•Chemotherapy-free regimens are highly effective in Ph+ ALL patients.•The addition of blinatumomab to TKIs significantly improved outcomes in Ph+ ALL.•Among TKIs, ponatinib-based regimens showed ...relatively better response rates.•High response rates warrant RCTs on chemotherapy and transplant free regimens.
The historical standard of care for Ph+ ALL is chemotherapy plus a tyrosine kinase inhibitor (TKI). Recently chemotherapy-free regimens have shown promising efficacy. We performed a meta-analysis to compare the efficacy of chemotherapy-free regimens for Ph+ ALL.
We searched PubMed and Embase for chemotherapy-free regimens for Ph+ ALL published between January 2000 and October 2023. Of the 5,348 articles screened, 9 nonrandomized clinical trials enrolling 413 patients were included. Two trials (N = 117) included treatment with 3 agents (blinatumomab, TKI, and steroid) and 7 trials (N = 248) included treatment with 2 agents (TKI and steroids). R software was used to conduct the meta-analysis (PROSPERO registration no. CRD42023482439).
The pooled complete molecular response (CMR) rate of patients receiving a TKI, blinatumomab, and steroids was 81% (95%CI, 69%-89%). TKIs plus blinatumomab were nearly 6 times as likely to have CMR (odds ratio OR, 5.98; 95%CI, 2.99-11.96) and more than 5 times as likely to be alive at 1-year (OR, 5.1; 95%CI, 1.74-14.9) as compared to TKIs alone. Patients receiving ponatinib were about twice as likely as those receiving dasatinib to achieve CMR (OR, 2.51; 95%CI, 0.72-8.72).
Adding blinatumomab to TKIs and steroids significantly improved Ph+ ALL patients’ response and survival rates. Regimens with ponatinib elicited higher molecular response rates than those with other TKIs. The high response and survival rates achieved with blinatumomab plus TKIs and steroids suggest that further studies are required to assess the need for intensive treatments such as chemotherapy or stem cell transplant in these patients.
Adding blinatumomab to tyrosine kinase inhibitors and steroids significantly improved the response rates and survival in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Regimens with ponatinib elicited higher molecular response rates than those with other tyrosine kinase inhibitors.
Colony-Stimulating Factor-1 Receptor (CSF1R) is a receptor tyrosine kinase that controls the differentiation and maintenance of most tissue-resident macrophages and bone-resorbing osteoclasts. ...Mutations of CSF1R have been implicated in neurodegeneration, skeletal anomalies, and cancers. Activation of CSF1R by endogenous cytokine ligation to the ectodomain triggers the autophosphorylation of the intracellular tyrosine kinase domain, and thereafter, activation of several downstream pro-survival kinase cascades, including PI3K, ERK1/2, and JNK. The immunological role of CSF1R in regulating tumor-associate macrophages (TAMs) have been well-documented. TAMs harboring activated CSF1R release tumorigenic cytokines, which further deconditioning tumor microenvironment to a protumoral phenotype. Pharmacological inhibition of CSF1R has emerged as a promising antitumor strategy, with PLX3397 (pexidartinib) been approved by the FDA for the treatment of tenosynovial giant cell tumor in 2019. Research around developing novel small-molecule CSF1R inhibitors, as well as expanding their potential indications, have drawn numerous attentions thenceforward. Herein, we've comprehensively reviewed the latest progression of CSF1R inhibitors under clinical and preclinical studies. Key findings of CSF1R targeted therapies either as monotherapy or combinatorial therapy have also been discussed.
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•Conclusive review of CSF1R inhibitors entered clinical trials.•Latest progression of CSF1R inhibitors under bench research.•Crystal structure-based binding modes analysis.•Antitumor potential of CSF1R inhibitors as monotherapy.•Potential antitumor combinations with CSF1R inhibitors.
Objective Chronic myeloid leukemia (CML) is a malignant hematological disorder, and allogeneic stem cell transplantation (allo-SCT) was its only curative treatment until the introduction of tyrosine ...kinase inhibitors (TKIs). Allo-SCT is still considered for CML patients who are resistant to TKIs and in an advanced phase. Currently, second- and third-generation (2/3G TKIs are typically incorporated into the first-line treatment of CML. However, the impact of 2/3G TKIs on subsequent allo-SCT remains unclear. We therefore evaluated the effect of 2/3G TKIs on allo-SCT. Methods We retrospectively evaluated the effect of pretransplant therapy with TKIs on the outcome of allo-SCT for CML using clinical data at our institution. Patients Thirty-two CML patients who received their first allo-SCT procedure at our institute from 2001 to 2020 were included. We divided the patients into three subgroups based on TKI treatment before allo-SCT. Patients receiving no TKIs, only imatinib (IM), and 2/3G TKIs were classified into the Non-TKI, IM, and 2/3G TKI groups, respectively. Results In a univariate analysis, the pretransplant use of 2/3G TKIs was significantly associated with a higher 5-year overall survival (91.7%) and relapse-free survival (75.0%) than the use of IM (37.5% and 12.5%) in patients presenting with or progressing to the advanced phase. In addition, pretransplant use of 2/3G TKIs did not increase the incidence of graft-versus-host disease (GVHD). Conclusion We demonstrated that the pretransplant use of 2/3G TKIs was safe and improved the outcome of CML patients who presented with or progressed to the advanced phase without increasing the frequency of GVHD.
Age and comorbidities are important factors to be considered in the selection of tyrosine kinase inhibitors (TKIs) for first‐line treatment in patients with chronic myeloid leukemia in chronic phase ...(CML‐CP). However, it is yet unclear whether TKI selection, particularly, imatinib versus second‐generation TKIs (2GTKIs), impacts treatment outcomes in the clinical practice. To address this, we compared the clinical outcomes of prospectively registered 452 patients with CML‐CP treated with imatinib and 2GTKIs, taking into consideration their age and/or comorbidities. A total of 136 patients (30.1%) were classified into an older cohort (≥65 years) and 316 (69.9%) into a younger cohort (18‐64 years). The TKI selection did not vary based on age (70.6% received 2GTKIs in the younger cohort and 66.2% in the older cohort). The median follow‐up period was 5.4 years. Treatment responses including the cumulative incidence of deep molecular response (BCR‐ABL1 international scale ≤0.0032%) at any time were similar between the two age cohorts regardless of the type of TKI. The 5‐year overall survival (OS) in the older cohort was lower than that in the younger cohort (95.9% vs 83.8%; p < 0.0001), whereas the 5‐year OS in patients treated with 2GTKIs was not influenced by age factors and comorbidities. Therefore, our results suggest that the selection of 2GTKIs as first‐line treatment is an effective option for both younger and older CML‐CP patients with or without comorbidities. This trial was registered at UMIN‐CTR as 00003581.
The overall survival in patients with chronic myeloid leukemia in chronic phase (CML‐CP) who treated with second‐generation tyrosine kinase inhibitors (2GTKIs) was not influenced by age factors, which was not observed in patients on imatinib. 2GTKI as first‐line treatment is a considerable option for both elderly and younger patients with CML‐CP.
Small amounts of epidermal growth factor receptor (EGFR) T790M mutation (micro-T790M), which is detected using droplet digital PCR (ddPCR) but not conventional PCR, in formalin-fixed and ...paraffin-embedded (FFPE) samples have been investigated as a predictive factor for the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). However, the predictive value of micro-T790M remains controversial, possibly owing to the failure to examine artificial T790M in FFPE specimens. Therefore, we examined the predictive value of micro-T790M in first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKI efficacy using a new method to exclude FFPE-derived artificial mutations in our retrospective cohort. The primary objective was time to treatment failure (TTF) of 1G, 2G, and 3G EGFR-TKIs according to micro-T790M status. In total, 315 patients with EGFR-positive non-small cell lung cancer treated with 1G, 2G, and 3G EGFR-TKIs were included in this study. The proportion of patients positive for micro-T790M in the 1G, 2G, and 3G EGFR-TKI groups was 48.2%, 47.1%, and 47.6%, respectively. In the micro-T790M-positive group, the TTF was significantly longer in the 2G and 3G EGFR-TKI groups than in the 1G TKI group. No differences in the micro-T790M-negative group were observed. Micro-T790M status detected using ddPCR, eliminating false positives, may be a valuable predictor of EGFR-TKI efficacy.
Background:
Evobrutinib is an oral, central nervous system (CNS)-penetrant and highly selective covalent Bruton’s tyrosine kinase inhibitor under clinical development for patients with relapsing ...multiple sclerosis (RMS).
Objective:
To investigate the effect of evobrutinib on immune responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinated patients with RMS from a Phase II trial (NCT02975349).
Methods:
A post hoc analysis of patients with RMS who received evobrutinib 75 mg twice daily and SARS-CoV-2 vaccines during the open-label extension (n = 45) was conducted. Immunoglobulin (Ig)G anti-S1/S2-specific SARS-CoV-2 antibodies were measured using an indirect chemiluminescence immunoassay.
Results:
In the vaccinated subgroup, mean/minimum evobrutinib exposure pre-vaccination was 105.2/88.7 weeks. In total, 43 of 45 patients developed/increased S1/S2 IgG antibody levels post-vaccination; one patient’s antibody response remained negative post-vaccination and the other had antibody levels above the upper limit of detection, both pre- and post-vaccination. Most patients (n = 36/45), regardless of pre-vaccination serostatus, had a 10–100-fold increase of antibody levels pre- to post-vaccination. Antibody levels post-booster were higher versus post-vaccination.
Conclusion:
These results suggest evobrutinib, an investigational drug with therapeutic potential for patients with RMS, acts as an immunomodulator, that is, it inhibits aberrant immune cell responses in patients with RMS, while responsiveness to foreign de novo and recall antigens is maintained.
Background and aims
Programmed cell death protein-1 (PD-1) inhibitors plus tyrosine kinase inhibitor (TKI) have dramatically improved survival of patients with advanced hepatocellular carcinoma ...(HCC). However, the risk of hepatitis B virus (HBV) reactivation from these antitumor medications remains unclear.
Methods
Patients receiving TKI monotherapy (TKI group) or TKI combined with PD-1 inhibitors (combination group) were included. The primary endpoint was HBV reactivation as defined by an increase in HBV DNA titer by at least 1 log (tenfold) from baseline. The secondary endpoints included tumor progression and overall survival.
Results
Four hundred and ninety-nine patients met the inclusion criteria, including 296 patients in the TKI group and 203 patients in the combination group. The 3-, 6- and 12-month cumulative incidence rates of HBV reactivation in the TKI group vs. combination group were 7.8%, 12.8% and 21.3% vs. 9.9%, 19.2% and 30.0%, respectively (
p
= 0.02). The Cox proportional hazard model indicated that combination therapy (HR 1.41, 95% CI 1.00–1.99,
p
= 0.05), ALT > 40 U/ml (HR 1.50, 95% CI 1.05–2.16,
p
= 0.03), and tumor size > 5 cm (HR 1.58, 95% CI 1.10–2.28,
p
= 0.01) were independent risk factors for HBV reactivation. Compared with the HBV reactivation group, the progression-free survival and overall survival of patients in the HBV non-reactivation group were significantly prolonged (
p
< 0.001 and
p
= 0.001).
Conclusions
Patients who received TKI combined with PD-1 inhibitors had a greater risk for HBV reactivation, and those with HBV reactivation had a higher rate of tumor progression and shorter survival time, than those receiving TKI alone.
Bruton's tyrosine kinase (BTK), a member of the Tec kinase family, is critically involved in a range of immunological pathways. The clinical application of BTK inhibitors for B‐cell malignancies has ...proven successful, and there is strong rationale for the potential benefits of BTK inhibitors in some autoimmune and allergic conditions, including immune‐mediated dermatological diseases. However, the established risk‐to‐benefit profile of “first‐generation” BTK inhibitors cannot be extrapolated to these emerging, non‐oncological, indications. “Next‐generation” BTK inhibitors such as remibrutinib and fenebrutinib entered clinical development for chronic spontaneous urticaria (CSU); rilzabrutinib and tirabrutinib are being studied as potential treatments for pemphigus. Promising data from early‐phase clinical trials in CSU suggest potential for these agents to achieve strong pathway inhibition, which may translate into measurable clinical benefits, as well as other effects such as the disruption of autoantibody production. BTK inhibitors may help to overcome some of the shortcomings of monoclonal antibody treatments for immune‐mediated dermatological conditions such as CSU, pemphigus, and systemic lupus erythematosus. In addition, the use of BTK inhibitors may improve understanding of the pathophysiological roles of mast cells, basophils, and B cells in such conditions.
This study aims to ascertain the prevalence of cavitations in pulmonary metastases among pediatric and young adult patients with sarcoma undergoing tyrosine kinase inhibitor (TKI) therapy, and assess ...whether cavitation can predict clinical response and survival outcomes.
In a single-center retrospective analysis, we examined chest computed tomography (CT) scans of 17 patients (median age 16 years; age range: 4-25 years) with histopathologically confirmed bone (n = 10) or soft tissue (n = 7) sarcoma who underwent TKI treatment for lung metastases. The interval between TKI initiation and the onset of lung nodule cavitation and tumor regrowth were assessed. The combination of all imaging studies and clinical data served as the reference standard for clinical responses. Progression-free survival (PFS) was compared between patients with cavitating and solid nodules using Kaplan-Meier survival analysis and log-rank test.
Five out of 17 patients (29%) exhibited cavitation of pulmonary nodules during TKI therapy. The median time from TKI initiation to the first observed cavitation was 79 days (range: 46-261 days). At the time of cavitation, all patients demonstrated stable disease. When the cavities began to fill with solid tumor, 60% (3/5) of patients exhibited progression in other pulmonary nodules. The median PFS for patients with cavitated pulmonary nodules after TKI treatment (6.7 months) was significantly longer compared to patients without cavitated nodules (3.8 months; log-rank p-value = .03).
Cavitation of metastatic pulmonary nodules in sarcoma patients undergoing TKI treatment is indicative of non-progressive disease, and significantly correlates with PFS.
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