Investigation of KIR/HLA relationship and other clinical variables after T-cell-replete haploidentical bone marrow transplantation in patients with acute myeloid leukemia (AML).

BACKGROUND: KIR/HLA mismatch in hematopoietic stem cell transplantation (HSCT), particularly in patients with acute myeloid leukemia (AML), was related to decreased recurrence rates, improved engraftment, and a reduction in graft-versus-host disease, according to recent research (GVHD). Uncertainty exists about the impact of KIR/HLA mismatch on haploidentical-HSCTs treated with post-transplant cyclophosphamide (PTCy). We attempted to analyze the effects of KIR/HLA mismatch on clinical outcomes on transplant outcomes using the cohort of 54 AML patients who received a haplo-HSCT with PTCy. RESULTS: In contrast to KIR/HLA match, our findings showed that donor KIR/HLA mismatch was substantially associated with superior OS (HR, 2.92; (P = 0.04)). Moreover, donor KIR/HLA mismatch (KIR2DS1D/C2+ R and KIR2DS2D/C1+ R mismatch versus KIR2DL1D/C2- R mm, KIR2DL2/3D/C1- R mm and KIR3DL1D/Bw4- mm) was correlated with the improvements in OS (HR, 0.74; P = 0.085) and activating. KIR/HLA mismatch versus KIR/HLA match was significantly correlated with improvements in OS (HR, .46; P = 0.03) and inhibitory. KIR/HLA mismatch versus KIR/HLA match was enhancement in the OS (HR, .93; P = 0.06). Despite a higher rate of aGvHD (grade I-IV) in the patients with KIR/HLA mismatch compared to KIR/HLA matched (57% vs. 33% (p = 0.04). However, the KIR/HLA mismatch group saw a decreased relapse rate (3.2% vs. 23%, p = 0.04). CONCLUSION: This analysis shows the significance of KIR/HLA Incompatibility, other clinical variables like CMV, the relationship between donor/recipient and donor age, and the relationship between donor/recipient and donor age in the haplo-donor selection process. It also suggests that KIR and HLA mismatching between donor and recipient could be routinely performed for haplo-donor selection and may improve clinical outcomes after haplo-HSCTs with PTCy.

In Vitro Generation of BK polyomavirus-specific T cells for adoptive cell therapy in refractory cystitis hemorrhagic patients after hematopoietic stem cell transplantation.

INTRODUCTION: BKPyV associated hemorrhagic cystitis (BKPyV-HC) is a major and prevalent outcome of hematopoietic stem cell transplantation (HSCT) with no standard treatment option. Adoptive T cell therapy (ACT) against transplant-associated viruses has shown promising potential. We sought to produce virus-specific T cells (VSTs) against BKPyV with the aim of treating refractory HSCT-associated HC. METHODS: Peripheral blood mononuclear cells (PBMC) from healthy donors were isolated by Ficoll-Hypaque density gradient centrifugation. BKPyV-pulsed, monocyte-derived dendritic cells (mo-DCs) and T cells were co-cultured and expanded over 2-3 weeks with the addition of IL-2. The T cells were examined for various functional assays. RESULTS: Comparison analysis of Carboxyfluorescein diacetate succinimidyl ester (CFSE) indicated that the percentage of proliferated cells were significantly higher in donors (49.62 ± 7.09%) than controls (7.96 ± 4.55%). Furthermore, expanded T cells exhibited specificity to BKPyV antigens by IFN-γ ELISPOT assay. The expanded cells showed cytotoxic function versus human lymphoblastoid cell line (LCL). Final VST products mainly comprised of CD8/CD69 double-positive T cells, which were significantly higher in donors (46.8 ± 7.1%) than controls (16.91 ± 3.40%). CONCLUSION: In this study we demonstrated the feasibility of producing functional BKPyV-specific T cells in healthy donors using BKPyV PepMixes. These functional cells were able to proliferate and produce IFN-γ cytokine in response to BKPyV PepMixes. In addition, these T cells had cytotoxic ability against BKPyV antigen-expressing target cells.

The effects of a combination oral spray (Mucosamin®) for the prevention of oral mucositis in pediatric patients undergoing hematopoietic stem cell transplantation: a double blind randomized clinical trial.

PURPOSE: Oral mucositis (OM) is a frequent complication of conditioning regimens for hematopoietic stem cell transplantation (HSCT). Damage to the nuclear and non-nuclear materials of the mucosal cells by the production of Reactive Oxygen Species (ROS) and proinflammatory cytokines could result to development and progression of OM. Previous studies have shown the effectiveness of Mucosamin® oral spray in the management of pain and acceleration of OM healing. The aims of the current study were to evaluate prophylactic effects of Mucosamin® oral spray in reducing the incidence and severity of OM in pediatric patients undergoing allogeneic HSCT. METHOD: The current study was designed as a double-blind, placebo-controlled randomized clinical trial. Sixty patients were enrolled in the study and received placebo or Mucosamin® spray. Patients in both groups used sprays 4 times daily. Product application was begun at the time of initiation of conditioning regimen and was continued for 14 days. RESULTS: Mucosamin® significantly reduced incidence and severity of OM compared to the placebo (P values: 0.027 and 0.035, respectively). This product could also decrease OM duration and delay OM onset (P values: 0.007 and 0.006, respectively). CONCLUSION: Mucosamin® could effectively reduce incidence, severity, and duration of OM and delay OM onset in pediatric patients undergoing allogeneic HSCT. TRIAL REGISTRATION: The study protocol was registered in the Iranian Registry of Clinical Trials under the registry number IRCT20190917044805N1.

Vancomycin pharmacokinetic parameters in patients undergoing hematopoietic stem cell transplantation.

INTRODUCTION: Current guidelines on vancomycin dosing lack specific recommendations about its dosing in hematopoietic stem cell transplant (HSCT) patients, the objective of the current study was to compare vancomycin pharmacokinetic variables in this population with those of general population. METHODS: A prospective study was designed and the calculated parameters of vancomycin pharmacokinetic were compared with individualized parameters. Two trough levels before 4th and 5th doses and a peak level after the 4th dose, were taken. All patients received a dose of 15 mg/kg of vancomycin two or three times a day. Pharmacokinetic parameters were calculated using a one compartmental model. The association between different variables and of acute kidney injury (AKI) development and achievement of target levels were also evaluated. RESULTS: A significant difference was observed between population Volume of distribution (Vd) and individualized Vd (mean 57.33 L vs 162.86 L, p value 0.019) and trough and peak levels (p values 0.0001 and 0.001; for mean trough and peak levels respectively). The achievement of the recommended trough levels and area under the concentration time curve per minimum inhibitory concentration (AUC24/MIC) was very low (5/71 and 24/71 patients respectively). No significant differences were observed between population and individualized clearance and rate of elimination of vancomycin (p values of 0.092 and 0.55 respectively). Concomitant receipt of cyclosporine was significantly related with development of AKI (p value 0.046). CONCLUSION: The dosing methods which use population-based pharmacokinetic variables does not result in desired therapeutic levels in HSCT patients, mainly because of larger vancomycin volume of distribution.

Circulating miR-455-3p, miR-5787, and miR-548a-3p as potential noninvasive biomarkers in the diagnosis of acute graft-versus-host disease: a validation study.

Currently, acute graft-versus-host disease (aGVHD) diagnosis is based on clinical features and pathological findings. Until now, there is no non-invasive diagnostic test for aGVHD. MicroRNAs may act as promising predictive, diagnostic, or prognostic biomarkers for aGVHD. The purpose of the current study was to validate circulating microRNAs as diagnostic biomarkers to assist clinicians in promptly diagnosing aGVHD, so that treatment can be initiated earlier. In the present study, we evaluated six microRNAs (miR-455-3p, miR-5787, miR-6729-5p, miR-6776-5p, miR-548a-3p, and miR-6732-5p) selected from miRNA array data in 40 aGVHD patients compared to 40 non-GVHD patients with RT-qPCR. Target genes of differentially expressed microRNAs (DEMs) were predicted using Targetscan, miRanda, miRDB, miRWalk, PICTAR5, miRmap, DIANA, and miRTarBase algorithms, and their functions were analyzed using EnrichNet, Metascape, and DIANA-miRPath databases. The expressions of plasma miR-455-3p and miR-5787 were significantly downregulated, whereas miR-548a-3p was significantly upregulated in aGVHD patients compared to non-GVHD patients. Moreover, DEMs showed potentially high diagnostic accuracy for aGVHD. In silico analysis of DEMs provided valuable information on the role of DEMs in GVHD, immune regulation, and inflammatory response. Our study suggested that miR-455-3p, miR-5787, and miR-548a-3p could be used as potential noninvasive biomarkers in the diagnosis of aGVHD in addition to possible therapeutic targets in aGVHD.

Effectiveness of adjuvant chemotherapy in patients with Stage II colorectal cancer: A multicenter retrospective study.

BACKGROUND: Adjuvant chemotherapy (ACT) for patients with Stage II colorectal cancer (CRC) is an area of controversy in oncology. International guidelines recommend the use of ACT in patients with specific high-risk features. This study aimed to investigate the effectiveness of ACT in improving survival in patients with and without high-risk features. MATERIALS AND METHODS: A total of 225 patients with Stage II CRC who underwent primary tumor resection were included in this study. Patients with one or more high-risk features including T4 tumor, poor differentiation, lymphovascular invasion, perineural invasion, bowel obstruction, local perforation, positive resection margins, or suboptimal lymph node sampling (fewer than 12 nodes) were classified as high risk. The survival analysis was performed between patients who only received curative surgery and those received single-agent (5-fluorouracil [5-FU] and leucovorin [LV] or capecitabine) or multiagent ACT (oxaliplatin and 5-FU + LV or oxaliplatin and capecitabine). RESULTS: The 5-year overall survival (OS) rate was 88.4%, and the 5-year disease-free survival (DFS) rate was 80.4%. The 5-year OS and DFS rates improved insignificantly with ACT (89.8% vs. 81.2%, P = 0.59 and 81.3% vs. 74.6%, P = 0.41, respectively); however, multiagent ACT results to inferior 5-year OS and DFS compared to single-agent ACT (82.1 vs. 92.8%, P = 0.14 and 70.1% vs. 86%, P = 0.07, respectively). ACT was associated with insignificant improved OS and DFS in both high-risk and low-risk groups, but high-risk patients who received multiagent ACT had a significant inferior OS and DFS in comparison with those received single-agent ACT. T4 tumor and obstruction were independent poor prognostic factors affecting OS and DFS. CONCLUSION: In our population, the improvement of OS and DFS with ACT was not statistically significant in high-risk and low-risk patients with Stage II CRC.

Diagnostic value of [ 68 Ga]Ga-Pentixafor PET/CT in malignant melanoma: a pilot study.

OBJECTIVE: To evaluate the diagnostic value of [ 68 Ga] Ga-Pentixafor in malignant melanoma patients. METHODS: In this prospective study, patients with histology-proven melanoma were included and underwent [ 18 F]fluoro-D-glucose ([ 18 F]FDG) and [ 68 Ga] Ga-Pentixafor PET/computed tomography (CT) within a week. Suspicious lesions were interpreted as benign vs. malignant, and the corresponding semi-quantitative PET/CT parameters were recorded and compared. RESULTS: Twelve consecutive melanoma patients (mean age: 60 ±â€…6) were included. Two patients were referred for initial staging, two for detecting recurrence and eight for evaluating the extent of metastases. Overall, [ 18 F]FDG PET/CT showed 236 tumoral lesions, including two primary tumors, two recurrent lesions, 29 locoregional metastases and 203 distant metastases. In [ 68 Ga]Ga-Pentixafor PET/CT, 101 tumoral lesions were detected, including two primary tumors, one recurrence, 16 locoregional metastases and 82 distant metastases. Notably, a documented brain metastasis was only visualized on [ 68 Ga]Ga-Pentixafor PET/CT images. Compared with [ 18 F]FDG, [ 68 Ga]Ga-Pentixafor PET/CT provided a 42% detection rate. Regarding semi-quantitative measures, the intensity of uptake and tumor-to-background ratios were significantly lower on [ 68 Ga]Ga-Pentixafor PET/CT [average maximum standard uptake value (SUV max ) of 2.72 ±â€…1.33 vs. 11.41 ±â€…14.79; P value <0.001 and 1.17 ±â€…0.53 vs. 5.32 ±â€…7.34; P value <0.001, respectively]. CONCLUSION: When comparing [ 68 Ga]Ga-Pentixafor PET/CT with [ 18 F]FDG PET/CT, not only did [ 68 Ga]Ga-Pentixafor PET/CT detect fewer lesions, but the intensity of uptake and the TBRs were also lower on [ 68 Ga]Ga-Pentixafor PET/CT. Thus, our results may indicate a limited potential of this novel tracer in cutaneous melanoma patients compared to [ 18 F]FDG PET/CT. Given the lower TBRs, applying this radiotracer in radioligand therapies is also questionable.

Hematopoietic Stem Cell Transplantation in Sickle Cell Disease: A Multidimentional Review.

While exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) have been approved by the US Food and Drug Administration (FDA) as the first cell-based gene therapies for the treatment of patients 12 years of age and older with sickle cell disease (SCD), this treatment is not universally accessible. Allogeneic hematopoietic stem cell transplant (HSCT) has the potential to eradicate the symptoms of patients with SCD, but a significant obstacle in HSCT for SCD is the availability of suitable donors, particularly human leukocyte antigen (HLA)-matched related donors. Furthermore, individuals with SCD face an elevated risk of complications during stem cell transplantation due to SCD-related tissue damage, endothelial activation, and inflammation. Therefore, it is imperative to consider optimal conditioning regimens and investigate HSCT from alternative donors. This review encompasses information on the use of HSCT in patients with SCD, including the indications for HSCT, conditioning regimens, alternative donors, and posttransplant outcomes.

Corrigendum: Determining the predictive impact of donor parity on the outcomes of human leukocyte antigen matched hematopoietic stem cell transplants: a retrospective, single-center study.

[This corrects the article DOI: 10.3389/fonc.2024.1339605.].

Determining the predictive impact of donor parity on the outcomes of human leukocyte antigen matched hematopoietic stem cell transplants: a retrospective, single-center study.

Introduction: Donor choosing remains to play a pivotal role in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Numerous criteria beyond HLA compatibility impact the selection of a suitable donor. Methods: We evaluated the effect of donor parity on transplant outcomes in a large homogeneously treated population that received an HLA-matched allo-HSCT between 2010 and 2021 at our center. All patients were transplanted from a peripheral blood stem cell source following a myeloablative Busulfan-based conditioning and an identical protocol for graftversus-host disease (GVHD) prophylaxis regimen. Results: A total of 1103 allo-HSCT recipients were included. 188 (17%) had transplants from parous female donors, whereas 621 (56.30%) and 294 (26.70%) received transplants from male and nulliparous female donors, respectively. HSCTs from parous female donors compared to male and nulliparous females were associated with a significantly higher incidence of grade III-IV acute (a) GVHD (55.27% vs. 11.34 and 10.84%) and extensive chronic (c) GVHD (64.32% vs. 15.52 and 13.65%), as well as lower relapse incidence (RI). Discussion: This study finds that while parous female donors are associated with higher incidences of grade III-IV aGVHD and extensive cGVHD post-allo-HSCT, the advantages, such as a lower RI, outweigh the risks. The results of our study provide valuable insights for donor selection.

Graft failure after allogeneic hematopoietic stem cell transplantation in pediatric patients with acute leukemia: autologous reconstitution or second transplant?

BACKGROUND: Graft failure (GF) is a rare but serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Prevention of graft failure remains the most advisable approach as there is no clear recommendation for the best strategies for reversing this complication. Administration of growth factor, additional hematopoietic progenitor boost, or a salvage HSCT are current modalities recommended for the treatment of GF. Autologous recovery without evidence of disease relapse occurs rarely in patients with GF, and in the absence of autologous recovery, further salvage transplantation following a second conditioning regimen is a potential treatment option that offers the best chances of long-term disease-free survival. The preconditioning regimens of second HSCT have a significant impact on engraftment and outcome, however, currently there is no consensus on optimal conditioning regimen for second HSCT in patients who have developed GF. Furthermore, a second transplant from a different donor or the same donor is still a matter of debate. OBSERVATIONS: We present our experience in managing pediatric patients with acute leukemia who encountered graft failure following stem cell transplantation. CONCLUSIONS AND RELEVANCE: Although a second transplantation is almost the only salvage method, we illustrate that some pediatric patients with acute leukemia who experience graft failure after an allogeneic stem cell transplant using Myeloablative conditioning (MAC) regimen may achieve long-term disease-free survival through autologous hematopoiesis recovery.

The Influence of KIR Gene Polymorphisms and KIR-ligand Binding on Outcomes in Hematologic Malignancies following Haploidentical Stem Cell Transplantation: A Comprehensive Review.

Natural killer (NK) cell behavior and function are controlled by a balance between negative or positive signals generated by an extensive array of activating and inhibiting receptors, including killer cell immunoglobulin-like receptor (KIR) proteins, main components of the innate immune system that contribute to initial responses against viral infected-transformed cells through generation of the release of cytokines and cytotoxicity. What is certain is that KIRs are genetically polymorphic and the extent of KIRs diversity within the individuals may have the potential outcomes for hematopoietic stem cell transplantation (HSCT). In this regard, recent studies suggest that KIR is as imperative as its ligand (HLA) in stem cell transplantation for malignant diseases. However, unlike HLA epitope mismatches, which are well-known causes of NK alloreactivity, a complete understanding of KIR genes' role in HSCT remains unclear. Because of genetic variability in KIR gene content, allelic polymorphism, and cell-surface expression among individuals, an appropriate selection of donors based on HLA and KIR profiles is crucial to improve outcomes of stem cell transplantation. In addition, the impact of the KIR/HLA interaction on HSCT outcomes needs to be investigated more comprehensively. The present work aimed to review the NK cell regeneration, KIR gene polymorphisms, and KIRligand binding on outcomes in hematologic malignancies following haploidentical stem cell transplantation. Comprehensive data gathered from the literature can provide new insight into the significance of KIR matching status in transplantations.

Incidence of hemorrhagic cystitis following unmanipulated peripheral blood stem cell transplantation in acute Leukemia: A retrospective single-center risk factor analysis.

BACKGROUND: Hemorrhagic cystitis (HC) is an important adverse event experienced after hematopoietic stem cell transplantation (HSCT). Severe HC could lead to significant morbidity, prolonged hospitalization with increased health-care costs, and may cause considerable mortality. OBJECTIVES: In order to investigate the influence of different contributing factors other than BK viruria on HC occurrence in a homogenous population, we retrospectively analyzed the potential risk factors. STUDY DESIGN: We conducted a retrospective study among 200 patients (median age 12.4 years, IQR: 7.9-16.1) with acute leukemia who received peripheral blood allogenic HSCT after radiation-free myeloablative conditioning regimen, in pediatric cell therapy department of Research Institute for Oncology, Hematology and Cell Therapy (RIOHCT), Tehran, Iran, between December 2014 and December 2021. Associations between risk factors and outcomes were examined by univariable and multivariable logistic regression models. RESULTS: A total of 46 patients (23%) had developed HC during the study period. The median onset of HC was 29 (IQR: 24-37) days post-transplant, and it persisted for a median of 33 (7-270) days. The incidence of HC in our patients was estimated to be 3 in 1000 cases (95% CI: 2-4). The results of multivariable logistic model shows that the chance of HC in T-cell acute lymphoblastic leukemia (ALL) compared to B-cell All is nearly five times more (OR = 4.88; 95%CI: (1.51-15.78), P = 0.008). The incidence of HC in patients who underwent HSCT from haploidentical donors was significantly higher than full matched donors (P < 0.001). Undergoing transplant from a matched unrelated and haploidentical donor both augment the chance of HC in about six times more than matched related donors (OR = 6.36; 95%CI: (1.58-25.49), P = 0.009 and OR = 5.7; 95%CI: (1.83-17.75), P = 0.003, respectively). In patients who developed HC compared to non-HC group, overall survival was much worse (P < 0.001). DISCUSSION: Most studies have failed to demonstrate any relationship between late-onset HC and the dose of cyclophosphamide. In our study, although the dose of cyclophosphamide was similar in HSCT from MRD and MUD, the hazard of HC incidence was significantly higher in the latter group. This could be accredited to ATG, as in patients in the MRD group who had not received any ATG, the incidence of HC was much lower than the patients who had underwent HSCT from MUD or haploidentical donor group. CONCLUSIONS: Patients with T-cell ALL and those who under haploidentical HSCT had the highest incidence of HC.

Clinical Features and Risk Factors of Relapse and Mortality in Thrombotic Thrombocytopenic Purpura Patients: A Seven-Year Experience.

Background: Thrombotic thrombocytopenic purpura (TTP) is associated with microangiopathic hemolytic anemia, thrombocytopenia, and microvascular thrombosis. No comprehensive report exists on clinical characteristics and risk factors of relapse and mortality in Iranian TTP patients. In this study, we aimed to report clinical features of Iranian TTP patients, to evaluate disease relapse and mortality rate and their associated risk factors. Materials and Methods: This study was a cohort study of patients diagnosed with microangiopathic hemolytic anemia admitted to the Shariati Hospital, Tehran, a referral center for TTP patients, from 2010 to 2017. Demographic, clinical, and laboratory data were recorded and patients were followed for 3 years regarding disease relapse and mortality. Results:  114 patients (80 females, 34 males) with a mean age of 39.3 ± 14.99 years were included.  Hematologic and neurologic symptoms were the most common manifestations. Abnormal laboratory findings at the presentation included thrombocytopenia, anemia, and elevated LDH. All patients were treated with plasma exchange, and 75.5% of them had a response to treatment, while the 3-year relapse and mortality rate was 23.6 and 26.3%.  Lower platelet count was a predictor of disease relapse. Age, hematological, or neurological initial presentation were associated with TTP mortality. Conclusion: Based on the largest study of TTP patients ever in Iran, the demographic and clinical characteristics of Iranian TTP patients are similar to other existing reports. Knowledge of the risk factors for TTP relapse and mortality could be useful to alert hematologists for prompt therapeutic actions when necessary.

Comparable Outcomes of Pre- Versus Post-Tyrosine Kinase Inhibitor Era Treatment in Chronic Myeloid Leukemia: A Retrospective Cohort Study With Long-term Follow-up.

Imatinib, a selective BCR-ABL tyrosine kinase inhibitor (TKI), was introduced after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with chronic myeloid leukemia (CML). However, the long-term effects of allo-HSCT in chronic phase CML patients are mostly unknown. We retrospectively analyzed the outcomes of 204 patients with sibling donors who received peripheral stem cells and underwent allo-HSCT of chronic phase I (CP1) in the pre- and post-TKI era at Shariati Hospital in Tehran, Iran, from 1998 to 2017 and followed up till the end of 2021. The median follow-up time for all patients was 8.7 (SD = 0.54) years. Fifteen-year overall survival (OS), disease-free survival (DFS), graft-versus-host disease-free relapse-free survival (GRFS), relapse, and non-relapse mortality (NRM) incidence were 65.70%, 57.83%, 17.56%, 13.17%, and 28.98%, respectively. Using multivariable analyses, the only risk factor increasing the hazard of death was the time between diagnosis to allo-HSCT greater than 1 year compared to this time less than 1 year by 74% [hazard ratio (HR) = 1.74, P = 0.039]. Also, age is a significant risk factor for DFS (HR = 1.03, P = 0.031). Our findings suggested that allo-HSCT is still an important treatment option for CP1 patients, especially those resistant to TKI treatment. TKI consumption can have a desirable effect on NRM after allo-HSCT for CP1 CML.

Spontaneous Complete Remission of Acute Myeloid Leukemia in the Absence of Disease-Modifying Therapy following Severe Pulmonary Involvement by Coronavirus Infectious Disease-19.

Coronavirus infectious disease-19 (COVID-19) usually alters the innate and adaptive immune setting by excessive production of proinflammatory cytokines, leading to a deviation in the natural course of simultaneous malignant disease. In the absence of disease-modifying therapy, complete remission of acute myeloid leukemia (AML) is an extraordinary event caused mainly by an immune-related mechanism secondary to a severe infectious process. We present a 57-year-old woman with a new diagnosis of AML associated with a 11q23/KMT2A abnormality who had achieved temporary spontaneous remission in the absence of disease-modifying therapy following the severe pulmonary infection with coronavirus lasting for six months. We review the literature and explain the potential impact of stimulated immune responses by COVID-19 on induction of remission in a patient with AML that could provide an excellent opportunity for new immune-based therapies to evolve for the hematologic malignancies. Despite the high ability of the immune process to destroy the malignant cells, the remission of duration is usually short. Therefore, it seems that continuing treatment after SR of AML by a consolidation regimen or bone marrow transplantation, based on a risk-adapted treatment approach, may reduce the recurrence risk.

The role of HER2 alterations in clinicopathological and molecular characteristics of breast cancer and HER2-targeted therapies: a comprehensive review.

Breast cancer (BC) is the most common malignancy in women and one of the leading causes of cancer mortality, despite significant treatment advancements over the last decades. Human epidermal growth factor receptor-2 (HER2) is a member of the ERBB family of receptor tyrosine kinases which have long been known to mediate cancer cell growth and invasion through constitutive activation of oncogenic downstream signaling, such as PI3K/Akt/mTOR and MAPK. Overexpression/amplification of HER2 in various tumors, especially BC, offers the possible therapeutic potential for target therapies. HER2-targeted therapies, either with a combination of chemotherapy or through multi-anti-HER2 therapies without chemotherapy, have significantly improved the prognosis of HER2-positive tumors. In recent years, novel anti-HER2 agents and combination therapies have garnered much attention, especially for heavily treated advanced or metastatic BCs. HER2-positive BC is biologically a heterogeneous group depending on HER2 activation mechanisms, hormone receptor status, genome variations, tumor heterogeneity, and treatment resistance, which affect the treatment benefit and patients' outcomes. This review will discuss HER2 alternations (gene amplification or receptor overexpression) in BC, their correlation with clinicopathological characteristics and molecular characteristics, and HER2-based therapies in tumors with HER2 overexpression/amplification.

Radiation-free reduced-intensity hematopoietic stem cell transplantation with in vivo T-cell depletion from matched related and unrelated donors for Fanconi anemia: prognostic factor analysis.

Fanconi anemia (FA) is a rare and complex genetic disorder, clinically characterized by bone marrow failure, congenital defects, and cancer predisposition. Hematopoietic stem cell transplantation (HSCT) represents the only therapeutic option to restore normal hematopoiesis after the occurrence of marrow failure or clonal hematopoietic abnormality. However, radiation exposure during transplant may increase the risk of later malignancies. In this retrospective study, we analyzed the results of HSCT with a radiation-free, busulfan-based conditioning regimen in FA patients. A total of 122 patients (median age: 8 years, range: 2-18 years) with FA who underwent HSCT between January 2008 and January 2020 were enrolled in this study and followed up to the end of 2020. The preparative regimen included busulfan (0.2 mg/kg/day, days -9 to -6), cyclophosphamide (15 mg/kg/day, days -5 to -2), and in vivo T-cell depletion with rabbit anti-thymocyte globulin. All patients received graft-versus-host disease prophylaxis with cyclosporine combined with methotrexate. We used the Kaplan-Meier method, log-rank test, and Cox proportional hazards models to analyze patient survival. Peripheral blood, bone marrow and cord blood hematopoietic stem cells were used in 84 (68.9%), 31 (25.4%) and 7 (5.7%) patients, respectively. Donors were matched siblings in 48 (39.3%), matched other relatives in 56 (45.9%), and matched unrelated persons in 18 (14.8%) patients. With a median follow-up time of 24.25 months, graft rejection occurred in only one patient. The 1- and 5-year overall survival rates were 84.14% (95% confidence interval: 76.02-89.70) and 82.16% (95% confidence interval: 73.01-88.45), respectively. Of the patient characteristics documented before transplant, the presence of cardiopulmonary, genitourinary tract, central nervous system, and limb malformations significantly affected survival rates. Our results indicate excellent outcomes in patients with FA undergoing HSCT with a radiation-free, busulfan-based conditioning regimen. It would be desirable to aim at optimizing the outcome of HSCT in FA patients in future studies.

Modified combination of anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) as compared with standard ATG protocol in haploidentical peripheral blood stem cell transplantation for acute leukemia.

In haploidentical peripheral blood stem cell transplantation (haplo-PBSCT), the combination of anti-thymocyte globulin and post-transplant cyclophosphamide (ATG/PTCy) has a synergistic impact in preventing graft-versus-host disease (GvHD). However, little is known about the long-term consequences of the new combination approach. Our goal is to evaluate the efficacy of ATG/PTCy versus a standard ATG regimen by focusing at long-term outcomes in a more homogeneous group of patients. We retrospectively included 118 adult patients up to 60 years with acute leukemia who underwent haplo-PBSCT at our single institution, following the same myeloablative conditioning regimen. From 2010 to 2020, 78 patients received a modified combination of ATG (2.5 mg/kg/day, on days -3, -2, and -1) and PTCy (40 mg/kg/day on days +3 and +4) compared to 40 patients who had a standard ATG-based regimen (2.5 mg/kg/day from days -4 to -1) from 2008 to 2015. The median follow-up time for all patients was 5.36 years, respectively. The cumulative incidence (CI) of neutrophil and platelet engraftment, as well as CMV reactivation, did not differ statistically between the two groups. The CI of the acute GvHD of grades II-IV and III-IV and extensive chronic GvHD were considerably lower in the ATG/PTCy (34.6%, 8.97%, and 13.63%) than in the ATG cohort (57.5%, 30%, and 38.23%) as validated by multivariable modeling. Additionally, compared to the ATG arm, the ATG/PTCy was a hazard factor associated with a higher risk of relapse (HR = 2.23, p = 0.039). The probability of 5-year overall survival, disease-free survival, and GvHD-free relapse-free survival in the ATG/PTCy group (53.34%, 49.77%, and 36.04%) was comparable with the ATG group (47.5%, 42.5%, and 22.5%), respectively. Our finding suggested that a modified ATG/PTCy combination resulted in a lower risk of acute and chronic GvHD and a higher risk of relapse than the standard ATG-based protocol but had no effect on long-term outcomes. However, certain adjustments in the immunosuppression protocol are warranted to improve the outcome.

Outcomes of haploidentical peripheral stem cell transplantation with combination of post-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG) compared to unrelated donor transplantation in acute myeloid leukemia: A retrospective 10-year experience.

In the evolution of haploidentical hematopoietic stem cell transplantation (haplo-HSCT), In vivo T-cell modulation with concomitant use of anti-thymocyte globulin (ATG) and high-dose post-transplant cyclophosphamide (PTCy) provides a novel promising method on transplant outcomes; however, the long-term effects of this therapy are mostly unknown. We retrospectively compared the long-term outcomes of adult acute myeloid leukemia (AML) patients undergoing a haplo-HSCT (n = 92) with a new modified combination of ATG and PTCy in the context of peripheral blood stem cell (PBSC) and myeloablative conditioning (MAC) with an otherwise similar group of AML patients who received an unrelated donor (URD) HSCT (n = 57) with ATG protocol from February 2010 to December 2020 at our single-center (HORCSCT). Median follow-up was 3.73 and 4.28 years for haploidentical and URD-HSCT, respectively. In haplo-HSCT, the cumulative incidence of grades II-IV and III-IV acute graft versus host disease (aGvHD) and extensive chronic GvHD (cGvHD) was much lower than in URD (27% versus 56% for grades II-IV, 8.7% versus 24.5% for grades III-IV, and 15.4% versus 34.7% for extensive cGvHD, respectively). Five-year overall survival (OS) was 54.03% for haplo and 54.48% for URD (p = 0.927); GvHD-free relapse-free survival (GRFS) was 44.1% and 29.86% (p = 0.149); relapse incidence was 15.79% and 26.95% (p = 0.72); and non-relapse mortality (NRM) was 29.48% and 26.32% (p = 0.73), respectively. Using multivariable analyses, when compared to Haplo, URD was a significant predictor of relapse (HR=1.80, p = 0.039); however, no difference in OS, GRFS, and NRM was noted between haplo and URD. Therefore, given the favorable results with haplo-HSCT and considering donor availability promptly with low cost, it conservatively suggested that haplo-HSCT with the introduced protocol could be viewed as the first alternative for patients with AML in the absence of matched sibling donors.