Azacitidine Maintenance Following Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia: A Systematic Review

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Muhammad Salman Faisal ◽  
Laila Hashim ◽  
Yazan Samhouri ◽  
Syed Maaz Abdullah ◽  
Ahsan Wahab ◽  
...  
Keyword(s):  
Systematic Review ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Control Group ◽  
Phase 2 ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Phase 2 Trial ◽  
Grade 3

Background and Objective: Disease relapse remains the primary cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Oral azacitidine (5-aza) was associated with clinical benefit as maintenance therapy in transplant ineligible patients. However, contradicting data have been reported regarding the role of 5-aza as a maintenance therapy to reduce relapse rate -post-allo-HSCT. We conducted this systematic review to describe the efficacy and safety of 5-aza in this context. Materials and Methods: We systematically searched multiple databases, including PubMed, Embase, Cochrane, and Clinicaltrials.gov. We also searched major conferences for oral or poster presentations. We used MeSH terms and keywords for MDS, AML, Allo-HSCT, and 5-aza. We included all retrospective and prospective studies of 5-aza (all formulations) published until March 2020. The primary database search yielded 1209 articles. We excluded irrelevant, duplicate, and review articles. The final search revealed 20 articles that we explored in detail for various efficacy and safety outcomes. Results: A total of 1211 patients were enrolled in 14 prospective and 6 retrospective studies. Of those, 1169 patients were evaluable. Prospective studies CALGB 100801 trial by Vij et al. (2015) reported overall survival (OS) of 45.7% and progression-free survival (PFS) of 41.2% at 24 months following reduced intensity conditioning (RIC) in a phase 2 trial of 41 patients. In a randomized control trial, Oran et al. (2018) evaluated relapse-free survival (RFS) as the primary outcome after 12 cycles of 5-aza at 32 mg/m2/day (n=187). Only 30% of the patients in the azacitidine arm completed the targeted number of cycles. The study showed a median RFS of 24.8 months in the treatment arm vs 15.3 months in the control arm (p=0.43). In a phase 2 trial conducted by Guillaume, T et al. (2019) the cumulative incidence of relapse was 27.6% in patients who received 5-aza, compared with 41.9% in 58 matched patients control group (p=0.21). Platzbecker et al. (2018-2019) studied a higher dose of azacitidine (75mg/m2/day) in a phase 2 trial as a pre-emptive strategy for patients who develop minimal residual disease (MRD) within 24 months. The 12-month OS and PFS were 94% and 44%, respectively. De Lima et al. (2018) studied the role of maintenance Oral 5-aza in Phase I/II trial (n=30). A dose-escalation design was used with a dosage ranging from 150 mg to 400 mg, received in a 7- or 14-day cycles. The 12-month PFS was 54% and 72% and estimated survival was 86% and 81% among 7-days and 14-days cycles, respectively. (Table 1) Retrospective studies: Mishra et al. (2017) reported a better OS in 14 patients who received 5-aza maintenance compared with a control arm (p-value 0.026). Cheikh et al. reported a 12-month OS of 70%. Ali, N et al. (2020) (n=107) compared 5-aza group vs. control group retrospectively. EFS was 53.1% vs. 49.5% (p=0.02) while OS was 56.8 and 53.4 months (p=0.01) in the treatment arm vs the control arm respectively. Safety: The most common grade 3 or 4 hematological adverse effect was neutropenia, while some patients also experienced grade 3 or 4 anemia, thrombocytopenia, or lymphopenia. The main non-hematological adverse effects were infections, fatigue, and gastrointestinal distress. The incidence of acute graft versus host disease varied from 13% to 50%. The most common reason for treatment discontinuation was disease relapse. A minority of patients discontinued treatment due to side effects. Conclusion: To our knowledge, this is the first comprehensive systematic review for the role of 5-aza maintenance -post-Allo-HSCT in patients with MDS or AML. The heterogeneity of the studies, in terms of dosing regimens, variable duration of treatment and patient selection, precludes definitive conclusions. Despite that, 5-aza seems to improve relapse rates and OS at least numerically but also significantly in some studies, as illustrated in this review. Low number of patients involved in most of these studies contributed to non-significant p-values. Azacitidine remains a valid and safe option, especially in patients with high risk of relapse. Further studies aiming at those high risk patients, such as AML with myelodysplasia related changes (AML-MRC) and high-risk MDS following RIC, are of utmost need. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau. Fazal:Takeda: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Gilead/Kite: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Karyopharm: Speakers Bureau; Jazz: Consultancy, Speakers Bureau.

The Role of Decitabine for the Treatment of Acute Myeloid Leukemia

2012 ◽  
Vol 46 (11) ◽  
pp. 1511-1517 ◽  
Author(s):  
Alex Ganetsky
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Remission Induction ◽  
Phase 2 ◽  
Phase 3 ◽  
Hematopoietic Stem ◽  
Phase 2 Trial ◽  
Acute Myeloid

OBJECTIVE: To review the available literature addressing the role of decitabine for the treatment of acute myeloid leukemia (AML). DATA SOURCES: Relevant literature was identified by a PubMed search (January 1970-March 2012) of English-language literature using the terms decitabine, acute myeloid leukemia, and DNA methyltransferase inhibitors. STUDY SELECTION AND DATA EXTRACTION: All published studies and abstracts, as well as relevant consensus guidelines, evaluating the current literature about the role of decitabine for the treatment of AML were included. DATA SYNTHESIS: Decitabine has been evaluated for the treatment of AML in several different settings. In patients with newly diagnosed AML who are not candidates for standard remission induction chemotherapy, a Phase 2 trial of decitabine administered for 5 days per cycle demonstrated a 24% complete remission rate (CR). A subsequent Phase 3 trial comparing decitabine and low-dose cytarabine or best supportive care in a similar patient population showed a greater CR rate (18% vs 8%; p = 0.001) but no overall survival benefit. A Phase 2 trial demonstrated a 47% CR rate with decitabine initially administered for 10 days per cycle, with subsequent doses customized to individual response and toxicity. This novel dosing schedule has yet to be evaluated in a Phase 3 trial. Decitabine is also being investigated for the treatment of relapsed/refractory AML and as bridge therapy to allogeneic hematopoietic stem cell transplantation. CONCLUSIONS: Decitabine offers a promising alternative therapeutic option for patients with AML who are not candidates for standard remission induction chemotherapy. Because of its acceptable safety profile, research is investigating the clinical benefit of decitabine in combination with other antileukemic therapies. The potential roles of decitabine in the treatment of AML continue to be explored in numerous clinical trials.

NGR-hTNF and doxorubicin in relapsed ovarian cancer (OC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5059-5059
Author(s):  
Domenica Lorusso ◽  
Giovanni Scambia ◽  
Giulia Amadio ◽  
Alessia di Legge ◽  
Antonella Pietragalla ◽  
...  
Keyword(s):  
Median Duration ◽  
Human Tumor ◽  
Progression Free Survival ◽  
Free Survival ◽  
Phase 2 Trial ◽  
Randomized Phase Ii ◽  
Common Grade ◽  
Grade 3 ◽  
Necrosis Factor

5059 Background: NGR-hTNF (asparagine-glycine-arginine human tumor necrosis factor) is able to promote antitumor immune responses and to improve the intratumoral doxorubicin (D) uptake by selectively damaging tumor vessels. Methods: OC patients (pts) with progressive disease (PD) after ≥ 1 platinum/taxane regimen and with a platinum free interval lower than 6 months (PFI <6) or ranging from 6 to 12 months (PFI 6-12) received NGR-hTNF (N) 0.8 µg/m2 and D 60 mg/m2 on day 1 every 3 weeks. Primary endpoint of this phase 2 trial was response rate by RECIST criteria with a target of ≥ 6/37 responding pts. Secondary aims were progression free survival (PFS) and overall survival (OS). Results: 37 pts (median age 57 years; PS 0/1 32/5; PFI < 6/6-12 25/12; prior regimens 1-5) were enrolled. Median baseline peripheral blood lymphocyte count (PBLC) was 1.6/mL (interquartile range 1.2-2.1). In all, 177 cycles were given, with 18 pts (49%) receiving ≥ 6 cycles and 12 pts (32%) 8 cycles. Neither grade 3/4 adverse events (AEs) related to N nor increase of D-related AEs were noted. Common grade 1/2 AEs included chills (65%). Eight pts (23%; 95% CI 12-39) had partial response (PR; 2 with PFI < 6 and 6 with PFI 6-12; median duration: 8.2 months). Fifteen pts had stable disease (SD, 43%; 10 with PFI < 6 and 5 with PFI 6-12; median duration: 4.9 months) for an overall disease control (DC, PR+SD) rate of 66%. Mean changes from baseline in target tumor size after 2, 4, 6, and 8 cycles were 2%, -54%, -69%, and -77%, respectively. Median PFS was 5.0 months (95% CI 3.1-6.9) and median OS was 17.0 months (10.4-23.6). In pts with PFI < 6 or 6-12, median PFS were 3.8 and 7.8 months (p=.03) and median OS were 14.3 and 20.1 months (p=.14), respectively. Pts with DC had longer median OS than those with early PD (24.0 and 4.9 months, respectively, p=.02). Longer PFI (p=.03) and higher PBLC (p=.01) were associated with better PFS, while OS correlated only with PBLC (p=.001). In the subset with PFI < 6, pts with PBLC ≥ or < 1.2/mL (1st quartile) had median PFS of 4.9 and 2.6 months (p=.02) and median OS of 15.8 and 4.3 months (p=.0001), respectivel Conclusions: A randomized phase II trial is currently testing D ± NGR-hTNF in pts with PFI < 6 (refractory/resistant). The role of PBLC as blood-based biomarker deserves further investigation.

Interim analysis of STARTAR: A phase II salvage trial of androgen receptor (AR) inhibition with androgen deprivation therapy (ADT) and apalutamide with radiation therapy (RT) followed by docetaxel in men with PSA recurrent prostate cancer (PC) after radical prostatectomy (RP).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 90-90
Author(s):  
Tian Zhang ◽  
Bridget F. Koontz ◽  
Scott T. Tagawa ◽  
Himanshu Nagar ◽  
Rhonda L. Bitting ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Interim Analysis ◽  
Salvage Treatment ◽  
Research Network ◽  
Phase 2 ◽  
Phase 2 Trial ◽  
Psa Recurrence ◽  
Grade 3

90 Background: ADT with salvage RT improves survival for men with PSA recurrence after RP. Current standard duration of ADT for high risk PSA recurrence is up to 2 years with RT; therefore shortening but intensifying systemic therapy may improve outcomes. The STREAM trial showed 6 mo of enzalutamide added to ADT/RT had a 3-year progression free survival (PFS) of 53% in high risk patients including lymph node (LN) positive. Given that docetaxel improves survival in men with mHSPC, we evaluated the combination of salvage RT, ADT/apalutamide and docetaxel in this setting. Methods: STARTAR is a multicenter phase 2 trial for salvage treatment of PSA recurrent PC following RP conducted within the US Dept. of Defense Prostate Cancer Clinical Trials Consortium (DOD PCCTC). Key inclusion criteria included PC with Gleason 7 with T3/positive margin/1-4 positive LNs or Gleason 8-10 disease and PSA relapse within 4 years of RP (min PSA 0.2 ng/mL to max PSA 4 ng/mL). Men with up to 4 positive resected LNs were eligible. Men started ADT with apalutamide, continued with RT (66-74 Gy to the prostate bed +/- pelvic LNs over 6-8 weeks), and finally completed docetaxel 75mg/m2 IV q3 weeks for 6 cycles. Men were treated with ADT and apalutamide for approximately 9 months. The primary endpoint was PSA PFS at 36 months. This interim analysis evaluated secondary endpoints of 1-year PSA recurrence, testosterone recovery, and safety of this treatment sequence. Results: From 3/2018 to 12/2019, 39 men were enrolled at Duke, Wake Forest, Cornell, and the GU Research Network. With a data cutoff in 9/2020, median follow up from enrollment was 14 months. Baseline patient characteristics included Gleason 4+3 = 7 in 54% and Gleason 8-10 in 46%, and 23% LN positive; median PSA at the time of enrollment was 0.58 ng/mL (range 0.21-3.40) and the median time from RP to enrollment was 7 mo (range 2-98). At 1 year, there have been no progression events with 38% (12/31) of men with post-treatment testosterone recovery into normal range (recovery time median 10 mos [1-17 mos]). Common adverse events (AEs) of any-grade at least possibly related to the regimen were 98% hot flashes, 88% fatigue, 77% alopecia, 57% dysgeusia, and 53% rash (28% grade 1; 15% grade 2, 10% grade 3), with neutropenia as the most common grade 3/4 AE (27/39 men, 70%) with two grade 3 febrile neutropenia. Conclusions: In this first phase 2 trial of ADT, apalutamide, radiation, and 6 cycles docetaxel in the salvage setting for high risk PSA recurrence, short term outcomes are excellent with no recurrences at 12 months of follow-up. This salvage treatment was well tolerated in the majority of men with the exception of a high rate of drug rashes and neutropenia related to the course of treatment, in line with known safety profiles of the study agents. Clinical trial information: NCT03311555.

scholarly journals Single-Nucleotide Polymorphisms in MICA and MICB Genes Could Play a Role in the Outcome in AML Patients after HSCT

2021 ◽  
Vol 10 (20) ◽  
pp. 4636
Author(s):  
Alena Machuldova ◽  
Lucie Houdova ◽  
Katerina Kratochvilova ◽  
Martin Leba ◽  
Pavel Jindra ◽  
...  
Keyword(s):  
Nk Cells ◽  
Myeloid Leukemia ◽  
Point Mutations ◽  
Single Amino Acid ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Negative Effect

NKG2D and its ligands, MICA and MICB, are known as the key regulators of NK cells. NK cells are the first reconstituted cells after the allogeneic hematopoietic stem cell transplantation (HSCT); therefore, it is crucial to understand their role in HSCT outcome. In the presented study, we investigated the single amino acid changes across the exons 2–4 of MICA and MICB genes, and point mutations within the NKG2D gene, which defines the type of NKG2D haploblock (HNK/LNK) in the donors (n = 124), as well as in patients with acute myeloid leukemia (n = 78). In our cohort, we found that graft from a donor with at least one MICA allele containing glycine at position 14 (MICA-14Gly) is significantly associated with deterioration of a patient’s overall survival (OS) (p < 0.05). We also observed a negative effect of MICB-58 (Lys → Glu) polymorphism on relapse-free survival (RFS), although it was not statistically significant in multivariate analysis (p = 0.069). To our knowledge, this is the first work describing the role of MICA-14 and MICB-58 polymorphisms on HSCT outcome.

Safety and efficacy of dasatinib in patients with advanced gastrointestinal stromal tumors refractory to imatinib and sunitinib: A single arm, multicenters, phase 2 trial.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 138-138 ◽  
Author(s):  
Jian Li ◽  
Ye Zhou ◽  
Xinhua Zhang ◽  
Xiaojun WU ◽  
Yongjian Zhou ◽  
...  
Keyword(s):  
Day Treatment ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Free Survival ◽  
Intention To Treat ◽  
Phase 2 Trial ◽  
Medical Centers ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Ct Dna

138 Background: Regorafenib is recommended to treat advanced gastrointestinal stromal tumor (GIST) refractory to imatinib and sunitinib. However, the efficacy is not satisfied, other active agents need to be explored to advanced patients. Methods: In this single arm, multi-center, phase 2 trial, we enrolled patients aged 18 years and older with advanced GIST who had received previous imatinib and sunitinib treatment. Participants were treated with oral dasatinib 50mg twice a day for 2 weeks. If patients were tolerable, then they received dasatinib 70mg twice a day treatment, to tumor progression or intolerable toxicities. The primary endpoint was RECIST-based progression-free survival (PFS) in the intention-to-treat population. The secondary endpoints included response rate, overall survival (OS) and advent events. ctDNA will be analysis in some patients to explore the sensitive biomarker to dasatinib. Results: From May 2016 to June 2018, 58 patients from nine medical centers were enrolled in this study. Two patients had partial response and disease control rate was 62.0%. The median PFS was 3.0 months (95% CI, 2.6-3.4 months). There was no statistic difference of PFS in both subgroup with different primary mutations and in subgroup with different secondary mutations. The patients with wild type GIST had a trend of longer PFS of 5.5 months. In 4 patients with PDGFRA D842V mutation, two patients had stable disease. The median OS was 14.0 months (95% CI, 10.8-17.2 months). The most frequently observed grade 3 adverse events included anemia (10.3%), diarrhea (1.7%). The analysis of ct DNA is ongoing. Conclusions: Dasatinib is an active treatment for patients with GIST who are refractory to imatinib and sunitnib. This study is registered with ClinicalTrials.gov, NCT02776878 . Clinical trial information: NCT02776878.

scholarly journals Potential Role of Adjuvant Lenvatinib in Improving Disease-Free Survival for Patients With High-Risk Hepatitis B Virus-Related Hepatocellular Carcinoma Following Liver Transplantation: A Retrospective, Case Control Study

2020 ◽  
Vol 10 ◽  
Author(s):  
Bing Han ◽  
Han Ding ◽  
Shuai Zhao ◽  
Yichi Zhang ◽  
Jian Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Transplantation ◽  
High Risk ◽  
Disease Free Survival ◽  
Control Group ◽  
Free Survival ◽  
Risk Patients ◽  
Disease Free ◽  
Hcc Recurrence

Background and AimAlthough liver transplantation (LT) is one of the most effective treatments for the patients with hepatocellular carcinoma (HCC), the high-risk patients suffer from a high ratio of tumor recurrence after LT. Lenvatinib, as a novel targeted drug, has shown an excellent effect in the treatment of advanced HCC, but there is no study on its effect in preventing HCC recurrence in the patients undergoing transplantation. Therefore, this study was designed to evaluate the role of adjuvant lenvatinib in preventing recurrence of high-risk LT recipients with HBV-related HCC.MethodsWe retrospectively analyzed 23 high-risk patients consisting of lenvatinib group (n=14) and control group (n=9) with HBV-related HCC who underwent LT in our center. Disease-free survival (DFS) and HCC recurrence of the two groups were compared. The adverse events (AEs) and drug tolerance of lenvatinib were evaluated.ResultsThe median DFS in lenvatinib group was 291 (95%CI 204–516) days, significantly longer than 182 (95%CI 56–537) days in control group (P=0.04). Three patients in lenvatinib group (21.4%) and five patients in control group (55.6%) had short-term HCC recurrence (P=0.11). All patients in lenvatinib group could tolerate oral lenvatinib for at least three cycles except six cases (42.9%) of dose reduction and 1 case of interruption (14.3%). Thirteen patients (92.9%) taking lenvatinib experienced AEs. The most common AEs were hypertension (64.3%) and proteinuria (42.9%), and the most serious AEs were Grade 3 for 4 cases (28.5%) according to common terminology criteria for adverse events (CTCAE) version 5.0. Additionally, no influence of lenvatinib on the dosage and blood concentration of FK506 was observed.ConclusionsAdjuvant lenvatinib had a potential benefit on prolonging the DFS and reducing the recurrence of high-risk HBV-related HCC patients following liver transplantation with an acceptable drug safety and patient tolerance.

Phase 2 Study of the Safety and Efficacy of Umbralisib in Patients with CLL Who Are Intolerant to BTK or PI3Kδ Inhibitor Therapy

Blood ◽  
2020 ◽  
Author(s):  
Anthony R. Mato ◽  
Nilanjan Ghosh ◽  
Stephen J Schuster ◽  
Nicole Lamanna ◽  
John M. Pagel ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Inhibitor Therapy ◽  
Pi3k Inhibitor ◽  
Phase 2 ◽  
Free Survival ◽  
Phase 2 Trial ◽  
Buccal Swabs ◽  
Secondary Endpoints ◽  
Grade 3

Purpose: Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in CLL. Umbralisib a novel, highly selective PI3Kδ/CK1ε inhibitor, is active and well tolerated in CLL patients. This phase 2 trial evaluated umbralisib in CLL patients who are intolerant to prior BTK or PI3K inhibitor therapy. Patients and Methods: In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg oral daily in CLL patients requiring therapy per investigator discretion who were intolerant to prior BTK or PI3K inhibitor therapy, until progression or toxicity. Primary endpoint was progression-free survival (PFS). Secondary endpoints included time to treatment failure and umbralisib safety profile. DNA isolated from buccal swabs was genotyped for polymorphisms in CYP3A4, CYP3A5 and CYP2D6. Results: Fifty-one patients were enrolled (44 BTKi and 7 PI3Kδi intolerant). Median age was 70 years (range 48-96), median of 2 prior lines of therapy (1-7), 24% had del17p and/or TP53 mutation, and 65% were IGHV unmutated. Most common AEs leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median progression free survival (PFS) was 23.5 months (95% CI 13.1-not estimable). 58% of patients were on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib due to an AE. Eight patients (16%) had dose reductions and were successfully re-challenged. Conclusions: Umbralisib is safe and effective in this BTK and alternate PI3K inhibitor intolerant CLL population. These are the first prospective data to confirm that switching from a BTK or alternate PI3K inhibitor to umbralisib can result in durable, well tolerated responses.

Seizures and Neuropsychiatric Toxicity in Patients with Non-Metastatic CRPC Treated with New Antiandrogens: Systematic Review and Meta-Analysis

2021 ◽  
Vol 44 (4) ◽  
pp. 153-160
Author(s):  
Raquel Sopeña Sutil ◽  
Jorge Silva Ruiz ◽  
Borja Garcia Gomez ◽  
Javier Romero-Otero ◽  
Lucia Garcia-Gonzalez ◽  
...  
Keyword(s):  
Systematic Review ◽  
Meta Analysis ◽  
Control Group ◽  
Castration Resistant Prostate Cancer ◽  
Free Survival ◽  
Castration Resistant ◽  
History Of ◽  
Neuropsychiatric Toxicity ◽  
Grade 3 ◽  
Risk Ratios

Introduction: Recently, enzalutamide, apalutamide, and darolutamide have shown benefits in metastasis-free survival in non-metastatic castration-resistant prostate cancer (nmCRPC) patients compared to placebo. Previous evidence about the safety profile of these new androgens is limited. This meta-analysis studies seizure and neuropsychiatric effects of new anti-androgens compared to placebo in nmCRPC patients. Methods: PubMed and Cochrane databases were systematically reviewed until 1 March 2020 by 2 independent researchers using a pre-specified search strategy. Placebo-compared randomized controlled trials (RCTs) of nmCRPC patients treated with new anti-androgens providing data on neuropsychiatric events and seizures were included. Variables were seizure, headache, mental impairment, and dizziness. Pooled risk ratios (RR) were calculated using the Mantel-Hansel random effects model and Review Manager v5.3 software. Results: After systematic review, 3 eligible RCTs were selected that included 4,104 patients; 2,687 comprised the treatment group and 1,417 the control group. No significant increase in RR for seizures was registered with the new anti-androgens compared to placebo (RR 1.96; 95% confidence interval [CI] 0.40–9.61). However, 2 trials excluded patients with risk factors or a history of seizures. There was also no significant increase RR for grade ≥3 seizures (RR 2.50; 95% CI 0.12–52.02). RR for suffering dizziness (any grade) was 1.57 (95% CI 1.07–2.32) with the new anti-androgens, but no significant differences were found in the other study regarding neuropsychiatric events or grade ≥3 events. Conclusions: New anti-androgens (i.e., enzalutamide, apalutamide, and darolutamide) are acceptably safe in terms of seizures and neuropsychiatric toxicity compared to placebo in patients with nmCRPC.

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