.8%, 48.3% and 52.8% during each subsequent 48‐wk period of TFR, respectively, among the 89 patients who remained in TFR for >144 wks (including 87 patients for >192 wks). Rates of musculoskeletal pain AEs (all‐grade) were 15.7% during consolidation, then increased during the first 48 wks of TFR (40.4%) and subsequently decreased during TFR to below levels seen during consolidation (9.0%, 3.4% and 3.4%, respectively). Rates of cardiovascular events were low across all periods (3.4%, 2.2%, 1.1%, 2.2% and 0%). Among the 91 patients who resumed nilotinib, the most common AEs were nasopharyngitis (18.7%) as well as pruritus, fatigue and increased lipase (14.3% each); the majority of AEs were grade 1/2. To further explore AEs that may affect quality of life, incidences of AEs grouped by category (rate >10% on treatment) were analyzed during consolidation and the 1st, 2nd, 3rd, and 4th 48‐wk periods of TFR, respectively: gastrointestinal disorders, 29.2%, 28.1%, 16.9%, 6.7% and 3.4%; infections and infestations, 39.3%, 34.8%, 24.7%, 19.1% and 20.2%; musculoskeletal and connective tissue disorders: 27.0%, 50.6%, 22.5%, 7.9% and 10.1%; and general disorders and administration site conditions (eg, asthenia, pyrexia): 14.6%, 11.2%, 10.1%, 6.7% and 4.5%. In these AE categories, similar trends toward decreasing incidences during TFR compared with consolidation were observed.Summary/Conclusion:These results demonstrate the long‐term durability and safety of TFR following 1L nilotinib. There were no disease progressions or CML‐related deaths, and musculoskeletal pain AEs were transient. AEs that may adversely affect patients’ quality of life tended to decrease in frequency during TFR vs during consolidation. Patients should continue to be regularly monitored during TFR.image

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

PF411 ENESTOP 192‐WK RESULTS: DURABILITY AND IMPACT ON QUALITY OF LIFE OF TREATMENT‐FREE REMISSION (TFR) FOLLOWING SECOND‐LINE (2L) NILOTINIB (NIL) IN PATIENTS (PTS) WITH CHRONIC MYELOID LEUKEMIA (CML)

Background:The ENESTop study (NCT01698905) is evaluating TFR in pts with CML in chronic phase who achieved sustained deep molecular response with 2L NIL. In the primary analysis, 57.9% of pts remained in TFR 48 wks after stopping NIL. Analyses at 144 wks showed durability of TFR.Aims:To assess the maintenance and safety of TFR after a longer follow‐up of 192 wks.Methods:Eligible pts had received ≥3 y of treatment (including >4 wks of imatinib followed by ≥2 y of NIL) and had achieved MR4.5 (BCR‐ABL1 IS ≤0.0032%) on NIL. Pts without confirmed loss of MR4.5 after 1 y of consolidation (CONS) treatment could attempt TFR. NIL was resumed upon loss of major molecular response (BCR‐ABL1 IS ≤0.1%) or confirmed loss of MR4 (BCR‐ABL1 IS ≤0.01%). By the data cut‐off (24 Sep 2018), all pts had either completed ≥192 wks of TFR, resumed NIL, or discontinued the study.Results:At the data cut‐off, of the 126 pts who entered TFR, 56 remained in TFR, 59 had resumed NIL and 11 had discontinued the study. At 192 wks, the TFR rate was 46.0% (58/126; 95% CI, 37.1–55.1%); all but 1 pt were in MR4.5. Of pts in TFR at 144 wks, only 1/61 had lost response (confirmed loss of MR4) by 192 wks; 2 other pts had discontinued due to pt/guardian decision and serious AE (polycythemia vera), respectively. Of pts who resumed NIL, 56/59 (94.9%) and 55/59 (93.2%) regained MR4 and MR4.5, respectively. Of 56 pts who regained MR4, 40 (71.4%) had stable MR4 96 wks later; the remaining 16 had either discontinued <96 wks after regaining MR4 (n = 12) or were ongoing with <96 wks after regaining MR4 (n = 4). Of 55 pts who regained MR4.5, 37 (67.3%) had stable MR4.5 96 wks later; the remaining 18 pts had either discontinued <96 wks after regaining MR4.5 (n = 12) or were ongoing with <96 wks after regaining MR4.5 (n = 6). There were no cases of disease progression or deaths due to CML. No new deaths have occurred since the 144‐wk analysis. The treatment‐free survival rate at 192 wks was 50.3% (95% CI, 41.2–58.7%; Figure). During CONS and the 1st, 2nd, 3rd and 4th 48‐wk periods of TFR, respectively, rates of all‐grade AEs were 80.6%, 85.5%, 67.7%, 51.6% and 56.5% among the 62 pts who remained in TFR for >144 wks. Musculoskeletal pain AE rates increased during the first 48 wks of TFR (53.2%) vs CONS (11.3%), then decreased during each subsequent 48‐wk period of TFR to levels below that seen in CONS (21.0%, 14.5% and 3.2%, respectively). In pts who resumed NIL (n = 59), the most common AEs were hypertension (20.3%) and arthralgia (13.6%), with the majority of AEs being grade 1/2. The rates of frequently occurring (>10% on treatment) additional AEs (grouped by category) that may affect quality of life were assessed during CONS and the subsequent 48‐wk periods of TFR to further explore the potential impact of TFR. During these study periods, respectively, incidences of these categories of AEs were: gastrointestinal disorders, 22.6%, 17.7%, 21.0%, 8.1% and 8.1%; infections and infestations, 35.5%, 37.1%, 21.0%, 17.7% and 16.1%; musculoskeletal and connective tissue disorders: 24.2%, 62.9%, 29.0%, 22.6% and 12.9%; general disorders and administration site conditions (eg, asthenia, pyrexia): 11.3%, 21.0%, 4.8%, 4.8% and 6.5%. Across these AE categories, incidences tended to decrease over time in TFR.Summary/Conclusion:These results demonstrate the long‐term durability and safety of TFR following 2L NIL. No disease progressions or CML‐related deaths were reported. Musculoskeletal pain AEs were transient and additional AEs that may impact quality of life tended to decrease in frequency during TFR.image

PS1177 PROGNOSTIC FACTORS FOR MOLECULAR RELAPSE‐FREE SURVIVAL AFTER DISCONTINUATION OF TYROSINE KINASE INHIBITORS IN CHRONIC MYELOID LEUKEMIA BASED ON RUSSIAN MULTICENTER PROSPECTIVE TRIAL (RU‐SKI)

Background:About 50% of chronic myeloid leukemia (CML) patients (pts) after TKI discontinuation lose a major molecular response (MMR) and should return to therapy. Despite the fact that, after TKI resumption, almost all pts re‐achieve deep molecular remission, facilitating a more accurate selection process for therapy cessation remains topicalAims:To define the prognostic factors for molecular relapse‐free survival after TKI discontinuation in Russian CML populationMethods:The base for the analysis was the Russian multicenter prospective study RU‐SKI on the discontinuation of TKI in pts with CML and deep molecular response (DMR). Ninety‐eight CML pts with chronic phase (CP), TKI therapy for at least three years and a stable DMR (BCR‐ABL<0.01%) for at least two years were enrolled. Pts with previous imatinib failure and treatment‐free remission (TFR) failure were eligible. The BCR‐ABL level was evaluated by RQ‐PCR according to the international scale (IS). The schedule of molecular tests was as follows: monthly during the first six months (mo) after TKI cessation, every two mo from six to 12 mo and every three mo thereafter. Treatment by the same TKI was resumed in case of MMR loss (BCR‐ABL>0.1%). We used the proportional hazards regression analysis to identify independently significant factors for molecular relapse‐free survival (MRFS). We categorized each independently significant factor into two groups, depending on the optimal cutoff level obtained by the minimum P‐value approach. We used the Kaplan‐Meier method for calculating the probability of MRFS and the log‐rank test for comparison.Results:One year MRFS in all group was 51%. MRFS rate in pts with history of previous TFR failure (n = 7) was 14%. We decided to exclude from multivariate analysis pts with history of previous TFR failure to identify significant factors for the first attempt of therapy cancellation. Baseline pts characteristics (1st stop, n = 91): male: 48%; median (Me) age at TKI cessation 46 years (range 22 to 80); Me duration of TKI therapy 8.3 years (range three to 16.2); Me duration of DMR 3.2 years (range two to 10.7). Therapy before treatment cessation: imatinib in 63 (69%) pts, second‐generation (2G) TKI in 28 (31%) pts. Me follow‐up time after TKI cessation was 24 mo (range 12 to 41). Probability of MRFS (1st stop) was 55% after 12 mo of follow‐up. We include in multivariate analysis the following factors: age, gender, history of previous resistance to imatinib, type and line of TKI, duration of therapy, length of DMR, depth of molecular response before cancellation, Sokal risk group. Sokal risk group, duration of therapy and depth of molecular response were found to be independently significant factors with p ≤0.05. Treatment duration more than 8 years, depth of DMR before cancellation at least MR4.5, non‐high Sokal risk group were attributed to favorable factors for MRFS after the optimal cutoff level was obtained (fig.1). We have found that the duration of TKI therapy, and not the duration of DMR has an independent prognostic value for the Russian CML population. The lack of molecular monitoring data at early stages of the disease in long‐term treated pts cause to the 1st DMR detection bias. Indeed, a longer time to the 1st DMR was observed in pts with the longer duration of TKI therapy (fig.2).Summary/Conclusion:Patients with treatment duration more than 8 years, depth of DMR before cancellation at least MR4.5, non‐high Sokal risk group and without history of previous TFR failure are more preferable for TKI discontinuationimage

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.

Kinetics of the Leukemic Clone in Patients with Chronic Myeloid Leukemia during Pregnancy

Kinetics of the Leukemic Clone in Patients with Chronic Myeloid Leukemia during Pregnancy

Multiparameter Single Cell Analysis to Identify Immune Cell States That May Contribute to Successful Treatment Discontinuation in Patients with Chronic Myeloid Leukemia

Background: Recently, numerous clinical trials have demonstrated that approximately half of CML patients who have achieved deep and durable remissions on TKI therapy can enjoy prolonged treatment-free remissions. A major question in the field concerns why treatment interruption is not universally successful. Two non-mutually exclusive theories have been proposed to explain successful discontinuation: CML stem cell exhaustion, and immune surveillance. Identification of mediators of CML stem cell exhaustion or successful immune surveillance could lead to adjunctive therapeutic approaches. We set out to determine potential immune mediators of disease control through interrogation of clinical samples using emerging technologies.Results: Consenting patients who discontinued TKI at our institution were grouped into three categories based upon BCR-ABL1 transcript kinetics following treatment discontinuation. Group 1 is characterized by stable undetectable or minimally detectable BCR-ABL1 transcripts. Group 2 exhibited molecular relapse, defined as loss of major molecular response (MMR) requiring treatment re-initiation, typically within the first 3-9 months of treatment discontinuation. Group 3 displays kinetics that are particularly intriguing, whereby the transcript level rises substantially upon treatment cessation, but remains below the MMR threshold despite remaining off TKI therapy. We hypothesize that disease control in group 3, and a subset of patients in Group 1, is mediated by the immune system.To investigate the immune system difference between these groups, we performed single cell immune profiling in the pre- (~ 1 week) and post- (~ 3 months) discontinuation PBMC samples obtained from 15 patients through CyTOF and 10x single cell RNA sequencing. Group 1 consist of 5 patients, group 2 consist of 8 patients, and group 3 consist of 2 patients, respectively. There were no meaningful differences in the immune cell composition prior to TKI discontinuation. Assessment of the immune phenotype 3 months after discontinuation in each group by CyTOF revealed an increase in the CD4+ T cell population in group 3 following TKI discontinuation. Specifically, memory CD4+ T cells and CD38+/HLA-DR+ activated CD4+ T cells were increased in group 3. While patients in groups 1 and 2 showed only decrease or moderate change in memory CD4+ T cells and activated CD4+ T cells, group 3 showed 53% increase of memory CD4+ T cells (21% to 32%) and 640% increase of activated CD4+ T cells (0.4% to 3.3%) following TKI discontinuation. While CD45RA-/CD4+ T cells were increased in abundance, the CD45RA- population was unchanged in CD8+ T cells. 10x single cell RNA sequencing of these samples is ongoing and will be presented.Conclusions: We have conducted multiparameter single cell immune profiling in CML patients with sustained deep molecular remission, loss of MMR, or maintenance of MMR despite a sustained rise in BCR-ABL1 transcript level. Our results suggest that an increase in memory and activated CD4+ T cells following TKI discontinuation may correlate with successful immune surveillance of CML. Assessment of a larger cohort of samples is required to confirm our findings. DisclosuresShah:ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding.

One Size May Not Fit All for TKI Dosing in Chronic Phase CML—Deep Molecular Responses Despite Dose Reduction

AbstractBackground: The development of tyrosine kinase inhibitors (TKIs) has dramatically changed the landscape of chronic myelogenous leukemia (CML) treatment. Dosing of TKIs is based on the phase of disease at presentation, but is not altered based on body surface area (BSA), gender, or other patient characteristics. Although TKIs are generally well tolerated, lower grade hematologic and non-hematologic toxicities are not infrequent. Inability to maintain dosing during the first year of therapy (missing as few as 10% of doses per month) has been associated with lower rates of major molecular response (MMR), which might have survival implications and/or prevent treatment-free remission attempts. While the package insert of three TKIs (imatinib, dasatinib, nilotinib) commonly used in first line therapy provides specific dose-reduction instructions for hematologic toxicity, only nilotinib has recommendations for non-hematologic toxicities. Long-term outcome data on the effects of dose-reduction of TKI therapy based on toxicity is lacking. Furthermore, there is little data on risk factors for TKI intolerance. Thus, we sought to identify characteristics of patients requiring dose reductions as a part of first-line TKI treatment for chronic phase CML who successfully achieved an MMR 4 or greater as well to determine the long-term outcome of these patients in a retrospective fashion.Methods: Using electronic medical records, we identified patients seen at the John Theurer Cancer Center for treatment of newly diagnosed chronic phase CML between November 1, 2012 and July 1, 2016 who had successfully achieved an MMR 4 or greater. These records were screened for individuals requiring chronic dose reductions as part of first-line treatment for chronic phase CML. We identified 35 consecutive patients that were able to tolerate full dose TKI therapy per package insert. This control group was used to determine risk factors for TKI intolerance compared to patients that required dose reduction.Results: A total of 20 patients were identified who achieved an MMR 4 or greater and required long-term dose reduction of first-line TKI therapy with a median follow up of 48.5 months (range 18.7-172.6). The median time on full dose therapy prior to dose reduction was 7.7 months (range 0-40.2). The median time spent on reduced dose therapy was 43.5 months (range 12.1-159.0). The time to MMR was 8.3 months (1.8-40.2). The majority of patients remained in MMR 4 despite maintenance on dose reduction. Median progression free survival (PFS), as defined by loss of MMR, of dose-reduced patients had not yet been reached. One, two, and three year PFS rates were 100%, 95.0%, and 88.7% respectively. When compared to the control group of patients tolerating front line therapy at full-dose, patients requiring dose reduction were more likely to be female: 80% vs 46% (P=0.028) and have a lower BSA: 1.78 versus 2.03 mg/m2 (P=0.0014). Other variables including age, TKI, Sokol score, and performance status were similar in both groups.Discussion: Among patients who achieved MMR4 or greater on first-line therapy, we noted that female sex and lower BSA were risk factors for TKI dose reduction. Based on the available control group, it cannot be determined if either of these are independent variables. This retrospective analysis demonstrates many patients are able to successfully achieve and maintain a deep molecular response with reduced doses of TKI therapy and perhaps provides justification for dose reduction to increase compliance and maximize treatment tolerability. The majority of patients remained in MMR4 despite dose reductions. DisclosuresMcCloskey:Celgene Pharmaceuticals: Consultancy, Speakers Bureau; Takeda Pharmaceuticals: Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Amgen: Speakers Bureau; COTA: Equity Ownership. Stanislaus:Celgene Pharmaceuticals: Consultancy, Speakers Bureau; Takeda Pharmacetucals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Koprivnikar:Otsuka Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Consultancy, Speakers Bureau; Amgen Pharmaceuticals: Speakers Bureau; COTA: Equity Ownership.

Feasibility of Treatment Discontinuation in Chronic Myeloid Leukemia in Clinical Practice in Spain: Results from a Nationwide Series of 236 Patients

Introduction: Over half of patients with chronic myeloid leukemia (CML) in sustained deep molecular remission do not lose the major molecular response (MMR) after stopping treatment with tyrosine kinase inhibitors (TKI). This strategy is safe in controlled clinical trials, but there is scarce information on its applicability in the real-life setting. We aimed to assess if treatment cessation was feasible in clinical practice in a large nationwide series of CML patients from Spain.Methods: This retrospective study comprised a series of 236 patients in chronic-phase CML who discontinued TKI treatment outside of clinical trials between April 2009 and February 2018 in 33 Spanish institutions. Inclusion criteria were: a) TKI treatment duration >3 years; b) sustained MR4.5 in >4 consecutive determinations (one single point in MR4 was acceptable) during >2 years; c) molecular monitoring in a reference laboratory expressing the results on the International Scale (IS). Patients who had undergone allogeneic hematopoietic stem-cell transplantation were excluded. Molecular relapse was defined as consecutively detectable BCR-ABL1 transcripts showing a ≥1 log increase or loss of MMR in any single sample. Treatment-free remission (TFR) was estimated by the method of Kaplan-Meier and defined as the time from TKI discontinuation to the date of restarting therapy for any reason or, if treatment was not restarted, the date of last contact. Incidence of molecular relapse was calculated using the cumulative incidence function with resumption of TKI treatment in the absence of molecular relapse and death in MMR as competing events. Analysis of factors predicting molecular relapse was done by the method of Fine and Gray.Results: Table 1 shows the main characteristics of the series. Median follow-up from treatment discontinuation was 21.5 months, and 5 patients died in MMR due to CML unrelated causes. TKI therapy was reinitiated due to molecular relapse (MMR loss: n=52, increase >1 log in BCR-ABL transcript level at two consecutive assessments without losing MMR: n=12), patient preference (n=2), and severe withdrawal syndrome (n=1). One additional patient lost MMR after 20 months from treatment cessation but decided not to be retreated, with spontaneous recovery of MMR. The probability of TFR at 4 years was 64% (95% Confidence Interval [CI]: 55%-72%)(Figure 1). The cumulative incidence of molecular recurrence was 33% (95% CI: 26%-38%) at 3 years (Figure 2). Forty-nine relapses (75% of total) occurred in the first 6 months. The latest MMR loss was detected 30 months after treatment stop. One patient restarted treatment 44 months after TKI discontinuation due to ≥1 log increase in BCR-ABL1 transcripts in two consecutive samples without losing MMR. In univariate analysis, duration of TKI treatment of less than 5 years (P=0.005) and time in RM4.5 shorter than 4 years before TKI discontinuation (P=0.003) were both significantly associated with a higher incidence of molecular recurrence.No patient progressed to the advanced phases of CML. At the time of restarting treatment, the median BCR-ABL1 IS was 0.3%, with this value being >5% in only 7 instances. Most patients (81%) received the same TKI that they were taking before the trial of treatment cessation. Median follow-up after treatment resumption was 20 months. Among the 64 patients who restarted treatment due to molecular relapse, 46 of 52 cases regained MMR after a median time of 3 months, and 47 of 64 regained MR4.5 after a median time of 5 months. 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).Fifty-one patients (22%) developed musculoskeletal or joint pain after treatment cessation. In patients stopping imatinib, a significant increase in Hb levels, leukocyte counts, total lymphocyte counts, platelet counts, and cholesterol levels was observed. At 6 months, an increase in Hb level >2 g/dL was observed in 47% of patients with anemia. By contrast, nilotinib discontinuation was not followed by any relevant change in laboratory values.Conclusions: Our results confirm that treatment discontinuation is feasible and safe in clinical practice in Spain. Duration of TKI treatment of less than 5 years and a time in RM4.5 shorter than 4 years before TKI discontinuation were significantly associated with a higher incidence of molecular recurrence. DisclosuresHernandez Boluda:Incyte: Consultancy; Novartis: Consultancy. García Gutiérrez:Incyte: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ferrer Marin:Incyte: Consultancy; Novartis: Consultancy, Research Funding. Cervantes:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hospital Clinic Barcelona: Employment.

Interferon May Help Control the Recurrence of Chronic Myeloid Leukemia after Discontinuation of Tyrosine Kinase Inhibitor

Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukemia (CML).Many patients have deep molecular responses(DMR), a prerequisite for TKIs therapy discontinuation. Many clinical studies have been done in discontinuation of TKIs worldwide. We aimed to explore the appropriate criteria for failure of TKIs discontinuation; and to observe the effect of interferon on patients with continuous low level positive BCR-ABL1 after TKIs discontinuation.Therefore, we analyzed the clinical data of 40 CML patients with DMR who have withdrawn TKIs from Match 2013 to January 2018. Eligible CML patients had received any TKI for at least 3 years, and had a confirmed deep molecular response for at least 2 year. The molecular relapse(MR) was defined as loss of major molecular response (MMR; BCR-ABL1 >0.1% on the International Scale). The patients with MR would be prescribed TKI, and patients with 0.0032% <BCR-ABL1IS <0.1% would be suggested to try interferon.Of these 40 patients, male/female was 24/16, the median age was 50 (13,70) years, and 2 cases were accelerated phase, while the rest were chronic phase at diagnosis. It was feasible for Sokal score in 35 cases, including 18 cases with low risk, 12 with intermediate risk and 2 with high risk. The median time to MR4.5 was 18 (6,82) months, and the median duration of MR4.5 before TKIs discontinuation was 52 (27,115) months. Thirty-two patients had been taking imatinib and eight had been taking second-generation TKIs. The median duration of TKIs was 83.7 (37.5, 125.4) months. After drug withdrawal, median follow-up was 17.6 (6,65) months. 17 patients eventually lost MMR.TFR was 65% (95%CI (47.6%, 82.4%) at 12 months. A total of 14 patients restarted TKI treatment, 1 lost the visit, and 13 patients regained MMR or MR4.5 within 3 months after taking the medicine. There were 23 patients without losing MMR, 10 of whom maintained CMR. There were 5 cases with single positive BCR-ABL1 that did not lose MR4.Eight cases were positive for BCR-ABL1 more than twice, of which four lost MR4 (3 received interferon treatment) and four did not lose MR4 (1 received interferon treatment).Of the 21 patients with BCR-ABL1 positive for more than 2 times after discontinuation (4 patients were excluded for loss of MMR in first positive test), 6 patients by follow-up did not lose the MR4, in 15 cases losing MR4, 12 cases eventually lose the MMR, 3 cases of follow-up did not lose the MMR (2 cases received interferon treatment), TFR for two groups was statistically difference (P = 0.026).In these 21 patients, 3 cases were non continuous positive, 18 cases of low level 2 consecutive positive, the median follow-up of 15.75 (6,55.5) months, 7 cases received interferon therapy, median follow-up after application of interferon was 9 (3, 20) months, in which 2 cases eventually lose the MMR, 11 cases treated without interferon, 10 cases eventually lose the MMR, TFR was statistically different between the two groups (71.4% vs 9.1%, P < 0.001).Among them, 2 female patients lost MMR 4 months after drug withdrawal, and because of pregnancy they did not take TKI again, they were given interferon treatment, and obtained and maintained MMR 2 months after interferon treatment. Patients with interferon are well tolerated.After the discontinuation of TKI in CML patients, early intervention should be conducted if MR4 is lost, and interferon treatment may help maintain MMR and prolong the survival without TKI treatment. DisclosuresNo relevant conflicts of interest to declare.

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

Prognostic Model of Successful Tyrosine Kinase Inhibitors Discontinuation Based on the Russian RU-SKI Multicenter Prospective Study

Background: A large number of tyrosine kinase inhibitors (TKI) discontinuation studies has shown that about 50% of chronic myeloid leukemia (CML) patients (pts) after TKI cessation lose a major molecular response (MMR) and should return to therapy. Despite the fact that, after TKI resumption, almost all patients re-achieve deep molecular remission, facilitating a more accurate selection process for therapy cessation remains topical.Aim: Develop a prognostic model for the better selection of CML patients for TKI discontinuation.Methods: The base for the training set was the Russian multicenter prospective study RU-SKI on the discontinuation of TKI in pts with CML and deep molecular response (DMR). Ninety-eight CML pts with chronic phase (CP), TKI therapy for at least three years and a stable DMR (BCR-ABL<0.01%) for at least two years were enrolled. Seven Pts with a previous history of unsuccessful treatment-free remission (TFR) were excluded from the analysis. The BCR-ABL level was evaluated by RQ-PCR according to the international scale (IS). The schedule of molecular tests was as follows: monthly during the first six months (mo) after TKI cessation, every two mo from six to 12 mo and every three mo thereafter. Treatment by the same TKI was resumed in case of MMR loss (BCR-ABL>0.1%). We used the Kaplan-Meier method for calculating the probability of TFR. Univariate analyses were performed using the log-rank test to identify prognostic factors for TFR. Variables found to be significant at the p<0.10 level were entered into a proportional hazards regression analysis. We categorized each independently significant factor into two groups, depending on the optimal cutoff level obtained by ROC analysis and the minimum P-value approach. The next step was a second multivariate analysis including categorized variables. A favorable factor from each variable was scored as 1, while the adverse factor was scored proportionally to the level of hazard ratio. The cumulative score for each patient was calculated. Patients were allocated to either a high or a low risk group concerning MMR loss after the cutoff level was determined by ROC analysis. The validation set included a series of 48 retrospective cases of discontinued patients selected according to RU-SKI inclusion criteria.Results: Baseline characteristics of the training set (n=91): male: 48%; median (Mе) age at TKI cessation 46 years (range 22 to 80); Me duration of TKI therapy 8.3 years (range three to 16.2); Me duration of DMR 3.2 years (range two to 10.7). Therapy before treatment cessation: imatinib in 63 (69%) pts, second-generation (2G) TKI in 28 (31%) pts. Me follow-up time after TKI cessation was 14 mo (range three to 36). Probability of TFR was 55% after 12 mo of follow-up. We analyzed the following factors: age, gender, history of previous resistance to imatinib, type and line of TKI, duration of therapy, length of DMR, depth of molecular response before cancellation, Sokal risk group. Age, Sokal risk group, duration of therapy and depth of molecular response were found to be independently significant factors and included in the survival prognostic model (Table 1). 73% (n=66) of pts scored 5.5 points or less and were assigned to the low risk group. The probability of TFR was 64% and 33% for the low risk and high risk groups, respectively (p=0.001) (Figure 1). Baseline characteristics of validation set (n=48): male: 36%; Ме age at TKI cessation 46 years (range 22 to 76); Me duration of TKI therapy six years (range 3.5 to 13.2); Me duration of DMR 2.8 years (range two to 10). Therapy before treatment stopped: imatinib in 31 (65%) pts, 2G TKI in 17 (35%) pts. Me follow-up time after TKI cessation was 36 mo (range six to 116). Probability of TFR was 47% after 30 mo of follow-up. In the validation set, 77% (n=37) of pts were assigned to the low risk group. The probability of TFR was 56% and 18% for the low risk and high risk groups, respectively (p=0.007) (Figure 2).Conclusion: RU-SKI prognostic model is effective in prediction of successful TFR and can be used for better selection of CML pts for TKI discontinuation. [Display omitted] DisclosuresShukhov:Novartis: Other: provided consultations and performed lectures ; Bristol Myers Squibb: Other: provided consultations and performed lectures . Chelysheva:Novartis: Other: provided consultations and performed lectures; Fusion Pharma: Other: provided consultations ; Bristol Myers Squibb: Other: provided consultations and performed lectures. Turkina:Novartis: Other: provided consultations; Bristol Myers Squibb: Other: provided consultations; Phizer: Other: provided consultations; Fusion Pharma: Other: provided consultations.

Long-Term Follow-up after Treatment Discontinuation in Patients with Chronic Myeloid Leukemia: The Korean Imatinib Discontinuation (KID) Study

Background With first-line imatinib (IM) therapy, approximately 50% of CP CML patients achieve undetectable molecular residual disease (UMRD). The recent several discontinuation clinical trials have demonstrated that IM discontinuation can be employed based on clinical study in patients who had enough IM therapy and UMRD durations prior to IM discontinuation. In our previous report, we have reported that of 90 patients with follow-up ≥12 months, the probability of sustained major molecular response (MMR) at 12 months and 24 months was 62.2% and 58.5%, respectively. However, currently, the issue on the occurrence of late relapse with a long-term follow-up after IM discontinuation is important. Therefore, here we analyzed the long-term follow-up results of the KID study.Methods CP CML patients who were treated with IM for more than 3 years and had undetectable levels of BCR-ABL1 transcripts determined by quantitative reverse transcriptase polymerase chain reaction for at least 2 years were eligible for KID study. After IM discontinuation, the molecular response was monitored using the following schedule: every month for the first 6 months, every 2 months up to 12 months, and every 3 months thereafter. In cases of MMR loss after 2 consecutive assessments (molecular relapse), IM treatment was re-introduced.Results Between October 2010 and June 2015, a total of 126 patients (70 females, 56 males) were enrolled on KID Study, with a median age of 47 years (range, 18 - 82), the percentages of patients with low, intermediate and high Sokal risk scores were 33%, 25% and 15%, respectively with unknown Sokal risk scores in 27%. And the median time on IM therapy and the median duration of sustained UMRD prior to discontinuation were 83 months (range, 32 - 141) and 41 months (range, 22 - 131), respectively. After a median follow-up of 43 months (range, 4.9 - 93.6) after IM discontinuation, 55 patients lost MMR in 2 consecutive analyses at a median time of 3 months (range, 0.9 - 53.2 months). The 12-month and overall probability of sustained MMR was 61.9 ± 4.3% and 55.1 ± 4.6%, respectively. UMRD (P = 0.001) and IM duration on treatment (P = 0.003) were associated with the probability of sustained MMR. Out of 55 patients with molecular relapse, 53 patients (except 2 patients with follow-up loss) were re-treated with IM for a median of 31.7 months (range, 5.8 - 82.9 months), 51 patients re-achieved MMR at a median of 1.9 months (range, 0.0 - 5.4 months) after resuming IM therapy and 48 of these patients re-achieved UMRD at a median of 5.8 months (range, 0.9 - 19.7 months). 2 patients who re-achieving of MMR after resuming IM therapy lost MMR again; One patient with 45.8 and 40.3 months of IM therapy duration and sustained UMRD duration prior to discontinuation, respectively lost MMR at 7.4 months after IM discontinuation and re-achieved MMR 1.7 later after IM restarting, but MMR was lost again on the assessment 8 months later. Another patient with 122.2 and 30.4 months of IM therapy duration and sustained UMRD duration prior to discontinuation, respectively relapsed at 53.2 months after IM discontinuation. Despite re-achieving MMR 1.4 later after IM restarting, the patient suddenly progressed to blast crisis at 6 months after restarting IM.Conclusions Our results showed that IM discontinuation can be applied with approximately 55% of probability of sustained MMR in the long term. Although sudden blast crisis occurring in responding patients with CML has already been reported in IM therapy, event of progression to BC in a clinical trial of IM discontinuation deserves to be followed-up with caution. Overall, both UMRD and IM duration on treatment were the most important predictors for successful IM-off. DisclosuresKim:Pfizer: Research Funding; Ilyang: Research Funding; Novartis: Research Funding; BMS: Research Funding.

Adolescent and Young Adult Chronic Myeloid Leukemia in Real-World Settings: Experience from a Tertiary Care Institute in Northern India.

The data on adolescent and young adult chronic myeloid leukemia (AYA-CML) from the Indian subcontinent are scarce. We studied characteristics of AYA-CML through a retrospective analysis of 1950 CML patients registered to a tertiary care hospital in Northern India. AYA-CML represented 22.1% of all CML patients, with cumulative overall survival (OS) of 84%, and 1 and 8 years OS of 94.2% and 74.2%, respectively. Of all cases, 8.91% patients had advanced disease at the time of diagnosis, and 13.95% had myelofibrosis in the diagnostic marrow, 79.6% had complete cytogenetic response (CCyR), and 84.5% had major molecular response (MMR). Loss of CCyR and MMR was noted in 37.2% and 28.4%, respectively. The cumulative OS was significantly better in patients on patient assistance program, and they were initiated on therapy within 3 months of symptom onset.

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.

Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial

Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment. In this prospective, non-randomised trial, we enrolled patients with chronic myeloid leukaemia at 61 European centres in 11 countries. Eligible patients had chronic-phase chronic myeloid leukaemia, had received any TKI for at least 3 years (without treatment failure according to European LeukemiaNet [ELN] recommendations), and had a confirmed deep molecular response for at least 1 year. The primary endpoint was molecular relapse-free survival, defined by loss of major molecular response (MMR; >0·1% BCR-ABL1 on the International Scale) and assessed in all patients with at least one molecular result. Secondary endpoints were a prognostic analysis of factors affecting maintenance of MMR at 6 months in learning and validation samples and the cost impact of stopping TKI therapy. We considered loss of haematological response, progress to accelerated-phase chronic myeloid leukaemia, or blast crisis as serious adverse events. This study presents the results of the prespecified interim analysis, which was done after the 6-month molecular relapse-free survival status was known for 200 patients. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01596114. Between May 30, 2012, and Dec 3, 2014, we assessed 868 patients with chronic myeloid leukaemia for eligibility, of whom 758 were enrolled. Median follow-up of the 755 patients evaluable for molecular response was 27 months (IQR 21-34). Molecular relapse-free survival for these patients was 61% (95% CI 57-64) at 6 months and 50% (46-54) at 24 months. Of these 755 patients, 371 (49%) lost MMR after TKI discontinuation, four (1%) died while in MMR for reasons unrelated to chronic myeloid leukaemia (myocardial infarction, lung cancer, renal cancer, and heart failure), and 13 (2%) restarted TKI therapy while in MMR. A further six (1%) patients died in chronic-phase chronic myeloid leukaemia after loss of MMR and re-initiation of TKI therapy for reasons unrelated to chronic myeloid leukaemia, and two (<1%) patients lost MMR despite restarting TKI therapy. In the prognostic analysis in 405 patients who received imatinib as first-line treatment (learning sample), longer treatment duration (odds ratio [OR] per year 1·14 [95% CI 1·05-1·23]; p=0·0010) and longer deep molecular response durations (1·13 [1·04-1·23]; p=0·0032) were associated with increasing probability of MMR maintenance at 6 months. The OR for deep molecular response duration was replicated in the validation sample consisting of 171 patients treated with any TKI as first-line treatment, although the association was not significant (1·13 [0·98-1·29]; p=0·08). TKI discontinuation was associated with substantial cost savings (an estimated €22 million). No serious adverse events were reported. Patients with chronic myeloid leukaemia who have achieved deep molecular responses have good molecular relapse-free survival. Such patients should be considered for TKI discontinuation, particularly those who have been in deep molecular response for a long time. Stopping treatment could spare patients from treatment-induced side-effects and reduce health expenditure. ELN Foundation and France National Cancer Institute.

Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: 96-week update of the ENESTfreedom study

PurposeENESTfreedom is evaluating treatment-free remission (TFR) following frontline nilotinib in patients with chronic myeloid leukemia (CML) in chronic phase. Following our primary analysis at 48 weeks, we here provide an updated 96-week analysis.MethodsAttempting TFR required ≥ 3 years of nilotinib, a molecular response of MR4.5 [BCR-ABL1 ≤ 0.0032% on the International Scale (BCR-ABL1IS)], and sustained deep molecular response (DMR) during a 1-year consolidation phase. Patients restarted nilotinib following loss of major molecular response (MMR; BCR-ABL1IS ≤ 0.1%).ResultsNinety-six weeks after stopping treatment (3.6-year median prior nilotinib duration), 93 of 190 patients (48.9%) remained in TFR. Of 88 patients who restarted nilotinib following loss of MMR, 87 regained MMR and 81 regained MR4.5 by the data cut-off. Ninety-six-week TFR rates were 61.3, 50.0, and 28.6% in patients with low, intermediate, and high Sokal risk scores at diagnosis, respectively. Patients consistently in MR4.5 during consolidation had higher TFR rates (50.6%) than patients with ≥ 1 assessment without MR4.5 during consolidation (35.0%). In a landmark analysis, 96-week TFR rates for patients with MR4.5, MR4 (BCR-ABL1IS ≤ 0.01%) but not MR4.5, and MMR but not MR4 at TFR week 12 were 82.6, 23.1, and 0%, respectively. There were no reports of disease progression or death due to CML; overall adverse event frequency decreased following TFR. Within the follow-up period, TFR did not adversely affect disease outcomes.ConclusionsThese results demonstrate the feasibility and durability of TFR following frontline nilotinib and emphasize the importance of sustained DMR for TFR.

Results of following up patients with chronic myeloid leukemia and a deep molecular response without tyrosine kinase inhibitor therapy

To assess the results of following up patients with chronic myeloid leukemia (CML) and a deep molecular response (MR) without tyrosine kinase inhibitor (TKI) therapy. The reasons for TKI discontinuation in 70 patients with CML and a deep MR of more than 1 year's duration were adverse events, pregnancy, and patients' decision. Information was collected retrospectively and prospectively in 2008-2016. The median follow-up after TKI therapy discontinuation was 23 months (2 to 100 months). At 6, 12 and 24 months after TKI therapy discontinuation, the cumulative incidence of major MR (MMR) loss was 28, 41 and 48%, respectively; the survival rates without TKI therapy were 69, 50, and 39%, respectively. MMR loss was noted in 28 (88%) patients at 12 months; it was not seen without TKI therapy at 2-year follow-up. Deaths due to CML progression were absent. The Sokal risk group was a reliable factor influencing MMR loss (p ≤ 0.05). The cumulative recovery rate for deep MR after resumption of TKI use was 73 and 100% at 12 and 24 months, respectively, with a median follow-up of 24 months (1 to 116 months). Deep MR recovered at a later time when the therapy was resumed more than 30 days after MMR loss. Safe follow-up is possible in about 50% of the patients with CML and stable deep MRs without TKI therapy. The introduction of this approach into clinical practice requires regular molecular genetic monitoring and organizational activities. Biological factors in maintaining remission after TKI discontinuation need to be separately studied.