A modified perfusion protocol for pulmonary endarterectomy in a patient with a hematologic malignancy treated with a tyrosine kinase inhibitor

Tyrosine kinase inhibitors (TKI) are known to be highly effective in the treatment of various cancers with kinase-domain mutations such as chronic myelogenous leukemia. However, they have important side effects such as increased vascular permeability and pulmonary hypertension. In patients undergoing pulmonary endarterectomy with deep hypothermic circulatory arrest, these side effects may exacerbate postoperative complications such as reperfusion edema and persistent pulmonary hypertension. We report on a simple modification of the perfusion strategy to increase intravascular oncotic pressure by retrograde autologous priming and the addition of packed cells and albumin in a patient treated with a TKI.

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Nilotinib therapy in an imatinib intolerant chronic myeloid leukemia patient with pulmonary severe hypertension

Clinical Management Issues ◽

10.7175/cmi.v4i2s.1072 ◽

2015 ◽

Vol 4 (2S) ◽

pp. 17-20

Author(s):

Mario Annunziata

Keyword(s):

Side Effects ◽

Tyrosine Kinase ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Chronic Myeloid Leukemia Patient ◽

Cytogenetic Response ◽

Myelogenous Leukemia ◽

Molecular Response ◽

Cutaneous Rash

Imatinib mesylate is a tyrosine kinase inhibitor that has significant efficacy in the treatment of chronic myelogenous leukemia. In general, hematologic and extrahematologic side effects of imatinib therapy are mild to moderate, with the large majority of patients tolerating prolonged periods of therapy. However, a minority of patients are completely intolerant of therapy, while others are able to remain on therapy despite significant side effects. Here, we describe a chronic phase CML patient with pulmonary arterial hypertension, mechanical hearth valve, who experienced extrahematologic adverse event (persistent grade III cutaneous rash, despite two discontinuations of imatinib and using of steroid). Necessitating switch to one of new tyrosine kinase inhibitors, nilotinib, has resulted in complete cytogenetic response and major molecular response, after 3 and 6 months, respectively. No cross-intolerance with imatinib was observed during nilotinib therapy. Besides, this clinical case suggests that warfarin and nilotinib can be used concurrently without the risk of increased anticoagulant effect.

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Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia

Nature Communications ◽

10.1038/s41467-020-20259-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Hu Lei ◽

Han-Zhang Xu ◽

Hui-Zhuang Shan ◽

Meng Liu ◽

Ying Lu ◽

...

Keyword(s):

Tyrosine Kinase ◽

Progenitor Cells ◽

Chronic Myelogenous Leukemia ◽

Drug Targets ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Myelogenous Leukemia ◽

Tki Resistance

AbstractIdentifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin−Sca1+c-Kit+ CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML.

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Pulmonary hypertension with dasatinib and other tyrosine kinase inhibitors

Pulmonary Circulation ◽

10.1177/2045894019865704 ◽

2019 ◽

Vol 9 (3) ◽

pp. 204589401986570 ◽

Cited By ~ 4

Author(s):

Ashraf El-Dabh ◽

Deepak Acharya

Keyword(s):

Pulmonary Hypertension ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Right Heart Catheterization ◽

Myelogenous Leukemia ◽

Heart Catheterization ◽

Early Therapy ◽

Pulmonary Vasodilators ◽

Small Series

Dasatinib and other tyrosine kinase inhibitors are commonly utilized in the management of chronic myelogenous leukemia. Pulmonary hypertension is an important adverse event associated with dasatinib. Mechanisms for pulmonary hypertension include pulmonary endothelial injury, apoptosis, and increased susceptibility to other triggers for pulmonary hypertension. The diagnosis is suspected based on symptoms, suggested by echocardiographic findings, and confirmed with right heart catheterization. Management includes discontinuation of dasatinib and initiation of pulmonary vasodilators. Persistent pulmonary hypertension is present in up to one third of patients after cessation of dasatinib. Other tyrosine kinase inhibitors, including bosutinib, lapatinib, and ponatinib have also been implicated in pulmonary hypertension in small series, although evidence for causation is less robust. A high index of suspicion, continued vigilance for pulmonary hypertension with long-term use, and early therapy are important in optimizing outcomes in this population.

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CML Patients Show Sperm Alterations At Diagnosis That Are Not Improved On Tyrosine Kinase Inhibitor Treatment

Blood ◽

10.1182/blood.v120.21.1669.1669 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1669-1669

Author(s):

Franck E. Nicolini ◽

Françoise Huguet ◽

Hélène Labussière-Wallet ◽

Yann Guillermin ◽

Madeleine Etienne ◽

...

Keyword(s):

Tyrosine Kinase ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Blast Crisis ◽

Chronic Phase ◽

Myelogenous Leukemia ◽

Control Group ◽

Semen Volume ◽

The Impact ◽

Williams Test

Abstract Abstract 1669 Most epidemiologic studies performed in chronic myelogenous leukemia (CML) relate that the disease occurs preferentially in males with a sex ratio of ∼1.2. In addition, CML can be diagnosed in young adults and masculine fertility is a matter of concern, particularly because tyrosine kinase inhibitors (TKI) may impact on spermatogenesis by a selective inhibition of Src kinases, PDGF-R and c-kit. Sperm cryopreservation is recommended by some authors at diagnosis in males that would expect to have children later on. In a retrospective analysis we have analysed the spermograms of 62 chronic phase (CP) and 2 onset blast crisis (BC) CML males referred to our 3 centres between 2001 and 2012, collected at diagnosis before TKI treatment, and we have compared the results obtained to those of 15 healthy volunteer donors from the cryopreservation bank database, after informed consent. In 10 patients we could collect some data for patients being on imatinib mesylate (IM). CML patients had a median age of 31 (16–48) years, significantly younger than that in the control group of healthy donors: 37 (34–45) years (p=0.001). Sokal scores were 24% high, 27% intermediate and 49% low for evaluable patients (13 patients unknown or not available). The median BCR-ABLIS value at diagnosis was 77.65%. Patients had a median duration of 26 (0–38) days of hydroxyurea prior to commencing any TKI and 65% of evaluable patients had HU before TKI. None of the patients got interferon prior to TKI. The semen cryopreservation was performed within a median of 10 (2–102) days after CML diagnosis and after a median abstinence of 5 (0.5–30) days. The median volume of semen obtained in CML patients was 2.95 (0.5–14.9) ml and 3 (1.4–5.3) ml for normal donors (p=0.3). Williams test showed 72 (0–87)% of necrospermia in patients versus 18 (4–32)% in donors (p=0.00003). The median number of spermatozoa obtained was not different in patients [46 (0.03–200) 106/ml] than that in donors [74 (19.2–253) 106/ml] (p=0.24), as well as the number of spermatozoa per ejaculate observed (p=0.49). The motility of spermatozoa at 30 minutes after collection was not different between patients (median = 47.5%) and donors (median = 50%) (p=0.12), however higher numbers of atypical spermatozoa were observed in patients [median = 77.5 (16–100)%] rather than in donors [median = 45% (22–89)%], p=0.008, and the multiple abnormalities index (MAI) was significantly higher in patients [median = 1.99 (1.14–2.7)] than that in donors [median = 1.33 (1.09–1.55)], p=0.00006. There was no correlation between age at diagnosis, Sokal index and the number of spermatozoa per ml obtained (p=0.7 and 0.21 respectively). Ten CP CML patients had spermograms after a median of 1440 (9–1456) days of IM treatment and the results obtained were compared to i) the results of each individual patient at CP diagnosis and ii) to the results of healthy comparators. In comparison to the characteristics observed at diagnosis, the semen volume (median = 3.1 ml), Williams test (median = 65%), the motility at 30 minutes (median = 37.5%) and the MAI (median = 1.71) were not different (p=ns for all), however, the numbers of spermatozoa (median = 14.9 106/ml and = 37.05 ml per ejaculate) collected on IM were significantly lower (p=0.014 and p=0.045 respectively). The different parameters evaluated on IM were compared to those of normal controls and showed significant alterations. The semen volume was not different (p=0.94), neither the motility of spermatozoa (p=0.24), but the Williams test was highly perturbed on IM [median 65 (24–79)% versus 18 (4–32)% in donors] p=0.00003, as well as the numbers of spermatozoa as 106 per ml, collected on IM [median 14.9 (0.67–179)) versus normal [74 (19.2–253)], p=0.0036 or as 106 per ejaculate collected on IM [median 37.5 (2.68–572.8)) versus normal [149 (30–535.3)], p=0.026. Atypical forms were significantly more abundant on IM [median = 80 (68–90)%] versus healthy controls [median = 45% (22–89)], p=0.0058. Finally, the MAI was severely altered on IM [median = 1.71 (1.61–1.98)] versus normal individuals [median = 1.33 (1.09–1.55)], p=0.00013. In conclusion, this work demonstrates the existence of significant sperm alterations in young males with CML at diagnosis of undetermined origin, prior to any treatment. These alterations persist on IM treatment and little is know about the impact of second generation TKI. Thus the most appropriate approach remains a matter of debate in thus setting. Disclosures: Nicolini: Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Huguet:Novartis, BMS: Speakers Bureau. Michallet:Novartis, Pfizer, Teva, Genzyme, Janssen Cilag, BMS, Merck, Pfizer, Gilead, Alexion: Consultancy, Speakers Bureau. Etienne:Novartis, Pfizer, speaker for Novartis, BMS: Consultancy.

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Generation of Specific Resistance Profiles in FLT3-ITD and FIP1L1-PDGFRalpha towards Specifically Acting Tyrosine Kinase Inhibitors.

Blood ◽

10.1182/blood.v108.11.1376.1376 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1376-1376

Author(s):

Nikolas von Bubnoff ◽

Silvia Thoene ◽

Sivahari P. Gorantla ◽

Jana Saenger ◽

Christian Peschel ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Point Mutations ◽

Kinase Domain ◽

Myelogenous Leukemia ◽

Resistance Mutations ◽

Abl Kinase ◽

Mechanism Of Resistance

Abstract BCR-ABL kinase domain mutations constitute the major mechanism of resistance in patients with chronic myelogenous leukemia treated with the ABL kinase inhibitor imatinib. Mutations causing resistance to therapeutic kinase inhibition were also identified in other target kinases in various malignant diseases, such as FLT3-ITD in acute myelogenous leukemia, cKit in gastrointestinal stromal tumors, EGFR in patients with lung cancer, and FIP1L1-PDGFRalpha in hypereosinophilic syndrome. Thus, mutations in kinase domains seem to be a general mechanism of resistance to therapeutically applicated tyrosine kinase inhibitors. We recently developed a cell-based screening strategy that allows one to predict the pattern and relative abundance of BCR-ABL resistance mutations emerging in the presence of imatinib, and the novel ABL kinase inhibitor AMN107 (nilotinib). We therefore intended to determine, if this method would also allow the generation of resistant cell clones with other oncogeneic tyrosine kinases as targets in the presence of specifically acting kinase inhibitors. When FLT3-ITD and su5614 were used as drug/target combination in our cell-based method, the frequency of resistant clones in the presence of su5614 at 10 times the IC50 was 0.17 per million cells. In 40 per cent of resistant clones, point mutations were detected leading to amino acid exchanges within the FLT3-ITD split kinase domain. The yield of resistant clones was increased by the factor of 14 to 2.37 per million cells by adding ethyl-nitrosourea (ENU), a potent inducer of point mutations. Also, the proportion of mutant clones increased from 40 to 74 per cent. In 83 mutant clones that were examined so far, we detected eight exchanges affecting kinase domain two (TK2) of the split kinase domain within or shortly behind the FLT3-ITD activation loop (A-loop). We did not detect exchanges affecting TK1. We next examined whether resistant clones would also come up with FIP1L1-PDGFRalpha-transformed cells in the presence of imatinib. Again, the yield of resistant clones increased when cells were pretreated with ENU, and a proportion of resistant clones contained mutations in the FIP1L1-PDGFRalpha kinase domain, affecting the nucleotide-binding loop (P-loop) and A-loop. We conclude that cell-based resistance screening is a simple and powerful tool that allows prediction of resistance mutations towards kinase inhibitors in various relevant oncogeneic kinases.

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Treatment Free Remission for Chronic Phase Chronic Myelogenous Leukemia Patients Who Stopped Tyrosine Kinase Inhibitor Therapy Due to Intolerance

Blood ◽

10.1182/blood-2019-129533 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5919-5919

Author(s):

Daulath Singh ◽

Sucha Nand ◽

Hanh Mai

Keyword(s):

Side Effects ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Chronic Myelogenous Leukemia ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Myelogenous Leukemia ◽

Median Treatment ◽

The Past ◽

Treatment Free Remission

Introduction: Chronic Myelogenous Leukemia (CML) is a myeloproliferative neoplasm that is often diagnosed in adults between the ages of 25-60. The outcome of the chronic phase CML has dramatically changed due to Tyrosine Kinase Inhibitor (TKI) therapy. There are well established guidelines from NCCN and ESMO on stopping TKI for patients achieving prolonged remissions with TKIs. We report clinical outcomes from a single tertiary care center in patients who stopped TKI therapy for reasons other than prolonged remission status. Methods: We retrospectively reviewed all the CML patients who were treated at our institution in the past 10 years (January 1st,2009 - December 31st,2018). We excluded patients who had accelerated or blast phase CML, atypical CML, patients on non-TKI therapy, and patients who received an allogeneic stem cell transplant. Results: A total of 117 patients were diagnosed with chronic phase CML at our institution in the past 10 years. Among the 117 patients, 12 of these discontinued TKI therapy. Six patients stopped TKI after achieving prolonged remission with TKI therapy and the remaining patients discontinued due to intolerance to treatment, fear of side effects, and loss of insurance. The median age of the whole cohort is 66 years (range 42-85). Six patients were male and 6 were females. Six patients were diagnosed with CML prior to year 2009 and rest after 2009. Prior to stopping, six patients received only 1 kind of TKI, 2 patients were treated with 2 types of TKIs, 2 patients received 3 types of TKIs, and 2 patients had 4 lines of TKIs (See Table). Cohort 1: 6 patients who stopped due to prolonged remission, median major molecular remission - MMR4 (BCR-ABL <0.01% IS by RT-PCR testing) prior to stopping TKI is 6 years (range 3-13 years). Of the six, only 1 relapsed (within 1 month of stopping) and was initiated back on the same TKI (imatinib). The relapsed patient has not achieved MMR4 level remission to date. Median treatment free remission for this cohort is 13 months (range 1-24 months). Cohort 2: Of those 6 patients who stopped TKI for other reasons: 4 stopped due to side effects/intolerance, 1 stopped due to fear of side effects after FDA label was updated, and 1 patient discontinued due to a loss of insurance. Median duration of MMR4 prior to stopping is 4 years (range 1-11 years). 5 of these 6 patients relapsed in the median time of 6 months (range 3-16 months). Of these 5, 4 were started back on the TKI therapy (three on the same TKI and one on a different TKI). Median treatment free remission for this cohort is 4 months (range 2-16 months). Conclusion: In this small cohort from a single institution's experience, CML patients who discontinued TKI therapy after achieving MMR4 for reasons other than prolonged remission have experienced poor outcomes including a higher rate of relapse and a shorter treatment free remission. We need studies with larger samples sizes and longer follow up to assess outcomes in patients stopping TKI therapy for various reasons. Disclosures No relevant conflicts of interest to declare.

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Adherence to Oral Tyrosine Kinase Inhibitor Therapy: Results of a Self-Reported Patient Survey

Blood ◽

10.1182/blood.v118.21.4432.4432 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4432-4432

Author(s):

Stuart L. Goldberg ◽

Miriam S Aioub ◽

William H Beluch ◽

Lacey Sara Kaplan ◽

Tarundeep Singh ◽

...

Keyword(s):

Side Effects ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Kinase Inhibitor ◽

Myelogenous Leukemia ◽

Second Line ◽

Clinical Progression ◽

First Line ◽

Entire Cohort ◽

History Of

Abstract Abstract 4432 Background: Although there have been tremendous improvements in the management of chronic myelogenous leukemia (CML), the success of treatment is dependent on adherence by the patient to oral tyrosine kinase inhibitor (tki) regimens in unmonitored situations. Little is known about the degree of adherence with tki chemotherapy over prolonged timeframes and the reasons/possible solutions for non-adherence. Method: Patients (pts) with CML evaluated at the John Theurer Cancer Center having at least one clinic visit since 2010 were identified from the institution’s computerized database. Pts were mailed a 22 item survey designed to elicit opinions regarding adherence with tki therapy. To encourage openness, the survey responses were blinded to the treating physician. A follow-up survey was sent two weeks later. Result: 123 pts were eligible for participation, and 88 returned completed surveys (72% response rate). Respondents were 46 male, 42 female, median age 58, and had a median duration of CML of 65 months (range 4–312). 44 were on first line imatinib, 5 on first line nilotinib, 14 on second line dasatinib, 11 on second line nilotinib, 2 on second line imatinib, 5 on third line tki, 4 on experimental therapies, and 6 status-post transplantation. 81 (92%) of respondents were currently in complete cytogenetic remission, with 19 (22%) having experienced prior cytogenetic relapse and 6 (7%) prior clinical progression. 18% of respondents changed therapies for intolerance and 23% for treatment resistance. There were no statistical differences between respondents and non-respondents based on gender (p=0.50), age (p=0.27), current tki agent (p=0.37), participation on a clinical trial (p=0.61), need for prior change in therapy (p=0.91), or history of disease relapse (p=0.98). In the 100 days prior to the survey, 66 (75%) subjects self-reported taking all their prescribed oral tki’s. However, one quarter (22pts) admitted to missing/skipping doses (most reported missing less than 10 days). Young pts (<50yrs) were less likely to be adherent by self-report (52% vs 85%, p=0.004). Being adherent to current tki therapy could not be predicted by gender (p=0.32), duration since diagnosis (p=0.70), or whether a caregiver was available to assist in medication administration (p=0.75). Participation in a clinical study did not increase adherence (p=1.0 for current participation and p=0.9 for any participation). Neither a history of a change in treatment for any reason (p=0.8) nor a history of change in tki treatment for intolerance vs change for resistance (p=1.0) predicted adherence. Pts who had experienced prior cytogenetic/clinical progression were just as likely to report subsequent non-adherence as those without relapse history (p=0.55). Although the current tki agent (ie, which medication the pt was taking) did not influence adherence in the entire cohort (p=0.12), in the subset of pts on second line therapy the use of dasatinib resulted in higher self-reported adherence compared to second line nilotinib (93% vs 45%, p=0.02). 61% stated that they currently had uncomfortable side-effects, but these pts were as likely to be adherent as those without toxicities (p=1.0). 10% (9pts) admitted to skipping doses due to side-effects without their physician’s knowledge. Among pts whose tki therapy was changed, 22% admitted non-adherence in 100 days preceding the change; which represented a similar rate to the entire cohort. The most commonly stated reasons for non-adherence were forgetfulness (26pts), nausea (9pts), inconvenience (7pts), diarrhea (6pts), and muscle cramps (6pts). 4% self-reported skipping doses due to financial concerns. Methods pts felt that might encourage adherence included improvements in side-effect management (14pts), 3 month prescriptions compared to monthly (12pts), “nothing will help” (9pts), better education (9pts), easier reporting of side-effects (7pts), mail order prescriptions-automatic refills (7pts), and reduced co-payments (7pts). Conclusion: Adherence with oral tki therapy among pts with CML remains challenging as 25% of our respondents admitted to missing doses; including pts who had been on prolonged therapy (>5yrs) and those pts who had already required treatment changes to second generation agents for resistance/progression. Additional efforts to foster adherence to tki therapy that will allow optimal clinical outcomes are needed. Disclosures: Goldberg: Novartis Oncology: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau. Off Label Use: Treatments of CML with experimental tyrosine kinase inhibitors, not the focus of the trial. Shah:Novartis Oncology: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau.

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Voice of Cancer Patients: Patient Experience Regarding Use of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

Blood ◽

10.1182/blood-2019-125195 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5843-5843

Author(s):

Sangeeta Aggarwal ◽

Singh Manish ◽

Guroosh Chaudhary ◽

Alok Aggarwal ◽

Himanshu Punetha ◽

...

Keyword(s):

Abdominal Pain ◽

Side Effects ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Second Generation ◽

Kinase Inhibitors ◽

Myelogenous Leukemia ◽

Line Treatment ◽

First Line ◽

Equity Ownership

Background: Use of Tyrosine Kinase inhibitors (TKIs) have significantly improved the prognosis of Chronic Myelogenous Leukemia (CML). Since the first clinical use of Imatinib 20 years ago, second generation TKIs have been approved for first line treatment, which include Dasatinib (approved in Nov. 2010), Nilotinib (June 2010) and Bosutinib (Dec. 2017). Ponatinib, a third generation TKI (approved for third line treatment in Dec. 2012), is the only effective TKI in patients with t315i mutation in bcr/abl gene. In this study, we analyzed patient experiences and use of various TKIs in CML patients. Method: Many patients share their experiences in online forums that contain clinically relevant information. However, data is unstructured and hence difficult to analyze. We collected 18.2 million messages from 97 different unrestricted cancer forums, including those 44 that were CML related. We created custom ontology for CML and TKIs regarding their efficacy and side effects. We then used our AI-based platform, VoCP, to analyze these messages by using artificial intelligence techniques, e.g., natural language processing, topic modeling and machine learning. Results: VoCP found 87,555 messages regarding CML from 10,605 unique users. Of these, 4,857 users shared 11,017 messages containing experiences with TKIs. 2,164 users mentioned the use of Imatinib, 819 used Dasatinib, 747 used Nilotinib, 97 used Bosutinib and 71 used Ponatinib. 47 patients mentioned undergoing bone marrow transplant. 1,139 patients mentioned being diagnosed before 2010 and at least 938 of them started with Imatinib. 1,082 patients reported diagnosis between 2010-2017; 357 started with Imatinib, 235 with Dasatinib and 236 with Nilotinib. 163 patients reported diagnosis after 2017; 47 started with Imatinib, 51 with Dasatinib, 27 with Nilotinib and 5 with Bosutinib. Imatinib: Switches: 501 patients switched to Dasatinib, 248 to Nilotinib, 14 to Bosutinib and 7 to Ponatinib. Side effects: 2,164 users mentioned 939 messages with side effects, which included pain 220 (23.4%), myelosuppression 154 (16.4%), fatigue 111 (11.7%), Skin rash (11.6%), GI upset 70 (2.4%), edema 84 (8.9%) heart problems 17, DVT/PE 5 and renal dysfunction 5. Dasatinib: Switches: 60 patients switched from Dasatinib to Imatinib, 79 to Nilotinib, 28 to Bosutinib and 9 to Ponatinib. Side effects: 819 patients shared 587 messages with side effects, which included Myelosuppression 113 (9.2%), rash 87 (14%), headache 78 (12.2%), pain 61 (1.7%), edema 30, Pleural effusion 24 and abdominal pain 11. Nilotinib: Switches: 95 patients switched to Dasatinib, 57 to Imantinib, 13 switched to Bosutinib and 5 to Ponatinib. Side effects: 747 users shared 390 messages with side effects, which included rash 135 (34.6%), pain 62 (15.9%), Myelosuppression 43 (11%), edema 16 (4.1%), cardiac issues 8 (2%), GI issues 13 (3.3%) and abdominal pain 2. Bosutinib: Switches: 1 patient switched from Bosutinib to Imatinib, 4 to Dasatinib, 2 to Nilotinib and 1 to Ponatinib. Side effects: 97 patients shared 39 messages with side effects, which included nausea 9 (23%), Myelosuppression 6(15%), edema 5 (12.8%) and diarrhea 4 (1.1%). Ponatinib: Switches: 3 patients mentioned switching from Ponatinib to Dasatinib, 3 patients to Bosutinib, 2 to Nilotinib, and 1 to Imatinib. Side effects: 71 users shared 25 messages with side effects, which included rash 13 (51%), pancreatitis 1 and fatigue 1. Conclusions: Despite the approval of second generation TKIs, Imatinib is most commonly used for treating CML in first line. MMR and CMR are similar for all TKIs. VoCP reliably provides meaningful insights from the patient's point of view and gives insight into unmet needs where more resources and research should be focused. Table Disclosures Aggarwal: Scry Analytics,Inc: Equity Ownership. Aggarwal:Scry Analytics, Inc.: Equity Ownership.

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Initial experience with the combination of atezolizumab and bevacizumab in patients with unresectable hepatocellular carcinoma progressing after tyrosine kinase inhibitor therapy: A multicenter prospective observational study

10.21203/rs.3.rs-590457/v1 ◽

2021 ◽

Author(s):

Rie Sugimoto ◽

Takeaki Satoh ◽

Akihiro Ueda ◽

Takeshi Senju ◽

Yuki Tanaka ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Side Effects ◽

Tyrosine Kinase ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Response To Treatment ◽

Therapeutic Effects ◽

Unresectable Hepatocellular Carcinoma ◽

Study Results ◽

Previously Treated

Abstract Background There is no evidence for the efficacy of atezolizumab plus bevacizumab treatment in patients with hepatocellular carcinoma previously treated with tyrosine kinase inhibitors (TKIs). Methods Twelve patients treated with atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma (HCC) and previously treated with TKIs were enrolled in the study. Results The treatment lines ranged from second line to sixth line. HCC staging was Barcelona Clinic Liver Cancer (BCLC) stage B in four cases and BCLC stage C in eight cases. The overall response rate and disease control rate according to the response evaluation criteria in solid tumors (RECIST) were 18.1% and 54.4%, respectively. Progression-free survival was 2.7 months, indicating that early response to treatment may differ depending on the type of previous therapy. The side effects profile also differed from that observed in IMbrave150, a phase 3 trial of atezolizumab plus bevacizumab, with many adverse events related to liver reserve. Conclusions The therapeutic effects and side effects differed from those previously reported during the treatment course of atezolizumab plus bevacizumab as first-line therapy.

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