scholarly journals Moving treatment-free remission into mainstream clinical practice in CML

Blood ◽  
2016 ◽  
Vol 128 (1) ◽  
pp. 17-23 ◽  
Author(s):  
Timothy P. Hughes ◽  
David M. Ross
Keyword(s):  
Clinical Practice ◽  
Kinase Inhibitors ◽  
Financial Burden ◽  
Molecular Response ◽  
Best Interest ◽  
Deep Molecular Response ◽  
Potential Risks ◽  
Treatment Free Remission ◽  
The Many

Abstract The dramatic success of tyrosine kinase inhibitors (TKIs) has led to the widespread perception that chronic myeloid leukemia (CML) has become another chronic disease, where lifelong commitment to pharmacologic control is the paradigm. Recent trials demonstrate that some CML patients who have achieved stable deep molecular response can safely cease their therapy without relapsing (treatment free remission [TFR]). Furthermore, those who are unsuccessful in their cessation attempt can safely re-establish remission after restarting their TKI therapy. Based on the accumulated data on TFR, we propose that it is now time to change our approach for the many CML patients who have achieved a stable deep molecular response on long-term TKI therapy. Perhaps half of these patients could successfully achieve TFR if offered the opportunity. For many of these patients ongoing therapy is impairing quality of life and imposing a heavy financial burden while arguably achieving nothing. This recommendation is based on the evident safety of cessation attempts and TFR in the clinical trial setting. We acknowledge that there are potential risks associated with cessation attempts in wider clinical practice, but this should not deter us. Instead we need to establish criteria for safe and appropriate TKI cessation. Clinical trials will enable us to define the best strategies to achieve TFR, but clinicians need guidance today about how to approach this issue with their patients. We outline circumstances in which it would be in the patient's best interest to continue TKI, as well as criteria for a safe TFR attempt.

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).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7005-7005
Author(s):  
Timothy P. Hughes ◽  
Carla Boquimpani ◽  
Naoto Takahashi ◽  
Noam Benyamini ◽  
Nelma Cristina D. Clementino ◽  
...  
Keyword(s):  
Musculoskeletal Pain ◽  
Chronic Phase ◽  
Molecular Response ◽  
Free Survival ◽  
Study Results ◽  
Deep Molecular Response ◽  
Treatment Free Remission ◽  
Clinical Trial Information

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.

scholarly journals Recommendations from a Portuguese Expert Group for Discontinuation of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia Patients in Clinical Practice

2019 ◽  
Vol 32 (7-8) ◽  
pp. 550
Author(s):  
Antonio Almeida ◽  
Francesca Pierdomenico ◽  
Blanca Polo Guerrero ◽  
Filipa Saraiva ◽  
Ana Montalvão ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
National Guidelines ◽  
Treatment Free Remission

Until recently, the main goal of chronic myeloid leukemia therapy was disease control with the best overall survival, which required lifelong treatment. However, currently, the treatment-free remission concept is becoming an important goal in clinical practice, and several tyrosine kinase inhibitors discontinuation studies have shown that round 50% of patients with a durable deep molecular response beyond major molecular response successfully interrupt tyrosine kinase inhibitors for at least three years without loss of molecular response. However, and regardless of the existing evidence, the exact conditions for attempting treatment-free remission remain poorly defined. Different authors tried to guide the clinical decision regarding this topic but there are some points that differ, namely with respect to the recommended duration of tyrosine kinase inhibitors therapy and the appropriate molecular response prior to treatment-free remission. The goal of this article is to propose an algorithm to guide clinical practice in Portugal concerning chronic phase-chronic myeloid leukemia patients who wish to attempt treatment-free remission, since there are no national guidelines.

scholarly journals Combination Therapies in Chronic Myeloid Leukemia for Potential Treatment-Free Remission: Focus on Leukemia Stem Cells and Immune Modulation

2021 ◽  
Vol 11 ◽  
Author(s):  
Hui Mu ◽  
Xiaojian Zhu ◽  
Hui Jia ◽  
Lu Zhou ◽  
Hong Liu
Keyword(s):  
Stem Cells ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Immune Modulation ◽  
Kinase Inhibitors ◽  
Treatment Strategies ◽  
Current Therapy ◽  
Molecular Response ◽  
Deep Molecular Response ◽  
Treatment Free Remission

Although tyrosine Kinase Inhibitors (TKI) has revolutionized the treatment of chronic myeloid leukemia (CML), patients are not cured with the current therapy modalities. Also, the more recent goal of CML treatment is to induce successful treatment-free remission (TFR) among patients achieving durable deep molecular response (DMR). Together, it is necessary to develop novel, curative treatment strategies. With advancements in understanding the biology of CML, such as dormant Leukemic Stem Cells (LSCs) and impaired immune modulation, a number of agents are now under investigation. This review updates such agents that target LSCs, and together with TKIs, have the potential to eradicate CML. Moreover, we describe the developing immunotherapy for controlling CML.

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

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 106-112
Author(s):  
Andreas Hochhaus ◽  
Thomas Ernst
Keyword(s):  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Immune Surveillance ◽  
Decision Making Process ◽  
Molecular Response ◽  
Depth Of Response ◽  
Speed Of Response ◽  
Deep Molecular Response ◽  
Treatment Free Remission ◽  
Tki Discontinuation

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

Successful use of long-term follow-up in patients with chronic myeloid leukemia with a deep molecular response at reduced doses of 2nd generation tyrosine kinase inhibitors: clinical cases and literature review

2020 ◽  
Vol 92 (7) ◽  
pp. 90-94
Author(s):  
M. A. Gurianova ◽  
E. Yu. Chelysheva ◽  
O. A. Shukhov ◽  
A. G. Turkina
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Term Treatment ◽  
Molecular Response ◽  
Long Term Treatment ◽  
Deep Molecular Response

Therapy with tyrosine kinase inhibitors (TKI) allows to achieve a deep molecular response in 6070% of patients with chronic myeloid leukemia (CML). According to the current guidelines CML patients receive a long-term treatment with TKI in standard dose. The frequently observed adverse effects (AE) of TKI therapy are mostly dose-dependent. A new treatment approach with TKI use in reduced dose is desirable for the CML patients with existing AE or with a high risk of AE occurrence. We report the two cases of successful long-term treatment of CML patients with reduced doses of second generation TKIs. The aim of the TKI dose reduction was to reduce the clinical manifestations of drug toxicities and to prevent the AE.

scholarly journals Ponatinib Facilitates Treatment-Free Remission By Inducing Deep Molecular Responses

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5460-5460 ◽  
Author(s):  
Brendan Wisniowski ◽  
Sally Mapp ◽  
Louise Knop ◽  
James Morton ◽  
Paul Eliadis ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Molecular Response ◽  
Vascular Events ◽  
Deep Molecular Response ◽  
Multiple Trials ◽  
T315i Mutation ◽  
Artery Disease ◽  
Grade 3 ◽  
Treatment Free Remission ◽  
The One

Abstract Multiple trials now demonstrate the potential for treatment-free remission (TFR) in patients with sustained deep molecular response to tyrosine kinase inhibitors (TKIs). We describe two patients who remain in treatment-free remission after achieving undetectable BCR-ABL with ponatinib on the phase II PACE trial, despite being multiply resistant/intolerant to other agents or carrying the T315I mutation. Patient 1 previously had a suboptimal response to imatinib (BCRABL >10% at 15mo) and then was intolerant of nilotinib and dasatinib due to grade 3 liver enzyme abnormalities. He achieved undetectable BCR-ABL (Molecular MD laboratories) by six months on ponatinib. His ponatinib dose was gradually reduced from 45mg/d to 15mg/d due to vascular events (myocardial infarction requiring stenting, carotid stenosis requiring endarterectomy, recurrent ischaemic colitis). At the time of his last episode of colitis, his BCR-ABL had been undetectable for 47 months and hence a decision to attempt TFR was made. He remains in TFR 11 months post-cessation. Patient 2 progressed on imatinib and was found to carry the T315I mutation. He achieved undetectable BCR-ABL by nine months on ponatinib. His ponatinib dose was also gradually reduced from 45mg/d to 15mg/d due to vascular events (popliteal stenosis requiring stenting, embolic stroke, coronary artery disease requiring stenting). At the time of his last event, his BCR-ABL had been undetectable for 30 months and hence a decision to attempt TFR was made. He remains in TFR 17 months post-cessation. This series adds to the one prior case report of ponatinib facilitating treatment-free remission (Engel NW et al. J Oncol Pract 2016. 12(6);592-4) and these remissions are notable because they occur in patients not considered for other TFR studies because of refractoriness to other agents or known T315I mutations. This is an alternative avenue to dose reduction to reduce the risk of vascular events in ponatinib-treated patients. Disclosures Mills: Ariad: Other: This clinical study funded by Ariad.

scholarly journals Cost effectiveness of treatment-free remission in chronic myeloid leukemia patients: A report from a developing country.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 131-131
Author(s):  
Wasim Sattar
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Financial Burden ◽  
Chronic Phase ◽  
Small Subset ◽  
Molecular Response ◽  
The Government ◽  
Treatment Free Remission ◽  
The Cost

131 Background: Current recommendations for first line therapy in chronic phase chronic myeloid leukemia (CP-CML) is life-time use of tyrosine kinase inhibitors (TKI's). Unfortunately, the financial burden of continuous TKI therapy is unsustainable especially in developing countries. In Pakistan, an access-program for Imatinib (IM) and Nilotinib is available; the cost of therapy is subsidized with the Government paying for 3 months and Novartis for 9 months. Updated results from several trials support continued long term durability of treatment free remission (TFR). We attempted TFR in our patients in an attempt to reduce financial burden and improve quality of life for the patients. We aimed to evaluate the economic impact of discontinuing imatinib versus continuous use of imatinib in patients taking IM 400mg. Methods: 57 patients of CP-CML taking Imatinib 400 mg for the last 10 years who were negative by FISH for at least 3 years or in MR 4.5 at least once in 12 months were evaluated. Of these 30 were screening failures, 4 patients refused consent prior to screening and 25 were eligible for the trial. Two consecutive RQ-PCR were performed 3 months apart prior to enrollment. Patients were eligible if they achieved MR 4.5 for at least 3 months prior to entering the study. Molecular response was assessed by Quantitative BCR-ABL RQ-PCR every 4 weeks after discontinuation for year 1 and 8 weeks at year 2. Cost of Imatinib 400 mg per month was calculated as well as the cost of BCR-ABL RQ-PCR by gene expert for the trial. Results: Of the enrolled 25 patients, 10 lost their deep molecular response and were restarted on therapy, 5 withdrew consent after screening.10 patients are currently on trial at varying time intervals (10-14 months) of cessation of imatinib. The cost of one month of imatinib is US $ 800 and the cost of RT PCR is $ 67. TFR translated into approximately US 1.2 million saved. Conclusions: The discontinuation of TKI in this small subset of patients has resulted in remarkably large savings with significant impact on the meager health budget in our resource limited setting.

scholarly journals Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis

Leukemia ◽  
2021 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Timothy P. Hughes ◽  
Richard A. Larson ◽  
Dong-Wook Kim ◽  
Surapol Issaragrisil ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Chronic Phase ◽  
Individual Treatment ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Treatment Free Remission

AbstractIn the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.

Sign in / Sign up

Export Citation Format

Share Document