Most reports on chronic myeloid leukaemia (CML) treatment with tyrosine kinase inhibitors (TKIs) focus on efficacy, particularly on molecular response and outcome. In contrast, adverse events (AEs) ...are often reported as infrequent, minor, tolerable and manageable, but they are increasingly important as therapy is potentially lifelong and multiple TKIs are available. For this reason, the European LeukemiaNet panel for CML management recommendations presents an exhaustive and critical summary of AEs emerging during CML treatment, to assist their understanding, management and prevention. There are five major conclusions. First, the main purpose of CML treatment is the antileukemic effect. Suboptimal management of AEs must not compromise this first objective. Second, most patients will have AEs, usually early, mostly mild to moderate, and which will resolve spontaneously or are easily controlled by simple means. Third, reduction or interruption of treatment must only be done if optimal management of the AE cannot be accomplished in other ways, and frequent monitoring is needed to detect resolution of the AE as early as possible. Fourth, attention must be given to comorbidities and drug interactions, and to new events unrelated to TKIs that are inevitable during such a prolonged treatment. Fifth, some TKI-related AEs have emerged which were not predicted or detected in earlier studies, maybe because of suboptimal attention to or absence from the preclinical data. Overall, imatinib has demonstrated a good long-term safety profile, though recent findings suggest underestimation of symptom severity by physicians. Second and third generation TKIs have shown higher response rates, but have been associated with unexpected problems, some of which could be irreversible. We hope these recommendations will help to minimise adverse events, and we believe that an optimal management of them will be rewarded by better TKI compliance and thus better CML outcomes, together with better quality of life.
Crizotinib is approved to treat advanced ALK-positive non-small-cell lung cancer (NSCLC), but most patients ultimately develop progressive disease (PD). We investigated whether continuing ALK ...inhibition with crizotinib beyond PD (CBPD) is clinically beneficial and attempted to identify clinicopathologic characteristics associated with patients who experience clinical benefit.
Patients with advanced ALK-positive NSCLC enrolled in two ongoing multicenter, single-arm trials who developed RECIST-defined PD were allowed to continue crizotinib if they were deriving ongoing clinical benefit. In the present retrospective analysis, continuation of CBPD was defined as >3 weeks of crizotinib treatment after PD documentation. Patients who had PD as best response to initial crizotinib treatment were excluded. Baseline and post-progression characteristics, sites of PD, and overall survival (OS) were compared in patients who continued CBPD versus those who did not. The impact of continuing CBPD on OS after adjusting for potential confounding factors was assessed.
Among 194 crizotinib-treated patients with RECIST-defined PD, 120 (62%) continued CBPD. A significantly higher proportion of patients who continued CBPD than patients who did not had an ECOG performance status (PS) of 0/1 at PD (96% versus 82%; P = 0.02). CBPD patients had significantly longer OS from the time of PD median 16.4 versus 3.9 months; hazards ratio (HR) 0.27, 95% confidence interval (CI): 0.17–0.42; P < 0.0001 and from the time of initial crizotinib treatment (median 29.6 versus 10.8 months; HR 0.30, 95% CI: 0.19–0.46; P < 0.0001). The multiple-covariate Cox regression analysis revealed that CBPD remained significantly associated with improved OS after adjusting for relevant factors.
Patients who continued CBPD were more likely to have good ECOG PS (0/1) at the time of PD. Continuing ALK inhibition with crizotinib after PD may provide survival benefit to patients with advanced ALK-positive NSCLC.
Chromosomal rearrangements involving RET, which are found in about 1% of non-small cell lung cancer (NSCLC), define a unique molecular subset. We performed this study to examine the efficacy and ...safety of vandetanib 300 mg daily in this patient population.
This study was a multi-center, open-label, phase II clinical trial. Patients were enrolled if they had metastatic or recurrent NSCLC with a RET rearrangement, which was confirmed by fluorescence in situ hybridization, had progressive disease against platinum-based doublet chemotherapy, and had a performance status of 0–2. The primary endpoint was the objective response rate.
A total of 18 patients were enrolled in this study between July 2013 and October 2015. Patients were aged 35–71 years; three had a performance status of 2, and the majority were a heavily pretreated population (≥ two different previous chemotherapy regimens in 72% of the patients). Among the 17 evaluable patients, three had a partial response (objective response rate = 18%) and eight had a stable disease (disease control rate = 65%). Among these patients, the partial response or disease stabilization was durable for more than 6 months in eight patients. Vandetanib also showed a progression-free survival of 4.5 months, and an overall survival of 11.6 months during a median follow-up duration of 14 months. The safety profile was comparable with previous studies of vandetanib. Most vandetanib-related adverse events were mild with prevalent hypertension and rash (in >70% of patients). Grade 3 toxicity included hypertension (n = 3), QT prolongation (2), and elevation of aminotransferases (1), and as a consequence the dose was reduced in four patients. There were no adverse events associated with grade 4 or 5 toxicity.
Vandetanib is moderately active in pretreated patients with advanced NSCLC-harboring RET rearrangements.
Background
In allogeneic stem cell transplantation (allo‐SCT), reduced‐intensity conditioning (RIC) is known for producing less regimen‐related toxicity. However, whether or not RIC reduces the risk ...for infection and infection‐related mortality (IRM) remains controversial.
Methods
We retrospectively analyzed infectious episodes and IRMs after allo‐SCTs by time period and by the intensity of the conditioning regimen (RIC n = 81 vs. myeloablative conditioning, MAC n = 150).
Results
The cumulative incidence of any kind of infection was lower in the RIC group through the entire period (72% vs. 87%; P = 0.007). The onset of infections was deferred in the RIC group as compared with the MAC group (P = 0.012). Bacteremia occurred less frequently in the RIC group through the entire period (5% vs. 14%; P = 0.044). However, the incidences of cytomegalovirus reactivation and disease, herpes zoster, virus‐associated hemorrhagic cystitis, and invasive fungal infection were not different between the two groups. Furthermore, there was no difference in relapse‐free survival and IRM between the two conditioning regimens.
Conclusion
Careful monitoring and appropriate preventive/therapeutic strategies for infectious complications, comparable to those for allo‐SCT recipients with MAC, should also be applied to those with RIC, especially after engraftment.
Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 ...(T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL).
We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months.
Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event.
Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).
•Investigator-assessed PFS data in the ALEX study are now mature (53% of events in the alectinib arm).•Alectinib significantly prolonged PFS vs crizotinib (stratified HR 0.43, 95% CI 0.32–0.58; ...median 34.8 vs 10.9 months).•OS data are immature (37% of events); median NR alectinib vs 57.4 months crizotinib (stratified HR 0.67, 95% CI 0.46–0.98).•5-year OS rate of 62.5% with alectinib and 45.5% with crizotinib.•Median treatment duration was longer with alectinib (28.1 vs 10.8 months crizotinib), with no new safety signals seen.
The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019).
Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety.
Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32–0.58; median PFS 34.8 versus 10.9 months crizotinib. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46–0.98). The 5-year OS rate was 62.5% (95% CI 54.3–70.8) with alectinib and 45.5% (95% CI 33.6–57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline HR 0.58 (95% CI 0.34–1.00) and those without HR 0.76 (95% CI 0.45–1.26). Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed.
Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC.
NCT02075840.
Background Complementary and alternative medicine (CAM) is being increasingly used among Koreans with chronic dermatologic diseases, such as androgenetic alopecia (AGA), atopic dermatitis (AD) and ...psoriasis.
Objective To quantify the usage of CAM in Korean patients with AGA, AD or psoriasis, and to offer valid information for the physicians frequently encountering such disorders.
Methods Outpatients (n = 678) from three tertiary hospitals were investigated independently by constructed and self‐directed questionnaire.
Results Of the respondents, 62.1% (421/678) of the subjects reported current or previous use of CAM for their dermatologic conditions (AGA, 67.2%; AD, 68.9%; psoriasis, 46.6%). In AGA, topical applicants (50.2%) were most often used, followed by dietary therapy and health supplements. In AD, bath therapy (39.4%) was most often used, followed by oriental medicine and topical applicants. In psoriasis, oriental medicine (33.9%) was most frequently used, followed by bath therapy and health supplements. The proportion of patients who believed that CAM helped to improve their skin condition was relatively low (AGA, 16.1%; AD, 31.7%; psoriasis, 15.0%).
Limitations The results may not be applicable to other countries and generalized to general populations.
Conclusion These results indicate that CAM is widely used in Korean patients with chronic dermatological diseases despite their dissatisfactions. Thus, the advantages and disadvantages of CAM must be considered before its clinical practice.
Quavonlimab (MK-1308), a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a phase I study.
Dose-escalation (DE) phase: patients with advanced/metastatic solid tumors ...received an initial flat dose of quavonlimab as monotherapy 25 mg (cohort 1), 75 mg (cohort 2), or 200 mg (cohort 3) followed by four treatments of the same quavonlimab dose plus pembrolizumab every 3 weeks (Q3W). Dose-confirmation phase (DC): patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) received first-line quavonlimab 25 mg Q3W (arm A), 25 mg Q6W (arm B), 75 mg Q6W (arm C), or 75 mg Q3W (arm E) plus pembrolizumab. Primary objectives were safety and tolerability and establishment of the recommended phase II dose (RP2D) of quavonlimab when used with pembrolizumab. Objective response rate (ORR) was a secondary endpoint. Efficacy based on PD-L1 expression, tumor mutational burden (TMB), and changes in circulating CD4+/CD8+ cells were exploratory endpoints.
Thirty-nine patients were enrolled in DE n = 14 (cohort 1); n = 17 (cohort 2); n = 8 (cohort 3) and 134 in DC n = 40 (arm A); n = 40 (arm B); n = 40 (arm C); n = 14 (arm E). Maximum-tolerated dose was not reached. Grade 3-5 treatment-related adverse events (AEs; graded according to NCI CTCAE v4.03) occurred in 0%, 23.5%, and 75.0% of patients in DE cohorts 1, 2, and 3, respectively, and 35.0%, 30.0%, 35.0%, and 57.1% of patients in DC arms A, B, C, and E, respectively. Efficacy was observed at all dose levels/schedules in patients with NSCLC. ORRs were 40.0% 95% confidence interval (CI), 24.9-56.7; arm A, 37.5% (95% CI, 22.7-54.2; arm B), 27.5% (95% CI, 14.6-43.9; arm C), and 35.7% (95% CI, 12.8-64.9; arm E). PD-L1 expression and total number of circulating CD4+ cells correlated with ORR.
Quavonlimab 25 mg Q6W plus pembrolizumab demonstrated similar efficacy and a better safety profile among all quavonlimab doses/schedules evaluated; this regimen was the chosen RP2D.
•Quavonlimab, a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a first-in-human study.•The combination therapy was safe and tolerable and showed antitumor activity in patients with advanced NSCLC.•Data from this study led to a recommended phase II dose of 25 mg Q6W for quavonlimab when used with pembrolizumab.
Background: Many patients with extranodal natural killer/T-cell lymphoma (NTCL) fail to the front-line therapy and need an effective second-line chemotherapy.
Patients and methods: This was ...single-institutional, phase II study. The primary end point was response rate and secondary end points were toxicity, time to treatment failure (TTF), and overall survival (OS). Patients with relapsed or refractory NTCL were eligible. They received the chemotherapy consisting of ifosfamide, methotrexate, etoposide, and prednisolone and it was repeated every 3 weeks.
Results: Thirty-two patients were enrolled and 15 patients had achieved partial remission (PR) or complete remission (CR) after the front-line chemotherapy. The International Prognostic Index scores were 0–1 in thirteen, 2 in five, 3 in five, and 4–5 in nine patients. Twelve and two patients achieved CR and PR, respectively. Median OS and TTF of all patients were 8.2 and 3.7 months, respectively. Non-hematologic toxic effects were well tolerated, but grade 3/4 leukopenia occurred in 11.7% of all cycles. Four patients developed febrile neutropenia and one patient died due to pneumonia.
Conclusions: This chemotherapy regimen was moderately effective for relapsed/refractory extranodal NTCL, nasal type. Toxic effects were moderate, but caution should be exercised to prevent severe infection.
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