Stem Cell Transplantation Procedures Research Articles

Left and right ventricular global longitudinal strain assessment together with biomarker evaluation may have a predictive and prognostic role in patients qualified for hematopoietic stem cell transplantation due to hematopoietic and lymphoid malignancies – a pilot study description

The hematopoietic stem cell transplantation (HSCT) procedure is considered a cardiovascular burden. This is due to the potentially cardiotoxic cytostatic agents used before and the risks associated with peri-transplant procedures. We designed a pilot study to determine the clinical utility of the new ST2 marker; furthermore, we routinely assessed cardiac parameters in HSCT recipients. Based on previous cardio-oncology experience in lung and prostate cancer, we can confirm the prognostic and predictive value of classic cardiac biomarkers and modern echocardiography parameters such as global longitudinal strain of the left and right ventricle. After conducting this pilot study we can create a predictive and prognostic model for patients undergoing HSCT. This will greatly enrich our clinical practice, especially in treating older people.

Novel ABCD1 variant causes phenotype of adrenomyeloneuropathy with cerebral involvement in Ukrainian siblings: first adult hematopoietic stem cell transplantation for ALD in Ukraine: a case report

BackgroundThis article presents a case study of two white male siblings of 24 and 31 years of age of self-reported Ukrainian ethnicity diagnosed with adrenomyeloneuropathy (AMN) associated with a novel splice site mutation in the ABCD1 gene. AMN represents a form of X-linked adrenoleukodystrophy (X-ALD) characterized by demyelination of the spinal cord and peripheral nerves. The case also presents the first adult haematopoietic stem cell transplant (HSCT) for adrenomyeloneuropathy in Ukraine. The rarity of this mutation and its cerebral involvement and the treatment make this case noteworthy and underscore the significance of reporting it to contribute to the existing medical knowledge.Case presentationThe patients of 24 and 31 years initially exhibited progressive gait disturbance, lower extremity pain, and urinary incontinence, with the older sibling experiencing more advanced symptoms of speech, hearing, and vision disturbances. A comprehensive genetic analysis identified an unreported splice site mutation in exon 3 of the ABCD1 gene, leading to the manifestation of AMN. The inheritance pattern was consistent with X-linked recessive transmission. The article also outlines the clinical features, magnetic resonance imaging (MRI), and nerve conduction study (NCS) findings. Moreover, it discusses the genetic profile of the affected individuals and female carriers within the family. The younger sibling underwent HSCT, which was complicated by mediastinal lymph node and lung tuberculosis, adding to the complexity of managing adult ALD patients.ConclusionsThis report emphasizes the importance of genetic testing in diagnosing and comprehending the underlying mechanisms of rare genetic disorders, such as AMN with cerebral involvement. The identification of a novel splice site mutation expands our understanding of the genetic landscape of this condition. Additionally, the challenges and complications encountered during the hematopoietic stem cell transplant procedure underscore the need for cautious consideration and personalized approaches in adult ALD patients.

A Nursing Pre-Transplant Intervention to Reduce Patients' Uncertainty about Allogeneic Hematopoietic Stem Cell Transplantation.

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) procedures often experience high levels of uncertainty. In this study, we developed and implemented a nursing intervention program to help patients recognize and reduce pre-transplant uncertainty. This study used a pretest-posttest single-group design without a control group. Eighteen patients undergoing HSCT participated in the intervention program-which included informational support, confirmation that the patients understood the information provided, and emotional support. Outpatients received the intervention at their initial outpatient visits after their procedure dates were determined, while inpatients received it at discharge following their procedures. The Universal Uncertainty in Illness Scale (UUIS), which consists of 26 items and six subscales, was used as the primary outcome measure. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the Hospital Anxiety and Depression Scale were used as secondary outcome measures. The sample included 18 individuals (13 male and five female participants; median age, 52 years). Most participants had acute lymphoblastic leukemia and had previously undergone bone marrow transplantations. Following our intervention, the total UUIS score significantly decreased, from 80.83 ± 18.42 before the intervention to 63.06 ± 23.53 afterward (t = 4.98, p < .001). Furthermore, significant post-intervention reductions were observed for all six subscales of the UUIS. There were no significant differences in the functional EORTC QLQ-C30 scale scores; however, the symptom scale showed a significant decrease in fatigue (pre = 35.19 ± 19.53, post = 25.93 ± 17.04, Z = -1.99, p < 0.046) and constipation (pre = 20.37 ± 20.26, post = 7.41 ± 14.26, Z = -2.11, p = 0.035). There were no significant differences in anxiety and depression levels pre- and post-intervention. Overall, the intervention effectively reduced both UUIS total and subscale scores related to pre-HSCT uncertainties. Assessing uncertainty prior to HSCT is vital to assisting patients in coping with the procedure. Nurses not only provide information but also tailor the information to the patients' cognitive abilities, thereby simplifying their understanding of the disease and its treatment.

Dynamics of Sex Hormones in Men with Diabetes Mellitus After Autologous Mesenchymal Stem Cell Transplant.

Our goal was to determine levels of sex hormones in men with type 1 diabetes mellitus and type 2 diabetes mellitus after autologous mesenchymal stem cell transplant. We examined 10 male patients (32-56 years old) with type 1 diabetes mellitus and type 2 diabetes mellitus, whom we subsequently divided into 2 groups and examined. Group 1 comprised 5 male patients who received autologous mesenchymal stem cell transplant (cells were obtained from patient's iliac crest and cultured for 3-4 weeks) by intravenous infusion. Group 2 comprised 5 male patients (control group) who were on hypoglycemic tablet therapy or insulin therapy. The quantity of autologous mesenchymal stem cells infused was 95 × 106 to 97 × 106 cells. We analyzed levels of testosterone, luteinizing hormone, estradiol, and glycated hemoglobin in patients both before and 3 months after the autologous mesenchymal stem cell transplant procedure. In men with type 1 diabetes mellitus and type 2 diabetes mellitus, autologous mesenchymal stem cell transplant led to an increase in testosterone levels from 5.31 ± 2.12 to 6.33 ± 2.12 ng/mL (P = .82), a decrease in luteinizing hormone from 8.43 ± 1.25 to 5.94 ± 1.57 mIU/mL (P = .04), and a decrease in glycated hemoglobin from 9.45 ± 1.24% to 8.53 ± 1.08% (P = .25) after 3 months. The increase in testosterone in men with autologous mesenchymal stem cell transplant group of 6.33 ± 2.12 ng/mL was significant compared with men in the control group (3.9 ± 1.18 ng/mL; P = .01). Testosterone level increased and luteinizing hormone level decreased within 3 months after autologous mesenchymal stem cell transplant in men with diabetes mellitus.

Women's Sexual Dysfunctions Following Stem Cell Transplant and the Impact on Couple Relationship.

Stem cell transplant proved its efficacy in increasing the survival rate among young patients diagnosed with hematological malignancies. A transplant conditioning regimen is particularly destructive on the genital system, often determining premature ovarian failure, accompanied by vulvovaginal atrophy and sexual dysfunctions. The aims of the present study were, first, to evaluate sexual dysfunctions among transplanted women, using clinical examination and the female sexual function index (FSFI), and second, to determine their impact on a couple's relationship. A prospective observational comparative study was performed and included 38 patients who underwent allogenic stem cell transplant (SCT) procedures for different hematological malignancies and 38 healthy patients (control group). This study included baseline evaluation, one-year, and three-year follow-up visits. In addition to anamnesis and medically obtained information, FSFI was evaluated to determine the impact of gynecological damage in a subjective manner. In the study group, vulvovaginal atrophy was diagnosed in 76.32%, with subsequent sexual dysfunctions in 92.10% of patients, based on FSFI scoring. Even though the results improved throughout the study, at the last visit, mild vulvovaginal atrophy was diagnosed in 81.58% of patients, and the FSFI score was abnormal for 21.05%. When compared to the control group, both sexual dysfunctions and FSFI results were considerably impaired, with statistical significance. There is a confirmed negative impact of sexual dysfunctions and self-declared FSFI on couple/marital status and couple relationships, with statistical significance, at the last visit. In conclusion, anatomical, functional, and psychological difficulties are a reality of long-term survivors after a stem cell transplant. They should be addressed and assessed equally to other medical conditions, as they may determine serious consequences and impact the sexual quality of life and the couple's relationship.

The Correlation between Alterations in the Intestinal Microbiome and Early Outcomes of Autologous Hematopoietic Cell Transplantation in Diffuse Large B-Cell Lymphoma

Introduction: Prior research has documented a decline in the diversity of fecal microbiota among individuals with diffuse large B-cell lymphoma (DLBCL) who undergo autologous hematopoietic cell transplantation (auto-HCT). Nevertheless, the potential influence of gut microbiota on hematopoietic reconstitution, immune reconstitution, and early complications in this specific patient cohort remains uncertain. Methods: A total of 42 fecal samples were obtained from 21 adult individuals who underwent autologous hematopoietic cell transplantation (auto-HCT) for diffuse large B-cell lymphoma (DLBCL), both prior to and two weeks following allogeneic stem cell transplantation (ASCT). The diversity of fecal microbiota was assessed using 16S ribosomal gene sequencing. Additionally, correlations between alterations in the fecal microbiome and clinical characteristics, as well as host immune indices, were examined. Results: The beta diversity index of intestinal microecology exhibited a significant decrease following transplantation, whereas the alpha diversity index remained unaltered. Prior to transplantation, the abundance of g_Prevotella_7, g_Sutterella, and g_Enterococcus demonstrated a positive correlation with intestinal infection caused by Carbapenem-resistant Enterobacteriaceae. Conversely, the abundance of g_Blautia prior to transplantation and g_Lachnospira following transplantation exhibited a negative correlation with the duration of post-transplant fever. The abundance of g_Enterocococcus, g_Veillonella, g_Sutterella, g_Prevotella_7, and g_Streptococcus following transplantation exhibited a positive correlation with the occurrence of diarrhea. Conversely, the abundance of g_Weissella displayed a negative correlation with the duration of neutrophil and megakaryocyte engraftment, while g_Prevotella_7 exhibited a positive correlation with the duration of neutrophil engraftment. Additionally, the abundance of g_Sutterella and g_Prevotella_7 prior to transplantation, as well as the abundance of g_Lachnoclostridium, g_Blautia, g_Lachnospira, g_Veillonella, and g_Sutterella following transplantation, were positively correlated with host immunity. Conclusions: The intestinal microbiome experienced significant fluctuations throughout the autologous stem cell transplantation (ASCT) procedure in patients with diffuse large B-cell lymphoma (DLBCL), and these changes exhibited a strong correlation with both early prognosis and post-transplant immune reconstitution. Consequently, additional investigation is necessary to establish strategies for modulating the gut microbiota and enhancing the efficacy of ASCT in DLBCL patients.

Real-World Treatment Patterns and Patient Outcomes in Relapsed/Refractory Hodgkin Lymphoma in the US

Introduction Brentuximab vedotin (BV), a CD30-directed monoclonal antibody, and programmed cell death-1 inhibitors (PD-1; e.g., nivolumab, pembrolizumab) are efficacious for the treatment of adult patients with Hodgkin lymphoma (HL) at high risk of relapse or progression post-autologous stem cell transplantation (ASCT). In this study, we investigated the real-world treatment patterns and outcomes of patients with relapsed/refractory HL (RRHL) who had received ≥1 line of therapy (LOT). Methods Patients ≥18 years old with evidence of RRHL in ≥1 inpatient or ≥2 outpatient physician medical notes or evidence of ≥1 autologous/allogeneic hematopoietic stem cell transplant (HSCT) procedure following evidence of HL in the Humedica Electronic Medical Record (EMR) database, were selected between October 1, 2016 and September 30, 2020. The earliest evidence of RRHL (medical note or HSCT procedure) was defined as the patient's index date. Patients were excluded if they had evidence of RRHL, non-Hodgkin's disease, other primary cancers, or metastatic disease in the 12 months prior to the index date (baseline period). Patient demographic and clinical characteristics were evaluated during the baseline period and the index date. Patients were followed from their index date until patient death or the end of recorded healthcare activity during which treatment patterns and outcomes were assessed. Results A total of 342 patients with ≥1 LOT post-RRHL during the follow-up period were included in the final study population. Mean age was 44.2 years, 56.7% were male, 75.7% were white, and 61.4% had commercial insurance; mean Charlson Comorbidity Index score was 3.2 (Table 1). Approximately one-third (34.5%) of patients were not eligible for HSCT based on available laboratory data and comorbidity diagnoses during the baseline period or the index date. Across the study population, the average follow-up duration was 25.6 months (median: 23.9 months). Among the overall study population, 90 (26.3%) patients received BV treatment, with most (~86%) receiving BV in LOTs 1 and 2 post-RRHL evidence (Table 2). The average time from index date to initiation of BV treatment was 2.5 months and mean duration of treatment (DOT) with BV was 4.3 months. Most patients treated with BV (n=68) had not received a HSCT. During the follow-up, among those who received BV but not a PD-1 (n=57), the progression-free survival (PFS) rate was 73.7% and overall survival (OS) was 82.5%. Among the overall study population, 56 (16.4%) patients received a PD-1, with most patients (~68%) receiving a PD-1 in LOTs 1 and 2 post-RRHL evidence. The average time from index date to initiation of PD-1 treatment was 5.5 months and mean DOT with a PD-1 was 5.3 months. Among those patients who received a PD-1 but not BV (n=23), the PFS rate was 56.5% and OS was 69.6%. One patient received post-HSCT BV+PD-1 combination maintenance therapy. Among the patients who received BV and/or a PD-1 prior- or post-HSCT, 12 (52.2%) received BV prior to the HSCT and 9 (39.1%) received BV after the HSCT. Among those who received BV and PD-1 treatments (i.e., not at the same time; n=33), the PFS rate was 60.6% and OS was 90.9%. Among the study population, a majority of patients (n=232; 67.8%) did not receive a HSCT during the follow-up period (including the index date). Of these patients without a HSCT, 68 (29.3%) received BV, 46 (19.8%) received a PD-1, and 25 (10.8%) received both BV and a PD-1 (i.e., not at the same time). Conclusions In this real-world evaluation of the treatment patterns and outcomes among patients in post-RRHL evidence setting, BV was administered more frequently in patients without HSCT. Increasing the use of BV in patients with ASCT at high risk for relapse or progression may lead to improved clinical outcomes. This study was based on EMRs from a single administrative database and has a limited sample size; these findings may not apply to all patient populations in post-RRHL evidence setting in the US.

A Complex Relationship between Clostridium Difficile Infection and Graft Versus Hoste Disease: Fundeni Clinical Institute Experience

Introduction: Clostridium difficile infection (CDI) is a common complication in patients who have undergone hematopoietic stem cell transplantation (HSCT) due to prolonged hospitalization, prolonged neutropenia, use of broad-spectrum antibiotics, mucosal damage, changes in gut microbiota and compromised immunity. The incidence of CDI in patients undergoing allogeneic HSCT varies between 12 and 34% in the literature and has gradually increased in recent years in Europe North America due to the NAP1 strain. In the patient who has experienced allogeneic HSCT, diagnostic testing for CDI should include both nucleic acid amplification test (NAAT) and enzyme immunoassays (EIA) for toxins A and B, because detection of toxins A and B tests have a sensitivity of 75-80%. 5 In HSCT patients, CDI appears to be strongly associated with graft versus host disease (GVHD), gut GVHD and/or severe GVHD, but this has not been universally demonstrated. The aim: For this reason, we wanted to see whether patients who developed a CDI between day 0 and day 100 were at higher risk for gut GVHD or for severe GVHD. Results: Between January 2017 and August 2022, we performed 290 of allogeneic hematopoietic stem cell transplant procedures, in the Fundeni Clinical Institute. 50/290 developed CDI within the first 100 days after HSCT and before the diagnosis of intestinal GVHD, and 240/290 did not develop CDI. 16/50 (32%) of those with CDI developed acute GVHD, respectively 402/240 (43%) of those without CDI. From these 13/16, respectively 50/102 hade gut involvement. Of the 118 patients with acute GVHD, 13/16 in the group with CDI, respectively 30/102 in the group without CDI were assigned to severe acute GVDH (grade III and IV). Mortality due to gut GVHD in the group with CDI was 46%, respectively 14% in the group without CDI. In conclusion: CDI is not a risk factor for GVHD, but gut damage is usually associated. CDI infection is associated with severe forms of GVHD, and the implication of the digestive tract in these patients increases mortality. Also, often in the patient with digestive GVHD, CDI can coexist, making them difficult to treat.

Glofitamab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Glofitamab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Outcomes of patients with hematological malignancies who undergo unrelated donor hematopoietic stem cell transplantation with ATG-Fresenius versus ATG-Genzyme

To compare the outcomes of patients with hematological malignancies who received ATG-Fresenius (ATG-F) 20 mg/kg versus those who received ATG-Genzyme (ATG-G) 10 mg/kg in an unrelated donor hematopoietic stem cell transplantation (HSCT) procedure, a total of 186 patients who underwent their first allogeneic HSCT with an unrelated donor were retrospectively analyzed. One hundred and seven patients received ATG-F, and seventy-nine patients received ATG-G. Multivariate analysis showed that the type of ATG preparation had no effect on neutrophil engraftment (P = 0.61), cumulative incidence of relapse (P = 0.092), nonrelapse mortality (P = 0.44), grade II-IV acute graft-versus-host disease (GVHD) (P = 0.47), chronic GVHD (P = 0.29), overall survival (P = 0.795), recurrence-free survival (P = 0.945) or GVHD-free relapse-free survival (P = 0.082). ATG-G was associated with a lower risk of extensive chronic GVHD and a higher risk of cytomegaloviremia (P = 0.01 and HR = 0.41, P < 0.001 and HR = 4.244, respectively). The results of this study suggest that the preparation of rabbit ATG used for unrelated HSCT should be selected based on the incidence of extensive chronic GVHD of each center, and the posttransplant management strategy should be adjusted according to the ATG preparation.

Gilteritinib Maintenance Therapy Post-Allogenic Stem-Cell Transplantation Improves the Prognosis of Patients with FLT3-Mutated AML

Introduction FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) and -tyrosine kinase domain (TKD) mutation were common mutations in acute myeloid leukemia (AML). FLT3-ITD mutation adversely affected the outcome of hematopoietic stem-cell transplantation (SCT). While sorafenib and midostaurin as maintenance therapy after SCT prolonged relapse-free and overall survival (OS), there are very few reports of post-transplant gilteritinib maintenance therapy outside of clinical trials. Hence, to explore the efficacy of the gilteritinib maintenance therapy post-SCT, we here report the prognostic impact of post-SCT gilteritinib maintenance in a clinical setting. Methods We retrospectively analyzed 25 FLT3-mutated relapsed or refractory AML patients who received allogeneic SCT at our center from January 1, 2011 to April 30, 2022. FLT3 mutation was analyzed by a commonly used polymerase chain reaction (PCR)-based assay. Measurable residual disease (MRD) was assessed by Wilms tumor 1 (WT1) mRNA expression in peripheral blood, and MRD positivity was defined as WT-1 >50 copies/μg in this study. Relapse was defined as an increase of 5% blasts or more. Non-relapse mortality (NRM) was defined as death without relapse. Leukemia-free survival (LFS) was defined as the time from transplantation to leukemia relapse or death from any cause, which comes first. OS was defined as the time from transplantation to death from any cause. Results The median age was 52 years. Twenty-two patients had ITD mutation and 5 had TKD mutation (2 had both ITD and TKD mutation). At the time of the transplant, 20 patients were in remission (6 were MRD-negative and 14 were MRD-positive) and five were in non-remission. All patients achieved hematologic complete remission (CR) after SCT and no patients relapsed within 30 days post-SCT. After hematological engraftment, 14 patients started to receive gilteritinib as maintenance therapy and 11 patients did not. Between the two groups, the patients' characteristics including disease status at transplant, SCT procedures, and donor sources were well balanced except for the administration of FLT3-inhibitor prior to SCT (100% in patients with gilteritinib maintenance and 45.5% in those without gilteritinib maintenance, p = 0.003). Eleven patients (78.6%) in the gilteritinib group and eight (72.7%) patients in the non-gilteritinib group had residual MRD in hematological CR or were non-CR prior to SCT. The median time from SCT to the initiation of gilteritinib was 36 days. The median dose at gilteritinib initiation was 40mg (range 20-120 mg). One patient developed grade 2 skin acute graft-versus-host disease (GVHD) after gilteritinib administration and 4/14 patients (28.6%) developed moderate-severe chronic GVHD (cGVHD, two developed pulmonary cGVHD, one eye and mouse, and one skin) with a median onset of 10.5 months (range 3.1-30.5 months), while only one patient temporary discontinued gilteritinib until the improvement of cGVHD. Late engraftment failure during gilteritinib maintenance was not observed. In terms of survival benefit, patients with gilteritinib maintenance showed significantly longer LFS and OS than those without gilteritinib (1-y LFS; 100% vs. 36.4%, 95% CI; 100-100% vs. 11.2-62.7%, p = 0.0028, Figure A, and 1-y OS; 100% vs. 45.5%, 95% CI; 100-100% vs. 16.7-70.7%, p = 0.0075, Figure B). The cumulative incidence of AML relapse at one-year in patients with gilteritinib maintenance group was significantly lower than those without (0% vs. 51.5%, 95% CI; 0-0% vs. 24.9-86.0%, p = 0.005). Especially, among patients with MRD positive or non-CR prior to SCT (n=19), patients who received gilteritinib maintenance showed a lower cumulative incidence of AML relapse at one-year than those without gilteritinib maintenance (0% vs. 68.8%, 95% CI; 0-0% vs. 35.9-95.2%, p = 0.0028, Figure C). Patients without MRD prior to SCT did not relapse with or without gilteritinib maintenance. These results suggest that gilteritinib maintenance therapy contributes to preventing post-transplant relapse in patients who remain MRD positive at the time of SCT. Conclusion Gilteritinib maintenance therapy post-SCT showed survival benefit in a clinical setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Time-Series Reconstruction of CBC Profile of Pediatric Cancer Patients for Two Years after Hematopoietic Stem Cell Transplantation Using Language Programming

In this single center and retrospective study, we analyzed every single patient totaling 249 patients who was admitted and undergone hematopoietic stem cell transplantation (HSCT) at our institution from year 2013 to 2019. Twenty three patients were excluded mainly due to returning home country after HSCT without further follow up at our institution. We re-analyzed the remaining 226 patients (169 alive patients and 57 expired patients) and re-constructed time-series laboratory data of white blood cell (WBC) count (Figure 1), hemoglobin, platelet, absolute neutrophil count (ANC), monocytes number, blood urea nitrogen, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, lactate dehydrogenase (LDH), cyclosporine level, and/or tacrolimus level for up to two years since their last HSCT. These large sets of data were visualized by custom-written codes using language programming. We performed subgroup analysis of these patients' laboratory data according to the tumor type, which was grouped into acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), other types of leukemia not aforementioned, lymphoma, solid tumor, aplastic anemia and other diseases including neurologic disease or immunodeficiency. We also compared these patients' laboratory data according to immunosuppressant used (cyclosporine versus tacrolimus), and hematopoietic stem cell transplantation procedures employed (allogeneic peripheral blood stem cell transplantation (PBSCT), autologous PBSCT or bone-marrow transplantation). In all patients analyzed who remain alive after HSCT (male 100 patients (59%), female 69 patients (41%), the median WBC engraftment time was 13 days with interquartile range (IQR) of 11-15 days). Both WBC and ANC steadily increased after engraftment up to 400 days since HSCT and reached plateau level at 7,000cells/uL for WBC and 3,000cells/uL for ANC. Hemoglobin and platelet showed faster recovery time since HSCT as hemoglobin level of 12 g/dL and platelet count of 200x10^9/L both reached at 300 days since HSCT. Patients underwent HSCT due to the occurrence of solid tumor generally showed shorter WBC engraftment time of 11 days with IQR of 10-12 days while those with hematologic malignancy showed relatively longer WBC engraftment time of 14 days with IQR of 12-16 days. In subgroup analysis of hematologic malignancy categorized into ALL, AML, other leukemia not aforementioned and lymphoma, no significant differences in engraftment time or general trend over two-year time-course of WBC, ANC, hemoglobin and platelet. In sharp contrast, 57 patients who have expired since HSCT showed WBC recovery after engraftment - the median WBC engraftment time was 13 days with IQR of 11-16 days - up to 3,000cells/uL but the WBC count did not increase thereafter in the following two years. The hemoglobin and platelet plateau for these expired patients were markedly lower than those alive as hemoglobin level was maintained around 9 g/dL (Figure 2) and platelet count ranged from 50 to 90x10^9/L since HSCT. HSCT is not the end but the beginning of return to normal daily activities for many patients and vigilant long-term care of these patients is crucial not only for the patients but also for their families. As analogous to Fenton growth chart being used for premature babies and their parents to visually aid their growth progression at outpatient clinic, we aimed at constructing time-series laboratory data of HSCT patients since transplantation to serve as reference curves for HSCT patients at our institution with hope that these reference curves as a visual aid may better assist and assure those patients and their families with successful recovery and for those without successful course, early intervention and further treatment may be better understood and accepted by the patients and their families. Figure 1. Time course of white blood cell count for each patient after HSCT. Each line is color-coded differently and represents a single patient. Red curve is the median of all patients with error bars denoting interquartile range. Shaded area also represents interquartile range. Figure 2. Time course of hemoglobin trend for two years after HSCT. Median average of 169 alive patients' data (red) was compared with that of 57 expired patients (blue). Error bars represent interquartile ranges. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostic Role of Cell Blood Count in Chronic Myeloid Neoplasm and Acute Myeloid Leukemia and Its Possible Implications in Hematopoietic Stem Cell Transplantation.

Numerous prognostic indexes have been developed in hematological diseases based on patient characteristics and genetic or molecular assessment. However, less attention was paid to more accessible parameters, such as neutrophils, lymphocytes, monocytes, and platelet counts. Although many studies have defined the role of neutrophil-to-lymphocyte or platelet-to-lymphocyte in lymphoid malignancies, few applications exist for myeloid neoplasm or hematopoietic stem cell transplantation procedures. In this review, we synthesized literature data on the prognostic value of count blood cells in myeloid malignancies and hematopoietic stem cell transplantation in the context of classical prognostic factors and clinical outcomes.

Incidence of chronic renal injury in patients undergoing autologous stem cell transplant therapy.

Haemopoietic stem cell transplant (HSCT) is a well-established treatment option for many haematologic immunologic and oncologic diseases, allowing the safe administration of high-dose chemotherapy. Increased risk of acute renal injury is associated with HSCT; however, the risk of chronic kidney injury in autologous HSCT remains unclear. This cohort study investigates the incidence of chronic renal injury and its predisposing factors in a single-centre population of 139 patients who underwent autologous HSCT. Estimated glomerular filtration rate (eGFR) was measured at baseline and at 3, 6, 12 and 24 months following autologous stem cell reinfusion and used as a marker of renal dysfunction. A significant reduction in mean eGFR of patients was observed from baseline (80.62 ± 2.97 mL/min) to 24 months (71.54 ± 4.14 mL/min), independent of primary diagnosis (P= 0.0019). At baseline, 12% of the cohort had stage 3 or worse chronic renal injury and this increased to 38% by 24 months. By univariate analysis, age at baseline greater than the mean of 58 years and the occurrence of acute kidney injury during the peritransplant period emerged as predictive factors for the development of chronic kidney disease at 24 months. The current results indicate there is an increased incidence of chronic renal injury in patients who have undergone autologous peripheral blood haemopoietic stem cell transplantation therapy and this injury is potentiated by the autologous stem cell transplant procedure.

Evaluation of CD34+ Cell Count at Different Time Points Following Plerixafor Administration in Autologous Hematopoietic Stem Cell Transplantation

Background: In apheresis, collecting an adequate number of CD34+ cells is required for successful autologous hematopoietic stem cell transplantation (auto-HSCT) procedure. It is difficult to harvest a sufficient number of stem cells in certain patients due to their old age and history of intensive chemotherapy. Plerixafor could mobilize stem cells and facilitate peripheral blood hematopoietic stem cell collection. However, not enough information is available on the appropriate time intervals from plerixafor administration to apheresis. Objectives: In this study, we aimed at evaluating the level of peripheral blood CD34+ cells at plerixafor administration time and every three hours to identify the peak time of circulating CD34+ cells. Methods: Circulating CD34+ cells were enumerated by flow cytometry on day 4 post mobilization. Plerixafor was administered to patients with poor mobilization based on the count of peripheral blood hematopoietic stem cells. The number of circulating CD34+ cells was evaluated before and 3, 6, 9, and 12 hours after plerixafor administration to assess the time it takes for stem cells to reach their peak level. Results: The highest level of stem cell concentration was found in 9 hours after plerixafor administration with an increasing trend. A statistically significant relationship was also observed between factors including platelet count on the first day of GCSF injection and the day of stem cell infusion, leukocyte count on admission, and basal levels of CD34+ cells in peripheral blood and the amount of harvested stem cells. Conclusions: We demonstrated that plerixafor causes an incremental trend in CD34+ cells mobilization, reaching its peak after 9 hours. Further research should be performed to provide insights into graft cells’ population and hematologic and immunological recovery.

The impact of HLA donor-specific antibodies on engraftment and the evolving desensitization strategies.

The majority of contemporary allogeneic hematopoietic stem cell transplantation (HCT) procedures utilize partially HLA-mismatched stem cell grafts. Donor-specific anti-HLA antibodies (DSA) are associated with primary graft failure independent of the graft source, conditioning intensity and other patient and donor factors. Here we provide an update on testing and monitoring of DSA, review the impact of DSA on stem cell engraftment, and present promising desensitization modalities. Ultimately, we attempt to provide practical recommendations for DSA screening and mitigation strategies.

Diphtheria Toxin Based Bivalent Anti-cMPL Immunotoxin Effectively Depletes Human Hematopoietic Stem and Progenitor Cells

Patient conditioning is a critical initial step in hematopoietic stem and progenitor cell (HSPC) transplantation procedures to enable marrow engraftment of infused cells. Preparative regimens have traditionally been achieved by delivering cytotoxic doses of chemotherapeutic agents, with or without radiation. However, these regimens impair host immune function and are associated with significant morbidity. The use of monoclonal antibodies, either alone or conjugated to an internalizing toxin, to target specific antigens on hematopoietic cells has been proposed as a tractable alternative, especially in contexts, such as ex vivo autologous gene therapy, where preservation of immunity is desired. Efficient clearance of marrow has been demonstrated in preclinical models using CD45- or CD117-targeting antibodies conjugated to the plant toxin Saporin. However, this approach still awaits demonstration of long-term safety and efficacy in humans. In this study, we investigated whether toxin-conjugated antibodies targeting the cMPL receptor on HSPCs can provide the basis for a conditioning regimen prior to transplant. Thrombopoietin (TPO) and its receptor cMPL act as primary regulators of HSPC self-renewal and survival. The TPO:cMPL axis also regulates megakaryopoiesis and platelet production but, unlike CD45 and CD117 proteins, cMPL is otherwise not expressed in other blood cell types or in non-hematopoietic tissues. Hence, this approach may uniquely allow effective and specific depletion of host HSCs while sparing most hematopoietic progenitors and mature blood cells.To investigate cMPL as an antigen for targeted depletion of human HSPCs, we produced a recombinant bivalent anti-cMPL single-chain variable fragment (sc(FV) 2) (Orita et al. Blood 2004) fused with diphtheria toxin truncated at residue 390 (DT390) to prevent toxin internalization in off-target cells. We first confirmed the cMPL receptor-dependent cytotoxic effects of the anti-cMPL-DT390 conjugate in a HEK293A cell line engineered to express the human cMPL receptor. We observed marked cellular killing in vitro (IC50 = 21 pM) compared to the cMPL-negative control HEK293A cell line (Fig. A). Next, we assessed anti-cMPL-DT390 for its ability to inhibit growth of human CD34+ cells in vitro. G-CSF mobilized peripheral blood (PB) CD34+ cells were obtained from five healthy individuals. Surface expression of cMPL was compared by flow cytometry in subsets increasingly enriched in cells with long-term repopulating activity, including bulk CD34+, CD34+CD38- and CD34+CD38-CD90+CD45RA-CD49f+ cells. Levels of cMPL expression increased congruently with levels of HSC purity (Fig. B). Consistent with a cMPL dependent cytotoxic effect, increased cellular death was measured in populations expressing higher densities of cMPL receptors (IC50 = 104 nM), suggesting preferential targeting of the most primitive hematopoietic compartment (Fig. C). We then assessed whether anti-cMPL-DT390 could safely target and deplete human HSPCs in vivo in humanized NBSGW immunodeficient mice. At 12 weeks post-transplantation, engrafted animals (mean 19.8% CD45+ cells in PB) received a single maximum tolerated dose of 1.2 mg/kg anti-cMPL-DT390 (n=7) or vehicle control solution (n=7) by tail vein injection. HSPC depletion was assayed by measuring human myeloid (CD45+CD13+) chimerism in the mouse PB after antibody administration. We observed a gradual decline in HSPC activity, as represented by the decreased production of human myeloid cells following administration of anti-cMPL-DT390, peaking at 6 weeks with a 2.6-fold reduction in frequency of human CD45+CD13+ cells compared to untreated animals (p = 0.003) (Fig. D).Overall, our study provides proof-of-concept that bivalent anti-cMPL immunotoxin can effectively target and deplete human HSPCs, and may thus provide a novel nontoxic preparative approach to improve HSPC engraftment in transplantation for genetic and other nonmalignant disorders. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cost Effectiveness Analysis of Venetoclax Plus Azacitidine Versus Azacitidine in Newly Diagnosed Adult Patients with Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy from a United States Payer Perspective

Background: The phase 3 VIALE-A trial (NCT02993523) demonstrated that venetoclax plus azacitidine (VEN+AZA) improved overall survival (OS) and led to higher remission rates compared with AZA monotherapy, in patients with newly diagnosed (ND) acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. Based on the results from VIALE-A, VEN+AZA received full United States (US) Food and Drug Administration approval in October 2020 for patients with ND AML aged ≥75 years, or who were ineligible for intensive induction chemotherapy due to comorbidities. This study aims to assess the long-term cost-effectiveness value of the VEN+AZA regimen from the VIALE-A trial from a US third-party payer perspective.Methods: A partitioned survival model with a 28-day cycle was developed to estimate costs and outcomes of treatment with VEN+AZA vs. AZA among patients with ND AML, who are ineligible for intensive chemotherapy, over a lifetime time horizon. The model included three health states: event-free survival (EFS), progressive/relapsed disease, and death. Within the EFS state, patients were further partitioned into time spent in complete remission (CR) or CR with incomplete marrow recovery (CRi), and time spent in non-CR/CRi. Efficacy inputs (OS, EFS, and CR/CRi rate) for both treatment arms were estimated using VIALE-A data. Best-fit parametric models per Akaike information criterion (AIC) were used to extrapolate OS until it reached EFS, and extrapolate EFS for each treatment until Year 5. Patients who remained in EFS after Year 5 were considered cured, and were assumed to have the same mortality as the US general population. Mean time on treatment (ToT) for both regimens was based on the time observed in VIALE-A. The costs for drug acquisition, drug administration for initial and subsequent treatments, subsequent stem cell transplant procedures, adverse events (AEs), and healthcare resource utilization (HRU) associated with each health state were obtained from the literature or publicly available data. All costs were inflated to 2021 US dollars. Utilities for each health state were estimated using EuroQol-5 dimension-5 level (EQ-5D-5L) data from VIALE-A, based on the US crosswalk value set. Information on disutilities due to Grade 3/4 AEs were obtained from the literature. Incremental cost-effectiveness ratios (ICERs) per life year (LY) and quality-adjusted life year (QALY) gained were estimated. Deterministic sensitivity analyses (DSA), scenario analyses and probabilistic sensitivity analyses (PSA) were performed to assess the robustness of the results.Results: Over a lifetime time horizon, compared with AZA, VEN+AZA was associated with an increase of 1.89 LYs (1.10 vs. 2.99, respectively) and 1.45 QALYs (0.84 vs. 2.30, respectively). Patients in the VEN+AZA arm incurred higher total costs ($250,486 vs. $110,034 for patients in the AZA arm). The ICER for VEN+AZA vs. AZA was estimated to be $74,141 per LY gained, and $96,579 per QALY gained. Results from the DSA and scenario analyses supported the base-case findings, with ICERs ranging from $60,922 to $138,554 per QALY gained. The results were most sensitive to alternative approaches for ToT estimation, subsequent treatment HRU costs, cure time point, and the extrapolation approach for EFS. Results from PSA showed that compared with AZA, VEN+AZA was cost-effective in 99.9% of cases at a willingness-to-pay (WTP) threshold of $150,000.Conclusions: Compared with AZA monotherapy, VEN+AZA results in a favorable ICER of $96,579 per QALY gained over a lifetime time horizon. The base-case results suggest that, compared with AZA, VEN+AZA is a cost-effective strategy based on a WTP threshold of $150,000 per QALY gained. Sensitivity analyses support the base-case results. Thus, VEN+AZA offers a cost-effective strategy in the treatment of patients with ND AML who are ineligible for intensive chemotherapy from a US third-party payer perspective. DisclosuresPratz: Agios: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; University of Pennsylvania: Current Employment; BMS: Consultancy, Honoraria; Novartis: Consultancy; Astellas: Consultancy, Honoraria, Research Funding; Cellgene: Consultancy, Honoraria; Millenium: Research Funding. Chai: Analysis Group, Inc.: Consultancy, Current Employment; Genentech, Inc.: Consultancy. Yin: Analysis Group, Inc.: Consultancy, Current Employment; Genentech, Inc.: Consultancy. Nie: Analysis Group, Inc.: Consultancy, Current Employment; Genentech, Inc.: Consultancy. Montez: Genentech, Inc: Current Employment, Other: May hold equity. Iantuono: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Downs: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Ma: Genentech, Inc.: Current Employment, Other: May hold equity.

Stem Cells in the Path of Light, from Corneal to Retinal Reconstruction.

The future of eye reconstruction invariably includes stem cells transplantation. Corneal limbus, corneal stroma, trabeculum, retinal cells, optic nerve, and all structures that are irreversibly damaged and have no means to be repaired or replaced, through conventional treatment or surgery, represent targets for stem cell reconstruction. This review tries to answer the question if there is any clinical validation for stem therapies, so far, starting from the cornea and, on the path of light, arriving to the retina. The investigation covers the last 10 years of publications. From 2385 published sources, we found 56 clinical studies matching inclusion criteria, 39 involving cornea, and 17 involving retina. So far, corneal epithelial reconstruction seems well validated clinically. Enough clinical data are collected to allow some form of standardization for the stem cell transplant procedures. Cultivated limbal epithelial stem cells (CLET), simple limbal epithelial transplant (SLET), and oral mucosa transplantation are implemented worldwide. In comparison, far less patients are investigated in retinal stem reconstructions, with lower anatomical and clinical success, so far. Intravitreal, subretinal, and suprachoroidal approach for retinal stem therapies face specific challenges.

ORAL MUCOSITIS – SIGNIFICANT COMPLICATION OF PEDIATRIC PATIENTS UNDERGOING HEMATOPOIETIC STEM CELL TRANSPLANTATION

Introduction. The prognosis of pediatric solid tumors has improved in recent years through the use of multimodal treatment – chemotherapy, local control (surgery and radiotherapy) and hematopoietic stem cell transplantation (HSCT) for high-risk forms. A limiting factor of these transplant procedures is short-term toxicity, oral mucositis (OM) being associated with potential severe evolution. The introduction of tandem stem cell transplant procedures, which increase the intensity of chemotherapy treatment and thus increase the response rate, is associated with increased toxicity. In this study we evaluated the impact of multiple transplant procedures on the severity and evolution of OM. Materials and methods. This retrospective study included 57 pediatric patients diagnosed with solid tumors (neuroblastoma, germ cell tumor, Ewing sarcoma, nephroblastoma) who underwent HSCT in the Pediatric Bone Marrow Transplantation Unit of Fundeni Clinical Institute, between January 2002 and December 2020. Patients were divided into 2 study groups: the first group included patients who had one HSCT procedure (43 patients) and the second group included patients who benefited from multiple HSCT procedures (14 patients). We evaluated the degree and average extent of OM, associated risk factors, duration of analgesic treatment and parenteral nutrition, as well as infectious risk. Conditioning regimens were based on administration of busulfan, thiotepa or ifosfamide. All patients received prophylactic antimicrobial therapy and followed a daily oral care protocol. Results. The 57 patients underwent 73 HSCT procedures for the following diagnoses: 36 neuroblastoma, 6 germinal cell tumor, 12 Ewing sarcoma and 3 Wilms tumor. Patients were diagnosed, staged and treated according to international protocols. The study highlights the influence on the degree of OM: delayed platelet engraftment and increased parenteral nutrition requirements correlated with the number of HSCT procedures per patient. Infectious risk was higher for patients from the second study group. Conclusions. OM treatment remains prevention-centered and identifying effective measures, encouraging modern treatment strategies and developing practical evidence-based guidelines are imperative.