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Comparison of early mortality between leukapheresis and non-leukapheresis in adult acute myeloid leukemia patients with hyperleukocytosis: a systematic review and meta-analysis
Rinaldi I, Sutandyo N, Winston K
Hematology (Amsterdam, Netherlands). 2022;27(1):141-149
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Editor's Choice
Abstract
OBJECTIVES One of the treatment modalities that can be used for hyperleukocytosis is leukapheresis. However, the result of studies showing the benefit of early mortality through the use of leukapheresis versus no leukapheresis is still inconclusive. Hence, we aimed to conduct a systematic review with meta-analysis to determine the effect of leukapheresis on early mortality in AML patients with hyperleukocytosis. METHODS We conducted a literature search on five databases (PubMed, EBSCOhost, Scopus, Clinicalkey, and JSTOR) up to October 2021 for studies comparing early mortality outcomes between hyperleukocytosis AML patients treated with leukapheresis versus no leukapheresis. Summary odds ratios (OR) and 95% confidence intervals (CI) were calculated using random-effects models. Heterogeneity tests were presented in I(2) value and publication bias was analyzed using a funnel plot. RESULTS Eleven retrospective cohort studies were eligible based on the inclusion and exclusion criteria. Pooled analysis showed that there was no significant difference in early mortality between patients receiving leukapheresis and not receiving leukapheresis in studies using hyperleukocytosis cutoff of 95,000/mm(3) or 100,000/mm(3) (OR: 1.17; 95% CI: 0.74-1.86; p: 0.50; I(2): 0%). Similarly, studies using hyperleukocytosis cutoff of 50,000/mm(3) also showed no benefits of early mortality (OR: 0.67; 95% CI: 0.43-1.05; p: 0.08; I(2): 0%). Most of the studies used had a moderate risk of bias due to being observational studies. Funnel plot showed an indication of publication bias on studies using hyperleukocytosis cutoff of ≥50,000/mm(3). CONCLUSION The use of leukapheresis does not provide early mortality benefit in adult AML patients with hyperleukocytosis.
PICO Summary
Population
Adult acute myeloid leukemia patients (11 studies, n= 1,407).
Intervention
Leukapheresis intervention (n= 1,090).
Comparison
Not receiving leukapheresis (n= 317).
Outcome
Pooled analysis showed that there was no significant difference in early mortality between patients receiving leukapheresis and not receiving leukapheresis in studies using hyperleukocytosis cutoff of 95,000/mm3 or 100,000/mm3. Studies using hyperleukocytosis cutoff of 50,000/mm3 showed no benefits of early mortality.
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Granulocyte and monocyte apheresis as an adjunctive therapy to induce and maintain clinical remission in ulcerative colitis: a systematic review and meta-analysis
Kiss S, Németh D, Hegyi P, Földi M, Szakács Z, Erőss B, Tinusz B, Hegyi PJ, Sarlós P, Alizadeh H
BMJ open. 2021;11(5):e042374
Abstract
OBJECTIVE The goal of treatment in ulcerative colitis (UC) is to induce and maintain remission. The addition of granulocyte and monocyte apheresis (GMA) to conventional therapy may be a promising therapeutic alternative. In this meta-analysis, we aimed to assess the efficacy and safety profile of GMA as an adjunctive therapy. DESIGN Systematic review and meta-analysis. METHODS We searched four databases (MEDLINE, Embase, Web of Science and Cochrane Central Register of Controlled Trials) for randomised or minimised controlled trials which discussed the impact of additional GMA therapy on clinical remission induction and clinical remission maintenance compared with conventional therapy alone. Primary outcomes were clinical remission induction and maintenance, secondary outcomes were adverse events (AEs) and steroid-sparing effect. ORs with 95% CIs were calculated. Trial Sequential Analyses were performed to adjusts for the risk of random errors in meta-analyses. RESULTS A total of 11 studies were eligible for meta-analysis. GMA was clearly demonstrated to induce and maintain clinical remission more effectively than conventional therapy alone (598 patients: OR: 1.93, 95% CI 1.28 to 2.91, p=0.002, I(2)=0.0% for induction; 71 patients: OR: 8.34, 95% CI 2.64 to 26.32, p<0.001, I(2)=0.0% for maintenance). There was no statistically significant difference in the number of AEs (OR: 0.27, 95% CI 0.05 to 1.50, p=0.135, I(2)=84.2%). CONCLUSION GMA appears to be more effective as an adjunctive treatment in inducing and maintaining remission in patients with UC than conventional therapy alone. PROSPERO REGISTRATION NUMBER CRD42019134050.
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Leukapheresis for the management of hyperleukocytosis in acute myeloid leukemia-A systematic review and meta-analysis
Bewersdorf JP, Giri S, Tallman MS, Zeidan AM, Stahl M
Transfusion. 2020
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Abstract
BACKGROUND Up to 20% of patients with acute myeloid leukemia (AML) present with hyperleukocytosis, usually defined as a white blood cell (WBC) count greater than 100 × 10(9) /L. Given the high early mortality rate, emergent cytoreduction with either leukapheresis, hydroxyurea, or chemotherapy is indicated, but the optimal strategy is unknown. STUDY DESIGN AND METHODS For this systematic review and meta-analysis we searched MEDLINE and EMBASE via Ovid, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science from inception through March 2020 for multiarm studies comparing early mortality rates of patients with AML treated with leukapheresis and those who were not. The risk ratio (RR) of early death for patients who received leukapheresis vs patients who did not was estimated using a sum of the log-ratio of individual study estimates weighted by sample size. RESULTS Among 13 two-arm, retrospective studies with 1743 patients (486 leukapheresis and 1257 nonleukapheresis patients), leukapheresis did not improve the primary outcome of early mortality compared to treatment strategies in which leukapheresis was not used (RR, 0.88; 95% confidence interval [CI], 0.69-1.13; P = .321) without statistically significant heterogeneity between studies (Cochran's Q, 18; P = .115; I(2) , 33.4%). Patients presenting with clinical leukostasis tended to be more likely to undergo leukapheresis (odds ratio, 2.01; 95% CI, 0.99-4.08; P = .052). CONCLUSION As we did not find evidence of a short-term mortality benefit and considering the associated complications and logistic burden, our results argue against the routine use of leukapheresis for hyperleukocytosis among patients with AML.
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Novel Leucocyte/Thrombocyte Apheresis for Induction of Steroid-Free Remission in Ulcerative Colitis: A Controlled Randomized Pilot Study
Kruis W, Nguyen P, Morgenstern J, Ramlow W, Dignass A, Stallmach A, Drebber U
Journal of Crohn's & colitis. 2019
Abstract
BACKGROUND AND AIMS In active ulcerative colitis [UC] refractory to mesalazine, escalation to either steroids or immunosuppression is common practice. The efficacy and safety of alternative escalation therapy with a novel leukocyte apheresis device were studied. METHODS This was a prospective, randomized, controlled multicentre pilot study comparing leukocyte apheresis with prednisolone in refractory UC (disease activity index [DAI] ≥ 4 and ≤8). Group A received weekly apheresis over five consecutive weeks. Group P received oral prednisolone 40 mg/day tapered to 0 mg at week 6. The primary end point was steroid-free clinical remission [DAI ≤ 2] at week 12. Clinical response was also analysed. RESULTS Twenty-four patients were enrolled, 13 of whom were randomized into group A and 11 into group P. Clinical remission off steroids at week 12 was achieved in 3/12 patients [25.0%] with apheresis and 2/10 [20.0%] with prednisolone [p = 1.0]. The response rate after 12 weeks was 75.0% in group A and 50.0% in group P. Mean DAI scores improved in both treatment groups [p = 0.008]. C-reactive protein decreased from 6.0 +/- 5.3 to 3.8 +/- 3.7 mg/L at 12 weeks in group A and increased from 5.2 +/- 6.0 to 6.3 +/- 7.9 mg/mL in group P. Both treatments were well tolerated. No unexpected serious adverse events were seen in group A. In group P one symptomatic infection with Clostridium difficile occurred. CONCLUSIONS In patients with active UC refractory to mesalazine a novel leukocyte apheresis showed promising results. A comparison with prednisolone revealed similar therapeutic effectivity and excellent safety, providing the chance to escalate without systemic steroids. CIV-12-01-003581.
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Addition of granulocyte/monocyte apheresis to oral prednisone for steroid-dependent ulcerative colitis: A randomized, multicentre, clinical trial
Domenech E, Panes J, Hinojosa J, Annese V, Magro F, Sturniolo G C, Bossa F, Fernandez F, Gonzalez-Conde B, Garcia-Sanchez V, et al
Journal of Crohn's & Colitis. 2018;12((6):):687-694
Abstract
Background and Aims: Steroid-dependency occurs in up to 30% of patients with ulcerative colitis (UC). In this setting, few drugs have demonstrated efficacy in inducing steroid-free remission. The aim was to evaluate the efficacy and safety of adding granulocyte/monocyte apheresis (GMA) to oral prednisone in patients with steroid-dependent UC. Methods: Randomized, multicentre, open trial comparing 7 weekly sessions of GMA plus oral prednisone (40mg/day and tapering) to prednisone alone in patients with active, steroid-dependent UC (Mayo score 4-10 and inability to withdraw corticosteroids in 3 months or relapse within the first 3 months after discontinuation). Patients were stratified by concomitant use of thiopurines at inclusion. A 9-week tapering schedule of prednisone was pre-established in both study groups. The primary end point was steroid-free remission (defined as a total Mayo score ≤2, with no subscore >1) at week 24, with no reintroduction of corticosteroids. Results: One hundred and twenty-three patients were included (63 GMA group, 62 prednisone alone). In the ITT analysis, steroid-free remission at week 24 was achieved in 13% (95%CI 6-24) in the GMA group and 7% (95%CI 2-16) in the control group (P=0.11). In the GMA group, time to relapse was significantly longer (HR 1.7 [1.16-2.48], P=0.005) and steroid-related adverse events were significantly lower (6% vs. 20%, P<0.05). Conclusions: In a randomized trial, the addition of 7 weekly sessions of GMA to a conventional course of oral prednisone did not increase the proportion of steroid-free remissions in patients with active steroid-dependent UC, though it delayed clinical relapse. ClinicalTrials.gov ID: NCT00702611.
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Shorter Relapse-Free Period after Leukocyte Removal Therapy in Younger than Older Patients with Ulcerative Colitis
Yamasaki S, Sakata Y, Yoshida H, Shirai S, Tanaka Y, Nakano R, Yukimoto T, Tsuruoka N, Shimoda R, Fukuda M, et al
Digestion. 2018;:1-7.
Abstract
BACKGROUND Leukocyte removal therapy (LRT) is an effective treatment for active ulcerative colitis (UC). The present study was performed to evaluate the relapse-free period after LRT and identify risk factors for relapse. METHODS In total, 94 patients who underwent first-time LRT for remission of moderate to severe UC from April 2004 to March 2016 were enrolled in the present study. The patients were randomly assigned to one of 2 treatments: leukocytapheresis (LCAP; n = 43) or granulocyte and monocyte/macrophage adsorptive apheresis (GMA; n = 51). The 5-year cumulative relapse-free rate and risk factors for relapse were evaluated. RESULTS The therapeutic response rate was 82% for GMA and 70% for LCAP without a statistically significant difference. The 5-year relapse-free rate was 34.7% in the LRT group. The 5-year relapse-free rate in patients aged > 40 years was 49.9%, which was significantly higher than that in patients aged ≤40 years (22.9%, p < 0.01). The relapse-free period was longer in the older than younger patients. CONCLUSIONS The relapse-free period after LRT was examined in patients with UC, and 34.7% of patients achieved clinical remission within a 5-year period. The risk factor for early relapse after LRT was younger age.
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Randomised, Double-blind, Placebo-controlled Trial of CCR9-targeted Leukapheresis Treatment of Ulcerative Colitis Patients
Eberhardson M, Karlen P, Linton L, Jones P, Lindberg A, Kostalla MJ, Lindh E, Oden A, Glise H, Winqvist O
Journal of Crohn's & Colitis. 2017;11((5)):534-542.
Abstract
Background and Aims: Ulcerative colitis patients display increased numbers of circulating pro-inflammatory monocyte human leukocyte antigen-DR [HLA-DRhi] monocytes expressing high levels of the gut-homing C-C chemokine receptor 9 [CCR9] and tumour necrosis factor [TNF]-alpha. The aim of this first-in-human, double-blind, randomised, placebo-controlled trial was to evaluate selective removal of circulating CCR9-expressing monocytes by leukapheresis in patients with moderate to severe ulcerative colitis, with regards to safety, tolerability, and immunological response. Methods: Patients with ulcerative colitis were treated every second day with leukapheresis during five sessions with a C-C chemokine ligand 25 [CCL25; CCR9 ligand] column or a placebo column. Results: No major safety concerns were raised and the procedure was well tolerated. Pro-inflammatory HLA-DRhi cells decreased significantly in the active treatment group [p = 0.0391] whereas no statistically significant change was seen in the placebo group [p = 0.4688]. There was a significant decrease of HLA-DRhi monocytes in the active group compared with the placebo group when corrected for the imbalance in weight between the groups [p = 0.0105]. Mayo score decreased in the active group [p = 0.0156] whereas the change in the placebo group was not significant [p = 0.1250]. Mayo score ≤ 3 was observed in five out of 14 patients [35.7%] in the active group compared with one out of eight [12.5%] receiving placebo. The number of responders in the active treatment group was eight out of 14 patients [57.1%], whereas in the corresponding placebo group three out of eight patients [37.5%] responded to placebo. A dose-response correlation was observed between the blood volume processed and clinical outcome. Conclusion: This clinical induction trial using CCL25-tailored leukapheresis demonstrates a safe and effective removal of activated monocytes with a clinical effect in patients with ulcerative colitis.
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Randomized, double-blind, placebo-controlled trial of CCR9-targeted leukapheresis treatment of ulcerative colitis patients
Eberhardson M, Karlen P, Linton L, Jones P, Lindberg A, Kostalla MJ, Lindh E, Oden A, Glise H, Winqvist O
Journal of Crohn's & Colitis. 2016;11((5):):534-542
Abstract
BACKGROUND AND AIMS Ulcerative colitis patients display increased number of circulating pro-inflammatory HLA-DRhi monocytes expressing high levels of the gut homing chemokine receptor CCR9 and TNF-alpha. The aim of this first-in-man double blind randomized placebo controlled trial was to evaluate selective removal of circulating CCR9-expressing monocytes by leukapheresis in patients with moderate to severe ulcerative colitis with regards to safety, tolerability and immunological response. METHODS Patients with ulcerative colitis were treated every second day with leukapheresis during 5 sessions with CCL25 (CCR9 ligand) column or a placebo column. RESULTS No major safety concerns were raised and the procedure was well tolerated. Pro-inflammatory HLA-DRhi cells decreased significantly in the active treatment group (p=0.0391) while no statistically significant change was seen in the placebo group (p=0.4688). There was a significant decrease of HLA-DRhi monocytes in the active group compared to the placebo group when corrected for the imbalance in weight between the groups (p=0.0105). Mayo score decreased in the active group (p=0.0156) whereas the change in the placebo group was not significant (p=0.1250). Mayo score ≤3 was observed in five out of 14 patients (35.7%) in the active group compared to one out of eight (12.5%) receiving placebo. The number of responders in the active treatment group was eight out of 14 patients (57.1%), whereas in the corresponding placebo group three out of eight patients (37.5%) responded to placebo. A dose response correlation was observed between the blood volume processed and clinical outcome. CONCLUSION This clinical induction trial using CCL25-tailored leukapheresis demonstrates a safe and effective removal of activated monocytes with a clinical effect in patients with ulcerative colitis.
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An open-label prospective randomized multicenter study of intensive versus weekly granulocyte and monocyte apheresis in active crohn's disease
Yoshimura N, Yokoyama Y, Matsuoka K, Takahashi H, Iwakiri R, Yamamoto T, Nakagawa T, Fukuchi T, Motoya S, Kunisaki R, et al
BMC Gastroenterology. 2015;15((1)):163.
Abstract
BACKGROUND Granulocyte and monocyte adsorptive apheresis (GMA) has shown efficacy in patients with active Crohn's disease (CD). However, with routine weekly therapy, it may take several weeks to achieve remission. This study was performed to assess clinical efficacy and safety of intensive GMA in patients with active CD. METHODS In an open-label, prospective, randomized multicentre setting, 104 patients with CD activity index (CDAI) of 200 to 450 received intensive GMA, at two sessions per week (n = 55) or one session per week (n = 49). Clinical remission was defined as a CDAI score <150. Patients in each arm could receive up to 10 GMA sessions. However, GMA treatment could be discontinued when CDAI decreased to <150 (clinical remission level). RESULTS Of the 104 patients, 99 were available for efficacy evaluation as per protocol, 45 in the weekly GMA group, and 54 in the intensive GMA group. Remission was achieved in 16 of 45 patients (35.6 %) in the weekly GMA and in 19 of 54 (35.2 %) in the intensive GMA (NS). Further, the mean time to remission was 35.4 +/- 5.3 days in the weekly GMA and 21.7 +/- 2.7 days in the intensive GMA (P = 0.0373). Elevated leucocytes and erythrocyte sedimentation rate were significantly improved by intensive GMA, from 8005/muL to 6950/muL (P = 0.0461) and from 54.5 mm/hr to 30.0 mm/hr (P = 0.0059), respectively. In both arms, GMA was well tolerated and was without safety concern. CONCLUSIONS In this study, with respect to remission rate, intensive GMA was not superior to weekly GMA, but the time to remission was significantly shorter in the former without increasing the incidence of side effects. UMIN registration # 000003666.
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Granulocyte/monocyte adsorptive apheresis in moderate to severe ulcerative colitis - effective or not?
Kruis W, Nguyen P, Morgenstern J
Digestion. 2015;92((1)):39-44.
Abstract
BACKGROUND AND AIMS Adsorptive granulocyte/monocyte apheresis (GMA) has shown promising efficacy in the treatment of patients with ulcerative colitis (UC). But a sham-controlled study was negative. A post-hoc analysis of this trial may haul out patients responding to GMA. METHODS A total of 168 UC patients with a disease activity (DAI) between 6 and 11 were enrolled in this study. Out of 168 patients, 112 received GMA and 56 sham apheresis. The basis for this post hoc analysis is the clinical study report issued by Otsuka America Pharmaceutical. RESULTS Baseline histology was available for 165 patients. Only 38% (63 of 165) of patients showed microscopic erosion/ulceration (group P). The remaining 62% of patients did not show microscopic erosion/ulceration (group A). The patients in group P showed significantly higher DAI, flexible proctosigmoidoscopy score and neutrophil infiltration into the colonic mucosa than those in group A (p = 0.0132, p = 0.0243 and p < 0.0001, respectively). Likewise, group P patients had a significantly (p = 0.0275) higher remission rate (11 of 46; 23.9%) when treated with GMA than with sham procedure (0 of 17; 0%). CONCLUSIONS Patients in group P who had more active UC than those in group A showed clear clinical efficacy in response to GMA. We believe that true DAI should be specified for further randomized controlled trials. © 2015 S. Karger AG, Basel.