Sustained Deep Molecular Response Research Articles

Kinetics of BCR::ABL1 transcript levels and molecular relapse after tyrosine kinase inhibitors discontinuation in chronic myeloid leukemia patients: preliminary results from the DES-CML study

Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of patients with chronic myeloid leukemia. Patients who achieve sustained deep molecular response are eligible for treatment discontinuation. DES-CML is an ongoing, phase 2 multicentric discontinuation trial. Adult patients with CML in chronic phase with typical BCR::ABL1 transcripts, stable deep molecular response (MR4.5 IS) for two years, and no previous resistance were eligible. Patients underwent a phase of TKI dose de-escalation for six months before discontinuation. TKI was reintroduced at the previous dose if the patient lost major molecular response (MMR) at any time. This study aimed to assess the impact of BCR-ABL transcript kinetics during TKI de-escalation and discontinuation phases on treatment-free survival. So far, the study recruited 41 patients, and 38 patients discontinued therapy (4 were in the second discontinuation attempt). Eleven patients lost MMR, one during the de-escalation phase and ten after discontinuation. 24-month treatment-free survival was 66% (95% CI: 48-84%) in a median follow-up of 7 (1–30) months. No patient lost hematological response or had disease progression. A higher rate of molecular relapses occurred in patients with fluctuating BCR::ABL1 levels after the discontinuation phase (with loss of MR4.5, but no loss of MMR) (P=0.04, HR-4.86 (1.03-22.9) but not confirmed in the multivariate analysis. The longer duration of TKI treatment (P=0.03, HR-1.02, 95%CI - 1.00-1.04) and MMR (P=0.004, HR-0.95, 95%CI - 0.92-098) were independent factors of a lower relapse rate.

E14a2 Transcript Favors Treatment-Free Remission in Chronic Myeloid Leukemia When Associated with Longer Treatment with Tyrosine Kinase Inhibitors and Sustained Deep Molecular Response

e14a2 Transcript Favors Treatment-Free Remission in Chronic Myeloid Leukemia When Associated with Longer Treatment with Tyrosine Kinase Inhibitors and Sustained Deep Molecular Response

Treatment-free remission after a second TKI discontinuation attempt in patients with Chronic Myeloid Leukemia re-treated with dasatinib – interim results from the DAstop2 trial

Tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML) has become part of routine care for patients with a sustained deep molecular response (DMR). Approximately 50% experience a molecular relapse upon TKI cessation. Most of them quickly regain DMR upon TKI resumption. Whether these patients can achieve a second treatment-free remission (TFR) remains unclear. DAstop2 (ClinicalTrials.gov ID: NCT03573596) is a prospective study including patients with a failed first TFR attempt re-treated with any TKI for ≥ one year. Upon entering the study, patients received the TKI dasatinib for additional two years. Patients with sustained DMR for ≥1 year qualified for a second TKI stop. Ninety-four patients were included between Oct 2017-Dec 2021. At the time of data analysis, 62 patients had attempted a 2nd stop. After a median follow-up of 27 months from 2nd stop, TFR rates were 61, 56 and 46% at 6, 12 and 24 months respectively. No progression to advanced stage disease was seen and 87% had re-achieved MR4 within a median of 3 months from TKI re-initiation. In summary, we show that a 2nd TFR attempt after dasatinib treatment is safe, feasible and TFR rates seem in the range of those reported in trials of a first TKI stop.

Estimated Savings After Stopping Tyrosine Kinase Inhibitor Treatment Among Patients With Chronic Myeloid Leukemia

Patients with chronic myeloid leukemia (CML) who have a sustained deep molecular response using tyrosine kinase inhibitors (TKIs) can safely attempt to stop their use. As these medications are very costly, this change in treatment protocols may result in large savings. To estimate future savings from attempting to stop TKI use among patients with CML who have deep molecular response. A microsimulation model was developed for this decision analytical modeling study to estimate costs for US adults moving from using a TKI, to attempting discontinuation and then reinitiating TKI therapy, if clinically appropriate. Estimates were calculated for US patients who currently have CML and simulated newly diagnosed cohorts of patients over the next 30 years. Attempting to stop using a TKI. Estimated savings after attempted discontinuation of TKI use. A simulated population of individuals with CML in 2018 and future populations were created using estimates from the SEER*Explorer website. The median age at diagnosis was 66 years for men and 65 years for women. Between 2022 and 2052, the savings associated with eligible patients attempting discontinuation of TKI therapy was estimated at more than $30 billion among those currently diagnosed and over $15 billion among those who will develop CML in the future, for a total savings of over $54 billion by 2052 for drug treatment and polymerase chain reaction testing. The estimate is conservative as it does not account for complications and other health care-associated costs for patients continuing TKI therapy. The findings of this decision analytical modeling study of patients with CML suggest that attempting discontinuation of TKI therapy could save over $54 billion during the next 30 years. Further education for patients and physicians is needed to safely increase the number of patients who can successfully attain treatment-free remission.

Full Treatment-Free Remission Outcome in Patients with Chronic Myeloid Leukemia in Chronic Phase Following One Year of Nilotinib De-Escalation: 96-Week Update of Dante Study

Introduction: Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is achievable and recommended for patients (pts) in sustained deep molecular response (DMR) who can discontinue tyrosine kinase inhibitor (TKI) treatment while maintaining responses. Studies investigating TKI de-escalation before TFR are mainly in imatinib-treated CML chronic phase (CP) pts and suggest that this stepwise approach is feasible. Although nilotinib (NIL) is the first and only TKI approved for stopping therapy, nilotinib-based TFR optimization strategy has not been formally studied. Our phase II, single-arm, prospective, multicenter DANTE study (NCT03874858) aims to shed light on frontline NIL de-escalation in terms of full treatment-free remission (FTFR) (primary endpoint) and TFR rate (secondary endpoint) 96 weeks after the start of consolidation in CML-CP Italian patients. Our previously analysis on 40 pts with sustained DMR who entered in the TFR phase showed that approximately 68% of pts remained disease-free 1 year after stopping NIL 1. Here we present the data of 89 patients who successfully completed NIL de-escalation and at least 1 year of TFR. Methods: Adults patients with CML-CP treated with NIL 300 mg twice daily (bid) in first line for ≥3 years who achieved sustained DMR for ≥1 year (≥MR 4.0; BCR-ABL level ≤0.01% IS) were enrolled in 27 centers. The study consisted of 4 phases: screening (week [wk] −4-0), consolidation (wk 0-48), TFR (wk 48-144), and follow-up (until wk 144). Ongoing treatment with ≥400 mg/day dose was allowed at study entry. During consolidation pts were treated with NIL 300 mg once daily (qd). At the end of consolidation phase, pts with sustained DMR entered TFR phase and NIL was discontinued. Patients with major molecular response (MMR [BCR-ABL ≤0.1% IS]) but without sustained DMR continued NIL 300 mg qd. At any time, pts with loss of MMR returned to NIL 300 mg bid. During TFR phase, BCR-ABL levels were monitored monthly from wk 52-96 and then every 3 months. Here we report updated results collected until the cut-off date of 8th February 2023, when all patients who entered the TFR phase had completed at least one year of TFR or switched to full-dose phase or entered in survival follow-up or discontinued the study. The primary endpoint of the study is FTFR, defined as the percentage of patients (in both TFR phase and NIL half-dose) in MMR or better at week 96. Results: Overall, 113 pts were screened and 107 entered in consolidation phase. The baseline characteristics and the clinical outcome of the 107 patients are shown in Tab 1. Specifically, 98/107 (92%) completed the consolidation phase, while 9 pts discontinued permanently (2 due to loss of MMR, 3 due to adverse events (AEs) and 4 due to patient decision). Noteworthy, 89/107 (83%) with sustained DMR entered in the TFR phase, while 9 pts maintained MMR but not sustained DMR (7 entered in NIL half dose follow-up period and were in FTFR at 96 weeks, while 2 discontinued the study before week 96). At 1 year cut-off data, 71/107 pts (66.4%) were in FTFR, meeting the primary endpoint of study. We observed 64/89 pts (72%) who entered in the TFR phase remained in MMR or better after a median duration of 20.4 months (interquartile range [IQR] 1.9-32.4), meeting the main secondary endpoint of the study. The median time to loss of MMR in TFR phase was not reached (Fig 1). The remaining 25/89 pts (28%) had discontinued the TFR phase (21 pts due to loss of MMR, 1 due to AEs and 3 pts for subject/guardian decision). The median time spent in TFR phase until loss of MMR was 3.6 months (IQR 2-19 months). At the cut-off data, 23/24 pts (96%) who restarted NIL after MMR loss regained MMR and MR4 after a median time of 2.7 months (IQR 1.0-5.6) and 4.1 months (IQR 1.2-10), respectively. Notably, 20/24 (83%) who restarted NIL after MMR loss achieved MR4.5 after a median time of 6.4 months (IQR 2.0-16.9). During the TFR phase, all-grade AEs were reported in 64/89 pts (72%). One pt (1.1%) had serious AE (pneumonia). No deaths and disease progressions were observed. Conclusions: Our findings show that 66.4% pts who entered in consolidation phase achieved FTFR 96 weeks after the start of the consolidation period, and approximately 72% of pts remained disease-free at 1 year after stopping NIL. Overall, our data suggest that de-escalation of NIL before TFR attempt in CML-CP pts with sustained DMR can be a successful dose-optimization strategy. 1Stagno F. et al., Blood (2022) 140 (Supplement 1): 9614-9616.

Predictive Value of BCR::ABL1 Transcripts Kinetics in the Molecular Relapse of Chronic Myeloid Leukemia Patients after Tyrosine Kinase Inhibitors Discontinuation: Results from the DES-CML Study

Duration of previous treatment, duration and depth of molecular response, previous resistance, BCR::ABL1 transcript, and lymphocyte subtypes are known predictive factors of molecular recurrence after tyrosine kinase inhibitors (TKI) discontinuation in chronic myeloid leukemia (CML) patients (pts). Few studies explored the kinetics of BCR::ABL1 during a dose de-escalation phase before discontinuation in predicting molecular relapse. This study aimed to evaluate the kinetics of BCR::ABL1 transcripts during the de-escalation phase of the DES-CML trial and to correlate with molecular relapse after TKI discontinuation. Methods: This prospective, multicenter, single-arm, phase 2 study included CML pts treated DES-CML Study. Inclusion criteria: Adult CML pts treated with TKI for a minimum of 3 years that achieved sustained deep molecular response (DMR), defined by a minimum duration of MR4.5 for two years, confirmed by four real-time quantitative reverse-transcription polymerase chain reaction (qPCR) tests with six months interval. Exclusion criteria: pts with atypical BCR::ABL1 transcripts, previous or current advanced stage CML, previous resistance to TKI or ABL mutations. The TKI dose was reduced by 50% for six months before discontinuation (de-escalation phase). Molecular monitoring was performed by qRT-PCR, using ABL as the control gene. The results were reported using the International Scale. BCR::ABL1 transcripts were evaluated monthly during the de-escalation phase. After discontinuation, assessments were performed monthly for six months, every two months at months 7-24, and then every three months. Therapy was restarted at the same dose before dose reduction if loss of MMR (qPCR<0.1%). Statistical analysis was performed by using SPSS software. Rates of MRFS were calculated by Kaplan-Meier analysis, and groups were compared using a log-rank test. P values of <.05 were considered statistically significant. This trial is registered at ReBEC (RBR-6f5xbq; UTN code: U1111-1252-7312) and was approved by the ethics committees of the participating centers. All pts signed informed consent. Results: This study is ongoing. Forty-one pts were enrolled from September 2020 to July 2023, with a median age of 61 years (23-85), 60% men, 33% Sokal low risk, 50% intermediate, 17% high; 78% with b3a2 BCR::ABL1 transcript type; 85% using imatinib, 7.5% dasatinib, 5% nilotinib, and 2.5% bosutinib. For 3 pts, it was the second attempt at stopping TKI. The median duration of TKI treatment until discontinuation was 11 years (3-20). The cutoff date was July 2023, with a median follow-up of six months (1-26) after TKI discontinuation. One patient had a screen failure; another was enrolled but has not started the de-escalation phase yet. Five patients are in the de-escalation phase, and 25 are in the discontinuation phase. Two patients did not complete the de-escalation phase due to a lack of medication and went to the discontinuation phase. One patient died from causes unrelated to CML in the discontinuation phase and was censored in the MRFS analysis. 15/33 (45%) patients lost MR4.5 at any time in the de-escalation phase, and 4/15 (31%) lost MMR after discontinuation. Three of the 18 patients who did not lose MR4.5 during de-escalation relapsed (16%, P=0.05). The two patients who did not undergo de-escalation were censored in this analysis. Nine pts lost MMR: one during de-escalation and 8/39 (20%) after discontinuation. The median time between discontinuation and loss of MMR was two months (0-10). The median time to MMR recovery was 1.5 months (1-5). The overall MRFS was 72% (95% CI: 56-88%)(Figure A) and 81% in the first-attempt discontinuation group. All pts in the second attempt relapsed (3 patients) (P<0.0001). There was no difference in MRFS by gender, BCR::ABL1 transcript type, Sokal, and ELTS. Molecular response status at discontinuation: 23 (74%) had MR4.5, 6 (19.5%) MR4.0, and 2 (6.5%) MMR. Patients with MR4.5 at discontinuation had a higher MRFS than those in MR4.0 and MMR (78% vs. 62% vs. 0%, respectively, P=0.012)(Figure B). No patient lost hematologic response or had disease progression. Conclusions: Loss of MR4.5 during the de-escalation phase or molecular status not in MR4.5 before discontinuation was predictive of subsequent loss of MMR. Treatment-free remission was not successful in the second attempt of discontinuation.

Outcomes of Chronic Myeloid Leukemia Patients after Therapeutic Failure to Asciminib, a Multicenter Observational Study

Introduction: Asciminib has recently entered the market as a promising option for patients with chronic myeloid leukemia (CML) and therapeutic failure to ³ 2 tyrosine kinase inhibitors (TKIs). It presents a relevant rate of therapeutic success thanks to its different mechanism of action, being the first in its class to produce an allosteric inhibition on the myristoylated pocket of ABL. However, a percentage of patients fail this drug due to intolerance or resistance. This group constitutes a highly polytreated population with few therapeutic options. The aim of this analysis is to determine the most frequent treatment strategies in this setting, as well as to ascertain the prognosis in this difficult to treat group. Material and methods: a retrospective descriptive multicenter observational study was carried out. Eligible patients were those with a diagnosis of CML, >18 years and who had presented a therapeutic failure to asciminib, due to resistance or intolerance. Patients were selected from a cohort of 85 CML patients who received asciminib through a managed-access program. Results: A total of 19 patients were recruited from 17 centers in Spain. Median age at the time of therapeutic failure to asciminib was 61.7 years. Median time from diagnosis to asciminib failure was 7.9 years (range 1.7-25.5), median number of previous lines was 5. 47% of patients had previously received ponatinib and 15.8% (3/19) had received an allogeneic hematopoietic stem cell transplantation (allo-HSCT) prior to asciminib. Median time on asciminib was 5.6 months (range 0.7- 40.9). 42% of patients (8/19) failed treatment due to intolerance and 58% (11/19) due to resistance. Four of them had progression to accelerated/blastic phase at the time of withdrawal. Of the intolerant patients, the most frequent reason for discontinuation was pancreatitis (50%, 4/8). The remaining causes were renal failure (1), pleural effusion (1), fatigue (1), and neurological symptoms (1). Regarding the intolerant group, 2 patients did not require restart of treatment due to a sustained deep molecular response (MR). The rest (6/8) required treatment, which in all cases involved restarting a classic TKI that they had already received (2 imatinib, 2 dasatinib, 2 nilotinib). In 50% (3/6) dose reductions were used to control adverse events (AEs), which in 2/3 patients compromised efficacy. In another case, low-dose corticosteroid therapy was used for the management of pleural effusion, maintaining standard dose. Only 1/8 intolerant patients required an additional change of treatment, and all of them are still alive and without progression to advanced stages at the last follow-up. Regarding the patients that required treatment change due to progression to advanced phases, one patient underwent allo-HSCT. The rest were not candidates due to age or clinical impairment (1 received dasatinib, 1 hydroxyurea (HU), 1 without treatment). Only the patient who underwent HSCT is alive more than one year after the procedure with a grade 5 MR. In the rest the median overall survival (OS) was less than 1 month. Of the remaining resistant patients, 4/7 (57%) received ponatinib (1 of 4 had received it previously), 1 imatinib, 1 allo-HSCT and the other patient received cytarabine + interferon + HU. Three of 7 patients required additional lines including change of TKI (asciminib, nilotinib, dasatinib) and other strategies (HU, busulfan, interferon, cytarabine). In terms of response, only the patient undergoing HSCT maintained a mayor MR (1/7). One patient maintained a complete cytogenetic response and the other 2 patients were unable to improve response despite treatment (maintaining worse response than CHR at the end of follow-up). Two patients died (1 acute myocardial infarction, 1 digestive neoplasia). With a median follow-up of 11.2 months, OS of the global cohort is 73%; 100% for intolerant patients, 71% for resistant patients and 25% for those in accelerated/blastic phase. Conclusions: Patients who fail asciminib are a particularly difficult to manage group. In intolerant patients, dose reductions and symptomatic management of AEs may be an appropriate strategy. Resistant patients currently represent an unmet therapeutic need, with low cytogenetic and molecular response rates and poor survival with current strategies. Patients with progression to advanced phases have a dismal prognosis, HSCT may be the only option that provides long-term survival in this group.

In-depth characterization of NK cell markers from CML patients who discontinued tyrosine kinase inhibitor therapy.

Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase is considered a safe option if suitable molecular monitoring is available. However, the question arises as to which factors can contribute to the maintenance of TFR, and immunologic surveillance of the remaining leukemic cells is believed to be one of them. Argentina Stop Trial is an open-label, single-arm, multicenter trial assessing TFR after tyrosine kinase inhibitors interruption, that after more than 4 years showed a successful TFR rate of 63%. In this context, we set up an immunological study by flow cytometry in order to analyze specific NK cell subsets from peripheral blood patient samples both at the time of discontinuation as well as during the subsequent months. At the time of discontinuation, patients show a mature NK cell phenotype, probably associated to TKI treatment. However, 3 months after discontinuation, significant changes in several NK cell receptors occurred. Patients with a higher proportion of CD56dim NK and PD-1+ NK cells showed better chances of survival. More interestingly, non-relapsing patients also presented a subpopulation of NK cells with features associated with the expansion after cytomegalovirus infection (expression of CD57+NKG2C+), and higher proportion of NKp30 and NKp46 natural cytotoxicity receptors, which resulted in greater degranulation and associated with better survival (p<0.0001). This NK cell subset could have a protective role in patients who do not relapse, thus further characterization could be useful for patients in sustained deep molecular response.

Treatment-free remission after dasatinib in patients with chronic myeloid leukaemia in chronic phase with deep molecular response: Final 5-year analysis of DASFREE.

Patients with chronic myeloid leukaemia in chronic phase (CML-CP) who have a sustained deep molecular response (DMR) are eligible to discontinue treatment and attempt treatment-free remission (TFR). In the DASFREE study (ClinicalTrials.gov; NCT01850004), the 2-year TFR rate after dasatinib discontinuation was 46%; here we present the 5-year update. Patients with a stable DMR after ≥2 years of dasatinib therapy discontinued treatment and were followed for 5 years. At a minimum follow-up of 60 months, in 84 patients discontinuing dasatinib, the 5-year TFR rate was 44% (n = 37). No relapses occurred after month 39 and all evaluable patients who relapsed and restarted dasatinib (n = 46) regained a major molecular response in a median of 1.9 months. The most common adverse event during the off-treatment period was arthralgia (18%, 15/84); a total of 15 withdrawal events were reported in nine patients (11%). At the 5-year final follow-up, almost half of the patients who discontinued dasatinib after a sustained DMR maintained TFR. All evaluable patients who experienced a relapse quickly regained a DMR after restarting dasatinib, demonstrating that dasatinib discontinuation is a viable and potentially long-term option in patients with CML-CP. The safety profile is consistent with the previous report.

Long-term outcomes of frontline imatinib therapy for chronic myeloid leukemia in China.

Imatinib is the first-line therapy recommended for chronic myeloid leukemia (CML) patients in China. We reported a long-term follow-up study of patients on imatinib as first-line treatment for chronic phase (CP) CML to provide an important reference for the actual clinical treatment regimen of CML patients in China. We evaluated the long-term efficacy, safety, low-dose attempt after years of treatment, and treatment-free remission (TFR) of 237 CML-CP patients receiving first-line imatinib therapy. The median age was 46 years (interquartile range: 33-55). After a median follow-up of 6.5 years, the cumulative complete cytogenetic response, major molecular response (MMR), and MR4.5 rates were 82.6%, 80.4%, and 69.3%, respectively. The 10-year transformation-free, event-free, and failure-free survival rates were 97.3%, 87.2% and 53.5%, respectively. Fifty-two (21.9%) patients with sustained deep molecular response (DMR) were treated with low-dose imatinib after years of imatinib treatment. No significant differences in the 1-year and 2-year molecular relapse-free survival in MMR and MR4 were observed between the standard-dose and low-dose groups. Twenty-eight (11.8%) patients discontinued imatinib, and the median time to maintain DMR before discontinuation was 8.43 years. Thirteen patients (5.5%) remained in TFR for a median of 43.33 months. No patients transformed to accelerate or blast phase or died. No new, late toxicity was observed, and the most frequent grade 3/4 adverse events were neutropenia (9.3%), anemia (7.6%), thrombocytopenia (6.3%), and rash (4.2%). This study confirmed the long-term efficacy and safety of imatinib for treating Chinese CML patients. Additionally, it demonstrated the feasibility of imatinib dose reduction and TFR attempts in patients with sustained stable DMR after years of imatinib treatment in real-life settings.

Efficacy and safety of nilotinib in chronic myeloid leukaemia patients who failed to achieve a treatment-free remission period after imatinib discontinuation: Results of the French Nilo post-STIM study.

Molecular recurrence (MRec) occurs in about half of all patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitors (TKI) in sustained deep molecular response. A second TKI discontinuation has been attempted in some patients who regain the discontinuation criteria after resuming treatment. Nilotinib treatment affords faster and deeper molecular responses than imatinib as first-line therapy. We prospectively evaluated the efficacy and safety of nilotinib (300 mg twice daily) in chronic-phase CML patients who experienced MRec, after imatinib discontinuation and analysed the probability of TFR after a new attempt in patients treated for 2 years with sustained MR4.5 for at least 1 year. A total of 31 patients were included in the study between 2013 and 2018. Seven (23%) patients experienced serious adverse events after a median of 2 months of nilotinib treatment leading to discontinuation of treatment. One patient was excluded from the study for convenience. Among the 23 patients treated for 2 years with nilotinib, 22 maintained their molecular response for at least 1 year (median: 22 months) and stopped nilotinib. The TFR rates at 24 and 48 months after nilotinib discontinuation were 59.1% (95% confidence interval [CI]: 41.7%-83.7%) and 42.1% (95% CI: 25%-71%) respectively (NCT #01774630).

Importance of TKI treatment duration in treatment-free remission of chronic myeloid leukemia: results of the D-FREE study

Treatment-free remission (TFR) is a new goal for patients with chronic myeloid leukemia in chronic phase (CML-CP) with a sustained deep molecular response (DMR) to treatment with tyrosine kinase inhibitors (TKIs). However, optimal conditions for successful TFR in patients treated with second-generation (2G)-TKIs are not fully defined. In this D-FREE study, treatment discontinuation was attempted in newly diagnosed CML-CP patients treated with the 2G-TKI dasatinib who achieved BCR-ABL1 levels of ≤ 0.0032% (MR4.5) on the international scale (BCR-ABL1IS) and maintained these levels for exactly 1 year. Of the 173 patients who received dasatinib induction therapy for up to 2 years, 123 completed and 60 (48.8%) reached MR 4.5. Among the first 21 patients who maintained MR4.5 for 1 year and discontinued dasatinib, 17 experienced molecular relapse defined as loss of major molecular response (BCR-ABL1IS > 0.1%) confirmed once, or loss of MR4 (BCR-ABL1IS > 0.01%) confirmed on 2 consecutive assessments. The estimated molecular relapse-free survival rate was 16.7% at 12 months. This study was prematurely terminated according to the protocol’s safety monitoring criteria. The conclusion was that sustained DMR for just 1 year is insufficient for TFR in CML-CP patients receiving dasatinib for less than a total of 3 years of treatment.

Non-albuminuric chronic kidney disease in diabetes: A different approach?

Background & objectives: Both innovator and generic imatinib are approved for the treatment of Chronic Myeloid Leukaemia-Chronic phase (CML-CP). Currently, there are no studies on the feasibility of treatment-free remission (TFR) with generic imatinib. This study attempted to determine the feasibility and efficacy of TFR in patients on generic Imatinib. Methods: In this single-centre prospective Generic Imatinib-Free Trial-in-CML-CP study, twenty six patients on generic imatinib for ≥3 yr and in sustained deep molecular response (BCR ABLIS ≤0.01% for more than two years) were included. After treatment discontinuation, patients were monitored with complete blood count and BCR ABLIS by real-time quantitative PCR monthly for one year and three monthly thereafter. Generic imatinib was restarted at single documented loss of major molecular response (BCR ABLIS>0.1%). Results: At a median follow up of 33 months (interquartile range 18.7-35), 42.3 per cent patients (n=11) continued to be in TFR. Estimated TFR at one year was 44 per cent. All patients restarted on generic imatinib regained major molecular response. On multivariate analysis, attainment of molecularly undetectable leukaemia (>MR5) prior to TFR was predictive of TFR [P=0.022, HR 0.284 (0.096-0.837)]. Interpretation & conclusions: The study adds to the growing literature that generic imatinib is effective and can be safely discontinued in CML-CP patients who are in deep molecular remission.

Feasibility of treatment-free remission with generic imatinib: Results of generic imatinib-free trial-in-chronic myeloid leukaemia-chronic phase study.

Both innovator and generic imatinib are approved for the treatment of Chronic Myeloid Leukaemia-Chronic phase (CML-CP). Currently, there are no studies on the feasibility of treatment-free remission (TFR) with generic imatinib. This study attempted to determine the feasibility and efficacy of TFR in patients on generic Imatinib. In this single-centre prospective Generic Imatinib-Free Trial-in-CML-CP study, twenty six patients on generic imatinib for ≥3 yr and in sustained deep molecular response (BCR ABLIS ≤0.01% for more than two years) were included. After treatment discontinuation, patients were monitored with complete blood count and BCR ABLIS by real-time quantitative PCR monthly for one year and three monthly thereafter. Generic imatinib was restarted at single documented loss of major molecular response (BCR ABLIS>0.1%). At a median follow up of 33 months (interquartile range 18.7-35), 42.3 per cent patients (n=11) continued to be in TFR. Estimated TFR at one year was 44 per cent. All patients restarted on generic imatinib regained major molecular response. On multivariate analysis, attainment of molecularly undetectable leukaemia (>MR5) prior to TFR was predictive of TFR [P=0.022, HR 0.284 (0.096-0.837)]. The study adds to the growing literature that generic imatinib is effective and can be safely discontinued in CML-CP patients who are in deep molecular remission.

Effect of BCR::ABL1 transcript type and droplet digital polymerase chain reaction on successful treatment-free remission in chronic myeloid leukemia patients who discontinued tyrosine kinase inhibitor.

Droplet digital polymerase chain reaction (ddPCR) is an exact method of measurement. We conducted this study to identify the prognostic factors for successful treatment-free remission in patients with chronic-phase chronic myeloid leukemia who discontinued tyrosine kinase inhibitors (TKIs). We also aimed to validate ddPCR for predicting molecular relapse. This is a prospective, multicenter study. We enrolled patients treated with TKIs for at least 3 years with a confirmed sustained deep molecular response (DMR) for at least 1 year. TKI was re-administered in patients who experienced the loss of major molecular response (MMR). A total of 66 patients from five institutions in South Korea were enrolled. During a median follow-up period of 16.5 months, 29/66 (43.9%) patients experienced molecular relapse; the probability of molecular relapse-free survival (RFS) at 6 or 12 months after TKI discontinuation was 65.6% or 57.8%, respectively, with most molecular relapses occurring within the first 7 months. All patients who lost MMR were re-treated with TKI, and all re-achieved MMR at a median of 2.8 months. E14a2 transcript type (p = 0.005) and longer DMR duration (⩾48 months) prior to TKI discontinuation (p = 0.002) were associated with prolonged molecular RFS and with sustained DMR. Patients with both e13a2 transcript type and detectable BCR::ABL1 (⩾MR5.0) by ddPCR at the time of TKI discontinuation showed shorter duration of molecular RFS (p = 0.015). Our data suggest that transcript type and BCR::ABL1 transcript levels on ddPCR should be taken into consideration when deciding whether to discontinue TKI therapy.

Asciminib in the Treatment of Philadelphia Chromosome-Positive Chronic Myeloid Leukemia: Focus on Patient Selection and Outcomes.

Tyrosine kinase inhibitors (TKIs) have significantly changed the treatment of chronic myeloid leukemia (CML) and improved outcomes for patients with CML in chronic phase (CML-CP) and accelerated phase (AP). Now armed with numerous effective therapeutic options, clinicians must consider various patient- and disease-specific factors when selecting the most appropriate TKI across lines of therapy. While most patients with CML expected to have a near-normal life expectancy due to the success of TKIs, emphasis has expanded beyond response and survival to include factors like quality of life, tolerability, and long-term toxicity management. Importantly, a subset of patients can achieve sustained deep molecular response and can attain treatment-free remission. Despite these successes, unmet needs remain related to CML treatment, including the persistent challenge of treatment resistance and intolerance, broadening treatment options for patients with resistance mutations or serious comorbidities, and focus on specific populations such as children and young adults. In particular, the only previously available treatments for patients with CML-CP with the T315I mutation were ponatinib, olverembatinib (exclusively approved for use in China at the time of this writing), omacetaxine, and hematopoietic stem cell transplantation. Asciminib has entered the CML treatment landscape as a new option for adult patients with CML-CP who have received ≥2 prior TKIs or those with the T315I mutation. Asciminib's unique mechanism of action, Specifically Targeting the ABL Myristoyl Pocket, sets it apart from traditional adenosine triphosphate-competitive TKIs. While asciminib may overcome unmet needs for patients with CML-CP and continues to be studied in other novel settings, guidance on how to integrate asciminib in treatment algorithms is needed. This review focuses on clinical data and how asciminib can overcome current unmet needs, discusses how to individualize patient selection, and highlights future directions to investigate asciminib in earlier lines of therapy and in children and adolescents.

Economic Impact Analysis of Treatment-Free Remission in Chronic Myeloid Leukemia Patients with Sustained Deep Molecular Response in the AST-2018 Trial

Introduction: The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myeloid leukemia (CML), bringing the life expectancy of patients close to that of the general population. However, TKI treatment is associated with adverse events, some of them serious or affecting quality of life. In addition, drug costs have a high economic impact, especially in low-income countries. Treatment-free remission (TFR) is an emerging goal for CML patients and it has been associated with cost savings in different country analyses. Main Objective: Assess the economic impact of TKI discontinuation in patients included in the AST2018 Trial. Secondary objective: Estimate the long-term saving in patients included in the AST2018 Trial, considering Argentinian life expectancy. Methods: AST2018 is a multicentric, prospective trial that recruited aged >18 years CML chronic phase patients, with confirmed typical BCR-ABL1 transcripts b3a2 and/or b2a2, under TKI treatment for at least ≥ 4 years and sustained MR4.0 for ≥ 2 years. Molecular tests were centralized in 2 harmonized laboratories and performed monthly for the first 6 months, every 2 months until the 1st year, and every 3 months until month 24. TKI was restarted at confirmed loss of major molecular response (MMR). The economic impact was evaluated by an Excel-based budget impact model, in order to estimate the costs of the patients in first-line pharmacological treatment for CML. We considered the costs of TKI-treatment, PCRs performing and medical visits as money flow. We calculated the present value of savings, in US dollars, in patients who discontinued treatment during the trial. Results: Between February 2018 and March 2022, we evaluated 50 CML patients in the AST2018 trial, 46 were enrolled from 7 centers in Argentina, and were included in this economic analysis. The median patients’ age was 57.5 years (24-85). TKI treatment before discontinuation was Imatinib 34/46 (74%), Nilotinib 4/46 (9%) and Dasatinib 8/46 (17%). After 24 months since first patient was enrolled, 30/46 (65%) patients continued free from TKI, Imatinib 21/34, Nilotinib 2/4 and Dasatinib 7/8, with a median follow-up of 31.3 months (range 25.9 - 38.1). Treatment was restarted after losing MMR in 16/46 (35%) patients. We considered the costs of TKI treatment, PCR performing and physician visits, and we calculated the estimated cost saving per patient at 24 months on TFR: Imatinib US$ 78,433; Dasatinib US$ 102,817 and Nilotinib US $106,161. For the 30 patients who persisted in TFR for 24 months, total cost saving was US$ 2,579,137. For 17 patients who lost MMR, US$ 335,043 dollars were saved previously to TKI reinitiation. Adding up both amounts, the total economic saving in AST2018 was US$ 2,914,181. We performed an analysis of the potential cost savings of remaining in TFR beyond 24 months and according to life expectancy in Argentina (76 years), median age of patients in this trial and cost per patient/year on TKI treatment, the estimated cost saving per patient was US$ 714,512. Conclusions: This is the first economic analysis of the AST2018 trial on TKI discontinuation in CML patients with sustained deep molecular response in Argentina. Our analysis shows that, in spite of the PCR spending, there is a considerable saving in patients on TFR. A careful approach for patients participating in TFR trials or programs will decrease the risk of relapse and make TFR a reality in our region. Potential advantages of TFR will not only impact in patients’ quality of life but also show considerable reduction in the use of economic resources. In developing countries, where lack of molecular monitoring is still an issue outside academic centers, these savings could be redirected to this unmet need making TFR feasible and a goal for the patient and the healthcare system. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase II, Single-Arm Study of De-Escalation and Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Treated with Nilotinib in First-Line Therapy Followed By a Second Attempt after Nilotinib and Asciminib Combination: Dante Study

Introduction: Treatment-free remission (TFR) is considered one of the main goals of therapy in patients with chronic myeloid leukemia (CML). Several studies have shown that treatment discontinuation can be successfully achieved in roughly 50% of patients with a sustained deep molecular response (sDMR). However, the remaining 50% require reintroduction of tyrosine kinase inhibitor (TKI) therapy. Although about 90% of patients who experience molecular relapse regain a major molecular response (MMR) after restarting TKI therapy, due to poorly understood mechanism(s), the probability for those patients of failing a second attempt to discontinue TKI (TFR2) is higher compared to the first attempt. The above-mentioned data implies that, to aim to a second TFR, a different therapeutic strategy might be needed. Asciminib (ASC), unlike all approved TKIs that bind to the ATP site of the BCR-ABL1 oncoprotein, is an allosteric, first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with a new mechanism of action that has shown efficacy in heavily pre-treated patients after two or more TKIs (Rea et al. 2021). An ongoing phase I dose-finding study (NCT02081378) has shown that ASC combined with TKI is both effective and well tolerated in heavily pretreated CML patients, suggesting that combination treatment between an allosteric and an ATP-competitive TKI may deepen clinical responses without serious safety concerns (Mauro et al. 2019). The changes introduced in the DANTE study (NCT03874858) by the amendment 4 aim to assess whether ASC in combination with nilotinib (NIL) can lead to higher and more durable TFR2 rates than those reported in other studies. Methods: After providing written informed consent, the TFR2 phase will enroll - from 29 Italian centers, approximately 60-70 adult CML patients in chronic phase, who have been (i) treated for at least 3 calendar years with NIL, (ii) failed a first TFR attempt, (iii) restarted NIL for at least 1 year and (iv) fulfill all inclusion/exclusion criteria. The study consists of 4 phases: screening, re-induction (week 0-96), TFR2 (week 96-144) and follow up phase. In the re-induction phase, patients will be treated with ASC 40 mg BID and NIL 300 mg BID for 96 weeks and will have scheduled biweekly/monthly visits until week 12, and then every 12 weeks. NIL dose may be less than 300 mg BID if appropriate by clinical judgement but must be at least 300 mg daily. During re-induction, sDMR is defined as no loss of MR4.0 (BCR-ABL level ≤ 0.01% IS) in any BCR-ABL RQ-PCR assessment. Patients with sDMR at the end of re-induction will enter in TFR2 and ASC plus NIL will be discontinued. If two or more consecutive quarterly BCR-ABL RQ-PCR assessments are not performed during re-induction or results are not available, the patient will not be eligible for TFR2 and will be treated with NIL 300 mg BID until the end of the TFR2 stage (week 144). Patients not eligible for TFR2 but with a response more than an MMR will continue treatment with ASC and NIL until the end of re-induction (week 96) and then continue NIL monotherapy at 300 mg BID until the end of the TFR2 stage (week 144). Patients with loss of MMR at any time during re-induction or during NIL monotherapy will be discontinued from the study. If MMR loss occurs during TFR2, NIL 300 mg BID will be restarted and administered until end of study (Fig1). Endpoints: The primary endpoint is the percentage of patients in TFR 48 weeks after stopping NIL and ASC combination. Key secondary endpoints are: (i) percentage of patients eligible for TFR2, (ii) the number of patients with loss of MMR in TFR2 and regain MMR/DMR by the end of the TFR2 stage (iii) BCR-ABL kinetics in the different study phases (iv), OS, TFS and PFS and (v) the safety of the combination. The TFR2 stage is descriptive and no formal statistical testing is necessary or applicable. Conclusions: The expected results from this phase II interventional study, will potentially represent a milestone in treatment strategy for those patients who aim to discontinue NIL for the second time by providing them with several benefits including an improved quality of life.

Treatment-Free Remission Outcome in Patients with Chronic Myeloid Leukemia in Chronic Phase Following One Year of Nilotinib De-Escalation: 96-Week Update of Dante Study

Introduction: Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is demonstrated to be achievable and recommended for patients (pts) in sustained deep molecular response (sDMR) who can discontinue tyrosine kinase inhibitor (TKI) treatment while maintaining responses. Studies investigating TKI de-escalation before TFR, mainly in CML chronic phase (CP) imatinib-treated pts, suggested that this stepwise approach is feasible. Despite nilotinib (NIL) is the first and only TKI approved for stopping therapy, nilotinib-based TFR optimization strategy has not been formally studied. Our phase II, prospective, multicenter DANTE study (NCT03874858) aims to shed light on frontline NIL de-escalation and successful TFR in Italian CML-CP patients. Our previously interim analysis showed that 1 year of NIL de-escalation before TFR in patients with sDMR is safe and effective. Here we present 1 year follow up results of those 40 patients who successfully completed NIL de-escalation and entered in TFR. Methods: Adults patients with CML-CP treated with NIL 300 mg twice daily (bid) in first-line for ≥3 years who achieved sDMR for ≥1 year (≥MR 4.0; BCR-ABL level ≤0.01% IS) were enrolled in 27 centers. The study consisted of 4 phases: screening (week [wk] −4-0), consolidation (wk 0-48), TFR (wk 48-144), and follow-up (until wk 144). Ongoing treatment with ≥400 mg/day dose was allowed at study entry. During consolidation pts were treated with NIL 300 mg once daily (qd). At the end of consolidation phase, pts with sDMR entered TFR phase and NIL was discontinued. Patients with at least major molecular response (MMR; BCR-ABL ≤0.1% IS), but without sDMR, continued NIL 300 mg qd. At any time, pts with loss of MMR returned to NIL 300 mg bid. During TFR phase, BCR-ABL levels were monitored monthly from wk 52-96, and then every 3 months. Here we report updated results collected until the cut-off date of 8th February 2022, at which time all patients who entered the TFR phase had completed at least one year of TFR, or switched to full-dose phase, or entered in survival follow-up or discontinued the study. Results: Overall, 113 pts were screened and 107 entered in consolidation phase. The baseline characteristics and the clinical outcome of the 52 patients that reached the end of consolidation phase by the first data cut-off period (February 8, 2021) have been previously reported (Breccia et al., 2021). Specifically, 47 out of 52 pts completed the consolidation phase and 40 (76.9%) of them, with sDMR, entered in the TFR phase. At 1-year data cut off, with a median duration of 12.7 months (range 1.9 - 20.6), 27 out of 40 pts (67.5 %) who entered in the TFR phase remained in MMR or better while 13 pts (32.5%) had discontinued the TFR phase (11 pts due to loss of MMR and 2 pts for subject/guardian decision). The median time spent in TFR phase until loss of MMR was 3.6 months (range 2-7 months). The median time to loss of MMR in TFR phase was not reached (Fig 1). At the data cut off, all patients except one (10/11, 90%) who lost MMR, regained MMR after NIL resumption. Overall, among the 13 patients who restarted NIL after MMR loss (2 pts from consolidation phase and 11 from TFR phase), 12 of them (92.3%) regained MMR and MR4 after a median time of 2.6 months (range 0.9 - 5.2) and 4.2 months (range 2.7- 8.0), respectively. Notably, 22/52 (42%) pts remained in DMR from consolidation phase until week 96. During the TFR phase, all grade AEs were reported in 26/40 (65%) pts. One pt (2.5%) had serious AE (pneumonia). No deaths and disease progressions were observed. Conclusions: Our finding show that approximately 68% of pts remained disease-free at 1 year after stopping NIL, indicating that de-escalation of NIL before TFR attempt in CML-CP pts with sDMR can be a successful dose optimization strategy. Reference: Breccia et al., Blood (2021) 138 (Supplement 1): 1474. https://doi.org/10.1182/blood-2021-145411 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk of Progression in Chronic Phase-Chronic Myeloid Leukemia (CML) Patients Eligible for Tyrosine Kinase Inhibitor Discontinuation: The Tfr-PRO Study

Background The possibility of treatment discontinuation (TD) in patients with Chronic Myeloid Leukemia (CML) achieving a sustained deep molecular response (DMR) became a reality in clinical practice and is recognized as one goal in the management of the disease. TD is considered successful if at least a major molecular response (MMR or MR3) is maintained. TD is generally considered safe, since MMR is achieved in almost all cases when TKI re-initiation is required. Progression to accelerated phase/blast crisis (AP/BC) after TD was considered virtually impossible for a long time. However, recent reports documented at least 8 cases of disease progression (DP) after TD, some of which were fatal. These observations raise concerns about the global safety of TD, since this practice can no longer be considered completely immune from the risk of disease progression, which drastically changes the patient situation and perspective. To obtain a numerical assessment of the risk of DP in patients (Pts) with durable DMR, independently of their decision to start TD, the TFR-PRO study was designed. Study Design and Methods This is a multicentre retro-prospective observational study which monitors CP-CML patients with stable and DMR followed at 20 centres in 5 different countries (Italy, Canada, Germany, Spain, France). Pts eligibility includes a history of at least 4 years of TKI treatment and at least 18 months of stable DMR, defined as a BCR-ABL1/ABL1 transcript level ratio lower than 1/10,000. The primary objective is to assess the risk of progression to AP/BC, expressed as time adjusted rates (TAR), and its relation to TD in the population of CML Pts who underwent a first or subsequent TD. Eligible Pts who did not discontinue TKI treatment are considered as a benchmark group. A flexible statistical approach allows to attribute Pts to the two groups according to their decision about TKI discontinuation (TD yes or no). Secondary endpoints are TAR of molecular relapse (MR, i.e. loss of MMR), Relapse Free Survival (RFS, defined as the time between eligibility or TD and MR), progression free survival and overall survival. Results The study opened on July 24th, 2020. As of July 24th 2022, 810 Pts were registered, of whom 778 patients are presently eligible, for a total of 3949 person years available for analysis. Median follow up is 6.0 years (range 0.2-15 years), median age at diagnosis was 50 years and 45% Pts are female. Sokal score (available in 406 patients) was low in 47.54%, intermediate in 33.25% and high in 19.21%. A total of 434 Pts (56%) attempted TD at some point; 35 Pts (4.40%) attempted TD twice. MR occurred in 154/434 (35.5%) Pts after TD for a TAR of 12.9/100 person years, (95% confidence interval (CI) [11-15.1]), but also in Pts who did not attempt TD (61/344, or 17.7%), with a TAR of 2.22/100 person years (95%CI [1.7-2.8], p<0.0001. A graphical representation of the estimated proportion of Pts with MR is provided in figure 1. One patient progressed to lymphoid BC 18 months from TD; he received allogeneic BMT and is presently in remission. Thus the risk of progression is 1/778 or 0.13% (95% CI [0.003-0.7]) in the entire cohort; this value goes from 1/434 or 0.23%, (95% CI 0.006%-1.3]) for Pts who attempted TD, to 0% (95% CI [0%-0.872%]) for Pts who did not attempt TD. The TAR of progression is 0.026/100 person years (95%CI [0.004-0.184]) in the entire cohort; this value ranges from 0.084/100 person years (95%CI [0.012-0.593]) for Pts who attempted TD to 0/100 person years (95%CI [0-0.11]) for Pts who did not attempt TD. Conclusions These results obtained in a real world scenario indicate that slightly more than half of 778 eligible Pts attempt TD. Pts who discontinue treatment have a significantly higher risk of losing MR3 than Pts who do not, although MR happen over time also in patients who do not discontinue, and the overall rate of MR after TD is lower than in previous studies. The risk of progression to AP/BC is estimated as 0.13% or 0.026/100 person years; this value is apparently higher for Pts who attempted TD but the 95% CI of the two groups overlap, indicating a lack of significant difference. We conclude that CML progression in Pts eligible for TD is a rare event (approximately 1 in 1000 patients or 0.026% per year in a single patient) and that its relationship with TD is possible but not proven. Additional data including 155 patients already registered but not yet analysed will be presented. Future studies will be needed to confirm our results. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal