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1.
Efficacy and Safety of Recombinant Thrombomodulin for the Prophylaxis of Veno-Occlusive Complication in Allogeneiccit Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis
Kashyap, R., Anwer, F., Iqbal, M. A., Khalid, F., Khan, A., Ali, M. A., Anwar, M. Y., Chaudhary, A., Jaan, A.
Hematology/Oncology and Stem Cell Therapy. 2023;16(2):93-101
Abstract
BACKGROUND Hepatic veno-occlusive disease (VOD), also termed as sinusoidal obstruction syndrome (SOS), is a lethal complication after hematopoietic stem cell transplantation (HSCT). Various factors put patients undergoing allogeneic HSCT at an increased risk for VOD. Thrombomodulin (TM) is an important factor which has a wide range of effects, including anticoagulant, anti-inflammatory, angiogenic, and protective effect, on endothelial cells. It plays a role in preventing excessive coagulation and thrombosis by binding with thrombin and inhibiting the coagulation cascade. There are a limited number of options for the prevention of this fatal complication. Recombinant thrombomodulin (rTM), an endothelial anticoagulant co-factor, as prophylactic therapy might be able to prevent veno-occlusive complications after stem cell transplantation. METHODS A literature search was performed on PubMed, Embase, and Web of Science. We used the following Mesh terms and Emtree terms, "Hepatic Veno-Occlusive Diseases" OR "Sinusoidal Obstruction" OR "Stem Cell Transplantations " AND "Thrombomodulin" from the inception of data up to April 1, 2021. The PICO (Patient/Population, Intervention, Comparison and Outcomes) framework was used for the literature search. RESULTS For the VOD incidence after HSCTstem cell transplantation, the result was in favor of rTM with a risk ratio (RR) of 0.53 (I(2) = 0%, 95% confidence interval [CI] = 0.32-0.89). The incidence of transplant-associated thrombotic microangiopathy (TA-TMA) after HSCT was reduced in rTM group. The RR for incidence of TA-TMA was 0.48 (I(2) = 62%, 95% CI = 0.20-1.17) favoring rTM. The RR for incidence of graft-versus-host disease (GvHD) was also lower in rTM group, 0.48 (I(2) = 64%, 95% CI = 0.32-0.72). CONCLUSION In our meta-analysis, we evaluate the efficacy and safety of rTM in the prevention of SOS after HSCT. According to our results, rTM use led to a significant reduction in SOS episodes, TA-TMA, and GvHD after HSCT.
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2.
Eltrombopag for Treatment of Thrombocytopenia Following Hematopoietic Stem Cell Transplantation
Güven, Z. T., Çelik, S., Eser, B., Çetin, M., Ünal, A., Kaynar, L.
Turkish journal of haematology : official journal of Turkish Society of Haematology. 2022;39(2):103-108
Abstract
OBJECTIVE This study aimed to evaluate the efficacy and safety of eltrombopag (ELT) in the treatment of thrombocytopenia following hematopoietic stem cell transplantation (HSCT). MATERIALS AND METHODS Forty-eight patients treated with ELT for thrombocytopenia after allogeneic or autologous transplantation at the Erciyes University Bone Marrow Transplantation Center between July 2017 and July 2021 were evaluated retrospectively. RESULTS Forty-eight HSCT recipients were included in this study. Thirty (62.5%) patients were evaluated as having experienced delayed platelet recovery (DPR) and 18 (37.5%) patients as having experienced secondary failure of platelet recovery (SFPR). The median platelet count before ELT treatment was 13x10(9)/L (range: 3-20x10(9)/L). Twenty-three patients responded to treatment and the cumulative incidence of successful platelet recovery was 48%. Patients with both DPR and SFPR responded, but patients with DPR had a higher response rate (50% vs. 44%). The median platelet count of the 23 responding patients was 12x10(9)/L (5-19x10(9)/L) before treatment and 68x10(9)/L (52-266x10(9)/L) after treatment (p<0.0001). While the number of bone marrow megakaryocytes before treatment was adequate in 22 (46%) cases, it was decreased in 26 (54%) cases. Patients with adequate bone marrow megakaryocytes had a better response rate than those without (77% vs. 23%, p<0.0001). The group with adequate megakaryocytes responded to treatment at a median of 33 days (range: 9-174 days). Patients with decreased megakaryocytes responded at a median of 55 days (30-164 days) (p=0.002). No drug-related side effects were observed in any patients. CONCLUSION This real-life experience demonstrates that ELT is an effective and safe treatment option for thrombocytopenia after HSCT. The adequacy of bone marrow megakaryocytes before ELT treatment was an important factor affecting response to treatment.
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3.
A Single Nucleotide Polymorphism (SNP) in the SLC22A3 Transporter Gene Is Associated With the Severity of Oral Mucositis in Multiple Myeloma Patients Receiving Autologous Stem Cell Transplant Followed by Melphalan Therapy
Li, J., Persaud, A. K., Johnson, J. A., Sborov, D. W., Phelps, M. A., Hofmeister, C. C., Poi, M. J.
Anticancer Research. 2022;42(1):385-395
Abstract
BACKGROUND It has been reported that expression of OCT3 enhanced the sensitivity to melphalan in cells, indicative of potential roles of OCT3 in melphalan transport. Herein we investigated the association of select single nucleotide polymorphisms in SLC22A3 (gene encoding OCT3) with clinical outcomes in multiple myeloma (MM) patients with hematopoietic autologous stem cell transplants followed by high-dose melphalan therapy. MATERIALS AND METHODS Melphlan concentrations in blood samples from 108 MM patients were measured using liquid chromatography-tandem mass spectrometry (LC-MS/ΜS); genotypes of rs2048327, rs1810126, and rs3088442 in these patients were determined using quatitive RT-PCR assays. RESULTS Rs3088442 A variant-carriers had a significantly increased risk of severe oral mucositis in comparison with homozygous rs3088442 G-carriers with adjusted odds ratio of 4.00 (95% CI=1.25-14.7; p=0.027). Rs3088442 A carriers tended to have lower creatinine clearance (p=0.10) and higher maximum plasma concentration of melphalan (p=0.07). CONCLUSION OCT3 might be involved in melphalan transport in MM patients.
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4.
Combining blinatumomab and donor lymphocyte infusion in B-ALL patients relapsing after allogeneic hematopoietic cell transplantation: a study of the SFGM-TC
Chauvet, P., Paviglianiti, A., Labopin, M., Labussière, H., Boissel, N., Robin, M., Maillard, N., Ouachée-Chardin, M., Forcade, E., Poiré, X., et al
Bone marrow transplantation. 2022
Abstract
Relapsed B-cell acute lymphoblastic leukemia (B-ALL) after allogeneic stem cell transplantation (allo-HCT) still represents a major concern with poor outcomes. The aim of this study is to compare the efficacy and safety of blinatumomab and donor lymphocyte infusion (DLI) versus blinatumomab alone in this setting. This is a multicenter retrospective study from centers of SFGM-TC. All transplanted patients who received blinatumomab salvage therapy were included. Patients who received DLI from 1 month before to 100 days after the starting of blinatumomab were included in the blina-DLI group. Seventy-two patients were included. Medium follow-up was 38 months. Fifty received blinatumomab alone and 22 the association blinatumomab-DLI. Two-year overall survival (OS) was 31% in the blinatumomab group and 43% in the blinatumomab-DLI group (p = 0.31). Studying DLI as a time dependent variable, PFS did not significantly differ between the 2 groups (HR:0.7, 95% CI: 0.4-1.5). In multivariate analysis, DLI was not a prognostic factor for OS, progression-free survival and progression/relapse incidence. Adverse events and graft-versus-disease rates were comparable in the 2 groups. In conclusion, adding DLI between 1 month before and 100 days after start of blinatumomab is safe and does not seem to improve outcomes in B-ALL patients who relapsed after allo-HCT.
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5.
Effectiveness of defibrotide in the prevention of hepatic venooclusive disease among adult patients receiving allogeneic hematopoietic cell transplantation: A retrospective single center experience
Kayikci, O., Akpinar, S., Tekgunduz, E.
Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2022;61(1):103369
Abstract
Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is one of the most life-threatening early complications following hematopoietic cell transplantation (HCT). Due to the high mortality rate of severe VOD/SOS accompanied with multiorgan failure, there is a great interest in preventive strategies. The efficacy of defibrotide (DF) on the prevention of VOD/SOS has been clearly shown in high-risk pediatric patients, but evidence-based data on adults is scarce. In this report, we aimed to assess the impact of DF on the incidence of VOD/SOS in our center by posttransplant day 30 among patients who were treated with allogeneic HCT (allo-HCT). The study included a total of 56 patiens (28 males, 28 females). The median age of the study cohort was 43 (20-68). The daily dose of DF was 10 mg/kg and 25 mg/kg in 53 (94.6 %) and 3 (5.3 %) patients, respectively. Patients also recieved oral ursodeoxycolic acid (UDCA) 250 mg three-times daily started with conditioning until D + 90. Twenty-three (41.1 %) patients had at least one major EBMT-defined risk factor for development of VOD/SOS. One patient who belonged to a very high-risk group (with at least two major risk factors) developed very-severe VOD/SOS at posttransplant D + 20 and died as a result of multiorgan failure. The cumulative incidence of VOD/SOS at D + 30 was 1.9 %. Our findings indicate that 10 mg/kg daily intravenous DF combined with UDCA is quite effective in prevention of VOD/SOS in patients who underwent first allo-HSCT.
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6.
Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab
Jodele, S., Dandoy, C. E., Lane, A., Laskin, B. L., Teusink-Cross, A., Myers, K. C., Wallace, G., Nelson, A., Bleesing, J., Chima, R. S., et al
Blood. 2020;135(13):1049-1057
Abstract
Overactivated complement is a high-risk feature in hematopoietic stem cell transplant (HSCT) recipients with transplant-associated thrombotic microangiopathy (TA-TMA), and untreated patients have dismal outcomes. We present our experience with 64 pediatric HSCT recipients who had high-risk TA-TMA (hrTA-TMA) and multiorgan injury treated with the complement blocker eculizumab. We demonstrate significant improvement to 66% in 1-year post-HSCT survival in treated patients from our previously reported untreated cohort with same hrTA-TMA features that had 1-year post-HSCT survival of 16.7%. Responding patients benefited from a brief but intensive course of eculizumab using pharmacokinetic/pharmacodynamic-guided dosing, requiring a median of 11 doses of eculizumab (interquartile range [IQR] 7-20). Treatment was discontinued because TA-TMA resolved at a median of 66 days (IQR 41-110). Subjects with higher complement activation measured by elevated blood sC5b-9 at the start of treatment were less likely to respond (odds ratio, 0.15; P = .0014) and required more doses of eculizumab (r = 0.43; P = .0004). Patients with intestinal bleeding had the fastest eculizumab clearance, required the highest number of eculizumab doses (20 vs 9; P = .0015), and had lower 1-year survival (44% vs 78%; P = .01). Over 70% of survivors had proteinuria on long-term follow-up. The best glomerular filtration rate (GFR) recovery in survivors was a median 20% lower (IQR, 7.3%-40.3%) than their pre-HSCT GFR. In summary, complement blockade with eculizumab is an effective therapeutic strategy for hrTA-TMA, but some patients with severe disease lacked a complete response, prompting us to propose early intervention and search for additional targetable endothelial injury pathways.
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7.
Impact of Palifermin on Transplant Outcomes in Children and Adolescents Undergoing Allogeneic Hematopoietic Cell Transplantation
CzyŻewski, K., DĘbski, R., Bartoszewicz, N., Demidowicz, E., Richert-PrzygoŃska, M., ŁĘcka, M., Tarasenko, S., StyczyŃski, J.
Anticancer research. 2020;40(11):6531-6537
Abstract
BACKGROUND Oral mucositis (OM) is considered to be one of the worst and most debilitating complications of conditioning for hematopoietic cell transplantation (HCT). Prevention and treatment of this complication is one of the utmost priorities of supportive therapy during transplant procedure. The objective of this study was the analysis of the influence of palifermin, keratinocyte growth factor (KGF), on transplant outcomes in patients undergoing allo-HCT. PATIENTS AND METHODS A total of 253 allo-HCTs performed between 2003-2018 in patients aged 0-19 years at a single center were analyzed. KGF was administered in 161 HCTs. Uni- and multivariate risk factor analyses were performed. RESULTS In spite of reducing the duration and grade of mucositis, no prognostic impact of KGF was shown for overall survival, event-free survival, relapse incidence, acute and chronic graft-versus-host disease (GVHD), nor GVHD-free relapse-free survival. CONCLUSION Palifermin had no impact on transplant outcomes in children and adolescents undergoing allo-HCT.
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8.
Transjugular Intrahepatic Portosystemic Shunt for Very Severe Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation with Post-transplantation Cyclophosphamide
Gómez-Centurión, I., Bailén, R., Oarbeascoa, G., Muñoz, C., Luque, AÁ, Boyra, M. E., Calleja, E., Rincón, D., Dorado, N., Barzallo, P., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020;26(11):2089-2097
Abstract
Hepatic veno-occlusive disease or sinusoidal obstruction syndrome (VOD/SOS) is a threatening complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT), with high mortality rates despite early medical treatment, including the use of defibrotide (DF). We retrospectively analyzed 185 unmanipulated haploidentical (haplo-) HSCT with post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis performed consecutively between 2011 and June 2019 in a single center. Seventeen patients (9.2%) were diagnosed with VOD/SOS. Based on revised European Society for Blood and Marrow Transplantation severity criteria, the VOD/SOS cases were classified as mild in 2 patients (11.7%), moderate in 2 (11.7%), severe in 2 (11.7%), and very severe in 11 (64.9%). Thirteen patients (76%) were treated with DF, including all patients with severe or very severe VOD/SOS, except 1 patient with CNS hemorrhage. Sixteen patients (94%) were alive at day +100 after HSCT. Seven patients (41%) with very severe VOD/SOS were treated with transjugular intrahepatic portosystemic shunt (TIPS) owing to rapid clinical or analytical deterioration or refractory hepatorenal syndrome despite medical treatment, including DF. TIPS insertion was performed at a median time since VOD/SOS diagnosis of 4 days (range, 1 to 28 days) without technical complications in any case. The median hepatic venous pressure gradient before and after TIPS treatment was 24 mmHg (range, 14 to 29 mmHg) and 7 mmHg (range, 2 to 11 mmHg), respectively, with a median drop of 16 mmHg (range, 9 to 19 mmHg). Following TIPS insertion, all patients showed clinical improvement with hepatomegaly, ascites, and renal failure resolution, and all showed analytical improvement with reduced alanine aminotransferase (ALT), creatinine, and international normalized ratio values, except for patient 2, whose indication for TIPS was refractory hepatorenal syndrome with a normal ALT level. The 6 patients who had initiated DF before TIPS insertion completed 21 days of treatment. All patients met the criteria for complete remission (CR) at a median of 8 days after TIPS insertion (range, 2 to 82 days). The 100-day overall survival was 100%. For patients with rapid progressive VOD/SOS, early TIPS insertion allowed completion of DF therapy. The use of TIPS together with DF resulted in CR and no associated complications with no VOD/SOS-associated mortality despite high severity. In our experience, timely and individualized use of TIPS significantly improves outcomes of very severe VOD/SOS after haplo-HSCT. Therefore, TIPS should be promptly considered in rapidly progressive cases.
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9.
Eltrombopag is an effective and safe therapy for refractory thrombocytopenia after haploidentical hematopoietic stem cell transplantation
Fu, H., Zhang, X., Han, T., Mo, X., Wang, Y., Chen, H., Han, W., Wang, J., Wang, F., Yan, C., et al
Bone marrow transplantation. 2019
Abstract
Refractory thrombocytopenia is a frequent and severe complication after haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HSCT) and lacks effective treatment strategies. Eltrombopag has shown promising results in several thrombocytopenia disorders. We report 38 patients treated with eltrombopag for refractory thrombocytopenia after haplo-HSCT. Eight patients had delayed platelet engraftment, 15 patients had secondary failure of platelet recovery, and 15 patients had poor graft function (PGF). Eltrombopag was initiated at 25 or 50 mg daily, and the dosage was adjusted to a maximum of 50-100 mg daily to maintain platelet between 50 x 10(9)/L and 100 x 10(9)/L. The cumulative incidence of platelet recovery to transfusion independence was 63.2% and to ≥50 x 10(9)/L without transfusion support was 52.3%. Furthermore, neutrophil counts and hemoglobin were also increased in the nine responders with PGF. Nineteen (79.2%) of the 24 responders were able to taper off eltrombopag, and the remaining 5 patients were able to begin a taper. The median duration of treatment was 64 (range 14-195) days. The presence of megakaryocyte before initiation was the only independent factor influencing the efficacy of eltrombopag (P = 0.044). Eltrombopag was well tolerated in all patients. In summary, eltrombopag was a safe and effective therapy for refractory thrombocytopenia after haplo-HSCT.
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10.
Consensus Report by the Pediatric Acute Lung Injury and Sepsis Investigators and Pediatric Blood and Marrow Transplantation Consortium Joint Working Committees on Supportive Care Guidelines for Management of Veno-Occlusive Disease in Children and Adolescents, Part 3: Focus on Cardiorespiratory Dysfunction, Infections, Liver Dysfunction, and Delirium
Ovchinsky, N., Frazier, W., Auletta, J. J., Dvorak, C. C., Ardura, M., Song, E., McArthur, J., Jeyapalan, A., Tamburro, R., Mahadeo, K. M., et al
Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. 2018;24(2):207-218
Abstract
Some patients with veno-occlusive disease (VOD) have multiorgan dysfunction, and multiple teams are involved in their daily care in the pediatric intensive care unit. Cardiorespiratory dysfunction is critical in these patients, requiring immediate action. The decision of whether to use a noninvasive or an invasive ventilation strategy may be difficult in the setting of mucositis or other comorbidities in patients with VOD. Similarly, monitoring of organ functions may be very challenging in these patients, who may have fulminant hepatic failure with or without hepatic encephalopathy complicated by delirium and/or infections. In this final guideline of our series on supportive care in patients with VOD, we address some of these questions and provide evidence-based recommendations on behalf of the Pediatric Acute Lung Injury and Sepsis Investigators and Pediatric Blood and Marrow Transplantation Consortium Joint Working Committees.