Tyrosine Kinase Inhibitors Intolerance Research Articles

High Efficacy and Safety of Asciminib in a Chronic Myeloid Leukemia Patient with Chronic Kidney Disease Following Renal Transplantation.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by the BCR::ABL1 tyrosine kinase. Tyrosine kinase inhibitors (TKIs) have been established as standard therapies for CML. However, some CML patients experience TKI intolerance. Asciminib was approved for CML patients either intolerant or refractory to TKI therapy. We herein report a 63-year-old CML patient who underwent renal transplantation and exhibited TKI intolerance. He was switched to asciminib, which achieved a deep molecular response without exacerbation of the renal function. Our experience revealed that asciminib is effective and safe for CML patients complicated with chronic kidney disease.

Microwave ablation and synchronous transarterial chemoembolization combined with PD-1 inhibitor in patients with hepatocellular carcinoma following tyrosine kinase inhibitor intolerance.

To determine the safety and efficacy of microwave ablation (MWA) and synchronous transarterial chemoembolization (TACE) combined with or without PD-1 inhibitor in patients with hepatocellular carcinoma (HCC) following tyrosine kinase inhibitor (TKI) intolerance. This study retrospectively enrolled TKI-intolerant HCC patients who underwent MWA-TACE combined with PD-1 inhibitor (MTP) or MWA-TACE (MT) from January 2019 to June 2021. MWA and TACE were performed simultaneously, and PD-1 inhibitor was administered intravenously at a dose of 200 mg once every three weeks after MWA-TACE. Adverse events (AEs) related to treatment were recorded during the follow-up. Progression-free survival (PFS) and overall survival (OS) were compared between the two groups. A total of 87 patients were included and classified into the MTP group (n =42) and MT group (n=45). Complications related to MWA-TACE in the MTP group were similar to that in the MT group (21.4% vs. 24.4%, P = 0.738). Moreover, 35 (83.3%) patients had eighty-four AEs related to PD-1 inhibitor in the MTP group, and 8 (19.0%) patients developed grade 3. Patients who underwent MWA-TACE combined with PD-1 inhibitor had better PFS (median, 10.0 vs. 4.7 months, P < 0.001) and OS (median, 17.0 vs. 8.5 months, P < 0.001) than those who underwent MWA-TACE alone. Treatment method and Child-Pugh class were independent prognostic factors for survival in the univariate and multivariate analysis. MWA and synchronous TACE combined with PD-1 inhibitor might be a favorable treatment option in TKI-intolerant HCC patients.

Efficacy and Safety Results from Ascembl, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, Vs Bosutinib in Patients with Chronic Myeloid Leukemia in Chronic Phase after ≥2 Prior Tyrosine Kinase Inhibitors: Update after 48 Weeks

Efficacy and Safety Results from Ascembl, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, Vs Bosutinib in Patients with Chronic Myeloid Leukemia in Chronic Phase after ≥2 Prior Tyrosine Kinase Inhibitors: Update after 48 Weeks

Intracellular delivery of anti-BCR/ABL antibody by PLGA nanoparticles suppresses the oncogenesis of chronic myeloid leukemia cells

BackgroundThe pathogenesis of chronic myeloid leukemia (CML) is the formation of the BCR/ABL protein, which is encoded by the bcr/abl fusion gene, possessing abnormal tyrosine kinase activity. Despite the wide application of tyrosine kinase inhibitors (TKIs) in CML treatment, TKIs drug resistance or intolerance limits their further usage in a subset of patients. Furthermore, TKIs inhibit the tyrosine kinase activity of the BCR/ABL oncoprotein while failing to eliminate the pathologenic oncoprotein. To develop alternative strategies for CML treatment using therapeutic antibodies, and to address the issue that antibodies cannot pass through cell membranes, we have established a novel intracellular delivery of anti-BCR/ABL antibodies, which serves as a prerequisite for CML therapy.MethodsAnti-BCR/ABL antibodies were encapsulated in poly(d, l-lactide-co-glycolide) nanoparticles (PLGA NPs) by a double emulsion method, and transferrin was labeled on the surface of the nanoparticles (Ab@Tf-Cou6-PLGA NPs). The characteristics of nanoparticles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Cellular uptake of nanoparticles was measured by flow cytometry (FCM). The effect of nanoparticles on the apoptosis and proliferation of CML cells was testified by FCM and CCK-8 assay. In addition, the anti-cancer impact of nanoparticles was evaluated in mouse models of CML.ResultsThe results demonstrated that the Ab@Tf-Cou6-PLGA NPs functioned as an intracellular deliverer of antibodies, and exhibited an excellent effect on degrading BCR/ABL oncoprotein in CML cells via the Trim-Away pathway. Treatment with Ab@Tf-Cou6-PLGA NPs inhibited the proliferation and induced the apoptosis of CML cells in vitro as well as impaired the oncogenesis ability of CML cells in vivo.ConclusionsIn conclusion, our study indicated that this approach achieved safe and efficient intracellular delivery of antibodies and degraded BCR/ABL oncoprotein via the Trim-Away pathway, which provides a promising therapeutic strategy for CML patients, particularly those with TKI resistance.

First-line treatment outcomes of CML patients in a real-world data setting in Lebanon.

e19031 Background: BCR–ABL-targeting tyrosine kinase inhibitors (TKIs) constitute the cornerstone of treatment of CML leading to a life expectancy that is currently very close to that of age matched individuals in the general population. The aim of the current study was to describe aspects of CML in a real world data setting in Lebanon including responses to first lines with a specific focus on the impact of first-line treatment with imatinib compared to that of the second-generation TKI, dasatinib and nilotinib. We also evaluated what proportion of patients become eligible to attempt to stop their TKI treatment. Methods: Chronic myeloid leukemia registry was analyzed to evaluate response rates in the first line and eligibility for a treatment cessation attempt in adults diagnosed between 2003 and 2019. The registry covered 60 patients. 46 eligible patients were included in the study. BCR-ABL1 levels of ≤ 0.1%, ≤0.01% and ≤0.0032% on the international scale were defined as the molecular response end-points major molecular response(MMR), MR4.0 and MR,4.5 respectively. In the case of a switch in TKI therapy, the clinical chart was reviewed for the reason why the treating physician had changed the therapy (‘treatment failure’ or ‘TKI intolerance’). For the determination of eligibility to stop TKI, the inclusion criteria for the EURO-SKI trial were applied. Results: Seventy-two percent of the patients were treated with imatinib, 28% with a second-generation tyrosine kinase inhibitor (nilotinib and dasatinib). 15% of patients had discontinued their first-line treatment, mainly due to intolerance (10%) or treatment failure (5%). At 24 months, deep molecular response (MR 4.0 and MR4.5) were achieved at 16.7% and 38.9% respectively for imatinib, and at 22.2% and 33.3% respectively for second generation (p=1). The 5-year cumulative incidence of eligibility for a tyrosine kinase cessation attempt, according to EURO-SKI criteria, was 37%. Conclusions: In the current study we report the experience in CML from two health care institutions in Beirut, Lebanon. Our findings showed no statistically significant difference in response between the first and second generations. The criteria for an attempt to stop tyrosine kinase inhibitor therapy are met by a third of the patients.

Excellent Outcomes Achieved with Medical Management of Chronic Phase CML Patients with Non-Hematologic TKI Intolerance

Introduction:Tyrosine kinase inhibitor (TKI) intolerance is commonly encountered in patients with chronic myeloid leukemia in chronic phase (CML-CP). Clinical trials define non-hematologic TKI intolerance as grade 3-4 toxicities, but lower grade toxicities may also impair patients' quality of life and lead to changes in medical management. We sought to compare TKI-intolerant and -tolerant CML-CP patients and their clinical outcomes, including molecular responses, rates of progression, survival, and utilization of allogeneic stem cell transplant (alloSCT). Methods:We performed a single-center, retrospective cohort study of active CML-CP patients in our Hematology clinic between January 2017 and December 2019. We defined TKI intolerance as any grade non-hematologic toxicity that led to a change in TKI management, such as dose reduction or change of TKI. We also reviewed CML-CP patients who underwent alloSCT in the TKI era (2002-2019). AlloSCT patients were identified for chart review by ICD-10 codes and query of the institution's transplant database. Descriptive statistics, Chi-Square tests, and two-tailed t-tests were used to summarize the data. Results:We identified 216 CML-CP patients (Table 1), and 161 (74.5%) met criteria for non-hematologic TKI intolerance. The median age was 59 years-old in TKI-intolerant patients and 49 in tolerant patients (P=0.011). Most patients experienced TKI-intolerance from symptoms (93.2%, n=150); symptoms included fatigue (n=77, 59.2%), arthralgias (n=36, 27.7%), nausea (n=29, 22.3%), headache (n=16, 12.3%), and edema (n=15, 11.5%). The remaining patients were TKI-intolerant based on abnormal laboratory findings such as transaminitis or hyperglycemia (6.8%, n=11/161). Of the 161 TKI-intolerant patients at last follow-up, 130 (80.7%) remained on TKI, 19 (11.8%) were on prescribed discontinuation, 6 (3.72%) were non-adherent, 5 (3.1%) were off TKI for non-CML medical problems, and 1 (0.6%) was on omacetaxine. Dose reductions occurred in the majority who remained on TKIs (n=103/130, 79.2%) and prior to TKI discontinuation (n=13/19, 68.4%). Most TKI-intolerant patients (n=122/161, 75.8%) switched TKIs, with a median of 2 agents used (range 1-5). Of 55 TKI-tolerant patients, 46 (83.6%) were on TKI, 8 (14.5%) were on discontinuation, and 1 (1.8%) was non-adherent. Only 19.6% (n=9/46) patients were dose-reduced, and they rarely changed TKIs (median of 1 agent used). MR4.5 was achieved in 49% (n=79/161) of TKI-intolerant and 41.8% (n=23/55) of TKI-tolerant patients. Only 1 patient in each group progressed to accelerated phase. TKI-intolerant and -tolerant patients had similar times since diagnosis (with a median follow up of 81.7 months and 79.7 months, respectively). Five of 161 (3.1%) TKI-intolerant patients died, all from causes unrelated to CML and TKI therapy. None of the TKI-tolerant patients died during the abstraction period. Twenty CML-CP patients underwent alloSCT from year 2002-2019; 10 (50%) were transplanted for TKI intolerance without other transplant indications (Tables 2 and 3). Three of those 10 patients also had hematologic intolerance. Four (40%) TKI-intolerant patients resumed TKI post-transplant: 3 for disease relapse, 1 for sclerotic GVHD. Seven (70%) developed GVHD, with most cases being chronic (n=6), extensive (n=6), and severe/moderate (n=6). While 80% of patients achieved MR4.5 post-transplant (n=8/10), 30% (n=3/10) experienced transplant-related mortality (TRM) with a mean post-transplant survival of 38.5 months; the remaining 7 patients were alive at a median follow-up of 37.1 months. Conclusion: CML-CP patients with non-hematologic TKI-intolerance achieved similar clinical outcomes as TKI-tolerant patients despite dose reductions and/or switching TKIs. The use of alloSCT was rare in our practice, and CML-CP patients transplanted for TKI intolerance commonly resumed TKI post-alloSCT and frequently developed extensive GVHD. In light of the high survival rate achieved with medical management in CML-CP patients with non-hematologic TKI-intolerance, including no disease- or treatment-related deaths, this analysis does not support the use of alloSCT for patients with non-hematologic TKI-intolerance. Disclosures Schoenbeck: American Society of Hematology:Research Funding.Olin:Astellas:Other: Site PI;Genentech:Consultancy;Daiichi Sankyo:Other: Site PI;Amgen:Consultancy;Genentech:Other: Site PI;Pfizer:Other: Site PI.Logan:Amphivena:Research Funding;Autolus:Research Funding;Jazz:Research Funding;Kadmon:Research Funding;Kite:Research Funding;Pharmacyclics:Research Funding;Abbvie:Consultancy;Amgen:Consultancy;Novartis:Consultancy.Smith:Revolution Medicines:Other: Research Support, Research Funding;Abbvie:Other: Research Support, Research Funding;FujiFilm:Other: Research support, Research Funding;Daiichi Sanyko:Consultancy, Honoraria;Astellas Pharma:Honoraria, Other: Research Support, Research Funding;Sanofi:Honoraria.Shah:Bristol-Myers Squibb:Research Funding.

CML-329: Allogeneic Stem Cell Transplantation Results in Chronic Myeloid Leukemia: A Single Center Experience

Context Two decades ago, the introduction of tyrosine kinase inhibitors (TKIs) has improved the outcome and overall survival of chronic myeloid leukemia (CML) patients and changed the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in this setting. Still, allo-HSCT remains the treatment of choice for patients diagnosed and/ or progressed to advanced phase (accelerated and blastic phase) and who have failed and/or are intolerant to multiple TKIs. Objective The aim of this study was to investigate the clinical outcome in 19 patients who were referred for this procedure to The Hematology and Bone Marrow Transplantation Center, Fundeni Clinical Institute. Design Retrospective single-center case series. Setting The Hematology and Bone Marrow Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania. Patients We analyzed the records of 19 CML patients who underwent allo-HSCT between 2012–2020 in the Hematology and Bone Marrow Transplantation Center of Fundeni Clinical Institute. Results Median time from CML diagnosis to allo-SCT was 34 months. Out of 19 CML patients, 6 patients were in the first chronic phase (CP), and 13 patients were in the second or later CP. TKI resistance was the most common transplant indication. Mutation status was positive in two patients. TKI intolerance was present in six patients. Out of 19 CML patients, 14 patients survived the transplantation procedure and achieved major molecular response (MMR). Conclusions Allo-HSCT still represents an important therapeutic option in CML, especially for patients diagnosed or/and progressed to advanced phase or are resistant or/and intolerant to TKI treatment.

Integrative Genomic Analysis Reveals Cancer-Associated Gene Mutations in Chronic Myeloid Leukemia Patients with Resistance or Intolerance to Tyrosine Kinase Inhibitor.

IntroductionWhile the acquisition of mutations in the ABL1 kinase domain (KD) has been identified as a common mechanism behind tyrosine kinase inhibitor (TKI) resistance, recent genetic studies have revealed that patients with TKI resistance or intolerance frequently harbor one or more genetic alterations implicated in myeloid malignancies. This suggests that additional mutations other than ABL1 KD mutations might contribute to disease progression.MethodsWe performed targeted-capture sequencing of 127 known and putative cancer-related genes of 63 patients with CML using next-generation sequencing (NGS), including 42 patients with TKI resistance and 21 with TKI intolerance.ResultsThe differences in the number of mutations between groups had no statistical significance. This could be explained in part by not all of the patients having achieved major molecular remission in the early period as expected. Overall, 66 mutations were identified in 96.8% of the patients, most frequently in the KTM2C (31.82%), ABL1 (31.82%), FAT1 (25.76%), and ASXL1 (22.73%) genes. CUX1, KIT, and GATA2 were associated with TKI intolerance, and two of them (CUX1, GATA2) are transcription factors in which mutations were identified in 82.61% of patients with TKI intolerance. ASXL1 mutations were found more frequently in patients with ABL1 KD mutations (38.1% vs 15.21%, P=0.041). Although the number of mutations was low, pairwise interaction between mutated genes showed that ABL1 KD mutations cooccurred with SH2B3 mutations (P<0.05). In Kaplan–Meier analyses, only TET2 mutations were associated with shorter progression-free survival (P=0.026).ConclusionOur data suggested that the CUX1, KIT, and GATA2 genes may play important roles in TKI intolerance. ASXL1 and TET2 mutations may be associated with poor patient prognosis. NGS helps improving the clinical risk stratification, which enables the identification of patients with TKI resistance or intolerance in the era of TKI therapy.

PVR and ICAM-1 on Blast Crisis CML Stem and Progenitor Cells with TKI Resistance Confer Susceptibility to NK Cells.

The BCR-ABL1 fusion gene generating an oncogenic tyrosine kinase is a hallmark of chronic myeloid leukemia (CML), which can be successfully targeted by BCR-ABL1 tyrosine kinase inhibitors (TKIs). However, treatment-free remission has been achieved in a minority of patients due to evolving TKI resistance and intolerance. Primary or acquired resistance to the approved TKIs and progression to blast crisis (BC), thus, remain a major clinical challenge that requires alternative therapeutic strategies. Here, we first demonstrate that donor natural killer (NK) cells prepared using a protocol adopted in clinical trials can efficiently eliminate CML-BC blasts, with TKI resistance regardless of BCR-ABL1 mutations, and preferentially target CD34+CD38− leukemic stem cells (LSC), a potential source of disease relapse. Mechanistically, the predominant expression of PVR, a ligand for the NK cell-activating DNAM-1 receptor, in concert with ICAM-1, a ligand for NK cell adhesion, confer this susceptibility to NK cells, despite the lack of ligands for NKG2D, a principal NK cell activating receptor, as an immune evasion mechanism. With these mechanistic insights, our findings provide a proof-of-concept that donor NK cell-based therapy is a viable strategy for overcoming TKI resistance in CML, particularly the advanced, multi-TKI-resistant CML with dismal outcome.

Chronic Myeloid Leukemia: Role of Allogeneic Hematopoietic Stem Cell Transplantation in the Era of Tyrosine Kinase Inhibitors

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a radical method of chronic myeloid leukemia (CML) treatment. In the 1990s CML became the most frequent indication for allo-HSCT worldwide. CML treatment drastically changed after tyrosine kinase inhibitors (TKI) had been introduced into clinical practice. However, despite considerable progress achieved in treatment, low survival rate is observed in patients with CML either diagnosed at an advanced stage or characterized with resistance, TKI intolerance, and loss of response. For such patients allo-HSCT remains the only and the best treatment solution. The present article discusses current views on the importance of allo-HSCT for CML treatment in the era of extensive use of TKIs.

Cross-Intolerance with Bosutinib after Prior Tyrosine Kinase Inhibitors in Patients with Chronic Phase Chronic Myeloid Leukemia: BYOND Phase 4 Study

Cross-Intolerance with Bosutinib after Prior Tyrosine Kinase Inhibitors in Patients with Chronic Phase Chronic Myeloid Leukemia: BYOND Phase 4 Study

Late mortality after bone marrow transplant for chronic myelogenous leukemia in the context of prior tyrosine kinase inhibitor exposure: A Blood or Marrow Transplant Survivor Study (BMTSS) report.

Late mortality was investigated in patients with chronic myelogenous leukemia (CML) who underwent blood or bone marrow transplant (BMT) with or without prior tyrosine kinase inhibitor (TKI) therapy. By using data from the Blood or Marrow Transplant Survivor Study, the authors examined late mortality in 447 patients with CML who underwent BMT between 1974 and 2010, conditional on surviving ≥2years post-BMT. For vital status information, the medical records, the National Death Index, and the Accurint database were used. Standardized mortality ratios (SMRs) were calculated using general population age-specific, sex-specific, and calendar-specific mortality rates. Kaplan-Meier techniques and Cox regression were used for all-cause mortality analyses. Cumulative incidence and proportional subdistribution hazards models for competing risks were used for cause-specific mortality analyses. The 10-year overall survival rate was 65.7% and 73% for those who underwent transplant with and without pre-BMT exposure to TKI therapy, respectively. Patients who underwent transplant with and without pre-BMT TKI experienced SMRs of 6.4 and 6.4, respectively (P=.8); and the SMRs were 11.6 and 8.1, respectively, for those with high-risk disease (P=.2). Independent predictors of non-CML-related mortality included chronic graft-versus-host disease (hazard ratio [HR], 2.8; 95% CI, 1.8-4.4) and busulfan/cyclophosphamide conditioning (HR, 0.5; 95% CI, 0.3-0.9; reference, total body irradiation/cyclophosphamide conditioning). The 20-year cumulative incidence of CML-related and non-CML-related mortality was 6% and 36%, respectively, for the entire cohort. Both CML-related mortality (HR, 1.0; 95% CI, 0.1-12.6) and non-CML-related mortality (HR, 1.3; 95% CI, 0.6-3.1) were comparable for those with and without pre-BMT TKI therapy. The similar late mortality experienced by patients with CML who undergo transplantation with or without pre-BMT TKIs suggests that allogeneic BMT can be considered in the context of TKI intolerance or nonadherence. The prevention of post-BMT non-CML-related mortality could favorably affect long-term survival.

Russian Experience of Bosutinib Use in Chronic Myeloid Leukemia Patients in Routine Clinical Practice

Background. The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKI) have diminished death probability and have changed the disease course. Achievement of complete cytogenetic response (CCyR) and major molecular response (MMR) are serve as warranties for freedom of progression and death from CML. There are many of CML patients are needed to change of initial TKI therapy with choice of the most efficient and safe drug for continuous life-long therapy to reach the optimal results of CML treatment. The newest of registered TKI drug in Russia is Bosutinib which has dual BCR-ABL and SRC kinase inhibitory activity and had showed good tolerability and efficacy in case of other TKIs resistance or intolerance.Aim. To analyze of own Bosutinib experience in patients with chronic myeloid leukemia with other TKIs resistance or intolerance and to make comparison with clinical trial results.Materials and methods. Clinical trials results from peer-reviewed journals. Outpatients charts of 51 patients (25 male and 26 females) with CML. Disease phase at the moment of Bosutinib therapy initiation was as follows: chronic - 37; acceleration - 8, blastic - 6. Bosutinib was used in the next lines of TKI therapy: second - 10; third - 18; fourth - 23. The indications for Bosutinib therapy were: intolerance to previous TKI - 21; resistance to previous TKI - 30.Results. Median of therapy duration was 6 months (1-50 months). The adverse events and tolerability of Bosutinib were similar with clinical trials data. The treatment was withdrawn by the adverse event only in 5 (10%) patients. The rates of the responses in the whole group of patients were as follows: CHR - 88%, stable in 76%; CCyR - 39%, stable in 37%, MMR - 31% and was 25% at the last follow-up. The Bosutinib efficacy in real life settings was slightly higher than clinical trials data. The factors influencing treatment responses were: disease phase, cause of switching to Bosutinib, line of therapy and presence and kind of BCR-ABL mutations, Therapy was continued in 22 (43%) patients, most them achieved stable optimal treatment response (CCyR and MMR).Conclusions. Bosutinib is a real alternative to other tyrosine kinase inhibitors and has its own mechanism of action and adverse events profile. The use of Bosutinib in real life clinical practice settings showed its efficacy and tolerability and could serve as base for recommendation to apply Bosutinib in hematology practice in Russia. DisclosuresNo relevant conflicts of interest to declare.

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

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

Dose escalating method in treatment of tyrosine kinase inhibitors intolerance chronic myeloid leukemia: report of one case and review of literature

目的 探讨酪氨酸激酶抑制剂（TKI）治疗慢性粒细胞白血病（CML）不耐受患者的临床特征和治疗方案。 方法 回顾性分析1例剂量爬坡法治疗TKI不耐受CML患者的临床资料，并复习相关文献。 结果 TKI治疗CML不耐受患者，通过剂量爬坡法甲磺酸伊马替尼小剂量开始逐渐加量治疗可耐受。 结论 剂量爬坡法治疗TKI不耐受CML患者有效且无明显血液学不良反应。

Tyrosine Kinase Inhibitor (TKI) Switching Patterns during the First 12 Months in Simplicity, an Observational Study of Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Patients (Pts) in Routine Clinical Practice

Introduction:SIMPLICITY (NCT01244750) is an ongoing observational study of CP-CML pts in routine clinical practice receiving first-line (1L) imatinib (IM) prior to 2010 (retrospective) or 1L IM, dasatinib (DAS) or nilotinib (NIL) since 2010 (prospective) in the US and Europe.Methods: This analysis was designed to identify baseline characteristics associated with TKI switching in pts pooled from the prospective and retrospective cohorts. Pts were characterized as ’early switchers’ (who discontinued 1L TKI and switched to a second-line [2L] TKI within 3 months of TKI initiation) or ’late switchers’ (who discontinued 1L TKI and switched to a 2L TKI between 3 and 12 months after TKI initiation). A comparator group of ’non-switcher’ pts did not discontinue 1L TKI within 12 months of TKI initiation; ’early non-switchers’ did not switch 1L TKI within the first 3 months and ’late non-switchers’ did not switch 1L TKI between 3 and 12 months after TKI initiation. Logistic regression analysis was used to identify factors associated with early vs. late switching (gender, age at diagnosis ≥65 years, 1L TKI, region, reason for discontinuation).Results: By March 07 2016, 1494 pts were enrolled at 197 sites in 7 countries. Within 12 months of initiating 1L TKI 238 pts (16%) had switched to 2L TKI. Of switchers, 31% and 69% were early and late, respectively. Of the overall cohort, 1189 pts were early non-switchers and 1146 were late non-switchers. Most early switchers received IM as 1L TKI (49%), followed by NIL (32%) and DAS (19%); most late switchers received IM (56%), followed by DAS (26%) and NIL (18%). Fewer early non-switchers than switchers received IM as 1L TKI (43%), followed by NIL (28%) and DAS (28%); fewer late non-switchers than switchers received IM (44%), followed by DAS (28%) and NIL (28%). Most switchers were female; a higher proportion of female switchers was early vs. late (63% vs. 52%, respectively). In comparison, 43% of pts in both non-switching groups were female. Median ages of early and late switchers were 54 (interquartile range [IQR]: 46-68) and 58 (IQR: 46-69) years, respectively; median ages of early and late non-switchers were 56 (IQR: 46-68) and 56 (IQR: 45-67) years, respectively.Logistic regression analysis showed that pts who switched due to intolerance had greater odds of switching early compared with those who switched due to resistance (odds ratio = 3.49; 95% confidence interval: 1.11-10.98; p=0.0323). Among the 238 pts who switched 1L TKI, the main reason for 1L TKI discontinuation was intolerance (early switchers: 76%; late switchers: 71%; Figure).The most common intolerances leading to changes in early and late switchers varied by 1L TKI. Most common for IM early switchers (n=26) was general disorders/administration site conditions (including fatigue, edema, pain) and skin/subcutaneous disorders; for IM late switchers (n=53), gastrointestinal (GI) disorders, general disorders/administration site conditions and skin/subcutaneous disorders. Most common for DAS early switchers (n=10) was GI disorders; for DAS late switchers (n=36), respiratory/thoracic/ mediastinal disorders. Most common for NIL early switchers (n=19) was GI disorders; for NIL late switchers (n=25), GI disorders, general disorders/administration site conditions and skin/subcutaneous disorders.TKI resistance less commonly contributed to 1L TKI discontinuation. Primary and acquired resistance were seen in higher proportions of late than early switchers (Figure). In late switchers, primary resistance was a more common reason for discontinuation in IM pts vs. DAS pts or NIL pts (22%, 5% and 4%, respectively). Acquired resistance was only reported as a reason for discontinuation in IM-treated pts (early switchers: 0.3%; late switchers: 11%).Conclusions: Of pts switching or discontinuing 1L TKI in the first 12 months of therapy, around one third switched within the first 3 months; compared with late switchers and non-switchers these pts were more likely to be younger and female. TKI intolerance was the main reason for switching and was significantly associated with early switching. Resistance was a less common reason for changing TKI therapy and was seen more frequently after 3 months and among pts treated with IM. More research is necessary to make definitive conclusions about comparisons between TKI groups, given the small numbers of pts in the TKI cohorts and the non-controlled nature of the trial. [Display omitted] DisclosuresGoldberg:COTA Inc: Employment; Novartis: Consultancy; Neostem: Equity Ownership; Pfizer: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Michallet:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Hehlmann:Bristol-Myers Squibb: Consultancy; Novartis: Research Funding; German CML-Group: Research Funding. Zyczynski:Bristol-Myers Squibb: Employment. Foreman:ICON Clinical Research: Employment. Calimlim:ICON Clinical Research: Employment. Paquette:Incyte: Consultancy, Honoraria; Novartis: Consultancy; Ariad: Consultancy. Gambacorti:Pfizer: Honoraria, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Zagorska:Bristol-Myers Squibb: Employment. Rong:Bristol-Myers Squibb: Employment. Mauro:BMS: Consultancy; Ariad: Consultancy; Pfizer: Consultancy; Novartis: Consultancy.

Tyrosine Kinase Inhibitor Discontinuation in Chronic Myeloid Leukemia: Single US Center Experience

Imatinib (IM) can be safely discontinued in patients with chronic myeloid leukemia (CML) with sustained complete molecular remission. Previous publications from France and Australia have shown that overall 40% maintain MMR or MR5 for up to 5 years after IM is stopped. We report single US center experience with tyrosine kinase inhibitor (TKI) discontinuation. Between 06/2010 and 7/2015, 22 patients with CML in chronic (CP, n=19), accelerated (AP, n=2) and lymphoid blast phase (LBP, n=1) discontinued IM (n=17), dasatinib (DAS, n=3) or bosutinib (BOS, n=2), and were monitored by qPCR for BCR-ABL1 monthly for the first 3 months, quarterly for the following 2 years and then bi-annually. TKI was restarted in case of confirmed loss of MMR on a repeat qPCR. Reason for TKI discontinuation was predominantly driven by patients' request and TKI intolerance. Median age was 66 (range, 21-84). The 3 who discontinued DAS had IM-resistant (loss of CCyR; n=1), IM-intolerant CP (n=1), or received DAS as first-line agent (n=1). BOS was discontinued for IM-intolerant CP (n=1), or while in CR2 in a patient with LBP that transformed from IM resistant CP and relapsed following chemotherapy (HCVAD). Median duration of TKI therapy pre-discontinuation for the entire cohort was 89 months (range, 26-106). Three patients are not evaluable due to short follow-up (TKI stopped between 5/2015 and 7/2015). With a median follow-up of 40 months (range, 8-60), 7 (41%, 6 CP and 1 AP), all previously on IM lost MMR a median of 3 months (range, 3-24) after TKI was stopped and restarted IM. Loss of CHR occurred 13 months after loss of MMR in 1 patient who elected not to restart IM at the time MMR was lost, due to complications from cardiac transplant rejection. All 7 achieved MMR following restart of IM. Median duration of TKI therapy pre-discontinuation for these 7 patients was 60 months (range, 48-98). 12 patients (59%, 10 CP, 1 AP, 1 LBP) remain off TKI and have not lost MMR, 8 with continuously undetectable BCR-ABL1; and 4 had 1-2 transient detectable BCR-ABL1 at MR4 levels. Median duration of TKI therapy pre-discontinuation for these 12 patients was 87 months (range, 26-106). Loss of MMR-free survival is depicted in the Figure. We conclude that, similar to previous reports, TKI can be safely discontinued in patients with CML without reappearance of BCR-ABL1 in 50-60%. Figure 1. Figure 1. Disclosures Jillella: Seattle Genetics, Inc.: Research Funding. Kota:Leukemia Lymphoma Society: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees.

A Single Institution Retrospective Review of Characteristics and Outcomes of Patients Requiring Chronic Dose Reduction of TKIs Given As Front-Line Therapy for Chronic Phase CML

Background: The development of tyrosine kinase inhibitors (TKIs) has dramatically changed the landscape of chronic myelogenous leukemia (CML) treatment. Dosing of TKIs is standardized and is based on the phase of disease at presentation, but is not altered based on body surface area (BSA), sex, or other patient characteristics. These medications are generally well tolerated, however, hematologic and non-hematologic toxicities are not infrequent. While the package insert of all three TKIs (imatinib, dasatinib, nilotinib) commonly used in first line therapy provides specific dose-reduction instructions for hematologic toxicity, only nilotinib has a standard recommended dose for nonhematologic toxicity. Long-term data on the effects of dose-reduction of TKI therapy based on toxicity is lacking. Furthermore, there is little data on risk factors for TKI intolerance. Thus, we sought to identify characteristics of patients requiring dose reductions as a part of first-line TKI treatment for chronic phase CML as well to determine the long-term outcome of these patients in a retrospective fashion.Methods: Using billing records, we identified all patients seen at our institution for treatment of chronic phase CML between November 1, 2010 and July 16, 2015. We then reviewed the records of all such patients to identify individuals requiring chronic dose reductions of first-line treatments for chronic phase CML. We identified a control group of patients by capturing all patients tolerating full dose first-line TKI therapy during a pre-specified period. This control group was used to determine risk factors for TKI intolerance.Results: A total of 18 patients were identified who required long-term dose reduction of first-line TKI therapy with a median follow up time of 34.72 months (range 12.47-124.07). The mean time on full dose therapy prior to dose reduction was 7.08 months (range 0-37.27). The median time spent on reduced dose therapy was 26.37 months (range 4.90-118.93). Eighty-nine percent of patients remained in a major molecular response 4 (MR4) despite dose reduction. Median progression free survival (PFS), as defined by loss of MMR, of dose-reduced patients had not yet been reached. One, two, and three year PFS rates were 100%, 93.8%, and 85.2% respectively. When compared to the control group of patients tolerating front line therapy at full-dose, patients requiring dose reduction were more likely to be female: 78% vs 48% (P=0.045) and have a lower BSA: 1.77 versus 1.99 mg/m2 (P=0.010).Discussion: This small, retrospective analysis identifies several potential important risk factors for TKI dose reduction including female sex and lower BSA. Based on the available control group, it cannot be determined if either of these are independent variables. The majority of patients remained in MR4 despite dose reductions. Both of the 2 patients (12.5%) who did not were able to regain MR4 status after switching to an alternate TKI, suggesting that long-term treatment with reduced dose TKIs is reasonable so long as patients are closely monitored. Our data suggest the possible utility of dose adjustments based on BSA for patients who are intolerant of TKI therapy.Table 1TKI administered degree of dose reduction.Patient NumberTKIDose1Dasatinib20 mg QOD2Dasatinib10 mg daily3Dasatinib40 mg daily*4Imatinib300 mg daily5Imatinib200 mg alternating with 300 mg daily6Dasatinib40 mg daily7Imatinib300 mg daily*8Dasatinib50 mg daily9Dasatinib40 mg daily10Dasatinib70 mg daily11Nilotinib450 mg daily12Dasatinib40 mg daily13Nilotinib450 mg daily14Dasatinib50 mg daily15Dasatinib40 mg daily16Imatinib300 mg daily17Dasatinib35 mg daily18Dasatinib70 mg daily*Indicates loss of MR4 while on therapyTable 2Risk factors for TKI dose reduction.Full dose groupDose reduction groupP valueNumber2918Gender Male Female15144140.045 (chi-square)BSA1.99±0.281.77±0.250.010 (t test)BMI30.27±6.3427.20±4.280.084 (t test) [Display omitted] DisclosuresKoprivnikar:Alexion: Consultancy. McCloskey:Novartis: Consultancy; Pfizer: Consultancy. Goldberg:Pfizer: Research Funding; COTA: Employment, Equity Ownership, Other: Leadership, Stock; Ariad: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Faderl:Celgene Corp.: Other: Advisory Board.

Allogeneic Hematopoietic Stem Cell Transplantation Is an Effective Salvage Therapy for Patients with Chronic Myeloid Leukemia Presenting with Advanced Disease or Failing Treatment with Tyrosine Kinase Inhibitors

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only known curative therapy for chronic myeloid leukemia (CML); however, it is rarely utilized given the excellent long-term results with tyrosine kinase inhibitor (TKI) treatment. The purpose of this study is to examine HSCT outcomes for patients with CML who failed TKI therapy or presented in advanced phase and to identify predictors of survival, relapse, and nonrelapse mortality (NRM). Fifty-one patients with CML underwent HSCT for advanced disease at diagnosis (n = 15), TKI resistance as defined by the European LeukemiaNet guidelines (n = 30), TKI intolerance (n = 2), or physician preference (n = 4). At a median follow-up of 71.9 months, the 8-year overall survival (OS), event-free survival (EFS), relapse, and NRM were 68%, 46%, 41%, and 23%, respectively. In univariate analysis, predictors of OS included first chronic phase (CP1) disease status at HSCT (P = .0005), European Society for Blood and Marrow Transplantation score 1 to 4 (P = .04), and complete molecular response (CMR) to HSCT (P < .0001). Donor (female) to patient (male) gender combination (P = .02) and CMR to HSCT (P < .0001) predicted lower relapse. In multivariate analysis, CMR to HSCT remained an independent predictor of OS (odds ratio [OR], 43), EFS (OR, 56) and relapse (OR, 29). This report indicates that the outlook is excellent for those patients who remain in CP1 at the time of HSCT and achieve a CMR after HSCT. However, only approximately 50% of those in advanced phase at HSCT are long-term survivors. This highlights the ongoing need to try to identify patients earlier, before disease progression, who are destined to fail this treatment to optimize transplantation outcomes.

Allogeneic Hematopoietic Stem Cell Transplantation Is an Effective Salvage Therapy for Patients with Chronic Myeloid Leukemia Failing Treatment with Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitor (TKI) therapy has revolutionized the treatment of patients (pts) with chronic myeloid leukemia (CML). While allogeneic hematopoietic stem cell transplantation (HSCT) remains the only known curative therapy for CML, it is now rarely utilized given the excellent long-term results with TKI treatment. Therefore, only a few reports are available detailing HSCT outcome for this pt population. The purpose of this study is to examine HSCT outcome for pts with CML who received TKI therapy and identify predictors of survival, relapse and non-relapse mortality (NRM). Between January 2002 and April 2012, 55 pts with CML underwent HSCT at the Leukemia/BMT Program of BC. Transplant indications were advanced disease at diagnosis (15), TKI resistance as defined by the ELN treatment guidelines (30), TKI intolerance (2), physician preferance (4). Four pts had not received TKI therapy during this time period and were excluded from further analysis. Of the 51 pts examined in this study there were 34 males and 17 females. The median age at HSCT was 45 years and the Sokal score at diagnosis was low risk or intermediate risk (22), high risk (28) and unknown (1). The median time from diagnosis to HSCT was 307 days. Therapy prior to HSCT was imatinib (IM) only (22); IM with chemotherapy (19); IM followed by dasatinib and/or nilotinib (10). Disease status at HSCT was first chronic phase (CP1) (19), accelerated phase (9), CP2 (19), CP3 (3), BP (1). Four pts had kinase domain mutations identified at HSCT. EBMT score was 1-4 (33), and 5-7 (18). HSCT was myeloablative in 48 pts [TBI-based (25); BuCY (23)] and reduced intensity in 3 pts. Stem cell source was bone marrow (8) or PBSC (43) from a HLA matched sibling (24), HLA matched unrelated donor (UD) (18) or mismatched UD (9). At a median follow-up of 5.9 years, 18 pts have relapsed [molecular (7), cytogenetic (1), hematologic (10)] and 16 pts have died [relapse (8), GVHD (3), infection (2) regimen related toxicity (2), cerebral hemorrhage (1)]. The overall survival (OS), event-free survival (EFS), relapse and NRM at 8 years was 68%, 46%, 41% and 23% respectively. The corresponding results for the 32 pts transplanted for TKI resistance/intolerance were 75% (OS), 52% (EFS), 39% (relapse) and 15% (NRM). In univariate analysis, disease status at HSCT (p=.0005), lower EBMT score (p=.04), complete molecular response (CMR) to HSCT (p<.0001), and Sokal score (p=.05) predicted for better OS. Donor (female) to pt (male) gender combination (p=.02), presence of cGVHD (p=.04) and CMR to HSCT (p<.0001) predicted for lower relapse. Predictors of NRM included disease status at HSCT (p=.008), lower EBMT score (p=.004) and CMR to HSCT (p<.0001). In multivariate analysis, CMR to HSCT remained an independent predictor of OS [odds ratio (OR) 43], EFS (OR 56), relapse (OR 29) and NRM. Donor (female) to pt (male) also remained an independent predictor of EFS (OR 6) and relapse (OR 3). In conclusion, HSCT remains an effective salvage therapy for pts with CML in the TKI era who present with advanced disease or resistance/intolerance to TKI therapy. Disease status at HSCT and achievement of CMR are strong predictors of OS, EFS, relapse and NRM. DisclosuresNo relevant conflicts of interest to declare.