Long-term Tyrosine Kinase Inhibitors Therapy Research Articles

Outcome of Children with B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) with Hypodiploidy or BCR-ABL1 Fusion Given Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): Results from the Prospective Forum Study

Introduction: Hypodiploid karyotype (HYPO) and bcr-abl1 fusion (BCRABL) define high-risk BCP-ALL subtypes, with historically worse outcomes. Many front-line treatment protocols recommend allogeneic HSCT for these patients (pts), either in first complete remission (CR1) irrespective of response (adolescents/young adults with HYPO), if minimal residual disease (MRD) signals persist at specific time points (younger pts with HYPO and all pts with BCRABL), or following leukemic relapse. We have assessed the outcomes of BCP-ALL pts aged 4 to 18 years (y) with either HYPO or BCRABL who participated in the phase III ALL SCT PED FORUM study (EudraCT: 2012-003032-22) and underwent HSCT from either a matched sibling (MSD) or matched unrelated donor (MUD). Patients and Methods: Between 2014 and January 2023, 741 evaluable BCP-ALL pts were enrolled in FORUM (Table 1). HYPO was present in 61 pts, BCRABL in 82 pts, and neither lesion in 598 pts (NEITHER). 43/61 (70%), 40/82 (49%) and 215/598 (36%) pts with HYPO, BCRABL and NEITHER were in CR1, respectively (p= n.s.). Prior to HSCT, 82 of 101 HYPO/BCRABL pts with available MRD data were MRD negative by PCR and/or flowcytometry (<10-4). Total body irradiation (TBI) + VP16 was administered to 42 and 50 pts in the HYPO and BCRABL groups, respectively, while 18 HYPO and 30 BCRABL pts received non-TBI conditioning (busulfan or treosulfan + fludarabine and thiotepa, as per study protocol). Randomization determined allocation to TBI/non-TBI treatment arms until randomization closure in 03/2019, while treatment in some pts was dictated by lack of access to TBI, or contraindication to TBI in individual pts. An MSD was available in 14 (23%) and 24 (29%) HYPO and BCRABL pts, respectively. Notably, 24 out of 143 pts (17%) with HYPO/BCRABL received immunotherapy before HSCT (blinatumomab, inotuzumab ozogamicin, and/or CAR-T cells). Post-HSCT, 14 out of 82 BCRABL pts (17%) received a tyrosine kinase inhibitor (TKI), either prophylactically or pre-emptively. Results: With a median follow-up of three years post-HSCT, the 5-y probabilities of overall survival (OS) for pts with HYPO, BCRABL and NEITHER were 0.79±0.06, 0.83±0.05, and 0.74±0.02 (p=n.s.), while those of event-free survival (EFS) were 0.73±0.06, 0.65±0.07, and 0.61±0.02, respectively (p=n.s.). The 5-y cumulative incidence of relapse (CIR) for HYPO/BCRABL and NEITHER pts was 0.21±0.04 and 0.29±0.02 (p=0.036), and 5-y non-relapse mortality (NRM) was nearly identical for these groups (0.07±0.2 and 0.08±0.1). Among pts who received TBI, 5-y OS and EFS for HYPO, BCRABL, and NEITHER groups were 0.76±0.08 and 0.70±0.08, 0.89±0.05 and 0.70±0.10, and 0.80±0.03 and 0.71±0.03, respectively (p=n.s., Figure 1), while 5-y CIR and NRM post TBI were 0.15±0.06 and 0.11±0.05, 0.15±0.06 and 0.11±0.05, and 0.20±0.02 and 0.07±0.02, for the three groups, respectively (p=n.s.). The 3-y GvHD-free/relapse-free survival (GRFS) was similar between HYPO/BCRABL and NEITHER (0.60±0.06 and 0.58±0.03, respectively) and reached a plateau at 5-years (0.60±0.06 and 0.57±0.03, respectively). In subgroup analyses of pts in CR1 and >CR1, comparable outcomes were observed for HYPO, BCRABL, and NEITHER, hence results were not affected by the remission status. BCRABL and NEITHER pts receiving non-TBI conditioning had inferior outcomes (5-y EFS of 0.56±0.10 and 0.47±0.04, respectively) with a high 5-y CIR (0.36±0.09 and 0.43±0.04, respectively) as compared to those who received TBI. Similar 5-y OS and EFS were seen in HYPO pts whether receiving TBI (0.76±0.8 and 0.70±0.08) or chemo conditioning (83±0.09 and 83±0.09). Rates of NRM and acute/chronic graft-versus-host disease were similar in pts receiving TBI/ non-TBI conditioning and in BCRABL/HYPO vs. NEITHER pts. In multivariate analysis adjusted for CR status, conditioning and MRD, EFS did not differ between HYPO/BCRABL and NEITHER pts. Conclusions: Children receiving HSCT for treatment of BCP-ALL with either hypodiploidy or bcr-abl1 fusion showed outcomes comparable to BCP-ALL pts without these genetic lesions. CIR and EFS reached plateaus beyond 3 y post-HSCT, indicating that approximately two-thirds of these pts can be cured by HSCT with low rates of treatment-related mortality. Pts with BCRABL achieved favorable outcomes without the need for long-term or lifelong TKI therapy.

Growth Disturbances in Pediatric Patients Receiving Long-Term Tyrosine Kinase Inhibitor Therapy

Background:Since their approval in 2003, Tyrosine Kinase Inhibitors (TKIs) targeting bcr-abl1 kinase activity have changed the treatment paradigm for children with chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). However, off-target inhibition of kinases, such as src and c-kit, can result in impaired osteoblast function, cause an imbalance in calcium and phosphate metabolism, and result in growth impairment in children. The aim of our study was to examine growth over time in pediatric patients receiving TKIs for CML or Ph+ ALL.Description: This is a single institutional retrospective longitudinal cohort study of patients (≤ 21 years of age) diagnosed with CML or Ph+ ALL between January 2000 and December 2015 who received a TKI and had ≥ 1 year of growth data available as of May 31, 2016. Patient demographics, treatment details including the type and duration of TKI therapy and details of concomitant conventional therapy (chemotherapy and radiation) were abstracted. Growth data was abstracted from the start of TKI at yearly intervals up to a maximum of five years or age 20 and from their last available appointment. Specific variables for growth included height, height percentile, height-SDS (height - standard deviation score or z score) and BMI-SDS (body mass index - standard deviation score). Height-SDS and BMI-SDS were determined using the CDC growth chart by age and gender. Age at diagnosis was used as a surrogate for expected pubertal status: pre-pubertal (3 - 8.9 years), pubertal/peri-pubertal (9 - 15.9 years), post-pubertal (16+ years). Overall change in height-SDS / BMI-SDS from baseline to 1-year and last follow-up were compared by diagnosis, gender, and pubertal age using ANOVA. Statistical analysis was performed using SAS® v9.3 (Cary, NC). For all analyses, a p-value of <0.05 was considered to be statistically significant.Results: Our cohort included 48 patients who received a TKI (n=29 CML, n=19 Ph+ ALL) - 46% were male and 38% were non-Hispanic white. The mean age at diagnosis was 12.1 ± 3.7 years for CML and 9.0 ± 4.6 years for Ph+ ALL patients (p=0.01). As expected, mean duration of TKI treatment was longer in CML (4.3 ± 2.8 years) versus Ph+ ALL (2.7 ± 1.7 years). The average duration of follow-up was similar in both groups (CML 4.6 ± 3.54 years vs Ph+ ALL 4.1 ± 2.9 years, p=0.60). At time of diagnosis, the mean Height-SDS for the entire cohort was 0.13 ± 1.28 with no difference between patients by diagnosis (p=0.92). At one year following treatment with TKI a decrease in mean height-SDS was noted, with a more significant difference in Ph+ ALL patients (-0.54 ± 0.21) compared to CML patients (-0.18 ± 0.39) (p=0.002). This difference remained significant at last follow-up (Ph+ ALL -0.96 ± 0.70, CML -0.52 ± 0.74, p=0.05) (Figure 1). There was no significant difference in mean change in height-SDS at 1 year or last follow-up by gender. Overall, the decrease in height-SDS at 1 year was most significant in the pre-pubertal age group (-0.51 ± 0.27) as compared to pubertal/peri-pubertal and post-pubertal groups (-0.26 ± 0.46 and -0.10 ± 0.24 respectively; p=0.04). BMI-SDS at baseline did not differ by diagnosis but did show a significant decrease at one year in Ph+ ALL versus CML patients (-0.18 ± 0.65 and 0.39 ± 0.54 respectively, p=0.003); this stabilized at the time of last follow up (-0.01 ± 0.75 and 0.38 ± 0.80 respectively, p=0.11).Conclusions: Our data underscores the concern of growth disturbances following prolonged TKI exposure in children, the role of exposure relative to pubertal change in bone growth, and the need for understanding off-target mechanisms in childhood survivors. Stabilization of BMI-SDS at the end of follow up with accompanying drop in mean height-SDS points to a mechanism of growth disturbance beyond nutritional deficiencies. This large pediatric cohort treated with TKIs is the first to include Ph+ ALL patients who were younger at onset of TKI treatment, and more likely to be pre/peripubertal at the start TKI exposure. Future directions will focus on a prospective study of musculoskeletal and other organ toxicities in patients treated with TKIs in childhood. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Results from Enestgoal: A Phase 2 Study of Treatment-Free Remission (TFR) in Patients (pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Who Switched from Imatinib to Nilotinib

Results from Enestgoal: A Phase 2 Study of Treatment-Free Remission (TFR) in Patients (pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Who Switched from Imatinib to Nilotinib

Cardiovascular and Metabolic Risk in Patients with Chronic Myeloid Leukemia in Chronic Phase Receiving First-Line BCR-ABL1 Tyrosine Kinase Inhibitors in the United States: Baseline and Six-Month Follow-up Results from a Prospective Real-World Observational Study

Introduction: Tyrosine kinase inhibitors (TKIs) are the standard-of-care for patients with chronic myeloid leukemia in chronic phase (CML-CP) and are associated with improved outcomes. The risk of cardiovascular (CV) events has emerged as an important consideration during TKI therapy, mostly due to associated complications and the need to understand causality and proper mitigation. While nilotinib has been associated with an increased risk of CV events, few prospective studies have assessed the CV and metabolic risk profile of TKIs administered during routine clinical practice in a real-world setting. Importantly, data regarding the role of baseline CV risk factors at initiation of specific TKIs and subsequent CV events are limited. Here we assess CV and metabolic risk in patients with CML-CP undergoing first-line treatment with TKIs in a real-world setting. Methods: CA180-653 (NCT03045120) is an ongoing, non-interventional, prospective clinical trial characterizing the impact of approved TKIs (bosutinib, dasatinib, imatinib, and nilotinib) on CV and metabolic risk factors following initial TKI therapy in newly diagnosed patients with CML-CP in the USA. Baseline clinical and demographic characteristics, including medical history, vital signs, and evidence of additional comorbid conditions were assessed. CV and metabolic risk factors, as well as CV disease surrogates, were also measured, including ankle brachial index (ABI), echocardiogram (ECHO), electrocardiogram (EKG), and Framingham coronary heart disease score. Metabolic risk variables included fasting blood glucose, HbA1c, and fasting lipid panel. Enrolled patients were analyzed at both baseline and at six months after study enrollment. Results: Between March 2017 and December 2019, 109 patients were enrolled at 16 study sites across the USA. The analysis included patients treated with dasatinib (n = 48), imatinib (n = 47), and nilotinib (n = 14); key characteristics and CV findings are summarized in the Table. In all, 48.9% of patients prescribed imatinib were ≥ 65 years of age, compared with 22.9% of dasatinib and 28.6% of nilotinib patients. Patients treated with dasatinib had a marginally lower proportion of reported baseline CV/metabolic conditions (50.0%) compared to imatinib (53.2%) and nilotinib (57.1%). Interestingly, among patients with baseline Ca2+ scoring, 57.1% of nilotinib patients had coronary artery calcification present at baseline compared to 35.7% of imatinib patients and 28.9% of dasatinib patients. Most patients receiving an ECHO (96%) or EKG (99%) were assessed as normal or presenting clinically not significant abnormalities both at baseline and at the 6-month follow-up. Baseline corrected QT (QTC) scores were similar for dasatinib, imatinib, and nilotinib patients. Among patients with a change in QTC at six months, patients on imatinib had a larger change in median score (13.5 msec) than patients on nilotinib (8.0 msec) or dasatinib (2.0 msec). At six months, changes in ABI scores were small and unlikely to be statistically significant: left ABI scores changed by -0.030, -0.020, and 0.015 for patients on dasatinib, nilotinib, and imatinib respectively; right ABI scores changed by -0.030, 0.055, and 0.060 for patients on dasatinib, imatinib, and nilotinib, respectively. Additional longitudinal data will be presented. Conclusions: These preliminary findings confirm that just over half of patients with CML-CP in the USA have CV/metabolic comorbidities present at baseline, as measured by reproducible and sequentially evaluable studies known to be predictive of systemic vascular disease risk. Measurement of baseline clinical data is vital for assessing CV and metabolic risk in the US oncology settings. CA180-653 was powered to capture the impact of first- and second-generation TKIs on CV and metabolic risk factor outcomes within treatment arms, rather than between treatment arms. Further analysis is ongoing to determine the differential effects of TKIs used in CML-CP, the effect of long-term TKI therapy, and the value of specific CV evaluations to assess optimally and manage risk in patients with CML-CP. Study support:BMS. Table Disclosures Mauro: Sun Pharma/SPARC:Research Funding;Pfizer:Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding;Takeda:Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding;Novartis:Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding;Bristol-Myers Squibb:Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding.Oehler:Pfizer:Research Funding;Bristol-Myers Squibb, Takeda:Consultancy.McCloskey:Jazz:Consultancy, Honoraria;AbbVie:Consultancy, Honoraria;Takeda:Consultancy, Honoraria;BMS:Consultancy, Honoraria;Amgen:Consultancy, Honoraria.Heinrich:Novartis:Consultancy, Patents &amp; Royalties: Patent on treatment of GIST licensed to Novartis;Blueprint Medicines:Consultancy;Deciphera:Consultancy, Speakers Bureau.DeGutis:Bristol-Myers Squibb:Current Employment, Current equity holder in publicly-traded company.Tabano:Bristol-Myers Squibb:Current Employment.Khan:Bristol-Myers Squibb:Current Employment, Current equity holder in publicly-traded company.Moslehi:AstraZeneca, Janssen, BMS, Boston Biomedical, Immunocure, Myovant, Boston Biomedical, Deciphera:Consultancy.

Patient adherence to tyrosine kinase inhibitor therapy in chronic myeloid leukemia: influence of coping strategies and psychological factors

BACKGROUND: Medication non-adherence is associated with poor health outcomes and increased healthcare costs. Although the use of tyrosine kinase inhibitor (TKI) for chronic myeloid leukemia (CML) treatment is satisfactory in clinical results, it is subject to non-adherence. In this study, we intend to verify if there are psychological factors, such as anxiety, depression, and coping style that can influence medication adherence. METHODS: The study was conducted on 120 patients with CML receiving long-term TKI therapy. The sample was collected in the years 2016-2017 at Department of Oncology-Hematology in Pescara, Italy. Adherence behaviour was measured with the eight-item Morisky Medication Adherence Scale (MMAS-8) and psychological factors investigated included: anxiety and depression symptoms [Hospital Anxiety and Depression Scale (HADS)] and coping strategies [abbreviated version of the Coping Orientation to Problems Experienced (Brief-COPE)]. T-test and logistic regression analyses were performed to investigate factors associated with medication adherence. RESULTS: The participants, 74 men and 46 women, reported a mean age of 56.65 ± 15.80 years. The results showed that 71.67% of the patients were adherent while 28.33% were non-adherent. Furthermore, adherence was positively associated with active coping (P < 0.050) and instrumental support (P < 0.001). Also, depression symptoms were risk factor for non-adherence (P < 0.050). CONCLUSION: This study suggests that active coping strategies with a good level of instrumental support are factors associated with greater adherence to long-term therapy. The results of this study support paying attention to factors identified as being helpful in monitoring patients with a risk of non-adherence. There is a need to provide increased psychosocial support for patients with chronic disease by planning effective client‐focused interventions.

Oral Effects and Early Implant Survival Results After Imatinib Discontinuation Therapy for Chronic Myelogenous Leukemia: A Case Report.

Little is known regarding the success, failure, or complication rates of advanced implant procedures in patients after discontinuation therapy of long-term medications for the treatment of chronic myelogenous leukemia (CML). This case report presents initial results of a case involving implant placement in the mandible and maxilla as well as reduction of palatal oral pigmentation in a patient discontinuing long-term tyrosine kinase inhibitor (TKI) therapy for CML. A 57-year-old male was referred to the Department of Periodontics, University of Washington, Seattle, Washington, for an assessment of edentulous areas (tooth sites #3 and #14) and failing tooth #19. Previous medical treatment included oral administration (>10 years) of TKI for the treatment of CML. Systemic complications arising from long-term TKI therapy were treated with discontinuation of this medication. Concurrently, after multispecialty dental and medical consultation, extraction of tooth #19 with immediate implant placement and bilateral sinus augmentation with simultaneous implant placement were successfully performed during three separate surgical appointments. Additionally, marked reduction of oral palatal pigmentation was observed during the surgical and restorative phases after TKI discontinuation. Patients with a history of long-term TKIs for CML are at risk for developing complications that result in discontinuation of therapy. Long-term benefits of therapy may allow these patients to enjoy remission with an extended and improved quality of life. Patients undergoing discontinuation therapy may seek dental care. Therefore, dental providers need to understand these systemic interactions and, with multispecialty consultation, may help effectively treat these individuals.

Future Perspectives of Tyrosine Kinase Inhibitors Discontinuation in Chronic Myeloid Leukemia

Stopping tyrosine kinase inhibitors (TKIs) treatment is an emerging goal of chronic myeloid leukemia (CML) management. Several studies have demonstrated the feasibility of stopping treatment. A sustained molecular response on long-term TKIs therapy seems to be necessary prior to attempting treatment-free remission (TFR). However, there were none available characteristics or indicators which can predict the outcome of TKIs discontinuation now. In our opinion, factors which could reflex the progression probability of minimal residual leukemia such as leukemia stem cells and microenvironment might play a pivotal role. Besides, novel methods for further monitoring would also attract much attention of the researchers in this area.

Kinetics of Regulatory T Cells Predict the Recurrence of CML after Stopping Imatinib in Japanese CML Patiens

Introduction: Imatinib have dramatically changed the natural history of chronic myeloid leukemia (CML) leading to significant improvement in clinical outcome and survival rates. Recently, treatment free remission (TFR) is proposed as one of the goals in CML treatment, and some prospective trials suggest that imatinib therapy may be safely stopped in CML patients with deep and sustained molecular responses (Lancet Oncol 2010, Blood 2013, JCO 2014). We have previously show that approximately 70% patients with deep and sustained molecular responses could stop imatinib (ASH 2015). On the other hands, the frequency of regulatory T (Treg) cells in imatinib-treated CML patients with complete molecular response (CMR) exhibited significantly lower compared with that in non-CMR (Haematologica, 2013), indicating the important roles of Tregs in CML treatment. Here, we analyzed T-cell profile in Japanese CML patients to identify biomarkers predicting patients that can successfully stop tyrosine kinase inhibitors (TKI) treatment.Methods: Japanese CML patients treated with imatinib for at least three years and confirmed in deeper molecular response (DMR) for at least two years (>4 log reduction of CML cells by four consecutive PCR tests with imatinib therapy for >24 months) were eligible. Patients who received other TKI or stem cell transplantations were excluded. MR4.5 was tested at the beginning of this study using Ipsogen BCR-ABL1 M-BCR IS-PCR kit in a central laboratory (Sysmex, Kobe, Japan). The patientfs peripheral blood was collected at pre- and 1, 3 months after stopping imatinb. Peripheral blood mononuclear cells (PBMCs) ware subjected to direct staining with T-cell markers and analyzed by flowcytometer.Results: Samples of 68 CML patients (77 patients ware enrolled and nine ware excluded due to consent withdrawal or ineligible) were analyzed. We classified these CML patients into three groups (TFR, Fluctuated and Retreatment groups) by clinical courses after stopping imatinib; TFR group (n=33) maintained MR4.5 without further treatment for 2years, Fluctuated group (n=12) moved below and above MR4.5, Retreatment group (n=23) lost MR4.5 and was re-started TKI retreatment. Frequency of CD4+ T cells and CD8+ T cells in CD3+ T cells ware approximately 60% and 25% in all patients at pre-stopping. FoxP3+ T cells are reportedly classified as three fractions with FoxP3 and CD45RA ; FoxP3loCD45+ naïve Treg (nTreg), FoxP3hiCD45- effector Treg (eTreg) which have highly suppressive function and FoxP3loCD45- effector non-Treg which do not possess suppressive activity (figure 1). Average of the frequency of nTreg, eTreg, and non-Treg fractions in CD4+ T cells were 0.6%, 2.9%, and 3.6% (pre-stopping), 0.7%, 3.5%, and 3.9% (On month after stopping) 0.6%, 2.5%, and 3.4% (3 month after stopping), respectively. The frequency of the each fractions (nTreg, eTreg, non-Treg) and total Foxp3+CD4+ T cells (nTreg+eTreg+non-Treg) elevated 1 month after stopping imatinib, but the frequency of Tregs were suddenly dropped to the basal level at 3 months after stopping imatinib. When the kinetics of T cells were evaluated based on three clinical courses, it is noteworthy that Treg elevation after stopping imatinib was not detected in Retreatment group, indicating that Treg repression by imatinib was not observed in this group (figure 2).Conclusion: Treg population in PBMCs elevated transiently after stopping TKI in CML patients with DMR after long-term TKI therapy. This may due to the release of imatinib suppression to Tregs. However, this transient increase of Tregs was not observed in patients who relapsed after stopping imatinib and received TKI retreatment. Together with our previous reports, it is proposed that activation of anti-CML immune responses by decreasing Tregs by imatinib is an important factor for long duration of anti-CML effect by imatinib. [Display omitted] [Display omitted] DisclosuresTakahashi:Novartis: Honoraria, Research Funding; BMS: Honoraria; Pfizer: Honoraria, Research Funding.

Cooperation of imipramine blue and tyrosine kinase blockade demonstrates activity against chronic myeloid leukemia.

The use of tyrosine kinase inhibitors (TKI), including nilotinib, has revolutionized the treatment of chronic myeloid leukemia (CML). However current unmet clinical needs include combating activation of additional survival signaling pathways in persistent leukemia stem cells after long-term TKI therapy. A ubiquitous signaling alteration in cancer, including CML, is activation of reactive oxygen species (ROS) signaling, which may potentiate stem cell activity and mediate resistance to both conventional chemotherapy and targeted inhibitors. We have developed a novel nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, imipramine blue (IB) that targets ROS generation. ROS levels are known to be elevated in CML with respect to normal hematopoietic stem/progenitor cells and not corrected by TKI. We demonstrate that IB has additive benefit with nilotinib in inhibiting proliferation, viability, and clonogenic function of TKI-insensitive quiescent CD34+ CML chronic phase (CP) cells while normal CD34+ cells retained their clonogenic capacity in response to this combination therapy in vitro. Mechanistically, the pro-apoptotic activity of IB likely resides in part through its dual ability to block NF-κB and re-activate the tumor suppressor protein phosphatase 2A (PP2A). Combining BCR-ABL1 kinase inhibition with NADPH oxidase blockade may be beneficial in eradication of CML and worthy of further investigation.

Moving treatment-free remission into mainstream clinical practice in CML

AbstractThe 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.

Is a cure for CML without allogeneic stem cell transplantation around the corner?

Is a cure for CML without allogeneic stem cell transplantation around the corner?

Overview and management of cardiac adverse events associated with tyrosine kinase inhibitors.

Small-molecule tyrosine kinase inhibitors (TKIs) may provide an effective therapeutic option in patients with hematologic malignancies and solid tumors. However, cardiovascular (CV) events, including hypertension, heart failure, left ventricular systolic dysfunction, and QT prolongation, have emerged as potential adverse events (AEs) with TKI therapy. We review what is known about the mechanism of action of CV AEs associated with TKI use and discuss therapeutic interventions that may prevent and manage these events in clinical practice. References for this review were identified through searches of PubMed and Medline databases, and only papers published in English were considered. Search terms included "cardiac," "cardiovascular," "cancer," and "kinase inhibitor." Related links in the databases were reviewed, along with relevant published guidelines. Although the link between rising blood pressure (BP) and CV AEs is observed but not proven, good clinical practice supports an aggressive policy on proper long-term BP management. There are insufficient data from randomized controlled clinical trials to show indisputably that aggressive or effective heart failure therapy in patients receiving TKIs will fundamentally change outcomes; however, clinical practice suggests that this is an effective long-term approach. Recognizing that QT prolongation is associated with TKI use facilitates identification of patients at high risk for this CV AE and increases awareness of the need for routine electrocardiograms and electrolyte monitoring for those receiving TKI treatment. Regular monitoring, early recognition, and appropriate interventions for CV AEs can help more patients derive the benefit of long-term TKI therapy.

Can Targeted Therapy for CML Still Learn From Transplant? Using Post-transplant RQ-PCR monitoring to Clarify the Importance of the Depth of Molecular Remission On the Risk of Subsequent Relapse.

AbstractAbstract 2789The use of tyrosine kinase inhibitors (TKI) in the management of chronic myeloid leukemia (CML) has dramatically improved survival, with some 80% of patients achieving a deep and durable molecular remission (MR). The current focus for these patients is the ability to withdraw long-term treatment and a number of ‘stopping' studies have been initiated worldwide. Many of these approaches are derived from the French STIM study which showed that 40% of patients who had been real-time quantitative PCR (RT-qPCR) negative for BCR-ABL1 for two years could cease treatment without experiencing disease relapse. However, the RT-qPCR assay used in this study was particularly stringent with a sensitivity of 10−5, compatible with a five log reduction in BCR-ABL1 transcripts (MR5), and it is not clear that the same level of success will result from studies using MR4 and MR4.5 as the indication for treatment cessation. Furthermore, because of the lack of accuracy in RT-qPCR assays when the number of BCR-ABL1 transcripts approach zero, some laboratories report as undetectable, transcript numbers <6 or even <11. In order to investigate the importance of the depth of molecular response on the risk of subsequent disease recurrence, we studied the long-term follow-up of, and RT-qPCR results from, patients who received allogeneic stem cell transplantation as treatment for CML at a time when minimal residual disease detection was performed by RT-qPCR using ABL1 as the control gene. We analysed data from 180 patients transplanted from January 1998 onwards who received an allo-SCT from an HLA-identical sibling or a matched unrelated donor and who had survived for at least 6 months post-transplant with a consistent sequence of 5 or more RT-qPCR results from the time of transplant to the end of follow-up. Patients were assessed on the depth of their MR; 9 categories of ‘complete' MR were defined based on BCR-ABL1 transcript threshold for negativity (BCR-ABL1=0, BCR-ABL1>0 but <6, BCR-ABL1>5 but <11) and control transcript number (CTN) (CTN>104 but <104.5, CTN>104.5 but <105, but CTN>105). We ranked these categories, firstly by BCR-ABL1 transcript threshold, defining negativity at a lower threshold as a deeper response, and then sub-ranked by CTN, defining a larger CTN as a deeper response. Of the 180 patients, 49 (27%) did not achieve ‘complete' MR by any definition and for the 131 (73%) patients who did reach some degree of ‘complete' MR, the median time from transplant to best molecular response was 8.7 months (range, 1.0–103 months). We defined relapse as progression to an RT-qPCR level that triggered the use of donor lymphocyte infusions i.e. BCR-ABL1/ABL ratio exceeded 0.02% in 3 samples, or exceeded 0.05% in 2 samples, or showed rising levels with the last 2 samples higher than 0.02%, or worse (loss of cytogenetic or haematological remission). The 2 year relapse incidence post SCT was 94% in the group who did not achieve any degree of ‘complete' MR, 94% in the group who achieved MR with BCR-ABL1<11 and >0, CTN>104 (n=32, 17.8%), 55% in the group BCR-ABL1=0, CTN>104 and <104.5 (n=19, 11%), 26% in the group BCR-ABL1=0, CTN>104.5 and <105 (n=47, 26%), and 6% in the group BCR-ABL1=0, CTN>105 (n=33, 18%) (p<0.0001). In multivariate analysis with adjustment for donor type, classifying the 33 patients who achieved BCR-ABL1=0, CTN>105 as the optimal molecular responders the relative risk of relapse was 90.1 in 49 patients who never achieved MR by any definition, (p<0.0001), 21.7 in the group BCR-ABL1<11 and >0, CTN>104 (n=32) (p<0.0001), 8.1 in the group BCR-ABL1=0, CTN>104 and<104.5 (n=19) (p<0.0001), and 2.11 in the group BCR-ABL1=0, CTN>104.5 and <105 (n=47) (p=0.002). In conclusion, fewer detectable BCR-ABL1 transcripts with larger numbers of control transcripts, i.e. a deeper response, predict a lower risk of relapse in post-transplant survivors and may have important implications for the ability to stop long-term TKI therapy. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Current issues in chronic myeloid leukemia: monitoring, resistance, and functional cure.

Despite the success with tyrosine kinase inhibitors (TKIs) in most patients with chronic myelogenous leukemia (CML), some patients still experience resistance or intolerance and need alternative therapies. Monitoring response to TKI therapy is a critical component of managing CML, and molecular response seems to be the most important milestone for predicting long-term outcomes. How best to assess response, including how to define treatment failure, and how monitoring should be conducted remain controversial. Strategies for overcoming imatinib resistance include increasing the imatinib dose or switching to a second-generation TKI. Another approach is to use higher doses of imatinib or second-generation TKIs up front to increase the rate of earlier responses, with the hope that this will translate into a reduced risk of resistance. Several investigational therapies are also being evaluated as a means of overcoming TKI resistance, including ponatinib (AP24534), omacetaxine, and bosutinib (SKI-606). Allogeneic hematopoietic stem cell transplantation has also shown efficacy in patients with imatinib-resistant disease. Alternatives to long-term TKI therapy that are currently being explored include discontinuation of treatment and eradication of minimal residual disease with investigational treatment regimens, such as those involving interferon, hydroxychloroquine, BCL6 inhibitors, and the smoothened antagonists LDF225 and BMS-833923.

Therapy of chronic myeloid leukaemia can benefit from the activation of stem cells: simulation studies of different treatment combinations

Background:Newly diagnosed patients with chronic myeloid leukaemia (CML) are currently treated with tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib or dasatinib. However, incomplete eradication of residual disease is a general problem of long-term TKI therapy. Activation of mouse haematopoietic stem cells by interferon-α (IFNα) stimulated the discussion of whether a combination treatment leads to accelerated eradication of the CML clone.Methods:We base our simulation approach on a mathematical model describing human CML as a competition phenomenon between normal and malignant cells. We amend this model to incorporate the description of IFNα activity and simulate different scenarios for potential treatment combinations.Results:We demonstrate that the overall sensitivity of CML stem cells to IFNα activation is a crucial determinant for the benefit of a potential combination therapy. We furthermore show that pulsed IFNα together with continuous TKI administration is the most promising strategy for a combination treatment in which the therapeutic benefit prevails adverse side effects.Conclusion:Our modelling approach is a highly beneficial tool to quantitatively address the competition between normal and leukaemic haematopoiesis in treated CML patients. We derive testable predictions for different experimental settings that are suggested before the clinical implementation of the combination treatment.

Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells

AbstractTreatment of chronic myeloid leukemia (CML) with the tyrosine kinase inhibitors (TKIs) imatinib mesylate and nilotinib represents a successful application of molecularly targeted anticancer therapy. However, the effect of TKIs on leukemic stem cells remains incompletely understood. On the basis of a statistical modeling approach that used the 10-year imatinib mesylate treatment response of patients with CML and a patient cohort receiving first-line nilotinib therapy, we found that successful long-term therapy results in a triphasic exponential decline of BCR-ABL1 transcripts in many patients. Within our framework, the first slope of −0.052 ± 0.018 (imatinib mesylate) and −0.042 ± 0.015 (nilotinib) per day represents the turnover rate of leukemic differentiated cells, whereas the second slope of −0.0057 ± 0.0038 (imatinib mesylate) and −0.0019 ± 0.0013 (nilotinib) per day represents the turnover rate of leukemic progenitor cells. The third slope allows an inference of the behavior of immature leukemic cells, potentially stem cells. This third slope is negative in most patients, positive in others, and not observable in some patients. This variability in response may be because of insufficient follow-up, missing data, disease heterogeneity, inconsistent compliance to drug, or acquired resistance. Our approach suggests that long-term TKI therapy may reduce the abundance of leukemic stem cells in some patients.

Controversies in the Treatment of CML in Children and Adolescents: TKIs versus BMT?

Chronic myeloid leukemia (CML) is a relatively rare hematopoietic malignancy in the pediatric and adolescent population. This makes it difficult to perform clinic trials that can define the best therapeutic option when considering the impact of tyrosine kinase inhibitors (TKIs) versus the established approach of allogeneic hematopoietic cell transplantation (HCT). With the relatively low toxicity of TKIs, there are little data regarding when HCT or long-term TKI therapy is a better option. There are even less data regarding the duration of TKI treatment in the pediatric CML in chronic phase (CML-CP) patients who may receive over 60 years of therapy. As children and adolescent are treated for longer times with TKIs, it has become clear that toxicities may make long-term TKI therapy less attractive compared to allogeneic HCT. HCT has the long-term complications of growth failure, infertility, chronic graft-versus-host disease (GVHD), metabolic syndrome, and secondary malignancies, whereas prolonged TKIs may cause growth failure, hepatic, and cardiac complications. Moreover, HCT is a potentially curative intervention, whereas TKI is not curative, requiring prolonged exposure. In this article, we discuss the relative merit of the 2 therapeutic approaches and recommend that all children and adolescents with CML-CP should initially be treated with imatinib and maintained with TKI therapy indefinitely if there is a good response. We recommend that allogeneic HCT with an HLA-identical sibling donor or closely matched unrelated donor be considered for patients with treatment failure or recurrence after receiving salvage second-generation TKI treatment. We also conclude that randomized international trials are urgently needed to evaluate the best therapies for pediatric CML.