Setting Of Stem Cell Transplantation Research Articles

Therapeutic Inducers of Natural Killer cell Killing (ThINKK): preclinical assessment of safety and efficacy in allogeneic hematopoietic stem cell transplant settings

BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT) remains the standard of care for chemotherapy-refractory leukemia patients, but cure rates are still dismal. To prevent leukemia relapse following HSCT, we aim to...

Treatment intensity affects immune reconstitution even after childhood cancer not treated with hematopoietic stem cell transplantation.

Only a few previous studies examine immune system recovery after completed cancer treatment. The aim of this study was to analyze immune reconstitution after childhood cancer therapy in a non-hematopoietic stem cell transplantation setting. We analyzed children (N = 79) who received chemotherapy with/without irradiation for cancer diagnosed between 2014 and 2019 at Turku University Hospital, Finland. We retrospectively collected data on baseline parameters and post-treatment immunological recovery, namely neutrophil and lymphocyte counts, IgG levels, CD19, CD4 and natural killer cell counts. Immunological parameters were followed until their normalization. Treatment intensity was stratified according to the Intensity of Treatment Rating Scale (ITR-3). We analyzed the effects of treatment intensity on normalization of immunological parameters across the entire treatment range. Treatment intensity had a major effect on immune system recovery after completion of treatment. Most patients had normal immunological parameters 1-4 months post-treatment both in high- and low-intensity treatment groups, but patients classified in the high-intensity group had low parameters more often than patients in the low-intensity group. Our data suggest a fast recovery of studied immunological parameters after the majority of current pediatric oncologic treatments. Treatment for high-risk acute lymphoblastic leukemia, acute myeloid leukemia, medulloblastoma, and mature B-cell lymphoma was associated with prolonged recovery times for a substantial proportion of cases. High treatment intensity was associated with prolonged immunological recovery.

Monitoring Humoral Response Following BNT162b2 mRNA Vaccination against SARS-CoV-2 in Hematopoietic Stem-Cell Transplantation Patients: A Single-Center Prospective Study along with a Brief Review of Current Literature.

Data on antibody response (AR) after vaccination against SARS-CoV2 in hematopoietic stem-cell transplantation setting (HSCT) were initially scarce, mainly due to the exclusion of such patients from approval studies. Shortly after the worldwide application of vaccination against SARS-CoV-2 in vulnerable populations such as patients with hematologic malignancies, limited single-center trials, including HSCT patients, were published. However, there was a great heterogeneity between them regarding the type of underlying malignancy, co-current treatment, type of vaccine, method of AR measurement, and time point of AR measurement. Herein, we present the results of a prospective study on AR after vaccination for SARS-CoV-2 using the BNT162b2 vaccine in a cohort of 54 HSCT recipients-mostly autologous from a single Unit-along with a broad review of the current literature. In our cohort, the AR positivity rate at 1 month was 80.8% and remained positive in 85.7% of patients at 3 months after vaccination. There were only nine non-responders, who were more heavily pretreated and more frequently hypogammaglobulinemic compared to responders. High antibody titers (AT), [AT ≥ 1000 U/mL], were detected in 38.5% and 30.6% of the patients at m1 and m3, respectively. A significant decline in AT between m1 and m3 was demonstrated-p < 0.0001; median AT1 and AT3 were 480.5 and 293 U/mL, respectively. A novel finding of our study was the negative impact of IgA hypogammaglobulinemia on response to vaccination. Other negative significant factors were treatment with anti-CD20 antibody at vaccination and vaccination within 18 months from HSCT. Our data indicate that HSCT recipients elicit a positive response to the BNT162b2 vaccine against SARS-CoV-2 when vaccinated at 6 months post-transplant, and vaccination should be offered to this patient population even within the post-pandemic COVID-19 era.

Serum Levels of miR-122-5p and miR-125a-5p Predict Hepatotoxicity Occurrence in Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation.

Hepatic complications are an acknowledged cause of mortality and morbidity among patients undergoing hematopoietic stem cell transplantation. In this study, we aimed to evaluate the potential role in the prediction of liver injury of five selected microRNAs (miRNAs)-miR-122-5p, miR-122-3p, miR-15b-5p, miR-99b-5p, and miR-125a-5p-in the setting of autologous hematopoietic stem cell transplantation (ASCT). A total of 66 patients were included in the study: 50 patients (75.8%) with multiple myeloma (MM) and 16 (24.2%) with lymphoma. Blood samples were collected after the administration of the conditioning regimen, on the day of transplant (day 0). The expression levels of selected miRNAs were quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) using the miRCURY LNA miRNA Custom PCR Panels (QIAGEN). In a multivariate logistic regression analysis adjusted for age, sex, and the administered conditioning regimen, two miRNAs, hsa-miR-122-5p (odds ratio, OR 2.10, 95% confidence interval, CI: 1.29-3.42, p = 0.0029) and hsa-miR-125a-5p (OR 0.27, 95% CI: 0.11-0.71, p = 0.0079), were independent for hepatic toxicity occurrence during the 14 days after transplant. Our model in 10-fold cross-validation preserved its diagnostic potential with a receiver operating characteristics area under the curve (ROC AUC) of 0.75, 95% CI: 0.63-0.88 and at optimal cut-off reached 72.0% sensitivity and 74.4% specificity. An elevated serum level of miR-122-5p and decreased level of miR-125a-5p on day 0 are independent risk factors for hepatotoxicity in ASCT recipients, showing promise in accurately predicting post-ASCT complications. Identifying patients susceptible to complications has the potential to reduce procedure costs and optimize the selection of inpatient or outpatient procedures.

Expedited evaluation of hereditary hematopoietic malignancies in the setting of stem cell transplantation.

Not available.

Diagnosing and Grading of Sinusoidal Obstructive Syndrome after Hematopoietic Stem Cell Transplant of Children, Adolescent and Young Adults treated in a Pediatric Institution with Pediatric Protocols

Sinusoidal obstructive syndrome (SOS), or veno-occlusive disease, of the liver has been recognized as a complex, life-threatening complication in the posthematopoietic stem cell transplant (HSCT) setting. The diagnostic criteria for SOS have evolved over the last several decades with a greater understanding of the underlying pathophysiology, with 2 recent diagnostic criteria introduced in 2018 (European Society of Bone Marrow Transplant [EBMT] criteria) and 2020 (Cairo criteria). We sought out to evaluate the performance characteristics in diagnosing and grading SOS in pediatric patients of the 4 different diagnostic criteria (Baltimore, Modified Seattle, EBMT, and Cairo) and severity grading systems (defined by the EBMT and Cairo criteria). Retrospective chart review of children, adolescent, and young adults who underwent conditioned autologous and allogeneic HSCT between 2017 and 2021 at a single pediatric institution. A total of 250 consecutive patients underwent at least 1 HSCT at UCSF Benioff Children's Hospital San Francisco for a total of 307 HSCT. The day 100 cumulative incidence of SOS was 12.1%, 21.1%, 28.4%, and 28.4% per the Baltimore, Modified Seattle, EBMT, and Cairo criteria, respectively (P < .001). We found that patients diagnosed with grade ≥4 SOS per the Cairo criteria were more likely to be admitted to the Pediatric Intensive Care Unit (92% versus 58%, P = .035) and intubated (85% versus 32%, P = .002) than those diagnosed with grade ≥4 per EBMT criteria. Age <3 years-old (HR 1.76, 95% [1.04 to 2.98], P = .036), an abnormal body mass index (HR 1.69, 95% [1.06 to 2.68], P = .027), and high-risk patients per our institutional guidelines (HR 1.68, 95% [1.02 to 2.76], P = .041) were significantly associated with SOS per the Cairo criteria. We demonstrate that age <3 years, abnormal body mass index, and other high-risk criteria associate strongly with subsequent SOS development. Patients with moderate to severe SOS based on Cairo severity grading system may correlate better with clinical course based on ICU admissions and intubations when compared to the EBMT severity grading system.

CRISPR-Cas9n-mediated ELANE promoter editing for gene therapy of severe congenital neutropenia

Severe congenital neutropenia (CN) is an inherited pre-leukemia bone marrow failure syndrome commonly caused by autosomal-dominant ELANE mutations (ELANE-CN). ELANE-CN patients are treated with daily injections of recombinant human granulocyte colony-stimulating factor (rhG-CSF). However, some patients do not respond to rhG-CSF, and approximately 15% of ELANE-CN patients develop myelodysplasia or acute myeloid leukemia. Here, we report the development of a curative therapy for ELANE-CN through inhibition of ELANE mRNA expression by introducing two single-strand DNA breaks at the opposing DNA strands of the ELANE promoter TATA-box using CRISPR/Cas9D10A nickases - termed MILESTONE. This editing effectively restored defective neutrophil differentiation of ELANE-CN CD34+ hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, without affecting the functions of the edited neutrophils. CRISPResso analysis of the edited ELANE-CN CD34+ HSPCs revealed on-target efficiencies of over 90%. Simultaneously, GUIDE-seq, CAST-Seq, and rhAmpSeq indicated a safe off-target profile with no off-target sites or chromosomal translocation. Taken together, ex vivo gene editing of ELANE-CN HSPCs using MILESTONE in the setting of autologous stem cell transplantation could be a universal, safe, and efficient gene therapy approach for ELANE-CN patients.

Incidence of Catheter-Associated Bloodstream Infections in Stem Cell Recipients-Should We Be "PICCy"?

The management of patients undergoing HSCT requires a multipurpose central venous catheter. Peripheral catheters (PCs), such as peripherally inserted central catheters (PICCs) and MidLine catheters (MLCs), appear to be adequate vascular catheters to be used for stem cell infusion, although their utilization in this indication is not yet common. We analyzed the infectious complications such as blood stream infection (BSI), febrile neutropenia (FN) and central line-associated bloodstream infection (CLBSI) in patients undergoing stem cell infusion through PC and conventionally inserted central catchers (CICCs), and evaluated their impacts on transplantation outcomes. Our results reveal no statistically significant differences between different types of catheter in terms of FN, BSI and CLABSI. Moreover, transplantation outcomes were comparable between the groups. Interestingly, according to our data, there were no differences in terms of abovementioned infectious complications between individuals who received antibiotic prophylaxis and those who did not. Our study has shown that infection complications are independent of the intravenous device and antibiotic prophylaxis. Considering that PCs are not associated with life-threatening complications, they should be considered more frequently in the stem cell transplantation setting.

Open-Label Randomized Controlled Study of Ciprofloxacin vs Rifaximin as Neutropenia Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplantation

Loss of microbiota diversity has been clearly associated with poor outcomes in the allogeneic hematopoietic stem cell transplantation setting. However, the choice of the optimal antibiotic prophylaxis during the pre-engraftment phase remains unclear. We designed a prospective randomized study to compare our standard-of-care neutropenia prophylaxis (ciprofloxacin) with rifaximin. We enrolled 38 consecutive adult patients who underwent allogeneic hematopoietic stem cell transplantation setting and were randomly assigned to receive ciprofloxacin (20 patients) or rifaximin (18 patients) at day -1. Pretransplant and transplant characteristics did not differ between groups. Cumulative incidence (CI) of acute graft-vs-host disease grade II to IV and moderate/severe chronic graft-vs-host disease was similar in both groups. With a median follow-up of 13.2 months (range, 6.8-30.2) in surviving patients, the 1-year CI of relapse was 20.8% in ciprofloxacin vs 17.8% in rifaximin (P = .616). Importantly, the 1-year CI of treatment-related mortality was significantly reduced in the ciprofloxacin group (10.2% vs 27.8%, P = .032), leading to higher 1-year overall survival (88.9% vs 74.6%, P = .038). In Cox-regression multivariate analysis, antibiotic prophylaxis remained the only predictor of overall survival, independently of donor type, disease risk index, and moderate/severe chronic graft-vs-host disease. Further studies are needed to assess the effects on microbiota diversity and confirm these outcomes.

Persistent Hypogammaglobulinemia after Receiving Rituximab Post-HSCT Is Not Caused by an Intrinsic B Cell Defect.

In the setting of hematopoietic stem cell transplantation (HSCT), Rituximab (RTX) is used for the treatment and prevention of EBV-associated post-transplantation lymphoproliferative disease or autoimmune phenomena such as autoimmune hemolytic anemia (AIHA). Persistent hypogammaglobulinemia and immunoglobulin substitution dependence has been observed in several patients after RTX treatment despite the normalization of total B cell numbers. We aimed to study whether this is a B cell intrinsic phenomenon. We analyzed four patients with different primary diseases who were treated with myeloablative conditioning and matched unrelated donor HSCT who developed persistent hypogammaglobulinemia after receiving RTX treatment. They all received RTX early after HSCT to treat EBV infection or AIHA post-HSCT. All patients showed normalized total B cell numbers but absent to very low IgG positive memory B cells, and three lacked IgA positive memory B cells. All of the patients had full donor chimerism, and none had encountered graft-versus-host disease. Sorted peripheral blood naïve B cells from these patients, when stimulated with CD40L, IL21, IL10 and anti-IgM, demonstrated intact B cell differentiation including the formation of class-switched memory B cells and IgA and IgG production. Peripheral blood T cell numbers including CD4 follicular T-helper (Tfh) cells were all within the normal reference range. In conclusion, in these four HSCT patients, the persistent hypogammaglobulinemia observed after RTX cannot be attributed to an acquired intrinsic B cell problem nor to a reduction in Tfh cell numbers.

Prevention of CINV in Patients with Multiple Myeloma or Lymphoma Undergoing Hematopoietic Stem Cell Transplantation: NEPA Versus Ondansetron. a Monocentric Real-Life Experience

INTRODUCTION: Chemotherapy-induced nausea and vomiting (CINV) are adverse events that compromise quality of life and treatment compliance in patients undergoing autologous hematopoietic stem cell transplantation (ASCT). Polychemotherapy regimens, used as conditioning regimens for ASCT in lymphomas, and high-dose melphalan (≥140 mg/mq), used in multiple myeloma (MM), have high emetogenic risk. Control of CINV is difficult and there is no uniformity for its prophylaxis. Antiemetic guidelines recommend, for prophylaxis, co-administration of a triplet regimen of a serotonine (5-HT3) receptor antagonist (RA), as Ondansetron, a neurokinin-1 RA, and dexamethasone. Netupitant-Palonosetron (NEPA), an oral formulation derived from the combination of Netupitant (NK1-RA) and Palonsetron, has been approved as prophylaxis of CINV but its experience in the stem cell transplant setting is still limited. AIMS: The primary aim of this study was to compare the efficacy of Ondansetron versus NEPA in terms of reduction of CINV in patients affected by lymphoma or MM who undergone ASCT. The secondary aims included comparing the duration of CINV, based on the use of Ondansetron or NEPA, and their safety profile in terms of reduction of extrahaematological toxicity (as mucositis or diarrhea). METHODS: In this retrospective monocentric study, we enrolled 76 patients (48 with MM and 28 with lymphoma), who underwent ASCT between March 2021 and March 2022. All patients with MM received high dose of melphalan, those with lymphoma received FEAM. Regarding antiemetics patients were divided according to whether they received NEPA or Ondansetron . Patients' characteristics are in Table 1. RESULTS: Among all, fifty patients (65%) reported CINV of any grade. In particular, the group experiencing CINV included about half of patients treated with NEPA (56%) and almost all those treated with Ondansetron (91%). Among the 26 patients who didn't report CINV (35%), the majority received NEPA (92%) (P = 0.0032) (Fig. 1a). Focusing on patients with MM, 33 experienced CINV (68%), and they were 59% of MM patients treated with NEPA and 93% of those treated with Ondansetron. Fifteen patients did not experience CINV (32%) and almost all of them (93%) had been treated with NEPA (P = 0.037) (Fig. 1b). Sixty-one percent of the 28 patients with lymphoma reported CINV (P= 0.1914) (Fig. 1c). Mean duration of CINV was significantly shorter for patients treated with NEPA than for those treated with Ondansetron (4.8 days vs 9.2 days) (P= 0.002) (Fig. 1d). Regarding extraematological toxicity of chemotherapy, as mucositis and diarrhea, we didn't find any significant difference between the two groups of patients. Regarding the outcome to NEPA, complete response rate (no emesis, no rescue medication) was 37% during overall phases of CINV, 28% of patients had complete control (complete response with no more than mild nausea) and 31% had uncontrolled nausea. Conversely, in the Ondansetron group, only 5% of patients had complete response and 95% had uncontrolled nausea (Fig. 1e). All patients with uncontrolled nausea required a rescue therapy. According to CTCAE, 69% of patients receiving NEPA had grade 1 nausea and 6% had none, while all patients receiving Ondansetron had CINV and 85% of them had grade 2 nausea. CONCLUSIONS: In our experience, NEPA has shown superiority in the prevention of CINV, in highly emetogenic regimens in both patients with myeloma or lymphoma, with advantages on the severity and the duration of CINV. Given the high burden of CINV in the whole population analyzed in the study, regardless of the antiemetic used, it would be useful to identify patients at greatest risk and standardize CINV prophylaxis and treatment protocols depending on the different chemotherapy regimens and their emetogenic risk.

A Universal CRISPR/Cas9n-Mediated Genome Editing Approach for ELANE-Related Severe Congenital Neutropenia

Severe congenital neutropenia (CN) is an inherited bone marrow failure syndrome characterized by impaired maturation of neutrophil granulocytes. Due to the lack or very low levels of neutrophils in the peripheral blood, patients experience severe, life-threatening bacterial infections as early as birth. Autosomal-dominant ELANE mutations are the most common cause of CN. Although most patients respond to daily treatment with recombinant human granulocyte colony-stimulating factor, about 15% of patients do not respond to this cytokine, and approximately 20% of patients develop myelodysplasia or acute myeloid leukemia. The only curative treatment available thus far is allogenic hematopoietic stem cell transplantation, which is associated with serious side effects. Autologous transplantation of gene-edited patients' HSPCs offers a novel curative therapy. Considering the wide range of mutations distributed throughout the ELANE gene, A universal, high-safety-profile approach could be advantageous for all ELANE-CN patients. Our group has already published a universal CRISPR/Cas9-mediated knockout approach for the ELANE gene; however, targeting the coding sequence region (CDS) of the ELANE gene could lead to the introduction of new disease-causing variants, so it may be harmful for patients. In order to address this concern, we reformatted our previously published knockout concept into a clinical-grade gene therapy strategy. We have screened cis-regulatory regions in the ELANE core promoter and, using CRISPR/Cas9n, introduced two nicks on opposing strands of the Goldberg-Hognes box region (TATA-box) to make the transcription starting process inefficient, as transcription factors and RNApol II cannot recognize the modified sequence. Theproposed strategy targets the non-coding region of the ELANE gene and thus does not generate new unwanted variants. Also, by replacing Cas9 with Cas9-ncikase, the off-target activity should decrease by up to 1000-fold. We have observed a markedly elevated neutrophil differentiation in gene-edited ELANE-CN patients HSPCs (n = 2), as assessed by the percentage of CD45 +CD11b +CD15 +, CD45 +CD15 +CD16 +, and CD45 +CD16 +CD66b + myeloid/granulocytic cells, compared to the mock electroporated ELANE-CN group, while no disruption of granulopoiesis in healthy donor HSPCs (n = 2) was detected. Results validated by the CFU assay. To have nucleotide-level resolution of on-target events, we performed targeted next-generation sequencing of edited loci on gene-edited healthy donors and ELANE-CN HSPCs. Next-generation sequencing results showed &amp;gt;90% on-target efficiency. CRISPR/Cas9n-mediated targeting of the TATA box rescued defective granulopoiesis in vivo, as gene-edited ELANE-CN HSPCs (n = 3) were transplanted in NSG mice and assessed by the percentage of neutrophils (hCD19 -hCD3 -hCD66b Int/lowhCD33 +hCD16 high) after 16 weeks. We have also observed efficient engraftment and preserved the multilineage potential of gene edited HSPCs in immunodeficient NSG mice. The strategy also depicted a safe profile upon applying gene editing to healthy donor CD34 + HSPCs and performing GUIDE-seq and CAST-seq. GUIDE-seq highlighted two potential off-target sites after &amp;gt;=6 mismatches, while no chromosomal translocations were detected by CAST-seq. RNA-sequencing of in vitro-generated neutrophils from gene-edited HSPCs of healthy donors (n = 2) confirmed a &amp;gt;9-fold reduction of ELANE gene expression level. Important to note, none of the other serine proteases or neighboring genes were down-regulated. Taken together, ex vivo CRISPR-Cas9n-based gene editing of ELANE's gene promoter in the setting of autologous stem cell transplantation could be a safe therapeutic approach for all ELANE-CN patients.

Post-Transplant Cyclophosphamide (PTCY) Compared to ATG in Patients with Myelodysplastic Neoplasms Allografted with an Unrelated Donor: A Registry Study of the Chronic Malignancies Working Party of the EBMT

Background Prospective randomized trials have reported a benefit for ATG-based GVHD prophylaxis in the setting of allogeneic hematopoietic stem cell transplantation (alloHSCT) with an unrelated donor (UD). However, the best GVHD prophylaxis has been recently challenged by the use of PTCY, first in haplo-identical transplant and then in HLA mismatched or matched unrelated transplantation. We here present the outcomes of PTCY vs ATG as GVHD prophylaxis in MDS patients from the EBMT registry transplanted with an unrelated donor. Method A total of 969 patients transplanted from 2012 to 2019 in 92 participating centers, receiving either PTCY or ATG, were included in this study. The primary outcomes were progression free survival (PFS) and overall survival (OS). Competing risks analyses were performed to analyze non-relapse mortality (NRM) with competing event relapse, and acute GvHD grade II-IV, chronic GvHD and neutrophil engraftment with competing events relapse and death. Cox proportional hazards regression with a predefined covariate constellation (age, IPSS-R cytogenetics, donor HLA matching, age, hypomethylating agents (HMA) prior to transplantation, comorbidity score and MDS classification (MDS with or without excess blast, EB) was used to obtain adjusted effect estimates of ATG compared to PTCY for OS and PFS. Results Overall, 214 patients received PTCY and 755 received ATG as GVHD prophylaxis for UD alloHSCT. Patients of the ATG group were older (60.1 year-old [IQR: 50.6-65.2] vs 57.2 year-old [IQR: 46.4-61.1], p=0.008). Disease characteristics were similar in both group: there were a total of 583 MDS with EB at diagnosis, 510 MDS-EB at transplantation, and 207 patients transformed into AML. Among patients with available data for IPSS-R at MDS diagnosis (n=760) 44 (5.8%) were Very Low, 114 (15%) Low, 209 (27.5%) Intermediate, 232 (30.5%) High and 161 (21.2%) Very High. Patients of the PTCY group received more frequently HMA before transplantation (72.4% vs 57.3%, p=0.001) and were preferentially transplanted from an HLA mismatched 9/10 donor (37.9% vs 21.6%, p&amp;lt;0.001). Conditioning regimen was more frequently myeloablative in the PTCY group (55.4% vs 38.7%, p&amp;lt;0.001). Neutrophil engraftment at 28 days was significantly better with ATG (93% vs 84%, p&amp;lt;0.001). With a median follow-up of 4.4 (95% CI 4.2 - 4.8) years, five-year OS was 57% (49-64) with PCTY and 49% (95% 46-53%) in ATG group, p=0.127. Five-year cumulative incidence of relapse was similar in both groups (22%, 95%CI 16-29 in PTCY vs 25%, 95%CI 22-28 in ATG; p=0.28). Notably, 5-year PFS was marginally higher for PTCY with 52% (95%CI 44-59) vs 44% (95%CI 40-48) for ATG, p=0.075, whereas 5-year NRM was 26% (95% CI 20-32%) vs 31% (95% CI 27-34) in PTCY and ATG, respectively, p=0.28. Grade II-IV acute GVHD incidence was lower using PTCY (22% [95% CI 17-28%] vs 30% [95% CI 26-33%]), p=0.035 while there was no difference for chronic GVHD (36% (29-43% with PTCY vs 38% (34-41%) in ATG at 5 years). Multivariable analyses confirmed a better OS and PFS for PTCY, with a HR of ATG of 1.34 (95% CI 1.02-1.76), p=0.04, and a better PFS for PTCY with a HR for ATG of 1.31 (95%CI 1.01-1.69) (Table 1). There was no apparent interaction between GvHD prophylaxis and IPSS-R or HLA matching, suggesting an effect exclusive to the type of GVHD prophylaxis used. Conclusion: This EBMT registry study suggests that MDS patients who received a transplant from an unrelated donor had a better OS and PFS using PTCY compared to ATG. This confirms that PTCY instead of ATG in this setting is a valid option.

Role of Preemptive Cytomegalovirus Hyperimmunoglobulin in Cytomegalovirus Viremia Following Stem Cell Transplant: An Integrative Review.

Cytomegalovirus (CMV) is a major cause of morbidity and mortality in stem cell transplant (SCT) patients. Cytomegalovirus hyperimmunoglobulin (CMV-HIG) therapy has been described in the solid organ transplant setting. However, no review has focused on preemptive use of intravenous CMV immunoglobulins in the SCT setting. This review aims to consolidate findings regarding the preemptive use of CMV-HIG for CMV viremia in SCT patients. PubMed and Scopus were searched using specific search criteria for publications from 2011 to 2021. Search terms were: cytomegalovirus, CMV, immunoglobulins, immunoglobulin, IVIG, CMVIG, hematopoietic stem cell transplantation, and stem cell. Included studies discussed stem cell transplantation, immunoglobulins, and cytomegalovirus. 366 articles were identified from the search. Five articles met the inclusion and exclusion criteria. Preemptive CMV-HIG resulted in an overall response in 65% to 100% of patients with a clearance time of 14 to 21 days. Early use of CMV-HIG may shorten clearance time. No treatment-related mortality or serious adverse events were associated. CMV-HIG is an effective treatment option in SCT patients that is as safe as antivirals alone. Preemptive CMV-HIG with antivirals may provide the added advantage of reduced time to viremia clearance without adding renal injury. Larger, prospective studies are needed to evaluate CMV-HIG's impact on time to viremia clearance and the effectiveness of preemptive CMV-HIG use with antivirals.

Long-Term Cryopreservation of Peripheral Blood Stem Cell Harvest Using Low Concentration (4.35%) Dimethyl Sulfoxide with Methyl Cellulose and Uncontrolled Rate Freezing at -80 °C: An Effective Option in Resource-Limited Settings

Long-term cryopreservation of peripheral blood stem cells (PBSCs) is highly useful in the setting of tandem/multiple transplantations or treatment of relapse in the autologous hematopoietic stem cell transplantation (HSCT) setting. Even in allogeneic HSCT, donor lymphocyte infusions may be stored for months to years if excess stem cells are collected from donors. Cryopreservation is a delicate, complex, and costly procedure, and higher concentrations of dimethyl sulfoxide (DMSO), a commonly used cryoprotectant, can be toxic to cells and cause adverse effects in the recipient during infusions. In this study, we examined the effect of long-term cryopreservation using 4.35% DMSO (as final concentration) with methyl cellulose and uncontrolled rate freezing in a mechanical freezer (-80 °C) on the viability and colony-forming ability of CD34+ human PBSCs. For patients undergoing autologous HSCT, PBSCs were cryopreserved using DMSO (final concentration of 4.35%) with methyl cellulose. The post-thaw viability of PBSCs was determined using Trypan blue exclusion and flow cytometry-based 7-amino-actinomycin-D (FC-7AAD) methods. Concentrations of CD34+ stem cells and immune cell subsets in post-thaw PBSC harvest samples were assessed using multicolor flow cytometry, and the clonogenic potential of post-thaw stem cells was studied using a colony-forming unit (CFU) assay. CD34+ stem cell levels were correlated with the prestorage CD34 levels using the Pearson correlation test. The viability results in the Trypan blue dye exclusion method and the flow cytometry-based method were compared using Bland-Altman plots. We studied 26 PBSC harvest samples with a median cryopreservation duration of 6.6 years (range, 3.8 to 11.5 years). The median viability of post-thaw PBSCs was >80% using both methods, with a weak agreement between them (r=.03; P=.5). The median CD34+ stem cell count in the post-thaw samples was 9.13×106/kg (range, .44 to 26.27×106/kg). The CFU assay yielded a good proliferation and differentiation potential in post-thaw PBSCs, with a weak correlation between granulocyte macrophage CFU and CD34+ stem cell levels (r=.4; P=.05). Two samples that had been cryopreserved for >8 years showed low viability. Cryopreservation of PBSCs using 4.35% DMSO with methyl cellulose and uncontrolled freezing in a mechanical freezer at -80 °C allows the maintenance of long-term viability of PBSC for up to 8 years.

Significance of CMV reactivation in non-allogeneic stem cell transplant patients with cancers: experience of single tertiary care cancer institute.

CMV reactivation is rare in hematological as well as solid organ malignancies in non-allogeneic stem cell transplant settings. An increasing number of patients undergoing active treatment or follow-up and diagnosed with CMV reactivation in recent years prompted us to investigate the risk factors and outcomes of CMV reactivation or disease. This was a hospital-based retrospective study that included 174 cancer patients suspected of CMV reactivation. Among them, forty-one tested positive for CMV viremia. The risk factors for CMV reactivation included the use of steroids in 78% of patients, active cancer in 43.9%, use of a monoclonal antibodyrituximabin 31.7%,a history of radiation in 26.8%, and autologous stem cell transplant in 12% of patients. The median age was 36 years, and the most common clinical feature was fever (58.5%; n = 24), followed by GI symptoms (12.1%; n = 5), respiratory symptoms (14.6%; n = 6), cytopenia (7.3%; n = 3), and visual/neurological symptoms (4.8%; n = 2). The mean CMV viral load was 37,332 copies/ml (range: 75.00-633,000.00 copies/ml). Nineteen patients received CMV treatment with an average treatment duration of 81.5 days. The median overall survival was 2 months, with 12.0% of patients alive at 5 years. CMV reactivation is associated with significant morbidity and mortality. We recommend vigilant monitoring of CMV-related symptoms, with a low threshold for testing and treatment, for patients with multiple risk factors for CMV reactivation.

The Role of Fecal Microbiota Transplantation in the Allogeneic Stem Cell Transplant Setting.

Microbiota changes during allogeneic hematopoietic stem cell transplantation has several known causes: conditioning chemotherapy and radiation, broad-spectrum antibiotic administration, modification in nutrition status and diet, and graft-versus-host disease. This article aims to review the current knowledge about the close link between microbiota and allogeneic stem cell transplantation setting. The PubMed search engine was used to perform this review. We analyzed data on microbiota dysbiosis related to the above-mentioned affecting factors. We also looked at treatments aimed at modifying gut dysbiosis and applications of fecal microbiota transplantation in the allogeneic stem cell transplant field, with particular interest in fecal microbiota transplantation for graft-versus-host disease (GvHD), multidrug-resistant and clostridium difficile infections, and microbiota restoration after chemotherapy and antibiotic therapy.

Predictive factors of sleep quality and burnout in nurses working in transplant units during the COVID-19 lockdown – A cross-sectional study

Background: There is minimal information regarding sleep disturbance and burnout during COVID-19 in nurses working within haematology-oncology and hematopoietic stem cell transplantation (HSCT) settings. Aim: To identify socio-demographic and professional factors that predicted burnout and sleep disturbance during COVID-19 in nurses working in HSCT settings. Design/Methods: Data were collected using the Maslach Burnout Inventory and the Pittsburgh Sleep Quality Index. Descriptive statistics and linear regression examined relationships. Results: 308 responses were received. Nurses working in outpatient settings had greater emotional exhaustion (Rpartial = −0.12, n = 308, p = 0.03). Negative predictors for quality of sleep were transplant programme setting (Rpartial = −0.19, n = 308, p < 0.01) and years working in HSCT (Rpartial = −0.17, n = 308, p < 0.01). Other relationships were found on univariate analysis. Conclusion: Institutions must offer programmes for nurses to develop sleep strategies, self-care, and work-related stress management.

A SYSTEMATIC REVIEW OF THE DIRECT COSTS ASSOCIATED WITH THE MANAGEMENT OF MUCOSITIS

Objective To evaluate and report the direct economic outcomes associated with the management of mucositis across several cancer treatments through a systematic review. Study Design A systematic search using the databases Scopus, MEDLINE/PubMed, and Embase to identify articles that provided data on costs associated with mucositis in cancer patients following antineoplastic therapies. Results 37 studies were included. The costs attributable to mucositis ranged from 1,124.47 to 29,9214.14 US dollars (USD) per patient in the hematopoietic stem cell transplantation setting; from 51.23 to 33,560.58 USD per patient in the radiotherapy/ chemoradiotherapy/radiotherapy plus molecular targeted therapy setting; from 4.18 to 31,963.64 USD per patient in the chemotherapy setting; from 565.85 to 20,279.12 USD per patient when cancer treatment was not specified; from 12.42 to 5,670.46 USD per patient for the multimodal therapy setting; and from 45.78 to 3,484.91 USD per patient in the molecular targeted therapy setting. Conclusion Mucositis is associated with increased resource use, consultations, hospitalizations and extended hospitalizations, leading to a substantial incremental cost that exacerbates the economic burden on the patient, health plan, and health system across several cancer treatments and diagnosis. More studies with a prospective evaluation of the economic costs associated with mucositis management are needed. To evaluate and report the direct economic outcomes associated with the management of mucositis across several cancer treatments through a systematic review. A systematic search using the databases Scopus, MEDLINE/PubMed, and Embase to identify articles that provided data on costs associated with mucositis in cancer patients following antineoplastic therapies. 37 studies were included. The costs attributable to mucositis ranged from 1,124.47 to 29,9214.14 US dollars (USD) per patient in the hematopoietic stem cell transplantation setting; from 51.23 to 33,560.58 USD per patient in the radiotherapy/ chemoradiotherapy/radiotherapy plus molecular targeted therapy setting; from 4.18 to 31,963.64 USD per patient in the chemotherapy setting; from 565.85 to 20,279.12 USD per patient when cancer treatment was not specified; from 12.42 to 5,670.46 USD per patient for the multimodal therapy setting; and from 45.78 to 3,484.91 USD per patient in the molecular targeted therapy setting. Mucositis is associated with increased resource use, consultations, hospitalizations and extended hospitalizations, leading to a substantial incremental cost that exacerbates the economic burden on the patient, health plan, and health system across several cancer treatments and diagnosis. More studies with a prospective evaluation of the economic costs associated with mucositis management are needed.

Absolute lymphocyte counts (ALC) recovery and risk of viral reactivation in the setting of haploidentical hematopoietic stem cell transplant.

e19065 Background: The impact of early absolute lymphocyte repopulation after allogeneic hematopoietic stem cell transplant has historically been shown to predict the risk of post-transplant infection, and subsequently, non-relapse mortality (NRM). Previous studies have shown that ALC recovery after allogeneic stem cell transplant is associated with risk of viral reactivation and survival. In this study we aim to investigate the role of ALC recovery in the contemporary era with myeloablative haploidentical hematopoietic stem cell transplant (HI-HSCT). Methods: We retrospectively analyzed adult patients at University of Southern California (USC) Norris Cancer Hospital who received myeloablative conditioning haplo-HSCT (Fludarabine with 12 Gy of radiation) from 2014 to 2020. The primary endpoint was correlation between ALC recovery day 21 and risk of viral reactivation including cytomegalovirus (CMV), Epstein-Barr Virus (EBV) and BK virus. ALC recovery cut off was chosen to be 175/uL on day +21 and 500/uL on day +60 based on prior reports. Results: 58 patients were identified as recipients of MAC haploidentical-HSCT. 17 had ALC recovery at day +21. Mean age was 49 years, 31 (53.4%) were males and 27 (46.6%) were females. 41 (70%) patients were Hispanic, 12 (20%) were non-Hispanic White, and the majority had AML (51%). 76% received &gt; 5*106/kg CD34+ cell dose and 78% received CD3 + cell dose &lt; 3*108/kg. Serum CMV, EBV and urine BK virus were detected in 38 (65.5%), 8 (15.7%) and 11 (32.4%) respectively. Clinically significant CMV reactivation (required treatment with antiviral therapy) was detected in 26 (44.8%) patients. Lack of ALC recovery on day +21 did not show correlation with CMV, EBV and BK virus reactivation. Also, the risk of CMV reactivation was not related to day +60 ALC recovery (p-value = 0.469). On univariate analysis, ALC recovery day +21, day +60, and CMV reactivation did not show correlation with overall survival. In multivariate analysis when adjusted for age and pre-transplant CMV status, higher CD 3+ cell dose of &gt; 3*108/kg was associated with reduced risk of CMV reactivation HR = 0.35 (0.15-0.85) p-value = 0.02. Conclusions: Previous studies have established ALC recovery as a predictor of better outcome. This has not been established in patients undertaking myeloablative HI-HSCT. Our study shows that lack of ALC recovery on day +21 does not affect CMV, EBV and BK virus reactivation and risk of CMV reactivation does not correlate with day +60 ALC recovery. Also, ALC recovery and CMV reactivation does not impact overall survival. The use of Letermovir, effective CMV therapies and close viral surveillance in contemporary practice is likely responsible for mitigating poor outcomes with CMV reactivation. Graft composition needs to be studied prospectively, as higher CD3+ cell dose may present an opportunity to reduce CMV reactivation in HI-HSCT.