Persistent Thrombocytopenia Research Articles

Thrombopoietin Levels Predict the Response to Avatrombopag Treatment in Patients with Persistent Thrombocytopenia after Haploidentical Hematopoietic Stem Cell Transplantation

Introduction: Persistent thrombocytopenia (PT) is a common and severe complication after haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HSCT), and there are currently no effective treatment strategies. Avatrombopag has shown promising results in the treatment of several thrombocytopenia disorders. However, no studies have examined the efficacy and safety of avatrombopag in the treatment of PT after haplo-HSCT, and predicting clinical response to avatrombopag before initiation is not possible. Thrombopoietin (TPO) is the chief cytokine that regulates megakaryocyte production and maturation, and endogenous TPO may be a biomarker of avatrombopag response. Methods: This study evaluated outcomes in patients who received the treatment of avatrombopag for persistent severe thrombocytopenia after haplo-HSCT between October 2019 and March 2022. On starting avatrombopag treatment, all included patients were with platelet counts ≤20×109/L and/or with platelet transfusion-dependence. Efficacy was assessed based on the platelet counts. Response was defined as platelet recovery to independence from platelet transfusion during or within 7 days after avatrombopag treatment, and complete response (CR) was defined as platelet recovery to ≥ 50×109/L for 7 consecutive days without platelet transfusion support. Endogenous TPO levels were measured by ELISA. Results: We report a cohort of 69 patients with PT after haplo-HSCT who were treated with avatrombopag. The 69 patients included 43 (62.3%) males and 26 (37.7%) females. The median age was 37 (11-60) years. Before starting avatrombopag therapy, the median platelet count was 15×109/L (range, 2-20×109/L). Forty patients (58.0%) had delayed platelet engraftment, and 29 patients (42.0%) had secondary failure of platelet recovery. Sixteen (23.2%) of the 69 patients had a history of using other TPO-RA (rhTPO or eltrombopag) for at least one round. Avatrombopag was initiated on a median of 59 (range 16-824) days after haplo-HSCT. Both the median starting and maximum doses were 40 mg daily. The rate of platelet recovery to transfusion independence was 72.5%, and the rate of platelet recovery to ≥ 50 ×109/L without transfusion support was 56.5%. Forty-seven (94.0%) of the 50 responders were able to taper off avatrombopag. The median duration of treatment was 40 (range 15-195) days. In addition, we present a novel clinical investigation of the use of TPO levels to predict the response to avatrombopag in patients with PT after haplo-HSCT. Logistic regression models demonstrated a significant predictive relation between TPO levels and probability of response. The TPO levels were inversely correlated with response (r = −0.998, P =0.011).(Figure) ROC analysis identified TPO levels ≤1714 pg/mL as the optimal threshold for discriminating responders and nonresponders. Based on univariate analysis, the presence of megakaryocytes in bone marrow before initiation (P=0.016), lower endogenous TPO levels (P =0.024) and no prior history of TPO-RA treatment (P =0.021) were independent factors that influenced the efficacy of avatrombopag. In the multivariate analysis, lower endogenous TPO levels (P =0.021) and no prior history of TPO-RA treatment (P=0.018) were independent factors that influenced the efficacy of avatrombopag. Avatrombopag was well tolerated in all patients, and patients responding to avatrombopag achieved improved overall survival (77.3% vs. 96.6%, P=0.008). Conclusions: Avatrombopag is a safe and effective therapy for severe PT after haplo-HSCT, and endogenous TPO levels prior to treatment could predict the response to avatrombopag. Key words: Avatrombopag, Persistent thrombocytopenia, Allogeneic hematopoietic stem cell transplantation, Haploidentical Figure legends：Multiple logistic regression models for the probability of response to avatrombopag based on endogenous TPO levels. The shaded area represents the 95% CI. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Feasibility and Efficacy of Romiplostim for the Treatment of Persistent Thrombocytopenia after Allogeneic Stem Cell Transplantation. a Single Centre Experience

Introduction. Persistent thrombocytopenia (PT) due to delayed primary platelet recovery or secondary graft failure with prolonged thrombocytopenia is a relevant and relatively common complication after allogeneic stem cell transplantation (alloSCT). It can result in transfusion dependence and hemorrhagic events, leading to increase of morbidity and mortality. Concomitant causes of PT after alloSCT are several and can include viral infections, graft-versus-host disease (GvHD), drug toxicity, thrombotic microangiopathy (TMA) and immune thrombocytopenia (ITP). Together with the treatment of the primary cause and the support with platelet transfusion, the use of thrombopoietin receptor agonists (TPO-RAs), which proved to be effective in several scenarios (e.g. ITP or aplastic anemia), is gaining a fundamental role also in the post alloSCT setting. To date, the use of TPO-RAs after transplant has been investigated in small studies or case reports. In this study, we evaluated the use of romiplostim in a larger patient cohort to determine its safety, efficacy and potential predictors of response. Materials and methods. We conducted a retrospective study on consecutive patients undergoing alloSCT and receiving romiplostim for the treatment of PT at the bone marrow transplantation unit of the University Hospital of Ulm. PT was defined as a platelet count < 20 Giga/l for 7 consecutive days after engraftment, the need for continuous transfusion during the post-transplant follow-up or a not rapidly reversible decrease of >50% of the platelet count not due to relapse of underlying hematological disease. Response to treatment was defined as a platelet count >50 Giga/l for at least 7 consecutive days without transfusion. Patients with residual bone marrow involvement of primary hematological disease were excluded. Univariate analysis was conducted using Fisher's exact test or Mann-Whitney-U-test. Results. Between 01/2019 and 12/2021 we identified a total of 119 out of 255 transplanted patients (46,7%) with PT receiving, as a part of the treatment, romiplostim during the post-transplant follow-up. Patient characteristics are listed in Table 1. The median platelet count at baseline was 32 Giga/l (r = 0 - 88). We started with romiplostim 250μg on a weekly basis, in 46,2% of cases the dose was escalated to 500 µg during treatment. Seventy-three percent showed a clinical response to treatment with a median time to response of 40 days (r = 7 - 565). We observed adverse events like thrombosis, pain syndrome, dizziness in only 8,4% of patients. The median duration of treatment was 168 days (r = 18 - 761). In patients with response, the median platelet count was 91 Giga/l (r = 53 - 212). In univariate analysis, we evaluated potential risk factors associated with poor response to romiplostim. While the presence of a viral reactivation (like CMV, EBV, BKV, HSV1) requiring systemic treatment was associated with a significant lower response rate (47.6% versus 79.6%, respectively for patients with or without reactivation, p= 0.005), the presence of active GvHD (also in case of steroid-refractory (SR) forms), of TMA and the number of CD34-positive stem cells of the graft did not play a role in determining the efficacy of romiplostim. We also evaluated the influence of graft cryopreservation, which was performed increasingly during the SARS-CoV-2 pandemic, on the rate of efficacy of romiplostim in PT treatment. We could not identify a significant difference as compared to the non-cryopreserved grafts. Conclusion. Our results indicate that romiplostim is overall well tolerated and represents a reasonable and effective treatment for PT after alloSCT. We observed that viral infections requiring systemic antiviral treatment could represent a predictor of worse response, which could potentially be explained by the myelotoxicity induced not only by the virus itself but also as a consequence of antiviral substances. Of note, especially considering that SR GvHD or TMA did not seem to impair the efficacy of romiplostim, the stimulation of TPO receptor could play a role in reducing the rate of morbidity and mortality associated with such severe complications of the post transplant follow-up. Also, cryopreservation did not impact on the rate of success of TPO-RAs based treatment strategy. These preliminary results need to be further validated in larger and prospective cohorts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Easix Score Predicts Overall Survival and Late Relapse in Patients Undergoing Reduced Intensity Conditioned Allogeneic Stem Cell Transplantation for Myeloid Disease

Background Allogeneic hematopoietic stem cell transplantation (alloSCT) is an effective treatment for myeloid malignancies, however outcomes post-transplant are variable and predictive scores limited. The Endothelial Activation and Stress Index (EASIX) measured at key timepoints pre- and post-transplant has been shown to predict outcomes in alloSCT, including overall survival, non-relapse mortality and incidence of sinusoidal obstructive syndrome (SOS). It can be readily calculated using standard biomarkers (LDH (U/L) x creatinine (mg/dL)/platelets (x109/L). We sought to examine its predictive role in a homogenous population of patients. Methods We conducted a retrospective national review of 117 patients undergoing reduced-intensity alloSCT for myeloid disease including AML (n=56), MDS (n=35) and MPN (n=26). All included received fludarabine, busulfan and rabbit anti-thymocyte globulin (Flu/Bu/ATG) conditioning from 2015-2020. We calculated the EASIX score on the day prior to conditioning, on day 0, at onset of acute graft versus host disease and 1 year post transplant. Univariate analysis was conducted in the STATA statistical package. Results At the pre-conditioning time-point the mean EASIX was 3.11 (0.3-17.54). Increased scores correlated with and were reliably predictive of reduced overall survival (p=0.034) (fig. 1). Higher scores at this time-point did not predict chronic GVHD or relapse, however an increased rate of acute GVHD was seen in those with lower EASIX (p=0.012). At day 0 the mean EASIX was 15.38 (1.07-179.02), however we could not demonstrate a predictive effect on SOS as no events occurred in this cohort. Nor did we identify a predictive value at this point for GVHD risk or relapse. At onset of acute GVHD (n=67, mean 3.52, 0.44-51.43), the EASIX score was predictive of overall survival (p=0.027) but did not predict risk of chronic GVHD or relapse. At 1 year post-transplant (n=88, mean 2.09, 0.48-13.59) a higher score showed a trend towards decreased overall survival (p=0.1) but was associated with an increased risk of subsequent relapse (p=0.01)(fig. 2). Conclusions The EASIX score is an easily applicable clinical tool using real world biomarkers readily available at serial time-points in transplant recipients. When applied to our homogenously treated cohort it retains its value in predicting overall mortality at the key time points of pre-conditioning and at onset of GVHD. Adoption of this simple score may be of benefit in risk stratifying the transplant process for reduced intensity conditioned allograft recipients, particularly when combined with established prediction tools for non-relapse mortality such as the HCT-CI. In addition to this, we have shown that the EASIX score may be a useful predictive tool for late relapse in those patients who are alive at 1 year post transplant. We suspect that this effect is primarily reflective of those patients with persistent thrombocytopenia and raised LDH, both markers of potential disease activity. Importantly, the use of this score in the reduced intensity population may be particularly relevant due to the increasing age of transplant eligibility and its use as a surrogate of endothelial dysregulation and potential for end organ complications through the transplant process. To assess the underlying T cell mediated and cytokine secretome effects on endothelial dysfunction, an observational study is ongoing at our institution, examining the interplay of immunomodulatory therapy, graft T cell content, early T and NK cell recovery and the cytokine secretion patterns at various time points before, during and after transplant in reduced intensity conditioned patients with myeloid disease. We plan to correlate these data with serial EASIX assessments to identify the determinants of the underlying biological process and identify potential time-points and biological targets for future study.

Retrospective, Observational, Multicenter Study Assessing the Thrombopoietin Receptor Agonist (TPO-RA) Romiplostim and Other Treatments for Patients with Newly Diagnosed or Persistent Primary Immune Thrombocytopenia (ITP) in Routine Clinical Practice in the United Kingdom (UK)

Background: The clinical course of ITP can be categorized into three phases: newly diagnosed (<3 months post-diagnosis), persistent (≥3-≤12 months) or chronic (>12 months). Romiplostim (a TPO-RA) is now approved in the USA and Europe for use across all phases of ITP in adults refractory to 1st line treatments. This extended indication is aligned with treatment guidelines, which recommend TPO-RAs at earlier stages to help patients avoid adverse events associated with prolonged steroid use (>8 weeks) (Neunert et al. Blood Adv 2019; Provan et al. Blood Adv 2019). To guide future recommendations and improve patient outcomes, further real-world data on romiplostim use in the earlier phases of ITP are warranted. Methods: A retrospective, observational, UK wide multicenter study of real-world treatment patterns in adult patients diagnosed with newly diagnosed or persistent primary ITP between 2 July 2015-23 March 2020 was undertaken. The study population was divided into two patient groups depending on what treatments they received during the 1st year from ITP diagnosis - Group 1: received romiplostim; Group 2: received other ITP treatments (excluding TPO-RAs). TPO-RAs, including eltrombopag, could be received in either group post 12 months. Patients in either group were able to receive the following therapies throughout the observation period: azathioprine, cyclosporine, danazol, dexamethasone, IVIg, methylprednisolone, mycophenolate (MMF), prednisolone, and/or rituximab. Exclusion criteria were: clinical trial participation in the observation period and eltrombopag within 12 months of ITP diagnosis. At baseline, data were collected on patient demographics and clinical characteristics. For the 24-month period following ITP diagnosis (observation period), data were collected on prescribed ITP treatments, platelet counts, rescue therapies, bleeding episodes and hospitalizations. All analyses were descriptive. Results: Overall, 78 patients were enrolled at 7 sites in the UK (Group 1: n=14; Group 2: n=64). Baseline demographics are shown in the Table. In Group 1, romiplostim was initiated at a median of 7 weeks from diagnosis and was continuing in 57% of patients (8/14) at the end of the 24-month observation period. Two patients (14%) discontinued romiplostim before 24 months as treatment-free remission was achieved (defined by investigator). The median duration of romiplostim was 46 weeks. The Table summarizes non-TPO-RA treatments received in both groups. The median duration of prednisolone was shorter for Group 1 vs 2 (3 vs 10 weeks for patients who discontinued prednisolone). A similar trend was seen for MMF (18 vs 54 weeks). During the 2nd year of observation, 4 patients in Group 2 received eltrombopag (none in Group 1) and 1 received romiplostim. At ITP diagnosis (i.e. baseline), the median platelet counts were 4 and 8 ×109/L in Groups 1 and 2, respectively. By the end of the 24-month treatment period, the median (interquartile range [IQR]) platelet counts had increased to 192 (81-279) and 121 (80-196) ×109/L in Groups 1 and 2, respectively. During the observation period in Groups 1 and 2, respectively, bleeding episodes occurred in 50% and 63% of patients, rescue therapies were required by 36% and 31%, and hospitalizations in 50% and 46% (81% and 60% were day cases, the rest inpatient stays). The mean number of rescue therapies/patient was 0.7 and 0.6 in Group 1 and 2, respectively. Thromboembolic events occurred in 1 patient in each group (Group 1: sub-acute left lower limb arterial ischemia; Group 2: stroke). Conclusion: In this real-world observational study, median platelet counts increased to 192×109/L after 24 months of observation in patients receiving romiplostim in the 1st 12 months of ITP diagnosis. Over the same period, patients receiving other treatments in the 1st year of ITP diagnosis had median platelet counts of 121×109/L. For patients who discontinued prednisolone, the duration of this steroid was 3 vs 10 weeks in those who received romiplostim in the 1st year vs those who did not. At the time of study data collection, romiplostim was not approved in the UK for use in patients with ITP <1 year from diagnosis. In accordance with treatment guidelines, these findings support further exploring the earlier use of romiplostim for adult patients with primary ITP, including the possibility of reducing prolonged exposure to steroids such as prednisolone. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Variable serotonin release assay pattern and specificity of PF4‐specific antibodies in HIT, and clinical relevance

BackgroundThe diagnosis of heparin‐induced thrombocytopenia (HIT) requires functional assays to demonstrate that platelet factor 4 (PF4)‐specific antibodies activate platelets, typically when therapeutic heparin (H) concentrations are tested (“classical” pattern). Some HIT samples also activate platelets without heparin (“atypical” pattern), but with unclear clinical significance. ObjectivesWe aimed to assess whether platelet activation pattern and some characteristics of PF4‐specific antibodies were associated with the severity of HIT. Patients/MethodsSerotonin release assay (SRA) pattern of 81 HIT patients were analyzed and compared with their clinical and biological data, including levels of anti‐PF4/H immunoglobulin G (IgG) and anti‐PF4 IgG in 47 of them. ResultsHigher anti‐PF4/H IgG titers were measured in patients with an “atypical” SRA (optical density 2.52 vs. 1.94 in those with a “classical” pattern, p < .001). Patients of both groups had similar platelet count (PC) nadir and time to recovery, but those with an “atypical” SRA more frequently developed thrombotic events (69% vs. 34%, p = .037). Significant levels of anti‐PF4 IgG were detected in both groups (38% and 61%, respectively). Whatever the SRA pattern, a lower PC nadir (35 vs. 53 G/L, p = .006) and a longer PC recovery time (6 vs. 3 days, p = .015) were evidenced in patients with anti‐PF4 antibodies, compared with those with anti‐PF4/H IgG only. ConclusionsAn atypical SRA pattern with elevated anti‐PF4/H IgG titers seems associated with an increased risk of thrombosis in HIT. IgG antibodies to native PF4 may contribute to more severe and persistent thrombocytopenia, and their detection could be useful in clinical practice.

Effects of interleukin-6 inhibition with ziltivekimab in patients at high risk of atherosclerotic events in Japan: results from the phase 2 RESCUE-2 trial

Abstract Introduction In the US phase 2 RESCUE trial, ziltivekimab, a fully human monoclonal antibody against the ligand of the pro-inflammatory cytokine interleukin-6, was shown to reduce biomarkers of inflammation in patients with chronic kidney disease (CKD) and elevated levels of high-sensitivity C-reactive protein (hsCRP), a marker of inflammation and cardiac risk.1 Here, we present outcomes from the phase 2 RESCUE-2 trial of ziltivekimab in a patient population from Japan. Purpose To evaluate the efficacy and safety of ziltivekimab 15 mg and 30 mg compared with placebo in Japanese patients with non-dialysis-dependent CKD (NDD-CKD). Methods We conducted a randomized, double-blind, placebo-controlled trial in 36 patients aged ≥20 years with stage 3–5 NDD-CKD and hsCRP ≥2 mg/L. Patients were randomly assigned to receive subcutaneous ziltivekimab 15 mg (n=11) or 30 mg (n=12), or placebo (n=13) at weeks 0, 4 and 8. The primary endpoint was percentage change in hsCRP levels from baseline to end of treatment (EOT) (average of week 10 and week 12 values); secondary endpoints included percentage change from baseline to EOT in levels of fibrinogen, serum amyloid A (SAA), N-terminal pro B-type natriuretic peptide (NT-proBNP) and lipids. Analysis of endpoints was performed using Wilcoxon two-sample test; differences between treatment groups were calculated using the Hodges–Lehmann estimator. Results Baseline characteristics are shown in the Table. At EOT, median hsCRP levels were reduced by 96% and 93% in the ziltivekimab 15 mg and 30 mg groups, respectively, compared with 27% for placebo (both p&amp;lt;0.001 vs placebo). At both doses, ziltivekimab provided rapid and sustained suppression of hsCRP over the 12-week treatment period (Figure). Statistically significant reductions in levels of the inflammatory markers SAA (15 mg: 71%; 30 mg: 58%; placebo: 30%; both p&amp;lt;0.01 vs placebo) and fibrinogen (38%; 34%; 2%; both p&amp;lt;0.0001 vs placebo) were also observed. Ziltivekimab was well tolerated, did not result in persistent neutropenia or thrombocytopenia, and had minimal effect on liver enzyme levels. There was a non-significant increase in low-density lipoprotein levels and a neutral effect on high-density lipoprotein levels. There was a limited, but statistically significant (p&amp;lt;0.05 vs placebo) increase in triglycerides, whereby levels increased in some patients and decreased in others. Conclusion Ziltivekimab effectively reduced inflammatory biomarkers associated with atherosclerosis in patients from Japan with CKD and residual inflammatory risk as measured by hsCRP. A significant reduction of more than 90% in hsCRP levels for both doses of ziltivekimab was demonstrated, with a safety profile similar to placebo. Overall, the results of the RESCUE-2 trial in Japan are consistent with the efficacy and safety results of the US-based RESCUE trial. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was funded by Novo Nordisk A/S. Medical writing support was provided by Johanna Scheinost PhD, PharmaGenesis Oxford Central, Oxford, UK, with funding from Novo Nordisk A/S.

ADAMTS13 protease or lack of von Willebrand factor protects irradiation and melanoma‐induced thrombotic microangiopathy in zebrafish

BackgroundSevere deficiency of plasma ADAMTS13 activity may result in potentially fatal thrombotic thrombocytopenic purpura and relative deficiency of plasma ADAMTS13 activity may be associated with adverse outcomes of certain malignancies. Here, we report the role of ADAMTS13 or lack of von Willebrand factor (VWF) in reducing irradiation and melanoma‐induced thrombotic microangiopathy (TMA) and mortality in zebrafish. MethodsZebrafish melanoma cell line (ZMEL) was injected subcutaneously into wild‐type (wt), adamts13−/− (a13−/−), von Willebrand factor (vwf−/−), and a13−/−vwf−/− zebrafish following total body irradiation; the tumor growth, its gene expression pattern, the resulting thrombocytopenia, and the mortality were determined. ResultsTotal body irradiation at 30 Gy alone resulted in a transient thrombocytopenia in both wt and a13−/− zebrafish. However, thrombocytopenia occurred earlier and more profound in a13−/− than in wt zebrafish, which was resolved 2 weeks following irradiation alone. An inoculation of ZMEL following the irradiation resulted in more severe and persistent thrombocytopenia, as well as earlier death in a13−/− than in wt zebrafish. The vwf−/− or a13−/−vwf−/− zebrafish were protected from developing severe thrombocytopenia following the same maneuvers. RNA‐sequencing revealed significant differentially expressed genes associated with oxidation–reduction, metabolism, lipid, fatty acid and cholesterol metabolic processes, steroid synthesis, and phospholipid efflux in the melanoma explanted from a13−/− zebrafish compared with that from the wt controls. ConclusionsOur results indicated that plasma ADAMTS13 or lack of VWF may offer a significant protection against the development of irradiation‐ and/or melanoma‐induced TMA. Such a microenvironment may directly affect melanoma cell phenotypes via alternation in the oxidation–reduction and lipid metabolic pathways.

Gaucher Disease Type 2 Manifested as Hemophagocytic Lymphohistiocytosis in a Neonate in the COVID-19 Era.

A term neonate presented with persistent severe thrombocytopenia, elevated liver enzymes, conjugated hyperbilirubinemia, hepatosplenomegaly, and mild hypotonia. A thorough workup for infections, congenital thrombocytopenias, and neonatal malignancies was negative. Because of increased anti-SARS-CoV-2 IgG antibodies after maternal COVID-19, multisystem inflammatory syndrome of neonates was considered and intravenous immunoglobulin was administered. The clinical condition of the neonate deteriorated and due to laboratory evidence of hyperinflammation, hemophagocytic lymphohistiocytosis was suspected, and treatment with etoposide and dexamethasone was initiated with temporary stabilization. Gaucher disease type 2 was eventually diagnosed. Gaucher disease can rarely present in neonates as hemophagocytic lymphohistiocytosis.

Impact of Rituximab and Corticosteroids on Late Cytopenias Post-Chimeric Antigen Receptor T Cell Therapy

Chimeric antigen receptor (CAR) T cell therapy represents a significant advancement in the treatment of patients with relapsed/refractory B cell lymphoid malignancies. Cytokine release syndrome and immune effector cell-associated neurotoxicity represent the most acute serious adverse events post CAR T cell therapy but the occurrence and persistence of cytopenias post CAR T cell therapy represent a significant adverse event and a management challenge. While most patients typically recover blood counts by 30 days, a significant subset of patients have persistent or late cytopenias beyond 30 days. Patients receiving CAR T cell are heavily pre-treated and the impact of prior therapies on late cytopenias is not well understood. In this study, we found an association between increased number of rituximab infusions and/or cumulative rituximab dose received prior to CAR T cell infusion and persistent anemia and thrombocytopenia at 90 and 180 days afterwards. An overall increased number of prior lines of therapy was also associated with persistent lymphopenia and anemia at 90 days while receiving a prior autologous hematopoietic cell transplant was associated with a greater risk of neutropenia and lymphopenia.

GCT-10. Successful Salvage of Relapsed intracranial Non-Germinaoteous Germ Cell Tumors NGGCTs in a Child With Renal Insufficiency with Novel platinum-Free chemotherapy Regimen

The Outcome for relapsed NGGCT is poor. Salvage therapy usually consist of reinduction platinum-based chemotherapy regimen followed by high-dose-chemotherapy and autologous-stem-cell-rescue (HDC/AuSCR) and re-irradiation with no consensus on optimal management and usually associated with remarkable toxicity. We present a 12-year-old boy diagnosed with a localized pineal Non-Germinaoteous Germ Cell Tumors NGGCTs of mixed origin with elevated AFP he had ETV and biopsy started on COG ACNS0122 protocol after receiving first cycle (carbo/Etoposide) he developed acute renal failure investigation showed small dysplastic kidney to avoid nephrotoxicity of platinum agents chemotherapy changed to VBE (Vinblastine, Bleomycin and Etoposide) post 3rd cycle MRI showed increase in size of the pineal mass with normal tumor markers representing Growing Teratoma Syndrome He had total surgical resection of the tumor Pathology showed predominant teratoma component He received radiation therapy CSI then another 3 cycles of VBE 4 months following treatment completion he presented with elevated AFB and new right anterior temporal lesion Spinal MRI and CSF were negative. He had 2 cycles of Salvage Non-nephrotoxic 4-drug regimens GEMPIV Gemcitabine 800 mg/m2 days 1 and 14. Paclitaxel 80 mg/m2 days 1 and14, Irinotecan 50 mg/m2 daily for 5 days Vinblastine 6 mg/m2 weekly days 1,8,14 MRI after 2 cycles showed remission with undetectable AFP then 2 consolidation cycles of etoposide and thiotepa (HDC/AuSCR) The 3rd consolidation cycles were cancelled due to hematological toxicity During treatment phases chemotherapy was well tolerated doses were adjusted according to his GFR with renal conservative and supportive therapy.post (HDC/AuSCR) he experienced delayed hematological recovery with persistent thrombocytopenia responded to Eltrombopag then he had focal Temporal lobe irradiation Currently patients in remission with chronic stage 3 renal Insufficiency Conclusions: this case showed that relapsed intracranial NGGCT can be successfully salvaged without platinum-based chemotherapy in patients with renal insufficiency.

Guidelines for Pediatric Immune Thrombocytopenia

&#x0D; Three guidelines included in this report recommend rituximab, thrombopoietic agents (drugs that promote platelet growth), and thrombopoietin receptor agonists (e.g., romiplostim, eltrombopag) over splenectomy as second-line treatment in children with immune thrombocytopenia who do not respond to first-line treatment.&#x0D; Three guidelines included in this report recommend for children with persistent or chronic immune thrombocytopenia who have no response to 1 thrombopoietin receptor agonist or who lose an initial response that treatment can be switched to another thrombopoietin receptor agonist and/or combined with mycophenolate mofetil or another immunosuppressant. For individuals who do not respond to thrombopoietin receptor agonists, the recommendation is to consider rituximab and dexamethasone, especially for adolescent females.&#x0D; No relevant evidence-based recommendation was identified regarding the use of dapsone for the treatment of children with immune thrombocytopenia.&#x0D;

Oseltamivir as rescue therapy for persistent, chronic, or refractory immune thrombocytopenia: a case series and review of the literature.

Immune thrombocytopenia (ITP) is an autoimmune disease that results from antibody-mediated platelet destruction and impaired platelet production. Novel therapies have emerged in the last decade, but 15-20% of patients will relapse or fail and require further therapy. We performed a prospective, single-arm intervention study on seven patients with chronic, persistent, or refractory ITP from the Hospital Universitario "Dr. José E González", in Monterrey, Mexico between 2015 and 2019. Eligible patients received oral oseltamivir 75mg twice daily for 5days and were followed up for six months. Most patients received a median of three distinct therapies (range 2-6). Four patients (57.1%) received combined therapy. The median time for any response was 55.5days (range = 14-150). All patients responded at some point in time (ORR = 100%, six had a proportion of loss of response [PR], and one achieved [CR]). Six months after oseltamivir administration, three patients (42.9%) maintained a response, and one patient had a CR (14.3%). Oseltamivir was well tolerated with a good overall response rate and was useful for treating chronic ITP. We observed an initial increase in the number of platelets; however, this response was not maintained.

Generic romiplostim for children with persistent or chronic immune thrombocytopenia: Experience from a tertiary care centre in North India

Thrombopoietin receptor agonists are important therapeutic option in children with immune thrombocytopenia (ITP). We evaluated the response, efficacy, safety of a generic form of romiplostim manufactured in India for treating children with persistent/chronic ITP at our centre. Study of 45 children with persistent/chronic ITP was conducted of which 5 discontinued and 40 were included between 2019-2020. Patients received romiplostim for 20 weeks, at a dose of 5 mcg/kg/week. Platelet count at week 1, 3, 20 and 26 was assessed. Predesigned algorithm was used for dose adjustment. After 20 weeks, patients who had platelet count of 50 × 109/L or above were tapered off medication and monitored till 26 weeks. Median platelet count at enrolment was 11 x 109/L (IQR 23 X 109/L). 13/40 children had received >/= three lines of prior ITP therapy. Platelet response (platelet count rise to more than 50×109/L without rescue medications) observed in 26 (65%) patients at week 20. Rescue medication was used in 12/40 children. Sustained platelet response after tapering and stopping romiplostim observed in 22/40 children. No adverse events were considered serious or led to discontinuation of treatment. Our data demonstrated generic romiplostim is well tolerated and efficacious in children with persistent/chronic ITP.

Nodular Regenerative Hyperplasia of the liver in Juvenile Dermatomyositis

BackgroundWe present two cases of Nodular Regenerative Hyperplasia (NRH) associated with Juvenile Dermatomyositis (JDM).Case PresentationCase 1: A nine-year-old Caucasian male with refractory JDM and anti-NXP2 autoantibodies was diagnosed at age two. Over seven years, he developed arthritis, dysphagia, dysphonia, severe calcinosis, and colitis. Complications included recurrent cellulitis, infections, and hepatosplenomegaly. Multiple medications were chronically used, including prednisone, methotrexate, azathioprine, cyclophosphamide, mycophenolate mofetil, rituximab, tacrolimus, etanercept, abatacept, infliximab, and tocilizumab.Case 2: A 19-year-old Asian female with chronically active JDM and anti-MDA5 autoantibodies was diagnosed at age 15. Symptomatology included ulcerative skin lesions, Raynaud’s phenomenon with digital ulcers, arthritis, interstitial lung disease with pulmonary hypertension, and calcinosis. Medications included chronic use of prednisone, methotrexate, abatacept, cyclophosphamide, mycophenolate mofetil, rituximab, tofacitinib, and sildenafil.In both patients, clinical symptomatology was not suggestive of liver disease or portal hypertension, but laboratory studies revealed elevated serum transaminases with progressive thrombocytopenia and no active liver-associated infections. The first patient’s liver ultrasound showed coarse hepatic texture with mild echogenicity, splenomegaly, and portal hypertension. The second patient’s liver ultrasound was normal, but elastography indicated increased stiffness. Liver biopsy confirmed NRH in both patients.ConclusionsIt is difficult to recognize NRH in JDM, as it often presents with elevated transaminases which may be mistaken for JDM muscle flare, corticosteroid-related fatty liver, or medication-related transaminitis. NRH has been associated with several medications used to treat JDM, including methotrexate, azathioprine, and cyclophosphamide, which should be discontinued if NRH develops. Providers should consider NRH in JDM patients with severe, refractory disease who have persistently elevated transaminases and persistent thrombocytopenia.

Bivalirudin Anticoagulation in Extracorporeal Membrane Oxygenation (ECMO) for Severe Coronaviral Disease (COVID-19) Related Acute Respiratory Distress Syndrome (ARDS)

PurposeECMO as a bridge, is a potential option in patients with severe COVID-19 who develop respiratory failure despite maximal conventional therapy. Heparin has been the standard anticoagulant, but is associated with bleeding and thrombocytopenia. Bivalirudin has been successfully used as an alternative in cases of heparin induced thrombocytopenia (HIT). We evaluated Bivalirudin as an anticoagulant in COVID-19 patients on ECMO who develop HIT or had persistent thrombocytopenia despite multiple platelet transfusions.MethodsAfter institutional clearance, we performed retrospective analysis of all the COVID-19 related ECMO managed in our centre between January to August 2021. Femoral vein to internal jugular vein ECMO was instituted in all these patients and anticoagulation targets were monitored daily as per institutional protocols. We compared incidence of ECMO circuit and oxygenator changes, post procedural bleeding and the number of blood products transfused between the Heparin and Bivalirudin group. Descriptive analysis was carried out by mean and standard deviation. The mean values were compared using student t-test and categorical outcomes using Chi square test.ResultsTotal of 42 COVID-19 ARDS related ECMO were managed in our centre during the study period. 8 patients were switched to Bivalirudin, as 2 patients were diagnosed with HIT and 6 had persistent thrombocytopenia despite multiple platelet transfusions. In patients with HIT, the platelet count improved by 72 hours. The incidence of post tracheostomy and intercostal drain insertion bleed was statistically higher in Heparin group (p <0.05). Total number of packed cell transfusion was significantly less in Bivalirudin group but platelet transfusion was lower, though not statistically significant. The usage of fresh frozen plasma and cryoprecipitate were similar. The rates of ECMO oxygenator and circuit exchanges were comparable with mean duration of 13.5 days for change from the date of initiation.ConclusionBivalirudin is a feasible alternative anticoagulant in the COVID-19 ECMO with the benefit of lower rates of bleeding and consequent need for transfusion. Further large studies are needed to assess the efficacy and benefits of direct thrombin inhibitors as a practical and safe substitute to Heparin in these situations.

Complete recovery of deep venous thrombosis from Coombs (+) thrombotic thrombocytopenic purpura: case report

BackgroundAcute thrombotic thrombocytopenic purpura (TTP) is an aggressive thrombotic microangiopathy that if not treated, can have a 90% mortality rate. Timely, extensive plasma exchange (PEX) has been indicated to reduce the mortality rate to < 10%, but its side effects are not well-known. We present here a case of a patient presented with Comb (+) TTP and developed catheter-associated deep vein thrombosis (DVT).Case presentationA 27-year-young man presented with persistent thrombocytopenia and Coombs positive anemia was firstly diagnosed with Evans syndrome. However, he was refractory to a methylprednisolone pulse therapy with a combination of platelet transfusion and eventually developed microangiopathy of central nerve system. Several pathological manifestations of the disease were prevented by PEX. The immediate start of PEX (1500 mL/d) induced a complete remission of acquired TTP and disappearance of neurological signs and symptoms. However, external iliac and femoro-popliteal venous thrombosis was diagnosed subsequently, inferior vena cava filter (IVC) filter was immediately implanted accompanied with anticoagulation therapy. Meanwhile, PEX session was sustained as well as oral anticoagulant (rivaroxaban). 14 days later, the patient got full recovery.ConclusionsCatheter-related DVT under the setting of TTP should be cautious. It is necessary to start anticoagulation and antiplatelet therapy for thrombosis early, especially in such cases when PLT count > 50 × 109/L.

Severe Thrombocytopenia in Patients With Advanced Neuroendocrine Tumor Treated With Peptide Receptor Radioligand Therapy.

BackgroundPeptide receptor radioligand therapy (PRRT) was Food and Drug Administration approved in 2018 for the treatment of unresectable somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (NETs) and provides an important option for patients with advanced disease. A known adverse effect of this treatment is hematologic toxicity, although usually transient. We present 3 patients with metastatic gastroenteropancreatic NETs treated with PRRT who were evaluated for severe persistent thrombocytopenia.MethodsThree patients who commenced therapy with PRRT were known to proceed to a bone marrow (BM) biopsy for persistent severe thrombocytopenia and were included in this study. These patients were identified retrospectively and evaluated for their tumor properties, including immunohistochemical markers, treatment modalities, and clinical outcomes.ResultsAll 3 patients had metastatic NETs that progressed on prior lines of therapy and were treated with 1 to 4 doses of 177Lu-DOTATATE 7.4 GBq (200 mCi) before developing grade 3 (25,000 to 50,000/μL) refractory thrombocytopenia. All patients had concurrent bone metastases, and 2 of the 3 had baseline grade 1 thrombocytopenia. In all 3 cases, BM biopsy documented widespread tumor infiltration.ConclusionsSevere refractory thrombocytopenia after PRRT is rare and may result from numerous known causes, including radiation-induced myelotoxicity, myelodysplastic syndrome, and tumor BM infiltration. We present 3 cases of thrombocytopenia related to persistent or progressive BM metastasis. Although known bone metastasis is not a contraindication to PRRT, thrombocytopenia may be a manifestation of tumor progression and should be considered when making decisions about continuation of therapy.

Avatrombopag for chemotherapy-induced thrombocytopenia in patients with non-haematological malignancies: an international, randomised, double-blind, placebo-controlled, phase 3 trial

Chemotherapy-induced thrombocytopenia is common and causes chemotherapy dose reductions or treatment delays, bleeding, and suboptimal oncological outcomes. We aimed to evaluate avatrombopag, a thrombopoietin receptor agonist that increases platelet counts, in patients with non-haematological cancer and platelet counts lower than 50 ×109 cells per L. In this randomised, double-blind, placebo-controlled, phase 3 study, patients aged 18 years or older at 71 hospitals or cancer treatment centres in China, Hungary, Poland, Russia, Serbia, Ukraine, and the USA and with ovarian, bladder, or lung cancer receiving chemotherapy who had severe thrombocytopenia were randomly assigned (2:1) to oral avatrombopag 60 mg or oral placebo once daily given 5 days before and after chemotherapy, with randomisation stratified by number of chemotherapy drugs used. Patients, investigators, and data collectors were masked to group allocation. Eligibility required two previous lines of chemotherapy or fewer, an ECOG performance status of 2 or less, and no previous history of chemotherapy-induced thrombocytopenia. The composite primary endpoint was the proportion of responders not requiring platelet transfusion or either a 15% or more chemotherapy dose reduction or a 4-day or more chemotherapy delay due to thrombocytopenia following study treatment until the start of the subsequent cycle. Analyses were done on the intention-to-treat and per protocol populations. Safety was analysed in all patients who received at least one dose of avatrombopag. The trial is registered with ClinicalTrials.gov, NCT03471078, and has been completed. Between Oct 12, 2018, and June 28, 2020, 122 patients were enrolled and randomly assigned to receive avatrombopag (n=82) or placebo (n=40). Median follow-up was 31 days (IQR 22-61). Similar proportions of patients reached the primary endpoint in the avatrombopag and placebo groups (intention-to-treat: 57 [70%, 95% CI 58-79] of 82 vs 29 [73%, 95% CI 56-85] of 40; difference -3·0% (95% CI -21·6 to 15·6); p=0·72; per protocol: 51 [85%, 95% CI 73-93] of 60 vs 27 [84%, 95% CI 67-95] of 32; 0·6% (95% CI -20·8 to 22·1); p=0·96). 15 (18%) of 82 patients had serious adverse events in the avatrombopag group and eight (20%) of 40 in the placebo group, of which thrombocytopenia was most common (4 [5%] of 82 and 4 [10%] of 40 patients). Common grade 3-4 treatment-emergent adverse events were neutropenia (22 [27%] of 82 and 16 [40%] of 40 patients), leukopenia (19 [23%] of 82 and 5 [13%] of 40), anaemia (16 [20%] of 82 and 9 [23%] of 40), and thrombocytopenia (16 [20%] of 82 and 14 [35%] of 40). Most adverse events were considered unrelated to study drug. No treatment-related deaths were reported. In this population of patients with non-haematological malignancies who are relatively chemotherapy naive, chemotherapy-induced thrombocytopenia treatment outcomes were similar between the avatrombopag and placebo groups. Given its safety and ability to augment platelet counts in patients with chemotherapy-induced thrombocytopenia, evaluation of avatrombopag in populations with more persistent chemotherapy-induced thrombocytopenia is warranted. Dova Pharmaceuticals, a Sobi company.

Persistence of Ad26.COV2.S-associated vaccine-induced immune thrombotic thrombocytopenia (VITT) and specific detection of VITT antibodies.

Rare cases of COVID‐19 vaccinated individuals develop anti‐platelet factor 4 (PF4) antibodies that cause thrombocytopenia and thrombotic complications, a syndrome referred to as vaccine‐induced immune thrombotic thrombocytopenia (VITT). Currently, information on the characteristics and persistence of anti‐PF4 antibodies that cause VITT after Ad26.COV2.S vaccination is limited, and available diagnostic assays fail to differentiate Ad26.COV2.S and ChAdOx1 nCoV‐19‐associated VITT from similar clinical disorders, namely heparin‐induced thrombocytopenia (HIT) and spontaneous HIT. Here we demonstrate that while Ad26.COV2.S‐associated VITT patients are uniformly strongly positive in PF4‐polyanion enzyme‐linked immunosorbent assays (ELISAs); they are frequently negative in the serotonin release assay (SRA). The PF4‐dependent p‐selectin expression assay (PEA) that uses platelets treated with PF4 rather than heparin consistently diagnosed Ad26.COV2.S‐associated VITT. Most Ad26.COV2.S‐associated VITT antibodies persisted for >5 months in PF4‐polyanion ELISAs, while the PEA became negative earlier. Two patients had otherwise unexplained mild persistent thrombocytopenia (140‐150 x 103/µL) 6 months after acute presentation. From an epidemiological perspective, differentiating VITT from spontaneous HIT, another entity that develops in the absence of proximate heparin exposure, and HIT is important, but currently available PF4‐polyanion ELISAs and functional assay are non‐specific and detect all three conditions. Here, we report that a novel un‐complexed PF4 ELISA specifically differentiates VITT, secondary to both Ad26.COV2.S and ChAdOx1 nCoV‐19, from both spontaneous HIT, HIT and commonly‐encountered HIT‐suspected patients who are PF4/polyanion ELISA‐positive but negative in functional assays. In summary, Ad26.COV2.S‐associated VITT antibodies are persistent, and the un‐complexed PF4 ELISA appears to be both sensitive and specific for VITT diagnosis.

Abstract P1-21-06: Phase I study of T-DM1 and metronomic temozolomide in secondary prevention of HER2+ breast cancer brain metastases following local radiation therapy

Abstract Background: The incidence of breast cancer brain metastases is rising, and, these lesions in the central nervous system (CNS) and their treatments cause physical and neurocognitive impairment. Only modest incremental advances in progression free survival have been achieved with drugs to treat CNS lesions, while nearly half of the patients who receive SRS will develop new brain metastases within 1 year. In murine models of breast cancer, we demonstrated that low doses of temozolomide (TMZ) administered in a prophylactic, metronomic fashion significantly prevented development of brain metastases. No effect, however, was seen in established brain metastases or systemic breast cancer metastases. We hypothesize that low dose, metronomic TMZ will prevent the outgrowth of brain lesions in HER2+ patients, when added to an active anti-HER2 treatment. We present here the results of the phase I trial combining T-DM1 to TMZ for the prevention of additional brain metastases after their first occurrence and local treatment. Methods: Eligible patients had HER2+ breast cancer with brain metastases and were within 12 weeks of local brain metastases therapy (WBRT, SRS and or surgery), with PS 0-2 and adequate end organ function. Standard doses of T-DM1 were administered IV every 21 days (3.6 mg/kg) and TMZ was given PO daily in a 3+3 design at 30, 40 or 50 mg/m2, continuously. The DLT period was one 21d cycle. Safety was assessed by CTCAEv4.0 and response by RECISTv1.1 and RANO-BM. Brain MRI and systemic CT scans were performed every 6 weeks. Blood samples for correlatives evaluation were collected at baseline and every cycle while on trial. CSF was collected at baseline and C3D1 for all patients. Questionnaires (MDASI-BT and PROMIS®) for evaluation of symptoms and quality of life were completed every 6 weeks. Results: Twelve women with median age 55.5yr (44-67) were enrolled. Only 3 (25%) patients had HR+/HER2+ tumors at initial diagnosis. Nine (75%) patients presented stages II and III disease at initial diagnosis, and developed brain metastases at the diagnosis of first recurrence. Nine (75%) patients received SRS therapy and 3 (25%) received WBRT prior to trial enrollment. Grade 3 or 4 AEs included thrombocytopenia (1/12), neutropenia (1/12), lymphopenia (6/12) and decreased CD4 (6/12), requiring pentamidine for PCP prophylaxis. No DLT was observed. Four patients underwent dose reductions (thrombocytopenia, fatigue and peripheral neuropathy), all of them enrolled on the highest TMZ dose. Median follow-up on study is now 9.6m (1.2-32) and no patient developed new parenchymal brain metastases. Five patients remain on study, while 7 are off study due to progression at previously irradiated CNS lesion (2), progression of systemic disease (2), focal leptomeningeal involvement (1), new cancer (1) and persistent thrombocytopenia (1). Completion rates for the questionnaires were 99% by Cycle 15 (81 completed out of expected 82) and 90% by Cycle 41 (123/137), and will be reported at presentation. Conclusion: Metronomic TMZ in combination with standard dose T-DM1 is tolerable and shows promising activity in secondary prevention of HER2+ brain metastases. Systematic longitudinal symptom assessments in breast cancer patients with brain metastasis are feasible. A randomized phase II expansion of this trial with T-DM1 or T-Dxd +/- TMZ is planned. Citation Format: Alexandra S Zimmer, Seth Steinberg, Mark Gilbert, Terri Armstrong, Eric Burton, Nicole Houston, Dee Dee Smart, Nadia Biassou, John Butman, Priscilla K Brastianos, Carey K Anders, Stanley Lipkowitz, Patricia S Steeg. Phase I study of T-DM1 and metronomic temozolomide in secondary prevention of HER2+ breast cancer brain metastases following local radiation therapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-21-06.