Age-dependent determinants of infectious complications profile in children and adults after hematopoietic cell transplantation: lesson from the nationwide study.

Incidence and outcome of microbiologically documented bacterial/viral infections and invasive fungal disease (IFD) in children and adults after hematopoietic cell transplantation (HCT) were compared in 650 children and 3200 adults in multicenter cross-sectional nationwide study. Infections were diagnosed in 60.8% children and 35.0% adults, including respectively 69.1% and 63.5% allo-HCT, and 33.1% and 20.8% auto-HCT patients. The incidence of bacterial infections was higher in children (36.0% vs 27.6%; p < 0.0001). Infections with Gram-negative bacteria were more frequent than Gram-positives in adults (64.6% vs 44.8%; p < 0.0001). Outcome of bacterial infections was better in children (95.5% vs 91.4%; p = 0.0011). The IFD incidence (25.3% vs 6.3%; p < 0.0001) and outcome (88.0% vs 74.9%; p < 0.0001) were higher in children. The incidence of viral infections was higher in children after allo-HCT (56.3% vs 29.3%; p < 0.0001), and auto-HCT (6.6% vs 0.8%; p < 0.0001). Outcome of viral infections was better in children (98.6% vs 92.3%; p = 0.0096). Infection-related mortality was 7.8% in children and 18.4% in adults (p < 0.0001). No child after auto-HCT died of infection. Adult age, mismatched transplants, acute leukemia, chronic GVHD, CMV reactivation, infection with Gram-negatives, and duration of infection > 21 days were risk factors for death from infection. In conclusion, pediatric patients have 2.9-fold higher incidence and 2.5-fold better outcome of infections than adults after HCT.

Incidence and Role of Recipient-Specific Antibodies in Allogeneic Hematopoietic Cell Transplantation from Mismatched Related Donors.

High titer of donor-specific antibodies (DSAs) increases the risk of graft rejection after mismatched related hematopoietic cell transplantation (HCT). There are no data regarding the incidence of anti-HLA recipient-specific antibodies (RSAs) and their role after transplantation. Here we aimed to identify the incidence of RSAs in a mismatched related hematopoietic cell donor population and their possible impact on immune-mediated complications, such as acute graft-versus-host disease (aGVHD), and complications resulting from endothelial injury, such as transplantation-associated thrombotic microangiopathy (TA-TMA) and veno-occlusive disease (VOD). We prospectively analyzed the incidence of anti-HLA antibodies in 28 mismatched related pairs of recipients and their donors who underwent HCT at our center between 2020 and 2022. In positive samples screened for anti-HLA class I and/or II antibodies, the specificity of the HLA antibodies was analyzed. All recipients had a hematologic malignancy and received a myeloablative conditioning regimen and immunosuppression consisting of post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Patients were tested for TA-TMA and aGVHD development during routine post-transplantation visits up to 100 days post-transplantation. We used modified Jodele criteria for TA-TMA diagnosis, and based aGVHD grading on the MAGIC criteria. VOD was assessed using the European Society for Blood and Marrow Transplantation. Anti-HLA antibodies were detected in 12 donors (43%) and in 9 recipients (32%). There were no significant differences between donors and recipients according to age (median, 42 years [range, 17 to 69 years] versus 39 years [range, 8 to 68 years]), sex, or pregnancy history. No transfusion history was noted in the donor group (P < .05). RSA antibodies were present more often than DSAs and were detected in 9 out of 12 (75%) anti-HLA-positive donors and in only 2 out of 9 (22%) recipients, respectively (P < .05). During the follow-up, 11 patients (39%) developed aGVHD, including grade I-II in 9 (32%) and grade III-IV in 2 (7%). Twelve patients (43%) met the criteria for TA-TMA, and only 1 patient (3.5%) was diagnosed with VOD by day 100 post-HCT. RSAs were detected significantly more often in the TA-TMA group; among 12 patients diagnosed with TA-TMA, 7 (58%) had RSAs (P < .05). We did not find a correlation between RSAs and aGVHD. The patient with VOD did not have an RSA-positive donor. There was no difference in membrane attack complex (MAC) concentration in the RSA-positive group on day 30 and day 60 post-HCT; however, there was a trend toward higher MAC concentration in the RSA-positive group on day 100 (median, 912 ng/mL [range, 788 to 1120 ng/mL] versus 616 ng/mL [range, 352 to 1244 ng/mL]; P = .055). Patients with RSA suffered more often from platelet and red blood cell decreases or transfusion refractoriness, and increased lactate dehydrogenase activity was observed in all RSA-positive cases. The donor immune status and the presence of RSA may be associated with higher rates of TA-TMA in mismatched HCT recipients. Antibody-mediated complement activation might be an additional factor influencing TA-TMA occurrence.

Effective treatment of Clostridioides difficile infection improves survival and affects graft-versus-host disease: a multicenter study by the Polish Adult Leukemia Group.

Clostridioides difficile infection (CDI) is the most common cause of infectious diarrhea after allogeneic hematopoietic cell transplantation (allo-HCT). The impact of CDI and its treatment on allo-HCT outcomes and graft-versus-host disease (GVHD), including gastrointestinal GVHD (GI-GVHD) is not well established. This multicenter study assessed real-life data on the first-line treatment of CDI and its impact on allo-HCT outcomes. Retrospective and prospective data of patients with CDI after allo-HCT were assessed. We noted statistically significant increase in the incidence of acute GVHD and acute GI-GVHD after CDI (P = 0.005 and P = 0.016, respectively). The first-line treatment for CDI included metronidazole in 34 patients, vancomycin in 64, and combination therapy in 10. Treatment failure was more common with metronidazole than vancomycin (38.2% vs. 6.2%; P < 0.001). The need to administer second-line treatment was associated with the occurrence or exacerbation of GVHD (P < 0.05) and GI-GVHD (P < 0.001) and reduced overall survival (P < 0.05). In the multivariate analysis, the risk of death was associated with acute GVHD presence before CDI (hazard ratio [HR], 3.19; P = 0.009) and the need to switch to second-line treatment (HR, 4.83; P < 0.001). The efficacy of the initial CDI treatment affects survival and occurrence of immune-mediated GI-GVHD after allo-HCT. Therefore, agents with higher efficacy than metronidazole (vancomycin or fidaxomicin) should be administered as the first-line treatment.

A hybrid protocol CLAG-M, a possible player for the first-line therapy of patients with mixed phenotype acute leukemia. A Polish Adult Leukemia Group experience.

Introduction: Mixed-phenotype acute leukemia (MPAL) is a rare disease with poor prognosis. So far, no standard approach has been established as the "know-how" of MPAL is based only on retrospective analyses performed on small groups of patients. Materials and methods: In this study, a retrospective analysis of the outcomes of adult MPAL patients included in the PALG registry between 2005 and 2024 who received the CLAG-M hybrid protocol as induction or salvage therapy was performed. Results: Sixteen of 98 MPAL patients received CLAG-M: eight as first-line and eight as salvage therapy. In the first line, two patients achieved partial response (PR), and six achieved complete remission (CR), of whom four successfully underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). Two patients who did not undergo alloHSCT promptly relapsed. Within the whole group, the overall response rate (ORR) was 75% (n = 12/16). With the median follow-up of 13 months, six out of eight patients remain in CR, however, two of them died due to acute graft versus host disease. Out of eight patients who received CLAG-M in the second line, four patients (50%) obtained CR. AlloHSCT was conducted in seven cases, six of which were in CR. Only two patients remained in CR at the time of the last follow-up. Tolerance to treatment was good. The median times for severe neutropenia and thrombocytopenia were 22 days (range, 16-24) and 17 days (range, 12-24), respectively. Overall, grade 3-4 infections were observed in 12 cases, and all infections presented successful outcomes. Conclusions: CLAG-M is an effective first-line salvage regimen for MPAL with an acceptable safety profile. Early achievement of CR with prompt alloHSCT allows for satisfactory disease control.

[Long-term survival results according to cytogenetic risk in patients with acute myeloid leukemia--singl center experience]. / Odlegle wyniki przezycia chorych na ostre bialaczki szpikowe w zaleznosci od grupy ryzyka cytogenetycznego--analiza jednoosrodkowa.

Cytogenetic analysis of leukemic blasts has become a part of the standard diagnosis approach of acute myeloid leukemia patients. Chromosomal aberrations findings separate AML patients into three broad prognostic categories: favorable, intermediate and high risk. We analyzed retrospectively 179 adults with de novo acute myeloid leukemia (AML), younger than 60 years admitted to our Department between January 1999 and April 2009 to evaluate the prognostic impact of cytogenetic abnormalities on complete remission (CR) rate, disease free survival (DFS), and overall survival (OS). All patients received similar induction therapy. Median follow-up of 3.8 years for favorable cytogenetic group CR rate was 85%, 3-year DFS was 70% and 3-year OS was 65%, for intermediate group CR rate, 3-year DFS and 3-year OS were respectively: 64%, 43%, and 38%. Among high risk patient CR rate was 40%, 3-year DFS was 24%, 3-year OS was 17%. We conclude that cytogenetics is among the most useful factors in predicting attainment of CR, DFS, and long-term overall survival in adult de novo AML patients younger than 60 years.

[High-dose chemotherapy and autologous stem cell transplantation in multiple myeloma patients--single center experience]. / Wysokodawkowana chemioterapia z przeszczepieniem autologicznych komórek macierzystych u chorych na szpiczaka plazmocytowego--wyniki analizy jednoosrodkowej.

Multiple myeloma (MM) is one of the hematologic malignancies in which the impact of dose intensity has been demonstrated. In 2005 it was the most common disease for which autologous stem cell transplantation (ASCT) was performed. However, ASCT is not curative, and most patients relapse within a median of 3 years, the introduction of high-dose therapy resulted in prolonged survival. Novel agents such as thalidomide, bortezomib, or lenalidomide have been introduced to improve high-dose therapy outcome. From April 1998 to December 2008, 65 patients with MM underwent in our Department high-dose chemotherapy supported by autologous transplantation of peripheral blood stem cells (APBSCT). Transplantation of progenitor cells was conducted as consolidation of first line treatment in the majority of patients. Double transplantation was performed in 20 patients (31%). Conditioning regimen consisted of high-dose melphalan (200 mg/m2), in the second procedure the dose of melphalan was reduced to 140 mg/m2. Transplant related mortality was not observed. The duration of hematological recovery after first and second transplantation did not differ significantly. At the time of the analysis (June 2009) 51/65 (78.5%) patients are alive, 14/65 (21.5%) died due to disease progression. Median overall survival (OS) and progression free survival ( PFS) obtained were 86 (range 24-128) and 33 (range 4-110) months respectively. This retrospective analysis confirms the efficacy and safety of APBST in multiple myeloma patients.

Infectious Complications in Patients With Multiple Myeloma After High-Dose Chemotherapy Followed by Autologous Stem Cell Transplant: Nationwide Study of the Infectious Complications Study Group of the Polish Adult Leukemia Group.

BACKGROUND: Multiple myeloma (MM) has become a chronic disease in majority of patients, and remission consolidation with autologous hematopoietic stem cell transplant (ASCT) remains the backbone of treatment in transplant-eligible patients. OBJECTIVE: The aim of this multicenter cross-sectional nationwide retrospective study was to evaluate the epidemiology, etiology, and outcome of infections in patients with MM undergoing ASCT in 13 Polish transplant centers, carried out on behalf of the Infectious Complications Study Group of the Polish Adult Leukemia Group. METHODS: A total number of consecutive 1374 patients with MM treated in Polish adult transplant centers from 2012 to 2014 were followed for infectious complications up to day +100 after ASCT in nationwide study. RESULTS: Altogether 490 infection episodes in 336 patients (49% male, aged 21-72 years) were reported, including 145 episodes of neutropenic fever (103 patients) and 34 episodes of clinically documented infections (CDIs) (27 patients). Among microbiologically confirmed infections there were 251 episodes of bacterial infections (180 patients), 42 episodes of fungal infections (38 patients), and 18 episodes of viral infections (17 patients). The overall incidence of infections reached 13.1% for bacterial, 3.6% for fungal, and 1.3% for viral infections. There were 16 cases of infection-related deaths after ASCT (1.2%). The mortality risk factors included multidrug-resistant bacteria etiology (odds ratio [OR], 3.5; P = .033), coexistence of bacterial and fungal infection (OR, 6.3; P = .002), and CDI (OR, 5.5; P = .007). CONCLUSION: ASCT in patients with MM was connected with low risk of life-threatening infections. However, multidrug-resistant bacteria bacterial etiology, mixed etiology, and CDI increased the risk of fatal outcome.

Targeting Immune Signaling Pathways in Clonal Hematopoiesis.

BACKGROUND: Myeloid neoplasms are a diverse group of malignant diseases with different entities and numerous patho-clinical features. They arise from mutated clones of hematopoietic stem- and progenitor cells which expand by outperforming their normal counterparts. The intracellular signaling profile of cancer cells is the sum of genetic, epigenetic and microenvironmental influences, and the multiple interconnections between different signaling pathways make pharmacological targeting complicated. OBJECTIVE: To present an overview of known somatic mutations in myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) and the inflammatory signaling pathways affected by them, as well as current efforts to therapeutically modulate this aberrant inflammatory signaling. METHODS: In this review, we extensively reviewed and compiled salient information with ClinicalTrials.gov as our source on ongoing studies, and PubMed as our authentic bibliographic source, using a focused review question. RESULTS: Mutations affecting immune signal transduction are present to varying extents in clonal myeloid diseases. While MPN are dominated by a few common mutations, a multitude of different genes can be mutated in MDS and AML. Mutations can also occur in asymptomatic persons, a finding called clonal hematopoiesis of indeterminate potential (CHIP). Mutations in FLT3, JAK, STAT, CBL and RAS can lead to aberrant immune signaling. Protein kinase inhibitors are entering the clinic and are extensively investigated in clinical trials in MPN, MDS and AML. CONCLUSION: In summary, this article summarizes recent research on aberrant inflammatory signaling in clonal myeloid diseases and the clinical therapeutic potential of modulation of signal transduction and effector proteins in the affected pathways.

[Epstein-Barr virus (EBV) infections in patients treated with allogenic hematopoietic cells transplantation (allo-HCT)]. / Zakazenia wirusem Epsteina-Barr (EBV) u pacjentów leczonych allogenicznym przeszczepieniem komórek hemopoetycznych (allo-HCT).

OBJECTIVE: Assessment of frequency and clinical course of EBV infection in patients that underwent non-manipulated allo-HCT from matched-related donors. METHODS: Active EBV infection was confirmed based on the presence of anti-EA antibodies (ELISA) and/or viral DNA (nPCR) isolated from peripheral leukocytes. For positive DNA-isolations semi-quantitative analysis were done. Patients were examined repeatedly, the time of monitoring was approximately 6 +/- 5 months. RESULTS: Active EBV infection was confirmed in 27 among 56 examined allo-HCT recipients. Primary infection was detected in 5 patients, in the remaining patients it was probably the result of virus reactivation. In most cases EBV-load was approximately 200 copies per 1 million of leukocytes, 1 patient with lymphoproliferative disorder (PTLD) had 2 million copies. EBV infection was asymptomatic in most cases (17), in 7 cases aminotransferase levels were insignificantly increased, in 2--diarrhea was observed and in 4 patients GvHD was intensified. CONCLUSIONS: In recipients without risk of PTLD, permanent monitoring of the EBV-load has no clinical justification.

Neopterin and other inflammatory markers in the early period following allogeneic bone marrow transplantation: series of 3 cases.

The 3 case reports presented here constitute a pilot study assessing the profile of changes in concentrations of selected inflammatory markers, including C-reactive protein, serum amyloid A, neopterin, and interleukin 18, in an early period after allogeneic stem cell transplantation.