This retrospective study assessed the effectiveness of eltrombopag (EPAG), a thrombopoietin receptor agonist, in the treatment of poor graft function (PGF) following an allogeneic haemopoietic stem ...cell transplantation (HSCT). Complete response was defined as normalization of blood counts, whereas partial response was defined as transfusion independence. A total of 48 patients with full donor chimerism after HSCT, received EPAG for a median of 120 days (range 10–591). Patients with uni- bi- or tri-lineage cytopenia started treatment at a median of 95 days (range 17–877) after HSCT. The overall response rate was 75%: 24 patients had a complete response and 12 had a partial response. Positive predictors of response were an HLA-matched donor, a CD34
+
dose at transplant > 4 × 10
6
/kg, and starting EPAG treatment at least 90 days after HSCT. Patients with more than one positive predictor had a response rate of 92% for the overall patient cohort and 94% for patients with tri-lineage cytopenia. One-year survival was 89% for complete responders, 60% for partial responders and 20% for non-responders (
p
= 0.0004). EPAG improves peripheral blood counts in patients with poor graft function following HSCT. Response to EPAG can be predicted and has a significant impact on survival.
Graft-versus-host disease (GVHD) remains the leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Steroids along with calcineurin inhibitors ...remain the standard initial therapy, however, less than half of the patients completely respond and there is no uniformly accepted therapy for patients with steroid-resistant GVHD.
This paper reviews the current role and ongoing development of mAbs in the treatment of GVHD. Various mAbs to cell surface antigens on GVHD effector cells have been investigated for the treatment of acute GVHD: these include anti-TNF-α antibodies, IL-2 receptor antagonists, anti-CD3 and anti-CD52 mAbs, while anti-CD20 mAb has been extensively investigated in the setting of chronic GVHD. Overall, response rates have been reported to be greater than 60%, although it should be emphasized that the long-term survival still remains suboptimal, mainly due to the detrimental side effects of infectious complications, progressive GVHD and relapse of underlying malignancy.
Future challenges will include more appropriate definition of these agents in the therapeutic scenario of GVHD. Combinations of mAbs or mAb combined with newer immunosuppressive drugs might potentially achieve greater success, especially if used early in the disease process.
The authors of this study found that single-nucleotide polymorphisms in long pentraxin 3 (PTX3) were associated with the development of invasive aspergillosis after hematopoietic stem-cell ...transplantation.
Long pentraxin 3 (PTX3) is a soluble pattern-recognition receptor produced by phagocytes and nonimmune cells at sites of inflammation or injury. In addition to its major role in female fertility and vascular biology,
1
PTX3 has a nonredundant role in modulating various effector pathways involved in immune resistance to
Aspergillus fumigatus,
including activating innate immune cells
2
and driving protective adaptive immunity.
3
PTX3 forms complexes on the conidial surface of the fungus and acts as an opsonin, enhancing recognition and phagocytosis of conidia through mechanisms that depend on Fcγ receptor, CD11b, and complement.
4
The interaction of PTX3 with the yeast phase of . . .
Mesenchymal stem cells (MSC) establish close interactions with bone marrow sinusoids in a putative perivascular niche. These vessels contain a large storage pool of mature nonproliferating ...neutrophils. Here, we have investigated the effects of human bone marrow MSC on neutrophil survival and effector functions. MSC from healthy donors, at very low MSC:neutrophil ratios (up to 1:500), significantly inhibited apoptosis of resting and interleukin (IL)‐8‐activated neutrophils and dampened N‐formyl‐l‐methionin‐l‐leucyl‐l‐phenylalanine (f‐MLP)‐induced respiratory burst. The antiapoptotic activity of MSC did not require cell‐to‐cell contact, as shown by transwell experiments. Antibody neutralization experiments demonstrated that the key MSC‐derived soluble factor responsible for neutrophil protection from apoptosis was IL‐6, which signaled by activating STAT‐3 transcription factor. Furthermore, IL‐6 expression was detected in MSC by real‐time reverse transcription‐polymerase chain reaction and enzyme‐linked immunosorbent assay. Finally, recombinant IL‐6 was found to protect neutrophils from apoptosis in a dose‐dependent manner. MSC had no effect on neutrophil phagocytosis, expression of adhesion molecules, and chemotaxis in response to IL‐8, f‐MLP, or C5a. These results support the following conclusions: (a) in the bone marrow niche, MSC likely protect neutrophils of the storage pool from apoptosis, preserving their effector functions and preventing the excessive or inappropriate activation of the oxidative metabolism, and (b) a novel mechanism whereby the inflammatory potential of activated neutrophils is harnessed by inhibition of apoptosis and reactive oxygen species production without impairing phagocytosis and chemotaxis has been identified.
Disclosure of potential conflicts of interest is found at the end of this article.
In a retrospective analysis, 21 acute myeloid leukemia patients receiving single-agent sorafenib maintenance therapy in complete remission (CR) after hematopoietic stem cell transplantation (HSCT) ...were compared with a control group of 22 patients without maintenance. Sorafenib was initiated a median of 3 months (IQR: 2.3–3.5) after allogeneic HSCT with a median daily dosage of 400 mg (range: 200–800) orally, and lasted a median of 11.3 months (IQR: 3.3–24.4). No significant increase in graft versus host disease or toxicity was observed. Adverse events were reversible with dose adjustment or temporary discontinuation in 19/19 cases. With a median follow-up of 34.7 months (IQR: 16.9–79.5), sorafenib maintenance significantly improved cumulative incidence of relapse (
p
= 0.028) as well as overall survival (OS) (
p
= 0.016), especially in patients undergoing allogeneic HSCT in CR1 (
p
< 0.001). In conclusion, sorafenib maintenance after allogeneic HSCT is safe and may improve cumulative incidence of relapse and OS in FLT3–ITD-mutated AML.
Despite the widespread use of rabbit anti-thymocyte globulin (ATG) to prevent acute and chronic graft-versus-host disease (aGVHD, cGVHD) after allogeneic hematopoietic cell transplantation ...(allo-HCT), convincing evidence about an optimal dose is lacking. We retrospectively evaluated the clinical impact of two different ATG doses (5 vs 6–7.5 mg/kg) in 395 adult patients undergoing HSCT from matched unrelated donors (MUD) at 3 Italian centers. Cumulative incidence of aGVHD and moderate-severe cGVHD did not differ in the 2 groups. We observed a trend toward prolonged overall survival (OS) and disease-free survival (DFS) with lower ATG dose (5-year OS and DFS 56.6% vs. 46.3%,
p
=0.052, and 46.8% vs. 38.6%,
p
=0.051, respectively) and no differences in relapse incidence and non-relapse mortality. However, a significantly increased infection-related mortality (IRM) was observed in patients who received a higher ATG dose (16.7% vs. 8.8% in the lower ATG group,
p
=0.019). Besides, graft and relapse-free survival (GRFS) was superior in the lower ATG group (5-year GRFS 43.1% vs. 32.4%,
p
=0.014). The negative impact of higher ATG dose on IRM and GRFS was confirmed by multivariate analysis. Our results suggest that ATG doses higher than 5 mg/kg are not required for MUD allo-HCT and seem associated with worse outcomes.
Artificial intelligence is gaining interest among clinicians, but its results are difficult to be interpreted, especially when dealing with survival outcomes and censored observations. Explainable ...machine learning (XAI) has been recently extended to this context to improve explainability, interpretability and transparency for modeling results. A cohort of 231 patients undergoing an allogeneic bone marrow transplantation was analyzed by XAI for survival by two different uni- and multi-variate survival models, proportional hazard regression and random survival forest, having as the main outcome the overall survival (OS) and its main determinants, using the survex package for R. Both models’ performances were investigated using the integrated Brier score, the integrated Cumulative/Dynamic AUC and the concordance C-index. Global explanation for the whole cohort was performed using the time-dependent variable importance and the partial dependence survival plot. The local explanation for each single patient was obtained via the SurvSHAP(t) and SurvLIME plots and the ceteris paribus survival profile. The survex package common interface ensured a good feasibility of XAI for survival, and the advanced graphical options allowed us to easily explore, explain and compare OS results coming from the two survival models. Before the modeling results to be suitable for clinical use, understandability, clinical relevance and computational efficiency were the most important criteria ensured by this XAI for survival approach, in adherence to clinical XAI guidelines.
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