Higher Incidence Of Thrombocytopenia Research Articles

The Non-Hodgkin Lymphoma Treatment and Side Effects: A Systematic Review and Meta-Analysis.

This paper aims to review studies regarding side effects found during Non-Hodgkin Lymphoma treatment, to suggest the drug class most associated with these effects, as well as the most prevalent side effect grade. This review is registered in PROSPERO (IDCRD42022295774) and followed the PICOS strategy and PRISMA guidelines. The search was carried out in the databases PubMed/MEDLINE, Scientific Electronic Library Online, and DOAJ. Medical Subject Headings Terms were used and quantitative studies with conclusive results regarding side effects during the non-Hodgkin lymphoma treatment were selected. Patent information was obtained from google patents. Monoclonal antibodies were the main drug class associated with side effects during NHL therapy. The combination of Rituximab (Rituxan®; patent EP1616572B) and iInotuzumab (Besponsa®; patent EP1504035B3) was associated with a higher incidence of thrombocytopenia (p<0.05), while the combination of Rituximab and Venetoclax (Venclexta®; patent CN107089981A) was associated with a higher incidence of neutropenia (p<0.05) when compared to Bendamustine combinations (Treanda ™; patent US20130253025A1). Meta-analysis revealed a high prevalence of grade 3-4 neutropenia and thrombocytopenia in men. Finally, Americans and Canadians experienced a higher prevalence of these side effects, when compared to others nationalities (p<0.05). Patents regarding the use of monoclonal antibodies in NHL treatment were published in the last year. Monoclonal antibodies associated with neutropenia (grade 3-4) and thrombocytopenia, especially in North American men treated for NHL, and with an average age of 62 years demonstrated importance in this study.

Developmental Differences between Neonatal and Adult Platelets in Regard to Immune Protein Content and Regulation of Monocyte Inflammatory Responses

Preterm neonates frequently receive platelet transfusions (PTx), owing to their high incidence of thrombocytopenia and bleeding. However, a recent large randomized trial found a significantly higher incidence of death or major bleeding among more liberally transfused preterm neonates. The mechanisms underlying these deleterious effects are unknown, but it has been suggested that they are related to the developmental differences between adult and neonatal platelets, and to a potential “developmental mismatch” occurring when adult platelets (comparatively hyperreactive) are transfused into neonates. While most studies so far have focused on the hemostatic effects of PTx, it is now clear that platelets are key modulators of immune and inflammatory responses. We hypothesized that adult platelets would be more pro-inflammatory than neonatal platelets. To test this hypothesis, we first compared the proteome of resting cord blood (CB, n=9) and adult (n=7) platelets. Using data-independent acquisition mass spectrometry, we identified 4173 high-confidence proteins present in both adult and neonatal platelets. In a principal component analysis, neonatal and adult platelets clustered separately, and 359 proteins were present at significantly different relative abundances between the two groups (≥1.5-fold change, p&amp;lt;0.05). Pathway analysis of the 169 proteins significantly more abundant in the adult platelet proteome revealed enrichment for immune and inflammatory pathways, while neonatal platelets were enriched for pathways involved in metabolic processes. Next, we compared the effects of neonatal and adult platelets on the inflammatory response of human neonatal monocytes. Platelets and monocytes were isolated from healthy adult blood or full-term CB (n=6/group). Platelet P-selectin surface expression was determined by flow cytometry, and key platelet-derived immune regulators (RANTES, β-2 Microglobulin [β2M], and TGF-β) were quantified in the supernatant of resting and activated platelets by ELISA. After washing, neonatal and adult platelets had similarly low P-selectin surface expression levels. Following thrombin activation, P-selectin surface expression was significantly higher in adult than in neonatal platelets (MFI 4010±1645 vs. 1987±816, p=0.04). Thrombin activation increased RANTES and TGF-β release from adult and neonatal platelets to similar levels. In contrast, β2M levels were significantly higher in the supernatant from activated adult compared to neonatal platelets (37.9±10.2 vs 17.9±5.0 ng/mL, p=0.0004). Next, we co-cultured activated adult or neonatal platelets with neonatal monocytes and quantified the pro-inflammatory cytokines IL-8 and MCP-1 (CCL2) in the supernatants after 18 hours. The presence of activated platelets significantly increased IL-8 production from neonatal monocytes compared to monocytes alone, 2.9±1.2-fold when neonatal platelets were added and 4.2±1.8-fold with addition of adult platelets (p=0.01 and p=0.001, respectively). MCP-1 increased to similar levels with the addition of either neonatal or adult platelets. In a regression model, both P-selectin expression and platelet-released β2M levels were significantly associated with monocyte-produced IL-8 levels (p=0.001 and p=0.04, respectively). In summary, we found that proteins related to inflammatory and immune responses are more abundant in adult compared to neonatal platelets, and that activated adult platelets express more P-selectin and release more β2M than neonatal platelets, resulting in higher IL8 production by neonatal monocytes. These findings support the hypothesis that the pro-inflammatory effects of adult platelets might contribute to the increased morbidity and mortality associated with neonatal PTx.

EBNEO commentary: Platelet transfusions in neonates and brain development: The new frontier.

Preterm neonates have a high incidence of thrombocytopenia and intraventricular haemorrhage (IVH). Because of this, they are traditionally transfused at higher platelet count (PC) thresholds compared to older children and adults, under the premise that higher PCs decrease bleeding risk.1 Paradoxically, the largest randomised platelet transfusion threshold trial in preterm neonates (PlaNeT-2), found a higher incidence of death or major bleeding within 28 days of randomisation (primary outcome) and a higher incidence of bronchopulmonary dysplasia (BPD) among neonates randomised to a higher platelet transfusion threshold (<50 × 109/L), compared to those randomised to a lower threshold (<25 × 109/L).2 Neonates with a high baseline risk of bleeding and/or death benefited from the lower platelet transfusion threshold as much as low-risk neonates.3 In this manuscript, Moore and collaborators provide evidence that high platelet transfusion thresholds are associated with increased mortality and neurodevelopmental impairment (NDI) at 2 years of corrected age.4 The study had a high follow-up rate (92%), combining results from formal neurodevelopmental (ND) assessment tools (41% of participants), review of medical records, practitioners' notes and early intervention services. Participants were dichotomised as having a favourable or unfavourable outcome (death or severe CP, developmental delay or visual or hearing loss). The combination of different methods to assess ND outcomes is a limitation of the study and restricted the ability of investigators to evaluate subtle deficits or specific neurologic domains. Future trials should include standardised ND assessments at 2 years and be powered for this outcome. Nevertheless, the fact that only severe deficits were included made the findings even more concerning. Given the initial finding that neonates randomised to a higher platelet transfusion threshold had a higher incidence of BPD, the authors performed a post hoc analysis that found a higher need for respiratory support at 2 years among children randomised to the high threshold group. While BPD is common among preterm infants, oxygen dependence or need for respiratory support at 2 years of age is not. Thus, the higher incidence of this outcome among children randomised to the higher threshold suggests platelet transfusions given to high-risk preterm neonates might trigger or enhance pathways leading to severe lung disease. The mechanisms underlying increased morbidity and mortality associated with platelet transfusions are likely related to non-hemostatic effects of platelets. Platelets are critical regulators of immune and inflammatory responses, and it has been hypothesised that adult (transfused) platelets are more pro-inflammatory than neonatal platelets.5-8 In support of this hypothesis, pre-clinical studies suggest platelet transfusions trigger inflammation or dysregulated immune responses in neonates, in a context-dependent manner.9 Whether NDI results from the direct effects of transfused platelets on the developing brain or is mediated by higher rates of IVH and BPD observed in infants randomised to the high threshold group (both of which are associated with NDI), is unknown. Additional studies are needed to define the mechanisms underlying the deleterious and beneficial effects of platelet transfusions, which remain lifesaving in neonates with bleeding or severe thrombocytopenia. In the meantime, this study further supports the use of a restrictive, evidence-based approach to neonatal platelet transfusions. URL LINK: https://ebneo.org/ebneo-commentary-platelet-transfusions-in-neonates-and-brain-development-the-new-frontier/. The authors are supported by grants PO1 HL046925 (MSV), K99 HL156051 (PD) and P01HL152961 (CD). None.

Phase II Trials of Iniparib (BSI-201) in Combination with Gemcitabine and Carboplatin in Patients with Recurrent Ovarian Cancer.

Iniparib (BSI-201), a novel anticancer agent thought to have poly(ADP-ribose) polymerase (PARP) inhibitory activity and synergy with both gemcitabine and carboplatin (GC) was evaluated in 2 cohorts with GC. Parallel multicenter, single-arm, phase II studies using a Simon two-stage design. Eligible patients had a histological diagnosis of epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma and demonstration of platinum-sensitive (≥6 months [mo]) or -resistant disease (relapse 2-6 mo post-platinum). Carboplatin (AUC 4 IV day 1), gemcitabine (1000 mg/m2 IV days 1 and 8), and iniparib (5.6 mg/kg IV days 1, 4, 8, and 11) were given on a 21-day cycle. The overall response rate (ORR RECIST 1.0) in platinum sensitive disease was 66% (95% CI, 49-80) with a higher response rate in the 15 pts with germline BRCA mutations (gBRCAmut) (73%). Median PFS was 9.9 (95% CI, 8.2-11.3) months. In the platinum resistant population the ORR was 26% (95% CI, 14-42), however in the 11 pts for whom BRCA mutation was present, the best overall response was PR in 5 (46%). Median PFS was 6.8 months (range, 5.7-7.7 months). Notably, among the 17 CA-125-response-evaluable patients who did not achieve tumor response, 7 (41.2%) patients had a CA125 response, and 93% has clinical benefit (CR + PR + SD). The GCI combination was generally well tolerated despite a high incidence of thrombocytopenia and neutropenia, with no new toxicities. Given the subsequent lack of efficacy demonstrated for iniparib in breast cancer, these are studies of GC and demonstrate a higher than traditionally appreciated activity in patients with platinum-sensitive and -resistant recurrent ovarian cancer, especially in patients that harbor a BRCA mutation, resetting the benchmark for efficacy in phase II trials. (ClinicalTrials.gov Identifiers: NCT01033292 & NCT01033123).

Platelet index on admission as a predictor of bacteremia in acute cholangitis: a 7-year retrospective observational study

Bacteremia frequently occurs in patients with acute cholangitis, which could increase the risk of mortality. This single-center retrospective observational study was conducted from July 2013 to July 2020 to evaluate the predictive value of platelet index for bacteremia at admission for acute cholecystitis. A total of 285 patients with acute cholangitis were divided into bacteremia group and non-bacteremia group. The incidence of bacteremia in acute cholangitis was 48.42%. The bacteremia group had more grade III patients, higher 30d mortality rate [17(12.32%) vs 8(5.44%), p = .040] and higher incidence of thrombocytopenia [76(55.07%) vs 35(23.81%), p < .001]. Platelet counts and plateletcrit were significantly lower in the bacteremia group [84.5(60, 180) vs 162(102,225) ×109/L and 0.10(0.07, 0.21)% vs 0.18(0.12, 0.25) %, both p < .001]. ROC analysis indicated a high predictive value of platelet count and plateletcrit for bacteremia in patients with acute cholangitis and the area under the ROC curve (AUC) were 0.649 and 0.655, respectively. These results support the value of platelet count and plateletcrit in early prediction of bacteremia at admission for acute cholangitis.

Higher incidence of thrombocytopenia during obinutuzumab plus bendamustine therapy for untreated follicular lymphoma: a retrospective analysis by the Okayama Hematology Study Group.

Progression-free survival in patients with untreated follicular lymphoma (FL) has significantly improved with obinutuzumab plus chemotherapy followed by obinutuzumab maintenance, compared with rituximab plus chemotherapy. However, the survival outcome and adverse event profile in Japanese FL patients treated with obinutuzumab plus bendamustine (GB) therapy are not well investigated. Recently, we encountered some cases of grade 3-4 thrombocytopenia during GB therapy in patients with FL. This retrospective multicenter survey aimed to identify the characteristics of patients who received GB therapy and developed thrombocytopenia. A total of 54 patients with FL treated by GB therapy between August 2018 and December 2020 were investigated. After a median follow-up of 12.6months, thrombocytopenia of any grade was observed in 48 (88.9%) patients, including 9 (16.7%) patients with grade 3-4 thrombocytopenia. Notably, although eight of nine patients with grade 3-4 thrombocytopenia were female, no patient characteristics (including gender) were significantly associated with grade 3-4 thrombocytopenia. Importantly, grade 3-4 thrombocytopenia frequently occurred in the first GB therapy cycle, which suggests that platelet count should be monitored carefully in patients who have just started GB therapy.

Incidence, clinical impact and predictors of thrombocytopenia after transcatheter aortic valve replacement

BackgroundThrombocytopenia is a common, yet poorly understood, complication after transcatheter aortic valve replacement (TAVR). Balloon-expandable transcatheter heart valve has been associated with higher incidence of thrombocytopenia, compared with self-expandable valves. The aim of this study was to analyze the incidence, clinical impact and predictors of acquired thrombocytopenia in patients undergoing TAVR. MethodsWe performed an observational study from consecutive patients with severe aortic stenosis undergoing TAVR (n = 679) in a single center. Association and best cut-off point of platelet decrease with early mortality was analyzed. Patients were classified according to postprocedural percentage decrease in platelet count (PDPC), comparing clinical outcomes and analyzing predictors of platelet decrease. ResultsThe median PDPC was 37.1 [IQR: 27.4–46.9]. PDPC was associated with early mortality (OR: 2.1, 95%IC: 1.7–2.5 for each 10% decrease, AUC:0.81, 95%CI:0.72–0.89) with an optimal cut-off point of 46%. PDPC≥46% and late nadir (≥4 days) were both independent predictors of early mortality (OR: 6.0 [IQR: 2.4–14.9] and OR: 5.1 [IQR: 2.2–11.6], respectively). The combination of both factors (PDPC≥46% and nadir ≥4 day) was associated with higher 2-year mortality (55.7%) compared to an early significant nadir (PDPC≥46% and nadir <4 day, 28.9%) and non-significant nadir (PDPC<46%, 21.0%), p < 0.001. Independent predictors of PDPC≥46% were baseline platelet count, Portico™, Abbott valve, intraprocedural major vascular complication and residual aortic regurgitation ≥grade 2. ConclusionThe platelet count decreased almost 40% after TAVR. Late nadir and PDPC≥46% predicted short-term clinical outcomes. Concomitant late and significant platelet decrease was associated with mid-term mortality.

Quantitative Analysis of Thrombocytes in Neonates in a Tertiary Care Centre of Southern India- A Retrospective Study

Introduction: Thrombocytopenia is defined as a platelet count of less than 150×109/L, which is also applicable to newborn infants. It may be a result of increased platelet destruction (immune and non immune), decreased platelet production, and a combination of both or unknown. A platelet count of more than 500×109/L is considered thrombocytosis, classified as primary or essential and secondary or reactive. Abnormal platelet count being quite common, is most often neglected and it can lead to devastating complications if untreated. Aim: To study the incidence of abnormal platelet counts and to determine the risk factors associated with abnormal platelet counts in neonates admitted to the Neonatal Intensive Care Unit (NICU). Materials and Methods: A retrospective analysis of platelet count of all neonates admitted to a tertiary NICU of RL Jalappa Hospital, Tamaka, Karnataka, India, between July 2020 and June 2021 was done to determine the incidence and risk factors associated with abnormal platelet count (thrombocytopenia and thrombocytosis). Data of all the neonates were collected retrospectively from July 2021 to August 2021 and analysed. A total of 562 neonates were included in the study. Categorical data was taken and expressed in the form of frequencies and percentages. Data were entered as frequencies using Microsoft excel version 2203 and analysed using Statistical Package for Social Sciences (SPSS) software version 22.0. Chi-square and Fischer’s exact test were used to determining the significance of the data. The p-value &lt;0.05 was considered statistically significant. Results: Out of 629 neonates admitted, 562 neonates were included in the study. Total 209 neonates had thrombocytopenia, with early thrombocytopenia being in 94 (45%) and late being in 115 (55%). Thrombocytosis was seen in only 15 neonates where 7 (46.6%) had early, and 8 (53.3%) had late thrombocytosis. The most common risk factor associated with both cases was sepsis. Placental insufficiency had a statistically significant association with thrombocytopenia (p&lt;0.001**). Term babies had a higher incidence of thrombocytopenia and thrombocytosis, and the association with thrombocytopenia was statistically significant (p=0.043*). Conclusion: Based on the present study, it can be concluded that abnormal platelet count is quite a common finding in sick neonates. Thrombocytopenia is more common than thrombocytosis. The most common risk factor is sepsis, it should not be neglected, and appropriate treatment should be initiated once an abnormal platelet count is detected in neonates.

Nab-paclitaxel plus S-1 versus oxaliplatin plus S-1 as first-line treatment in advanced gastric cancer: results of a multicenter, randomized, phase III trial (GAPSO study).

Background:This study aimed to investigate the superiority of nab-paclitaxel plus S-1 (AS) over oxaliplatin plus S-1 (SOX) in patients with advanced gastric cancer (AGC).Methods:In this multicenter, randomized, phase III superiority trial, eligible patients with unresectable, locally advanced gastric adenocarcinoma were recruited and randomly assigned (1:1) to receive AS (nab-paclitaxel 260 mg/m2 on day 1 or 130 mg/m2 on days 1 and 8; oral S-1 40–60 mg twice daily for 14 days) or SOX (130 mg/m2 oxaliplatin on day 1; oral S-1 40–60 mg twice daily for 14 days) every 3 weeks for up to six cycles. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival, objective response rate, and safety.Results:Owing to slow enrolment, an unplanned interim analysis was performed, resulting in the early termination of the study on 31 December 2021 (data cutoff). Between March 2019 and March 2021, 97 patients (AS, n = 48; SOX, n = 49) were treated and evaluated for efficacy and safety of AS and SOX. As of the data cutoff, the median follow-up was 23.13 months [95% confidence interval (CI), 13.39–32.87]. The median PFS was 9.03 months (95% CI, 6.50–11.56) in the AS group and 5.07 months (95% CI, 4.33–5.81) in the SOX group, demonstrating a better PFS tendency following AS treatment than SOX treatment (hazard ratio = 0.59; 95% CI, 0.37–0.94; p = 0.03). The most common grade 3 or worse adverse events were anemia, neutropenia, and leukopenia in both groups, with a higher incidence of thrombocytopenia in the SOX group.Conclusion:Although this study was terminated early, the results demonstrated a better PFS tendency in patients with AGC who were treated with AS than in those treated with SOX, with controllable toxicities.Trial registration:Clinical Trials.gov identifiers: NCT03801668. Registered January 11, 2019.

Lenalidomide Compared to Ixazomib Maintenance in Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis

BackgroundMaintenance therapy is considered a standard of care in transplant eligible (TE) and non transplant eligible (NTE) patients with newly diagnosed multiple myeloma (NDMM). While immunomodulators (IMID) and proteasome inhibitors (PI) have been proposed as maintenance therapy options, there are no randomised trials (RCTs) directly comparing these agents in the maintenance setting. The IMID lenalidomide (Len) and the PI ixazomib (Ixa) have been compared against placebo as maintenance strategies in NDMM. We present a network meta-analysis (NMA) of RCTs comparing the efficacy and safety of Len and Ixa maintenance therapies in NDMM.MethodsWe searched various biomedical databases for eligible studies evaluating Len or Ixa against placebo/ observation as maintenance therapy in patients with NDMM from date of inception through November 2020. The primary outcome was progression-free survival (PFS). Secondary outcomes include overall survival (OS) and adverse events (AE). The Cochrane risk of bias tool version 2.0 was used to assess trial quality. A Bayesian NMA model was used to assess the relative effects of competing treatments on PFS and OS outcomes. Adverse events were assessed using the synthesis without meta-analysis (SWIM) approach due to variability in the toxicity scoring criteria. The GRADE approach was used to rate the certainty of the evidence. This study is registered with PROSPERO, CRD42021226157.ResultsWe identified eight studies including 3229 transplant eligible (TE) and 1689 non transplant eligible (NTE) patients. All studies were judged to have low risk of bias. Len but not Ixa was associated with statistically significant improvement in PFS when compared to placebo in TE (Len: Hazard Ratio (HR) 0.46, 95% Credible Interval (CrI) 0.35-0.56, high certainty; Ixa: HR 0.72, 95% CrI 0.46-1.13, moderate certainty) and NTE (Len: HR 0.46, 95% CrI 0.29-0.75, high certainty; Ixa: HR 0.69, 95% CrI 0.43-1.18, moderate certainty). Bayesian modelling demonstrated a 97% and 93% probability that Len resulted in superior PFS compared to Ixa in TE and NTE patients respectively. Both Len and Ixa were not associated with statistically significant improvement in OS compared to placebo in TE and NTE patients. There was no significant effect modification on the effect of Len vs placebo and Ixa vs placebo by cytogenetics status, use of proteasome inhibitors for induction or duration of maintenance therapies for PFS and/or OS outcomes. Len were judged to have a higher incidence of second malignancies and grade 3 or 4 neutropenia than Ixa while Ixa was judged to have a higher incidence of thrombocytopenia than Len.ConclusionsMaintenance therapy with Len may provide a larger PFS benefit than Ixa regardless of type of induction therapy and cytogenetic risk in patients with NDDM. The differing toxicity profile of these agents is also an important consideration for treatment decisions. RCTs directly comparing these maintenance strategies are warranted. [Display omitted] DisclosuresOoi: Jansen: Honoraria; Teva Pharmaceuticals: Honoraria; GSK: Honoraria; Abbvie: Honoraria; Amgen: Honoraria. Chng: Sanofi: Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Amgen: Honoraria; BMS/Celgene: Honoraria, Research Funding; Johnson and Johnson: Honoraria, Research Funding; Pfizer: Honoraria.

A systematic review and meta-analysis of myelosuppression in pediatric patients treated with linezolid for Gram-positive bacterial infections

BackgroundThe incidence of linezolid-induced myelosuppression in pediatric patients was reported at large difference among prospective studies, with a range of 0–24%. Additionally, there is little study which evaluated the impact of linezolid administration period on myelosuppression in pediatric patients, while it is one of the most frequent reason that linezolid therapy has to be discontinued in adult patients. Here, we performed a systematic review and meta-analysis to reveal the incidence of linezolid-induced thrombocytopenia and anemia, and impact of the administration period of linezolid on myelosuppression based on individual data analysis of pediatric patients. MethodsWe systematically searched the Scopus, EMBASE, Cochrane Central Register of Controlled Trials, PubMed, and CINAHL until April 2020. We investigated the incidence of linezolid-induced thrombocytopenia and anemia using pooled analysis, and evaluated the impact of linezolid administration period on myelosuppression using meta-analysis. ResultsThirteen studies with 969 pediatric patients were identified. The pooled incidences of thrombocytopenia and anemia were 9% (95% confidence interval (CI), 3–18%) and 4% (95% CI, 0–12%), respectively. Our meta-analysis showed the extension of linezolid administration period (more than 14 days) resulted in higher incidence of thrombocytopenia (OR 4.86, 95% CI 1.10–21.55) and anemia (OR 4.57, 95% CI 0.13–160.49). ConclusionsThe incidence of linezolid-induced myelosuppression in pediatric patients was less than 10%. However, our meta-analysis revealed linezolid administration period for more than 14 days was one of risk factors associated with linezolid-induced myelosuppression. Therefore, especially for pediatric patients treated with linezolid for more than 14 days, careful monitoring of myelosuppression is required.

Comparison of irinotecan and oxaliplatin as the first-line therapies for metastatic colorectal cancer: a meta-analysis

BackgroundIrinotecan (IRI) and oxaliplatin (Ox) are standard therapeutic agents of the first-line treatments for metastatic colorectal cancer (mCRC). Previous meta-analyses of randomized controlled trials (RCTs) showed that treatment with Ox-based compared with IRI-based regimens was associated with better overall survival (OS). However, these reports did not include trials of molecular targeting agents and did not take methods for the administration of concomitant drugs, such as bolus or continuous infusion of 5-fluorouracil, into account. A systematic literature review was performed to compare the efficacy and toxicity profiles between IRI- and Ox-based regimens as the first-line treatments for mCRC.MethodsThis meta-analysis used data from the Cochrane Central Register of Controlled Trials, PubMed, and SCOPUS. The primary endpoint was OS, and the secondary endpoints were progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs).ResultsNineteen trials involving 4571 patients were included in the analysis. No statistically significant difference was observed between the two groups in terms of OS, PFS, and ORR. There was no significant heterogeneity. Regarding ≥ grade 3 AEs, IRI-based regimens were associated with a high incidence of leukopenia, febrile neutropenia, and diarrhea. Moreover, there was a high incidence of thrombocytopenia and peripheral sensory neuropathy in patients who received Ox-based regimens. In a subgroup analysis, IRI combined with bevacizumab was correlated with a better PFS (HR = 0.90, 95% CI = 0.82–0.98, P = 0.02), but not with OS (pooled HR = 0.91, 95% CI = 0.80–1.03, P = 0.15).ConclusionAlthough the safety profiles of IRI- and Ox-based regimens varied, their efficacy did not significantly differ. The combination of anti-VEGF antibody and IRI was associated with better PFS compared with anti-VEGF antibody and Ox. Both regimens could be used as the first-line treatments for mCRC with consideration of the patients’ condition or toxicity profiles.

Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease

BackgroundAcute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD.MethodsWe conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator’s choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56.ResultsA total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non–relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]).ConclusionsRuxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy. (Funded by Novartis; REACH2 ClinicalTrials.gov number, NCT02913261.)

Splenomegaly during oxaliplatin-based chemotherapy in colon cancer.

88 Background: Splenic enlargement has been reported in patients treated with oxaliplatin. However, the characteristics of oxaliplatin-induced splenomegaly were not well studied. Here we evaluated the change of splenic volume and its clinical significance in patients treated by oxaliplatin-based regimen. Methods: Patients with stage II-IV primary colon cancer treated with oxaliplatin and capecitabine in China National Cancer Center from January 2016 to December 2017 were screened for this retrospective study. Those with complete laboratory tests and computed tomographic data before, during and up to 1.5 years after the chemotherapy were selected. The splenic size was measured by AWVolumeshare5. Splenomegaly was defined as an over 30% increase of splenic size from baseline. Recovery of splenomegaly was defined as the splenic size fell back to a 0.9 to1.1-fold range of baseline. Results: Out of a total of 144 patients, 102 (70.8%) had over 30% increase, 72 (50.0%) had over 50% increase, and 22 (15.3%) had over 100% increase in splenic size after oxaliplatin-based regimen. Among the 102 splenomegaly patients, 5 (4.9%) develop splenomegaly within 3 chemotherapy cycles, 53 (53.0%) within 6 cycles, 73 (71.6%) within 9 cycles, and 102 (100.0%) within 3 months after the last administration of oxaliplatin. Compared to the group without splenomegaly, patients with splenomegaly received more cycles of oxaliplatin administrations (median 8 vs 6, p &lt; 0.001) and greater dose intensity (total dose per square meter) (median 822.8mg/m2 vs 629.3mg/m2, p &lt; 0.001). Patients with splenomegaly had higher incidence of thrombocytopenia (61.7% vs 38.1%, p = 0.009) and are more likely to undergo oxaliplatin dose reduction due to thrombocytopenia (21.6% vs 7.1%, p = 0.038). The recovery rates of splenic size within 0.5, 1 and 1.5 years after the end of oxaliplatin treatment were 23.2%, 50.6% and 74.3%, respectively. Conclusions: Splenomegaly are common in patients treated with oxaliplatin-based chemotherapy, and most would recover in 1.5 years after completion of therapy. Patients with splenomegaly are prone to experience thrombocytopenia and oxaliplatin dose reduction. Further studies are needed to reveal the mechanism how oxaliplatin induce splenomegaly.

Clinical characteristics and risk factors of microvascular involvement in primary antiphospholipid syndrome: a longitudinal single-center study in China.

The objective of this study was to investigate risk factors of microvascular involvement and survival in Chinese patients with primary antiphospholipid syndrome. In this single-center, retrospective study, we enrolled 112 patients with a confirmed diagnosis of primary antiphospholipid syndrome who were admitted to Peking Union Medical College Hospital from January 2004 to December 2016. Demographic data, clinical characteristics, laboratory results, and follow-up records were collected. A total of 112 patients with primary antiphospholipid syndrome were studied. Microvascular involvement was identified in 21 patients (18.75%). Patients with microvascular involvement experienced fewer episodes of arterial or venous thrombosis (28.6% vs. 84.6%) and a higher incidence of thrombocytopenia (85.7% vs. 54.9%), respectively. Low complement and elevated high-sensitivity CRP levels were observed more frequently in the microvascular group compared with the non-microvascular group (complement 38.1% vs. 18.7%; high-sensitivity CRP 71.4% vs. 31.9%, respectively). Anti-β2-glycoprotein I antibodies were more prevalent in patients with microvascular involvement than in patients without (66.7% vs. 33.0%, respectively). Multivariate logistic regression analysis revealed that thrombocytopenia (odds ratio = 4.523, 95% confidence interval 1.139-17.962), elevated high-sensitivity CRP levels (odds ratio = 6.385, 95% confidence interval 1.969-20.704), and anti-β2-glycoprotein I antibody positivity (odds ratio = 5.042, 95% confidence interval 1.555-16.352) were independent risk factors for microvascular involvement. A Kaplan-Meier analysis revealed that survival was significantly poorer in patients with microvascular involvement compared with patients without (p = 0.0278). In addition to arterial and venous thrombosis, antiphospholipid syndrome can affect the microvasculature of select organs. It is thus important for clinicians to be aware that antiphospholipid syndrome-associated microvascular involvement has a unique pathogenesis and can be a life-threatening condition.

Is triple-positive serology for Epstein-Barr virus (VCA-IgG, VCA-IgM, EBNA-IgG) a specific feature of angioimmunoblastic T-cell lymphoma?

We assessed the frequency of triple-positive serology (viral capsid antigen [VCA]-immunoglobulin G [IgG], VCA-immunoglobulin M, Epstein-Barr nuclear antigen-IgG) for Epstein-Barr virus (EBV) in a small number of patients with angioimmunoblastic T-cell lymphoma (AITL) at disease onset. Nine patients with newly diagnosed AITL were retrospectively enrolled in the present study. For all of them, EBV serology data were available. Of 9 patients, 7 (77.7%) had a triple-positive serology (VCA-IgG, VCA-IgM, EBNA-IgG ) for EBV. These patients were characterized by bone marrow involvement, high incidence of thrombocytopenia, and poor prognosis according to Revised International Prognostic Index and Prognostic Index for Angioimmunoblastic T-cell Lymphoma scores. Assessment of both viremia and serology for EBV could be useful in patients with clinical and laboratory data suggesting lymphoma diagnosis; furthermore, although our data need to be validated in a larger cohort of patients, triple positivity for EBV serology might help to direct the diagnosis toward AITL.

Comparison of two dose calculation methods of intra-arterial carboplatin in the treatment of recurrent glioblastoma multiforme.

e13503 Background: Glioblastoma is a deadly brain cancer, and as part of the natural evolution, its relapses will mostly occur 32 to 36 weeks after the initial diagnosis. The standard of care for recurrent glioblastomas is not well defined and multiple options exist. Intra-arterial chemotherapy as one option is currently practiced at the Centre hospitalier universitaire de Sherbrooke, the only center doing this procedure in Canada. The aim of this study is to evaluate the impact of using the area under the curve (AUC) or body surface area (BSA) dosing formula to guide intra-arterial carboplatin administration. It was designed to explore the relation of two dose calculation methods on efficacy and toxicity, determined by progression-free survival (PFS) and hematologic toxicity, respectively. Methods: A retrospective observational study was conducted, which includes adult in-patients who received intra-arterial carboplatin for recurrent glioblastoma from June 1st, 2000 to December 31st, 2017. It examined the associations of the method used to calculate the doses, in mg or mg/mL x min-1, with clinical outcomes. Results: One hundred ninety patients were included in the analysis. For the primary endpoint, an exposure greater than 6 of AUC was found potentially harmful in terms of efficacy compared to AUC under 6 (HR 0.529, p = 0.0044). In terms of toxicity, a higher AUC is highlighted to correlate with a slightly higher incidence of thrombocytopenia and neutropenia (OR 1.051 p = 0.0271; OR 1.072 p = 0.049). No significant association between toxicity and dose calculated with BSA could be established. Conclusions: AUC greater than 6 is detrimental in terms of effectiveness according to progression free survival. Moreover, AUC could be used to predict neutropenia and thrombocytopenia. However no significant predictions were found using BSA method. We recommend the use of AUC method in intra-arterial carboplatin instead of BSA method since the latter was not statistically related to toxicity. A prospective trial comparing the two dosage methods would be needed.

Platelet Biogenesis in the Lung Circulation

Platelets are indispensable in hemostasis, thrombosis, and immune responses. In humans, billions of platelets are produced each day from megakaryocytes, however the mechanisms of mature platelet production are incompletely understood. Megakaryocytes are produced in the bone marrow and have been visualized to communicate with the bone marrow sinusoids to release proplatelet fragments. Megakaryocytes have also been found in other tissues, including the lung, but the function of megakaryocytes in these locations is unclear. Historical data indicate that the lung may be a site of platelet biogenesis. The concentration of megakaryocytes in the blood exiting the lung is much lower than the blood entering the lung (implying filtering) and conversely, platelet counts are higher in blood draining from the lungs. Additionally, when the lung circulation in entirely bypassed, megakaryocytes accumulate in the blood and there is a high incidence of thrombocytopenia. However, direct proof of platelet biogenesis in the lung is lacking. We used lung intravital microscopy combined with fluorescently labeled mouse strains and directly visualized intravascular megakaryocytes releasing platelets in the lung circulation. We also visualized megakaryocytes in the bone marrow and spleen releasing proplatelet fragments, and megakaryocyte migration in toto from the bone marrow, which are presumably the source material for lung platelet production. The megakaryocyte-releasing events in the lung were quantified and represent at least half of the total platelet production in mice, which can be increased by the application of thrombopoietin. We also observed a much larger extravascular pool of megakaryocytes in the lung that were not platelet generating as observed by lung intravital imaging. The function of these lung-resident megakaryocytes is unknown, but RNA-Seq data points to a potential role in lung immunity. Orthotopic, single-lung transplantation experiments into thrombocytopenic and hematopoietic progenitor-deficient animals (c-mpl-/-) revealed that peripheral blood platelet counts and bone marrow hematopoietic progenitors could be fully reconstituted by the lung transplant procedure implying the presence of hematopoietic progenitors in the mouse lung. Indeed, these progenitors were directly detected in the extravascular lung and purified populations of hematopoietic progenitors in the lung could correct thrombocytopenia in c-mpl-/-animals. Finally, the lung transplant procedure produced donor-derived chimerism of other hematopoietic lineages such as neutrophils and lymphocytes. We conclude that the lung has significant hematopoietic potential including being a major site of platelet biogenesis. DisclosuresNo relevant conflicts of interest to declare.

Phase II study of S-1 plus oxaliplatin (OX) at dose of 130 mg/m2 (SOX130) in Japanese patients (pts) with advanced gastric cancer (AGC).

112 Background: The phase III G-SOX trial had adopted SOX100 due to high incidence of thrombocytopenia in the previous phase I/II study, and failed to demonstrate the non-inferiority of SOX100 to S-1 plus cisplatin in chemotherapy-naïve Japanese pts with AGC. However, OX 130 mg/m2 has been approved for AGC in Japan since Sep 2014 on the evidence of the REAL-2 trial. Therefore, we conducted a study to evaluate the feasibility of SOX130 in Japanese AGC pts. Methods: This is a single-arm, open-label, multicenter, phase II study. Pts with unresectable or recurrent adenocarcinoma of stomach, no prior chemotherapy and ECOG PS 0 or 1 were treated with SOX130 (S-1 80-120 mg/day according to BSA for 2 weeks, OX 130 mg/m2 on day 1, every 3 weeks). The primary endpoint was the 3-cycle completion rate, defined as the proportion of pts who receive at least 80% of the planned OX dose for the first 3-cycle. We set the threshold 3-cycle completion rate at 50% and the expected rate at 75%. A sample size of 23 pts was needed with 80% power at a 5% α-level (one-sided). Results: From April 2015 to June 2016, 25 pts were enrolled. Pts’ characteristics were as follows: median age 64.5 years (range, 32-76), male/female 21/4, PS 0/1 15/10, unresectable/recurrent 21/4, and intestinal/diffuse 7/18. The 3-cycle completion rate was 72.0% (90% CI 53.8-86.1%). Among the 12 pts with measurable lesions, objective response rate and disease control rate were 58.3% and 83.3%, respectively. With a median follow-up period of 5.2 months, median progression-free survival was 7.5 months. Grade 3 adverse events were anorexia (n = 5), anemia (n = 3), thrombocytopenia (n = 2), neutropenia (n = 1) and nausea (n = 1). No treatment-related death was observed. Conclusions: SOX130 could be a first-line treatment option even in Japanese AGC pts. Clinical trial information: UMIN000016973.

Hepatitis B infection is associated with an increased incidence of thrombocytopenia in healthy adults without cirrhosis.

The association between HBV infection and incident thrombocytopenia among subjects without cirrhosis or splenomegaly is unknown. Therefore, we sought to elucidate the association between HBV infection and the development of thrombocytopenia in a large cohort of apparently healthy men and women. A cohort study was performed in 122200 participants without liver cirrhosis or splenomegaly who underwent comprehensive health examinations and were followed until December 2014. HBV infection was defined by the presence of hepatitis B surface antigen (HBsAg) at baseline. Thrombocytopenia was defined as a platelet count <150000/μL. Cox proportional hazard models were used to estimate adjusted hazard ratios with 95% confidence intervals (CIs) for incident thrombocytopenia. HBsAg was positive in 4857 of 122200 subjects (4.0%) at baseline. During 883983 person-years of follow-up, 2037 incident cases of thrombocytopenia were identified (incident rate 2.3 per 1000 person-years). HBsAg-positive subjects had a higher incidence of thrombocytopenia than did healthy controls (11.2 vs 1.9 per 1000 person-years, respectively). The multivariate-adjusted hazard ratio (95% CI) for incident thrombocytopenia comparing HBsAg-positive to HBsAg-negative subjects was 5.71 (5.10-6.38). Strong associations between HBsAg positivity and thrombocytopenia were consistently observed across prespecified subgroups. In this large cohort study of an apparently healthy population, HBsAg positivity was strongly and independently associated with incident thrombocytopenia, indicating that mechanisms of thrombocytopenia other than portal hypertension may exist in healthy HBV carriers.