Pneumocystis Jirovecii Infection in Autologous Hematopoietic Stem Cell Transplant Recipients

Background Infections remain a common cause of morbidity and mortality following hematopoietic stem cell transplant (HSCT). Pneumocystis jiroveci pneumonia (PJP) is an opportunistic infection that can occur in HSCT patients, although the association is best demonstrated in allogeneic HSCT, occurring less commonly in autologous HSCT. However, reports on PJP incidence, timing of infection, and outcomes among autologous HSCT cohorts are limited. Furthermore, while current guidelines recommend 3-6 months of prophylaxis against PJP following autologous HSCT, the optimal duration and even necessity of prophylaxis is not well established. Patients and Methods We performed a retrospective analysis of all consecutive patients who had autologous HSCT at the University of Michigan Blood and Marrow Transplantation program over a 20-year period from 1/1/2000 through 12/31/2019. The cohort consisted of a total of 2082 patients, 1221 male (58.6%), with median age 56 (range 10 months - 77 years, 91.2% ≥ 18 years). Records were searched for use of PJP prophylaxis over 6-month and 2-year follow-up periods post-HCT to determine rates of prophylaxis and choice of agent. Cases of polymerase-chain reaction (PCR)-confirmed PJP occurring within two years of HSCT were identified. The timing, clinical and laboratory features at diagnosis, use of concurrent immunosuppression, treatment, and outcomes were determined. Results Of the 2082 patients undergoing autologous HCT, 704 patients (33.8%) received PJP prophylaxis in the first 6 months following transplant. Prophylaxis rates varied over time, ranging from 14.6% to 80.0% when calculated by year of transplant (Figure 1). Trimethoprim-sulfamethoxazole (TMP-SMX) was the most used prophylaxis agent (70.3%), followed by inhaled pentamidine (31.8%), with intravenous pentamidine (8.1%), dapsone (7.1%), and atovaquone (2.6%) being used less frequently. There were 9 cases of PJP identified in our cohort, with an incidence of 0.43%. There were 6 males, with median age of 50 (range 34 - 69). Cases occurred a median of 126 days following HSCT (range 65 - 496), with 4 cases occurring after 6 months. None of the patients were on PJP prophylaxis at the time of diagnosis, and only 2 patients had received prophylaxis at any point after transplant. In 8 of 9 cases, patients were receiving concurrent pharmacologic immunosuppression in the form of steroids or maintenance brentuximab (Table 1). All patients presented with symptoms compatible with PJP, most often with fevers, dyspnea, and cough. Diagnosis was made by PCR from bronchoalveolar lavage specimen in 8 cases, and from sputum sample in 1 case. All patients were lymphopenic at the time of diagnosis, with median absolute lymphocyte count of 400 cells/µL (range 200 - 1100). Patients were most often treated with TMP-SMX. Three patients required transfer to the intensive care unit and 2 were intubated. Ultimately, 2 patients died from PJP infection; the remaining 7 recovered (Table 2). Conclusion Our analysis reveals that among a large cohort, incidence of PJP following autologous HSCT is low. This was the case even with relatively modest rates of PJP prophylaxis in the first 6 months following transplant. Most cases of PJP occurred in patients receiving additional immunosuppression and often occurred late following transplant. Figure 1 Figure 1. Disclosures Pianko: Karyopharm: Honoraria.

Serological Response Following BNT162b2 Anti-Sars-Cov-2 mRNA Vaccination in Hematopoietic Stem Cell Transplantation Patients

Patients with hematological malignancies (HM) undergoing hematopoietic stem cell transplantation (HSCT) have an increased vulnerability to SARS-Cov-2 (Sharma et al, Lancet Haematology 2020; Ljungman et al, Leukemia 2021), the reason why international guidelines strongly support the need for a protective vaccination for these subjects. The most relevant data currently available on the response to a complete anti-SARS-Cov-2 vaccination cycle in HM patients after HSCT refer to 314 patients reported in a Lithuanian national survey (Maneikis et al, Lancet Haematol 2021). In this study, the median titers of antibodies against SARS-Cov-2, determined 7-21 days after the second vaccination, were comparable to that of healthy controls (HC) in both autologous and allogeneic groups, with no patient found below the protective threshold of 50 arbitrary units (AU)/ml. Notably, the large majority of patients had received the transplant more than 1 year before vaccination. In a prospective, cohort study, we compared 114 patients, who had received an autologous or allogeneic HSCT at least three months before the first dose of vaccination, to 107 HC, matched for age and sex. Study population and HC received two doses of BNT162b2 anti-SARS-Cov-2 mRNA vaccine on days 1 and 21, between April and May 2021. Serological tests were performed by a commercially available immunoassay for the quantitative determination of anti-spike IgG antibodies to SARS-Cov-2. The cut-off for defining responders was 50 or greater AU/ml. Patients and HC samples were collected four weeks after the second dose of the vaccine. Table 1 reports the main clinical characteristics of patients and HC. Eighteen of 114 patients (16%) did not respond (24% in the allogeneic group, 6% in autologous recipients). Overall, median antibodies titers did not differ between HC and the entire cohort of transplanted patients, recipients of allogeneic HSCT, all patients responding to the vaccine or responders in the autologous subgroup (Figure 1A). All autologous HSCT recipients had significantly lower titers of antibodies than HC, while higher levels were found in responders who had received allogeneic HSCT (Figure 1A). Responders in the allogeneic subgroup showed antibodies titers significantly higher than responders in the autologous subgroup (Figure 1B). We further stratified patients in three groups, according to the time elapsed from transplant to vaccination: G1:<1 year; G2:1-5 years; G3:>5 years. Higher antibodies titers were observed in HC compared to all transplanted patients in G1 (Figure 1C), including both allogeneic (Figure 1D) and autologous (Figure 1E) HSCT recipients. No differences emerged in G2 between HC and all patients (Figure 1C), allogeneic (Figure 1D) or autologous (Figure 1E) HSCT recipients. Finally, no differences were found in G3 when comparing HC with all patients (Figure 1C) or allogeneic recipients (Figure 1D), whereas patients in the autologous subgroup showed significantly lower titers than HC (Figure 1E). Myeloma patients with controlled disease showed higher titers than patients with active disease (Figure 1F). According to median age, autologous HSCT recipients older than 57 years had significantly lower antibody levels than younger patients (Figure 1G). Autologous vs allogeneic HSCT, age of all patients and of allogeneic HSCT recipients, sex, type of allogeneic HSCT, conditioning regimen, age and sex of donor, occurrence of GVHD, disease type and single vs double autologous HSCT did not significantly impact on antibody levels (data not shown). No relevant side effects were recorded after vaccination. With a median follow up of 12 weeks, no case of COVID19 occurred among vaccinated patients. In our single center study, patients with a previous history of HSCT tolerated well BNT162b2 vaccine and mounted a potentially protective immune response in the majority of cases one month after two doses of vaccine. However, lack of response was not rare, especially in the allogeneic setting. The main factor associated with the quality of response was the time from HSCT, with lower responses within the first year from transplant and differences between autologous and allogeneic groups transplanted more than five years before vaccination. Here, a consolidated, complete immune reconstitution in allogeneic HSCT recipients, as well as age and a still active disease in the autologous setting, could have played opposite pivotal roles. Figure 1 Figure 1. Disclosures Delia: Gilead: Consultancy; Amgen: Consultancy; abbvie: Consultancy; Jazz pharmaceuticals: Consultancy.

Risk of respiratory viral infections after hematopoietic stem cell transplantation in Indian patients

Haematopoietic stem cell transplant (HSCT) recipients are at higher risk of morbidity and mortality due to respiratory infections and their frequency is not well studied in Indian HSCT recipients. A cohort of 55 HSCT recipients were enrolled prospectively for respiratory episodes. Real-time polymerase chain reaction was performed for respiratory viral aetiology. A total of 153 episodes of acute respiratory infections occurred, [107 episodes (mean; 2.8/patient) in autologous HSCT (n=38); 46 episodes (mean; 2.7/patients) in allogeneic HSCT (n=17)]. From these episodes, 70 samples could be tested for respiratory viruses, of which 33 (47.1%) samples tested positive. A higher infection rate (52%; 26/50) was seen in autologous HSCT compared with allogeneic HSCT (35%; 7/20). Rhinoviruses were detected most often (18/33; 54.5%), followed by parainfluenza viruses, (PIV, 6/33; 18.1%). Human metapneumoviruses, (hMPV) and influenza A/H3N2 were detected in 4 samples each (4/33; 12.1%) followed by respiratory syncytial virus (RSV, 2/33; 6.1%). Of the 13 patients with an unfavourable outcome, 4 had respiratory viral infections. Significantly higher fatality was observed in allogeneic than in autologous recipients. Respiratory viruses cause multiple episodes of infection contributing to morbidity and mortality in HSCT recipients.

Innovator Filgrastim versus Generic Filgrastim in Hematopoietic Stem Cell Transplantation Mobilization

Methods This is a retrospective study. G-CSF was administered in the dose of 10 μg/kg subcutaneous as a single dose for 4 days. On day 5, peripheral blood stem cell (PBSC) apheresis was performed using Haemonetics MCS plus or COBE Spectra apheresis machine through a double-lumen central venous catheter. Primary outcome parameters were the total number of CD34+ HSCs/kg of recipient weight mobilized in peripheral blood and the number of days required for neutrophil and platelets engraftment, respectively. Objective We compared the effectiveness and safety of innovator filgrastim versus generic filgrastim in patients who underwent hematopoietic stem cell transplantation (HSCT). Results A total of 91 stem cell mobilizations was analyzed. There were 58 normal healthy donors for allogeneic HSCT and 33 patients for autologous HSCT. There was no statistically significant difference among groups in terms of total collected CD34+ cells value (p = 0.609). The mean time to neutrophil engraftment was 13.7 days in the innovator group and 13.2 days in the Grafeel group (p = 0.518). The mean time to platelet engraftment was 16.2 days in the innovator group and 14.8 days in the generic group (p = 0.435). The patient who received generic filgrastim had more febrile episodes during the course of transplantation (p = 0.020). Conclusion Generic filgrastim was found to be comparable to original filgrastim for peripheral blood stem cell mobilization in normal healthy donors for allogeneic HSCT and patients for autologous HSCT.

Prospective study on Prophylactic Micafungin sodium against Invasive Fungal Disease during Neutropenia in Pediatric & Adolescent Patients undergoing Autologous Hematopoietic Stem Cell Transplantation

Background Invasive fungal diseases (IFDs) increase the mortality rate of patients with neutropenia who receive chemotherapy or have previously undergone hematopoietic stem cell transplantation (HSCT). Micafungin is a broad-spectrum echinocandin, with minimal toxicity and low drug interactions. We therefore investigated the efficacy and safety of prophylactic micafungin in pediatric and adolescent patients who underwent autologous HSCT. Methods This was a phase II, prospective, single-center, open-label, and single-arm study. From November 2011 to February 2017, 125 patients were screened from Seoul National University Children’s Hospital, Korea, and 112 were enrolled. Micafungin was administered intravenously at a dose of 1 mg/kg/day (maximum 50 mg/day) from day 8 of autologous HSCT until neutrophil engraftment. Treatment success was defined as the absence of proven, probable, or possible IFD up to 4 weeks after therapy. Results The study protocol was achieved without premature interruption in 110 patients (98.2%). The reasons interrupting micafungin treatment included early death (n=1) and patient refusal (n=1). Treatment success was achieved in 109 patients (99.1%). Only one patient was diagnosed with probable IFD. No patients were diagnosed with possible or proven IFD. In the full analysis set, 21 patients (18.8%) experienced 22 adverse events (AEs); however, all AEs were classified as “unlikely” related to micafungin. No patient experienced grade IV AEs nor discontinued treatment and none of the deaths were related to micafungin. Conclusions Our study demonstrated that micafungin is a safe and effective option for antifungal prophylaxis in pediatric patients who underwent autologous HSCT, with promising efficacy without significant AEs.

STING and transplantation: can targeting this pathway improve outcomes?

Stimulator of interferon genes (STING) is an innate immune sensor of cytoplasmic dsDNA originating from microorganisms and host cells. STING plays an important role in the regulation of murine graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be similarly activated during other transplantation modalities. In this review, we discuss STING in allo-HSCT and its prospective involvement in autologous HSCT (auto-HSCT) and solid organ transplantation (SOT), highlighting its unique role in nonhematopoietic, hematopoietic, and malignant cell types.

Human NK Cells in Autologous Hematopoietic Stem Cell Transplantation for Cancer Treatment

Natural killer (NK) cells are phenotypically and functionally diverse lymphocytes with the ability to recognize and kill malignant cells without prior sensitization, and therefore, they have a relevant role in tumor immunosurveillance. NK cells constitute the main lymphocyte subset in peripheral blood in the first week after hematopoietic stem cell transplantation (HSCT). Although the role that NK cells play in allogenic HSCT settings has been documented for years, their significance and beneficial effects associated with the outcome after autologous HSCT are less recognized. In this review, we have summarized fundamental aspects of NK cell biology, such as, NK cell subset diversity, their effector functions, and differentiation. Moreover, we have reviewed the factors that affect autologous HSCT outcome, with particular attention to the role played by NK cells and their receptor repertoire in this regard.

The Cost Effectiveness of Immunoglobulin vs. Hematopoietic Stem Cell Transplantation for CIDP

Background: Intravenous immunoglobulin (IVIG) is effective as standard first line therapy for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but some patients remain dependent on its long-term use. Recently, we have reported that autologous non-myeloablative hematopoietic stem cell transplantation (HSCT) is an effective second line therapy for CIDP.Objectives: To compare the cost of chronic IVIG vs. autologous HSCT (a one-time therapy), we collected data on patients with CIDP undergoing HSCT between 2017 and 2019. This was compared with published literature on the costs and efficacy defined by the Inflammatory Neuropathy Cause And Treatment (INCAT) disability score, Medical Research Council (MRC) sum score, hand grip strength, and SF-36 quality of life (QOL) for CIDP.Methods: Between 2017 and 2019, nineteen patients with chronic CIDP (mean disease treatment duration prior to HSCT of 6 years) underwent autologous HSCT with mean cost of $108,577 per patient (range $56,327–277,119, standard deviation $53,092). After HSCT, 80% of patients remain IVIG and immune treatment free for up to 5 years. In comparison, published cost of IVIG treatment in the USA for an average CIDP patient exceeds $136,000 per year. Despite remaining treatment free, HSCT demonstrated greater improvement in efficacy compared to immunoglobulins.Recommendations: Given the long-term treatment-free remission and better outcome measurements, autologous HSCT is more cost effective than long-term IVIG treatment in patients with chronic CIDP. However, costs will depend on patient selection, the HSCT regimen, and regional variations. Further analysis of the health economics, i.e., cost/outcome ratio, of HSCT as therapy for chronically IVIG dependent CIDP is warranted.

Cell-density independent increased lymphocyte production and loss rates post-autologous HSCT

Lymphocyte numbers need to be quite tightly regulated. It is generally assumed that lymphocyte production and lifespan increase homeostatically when lymphocyte numbers are low and, vice versa, return to normal once cell numbers have normalized. This widely accepted concept is largely based on experiments in mice, but is hardly investigated in vivo in humans. Here we quantified lymphocyte production and loss rates in vivo in patients 0.5–1 year after their autologous hematopoietic stem cell transplantation (autoHSCT). We indeed found that the production rates of most T- and B-cell subsets in autoHSCT-patients were two to eight times higher than in healthy controls, but went hand in hand with a threefold to ninefold increase in cell loss rates. Both rates also did not normalize when cell numbers did. This shows that increased lymphocyte production and loss rates occur even long after autoHSCT and can persist in the face of apparently normal cell numbers.