Type I Interferon Autoantibodies Correlate With Cellular Immune Alterations in Severe COVID-19.

BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to severe disease with increased morbidity and mortality among certain risk groups. The presence of autoantibodies against type I interferons (aIFN-Abs) is one mechanism that contributes to severe coronavirus disease 2019 (COVID-19). METHODS: This study aimed to investigate the presence of aIFN-Abs in relation to the soluble proteome, circulating immune cell numbers, and cellular phenotypes, as well as development of adaptive immunity. RESULTS: aIFN-Abs were more prevalent in critical compared to severe COVID-19 but largely absent in the other viral and bacterial infections studied here. The antibody and T-cell response to SARS-CoV-2 remained largely unaffected by the presence aIFN-Abs. Similarly, the inflammatory response in COVID-19 was comparable in individuals with and without aIFN-Abs. Instead, presence of aIFN-Abs had an impact on cellular immune system composition and skewing of cellular immune pathways. CONCLUSIONS: Our data suggest that aIFN-Abs do not significantly influence development of adaptive immunity but covary with alterations in immune cell numbers.

The Impact of Pretransplant Respiratory Virus Detection on Posttransplant Outcomes in Children Undergoing Hematopoietic Cell Transplantation.

BACKGROUND: Pretransplant respiratory virus (RV) infections have been associated with negative transplant outcomes in adult hematopoietic cell transplantation (HCT) recipients. In the era of HCT delay because of high-risk RVs, we examined the impact of pretransplant RV detection on transplant outcomes in pediatric HCT recipients. METHODS: This retrospective cohort study included pediatric myeloablative allogeneic HCT recipients from 2010 to 2019. All patients were screened for RV at least once within 90 days before HCT using reverse transcriptase polymerase chain reaction (PCR), regardless of symptoms. Posttransplant outcomes included days alive and out of hospital and progression to lower respiratory tract infection (LRTI). RESULTS: Among 310 patients, 134 had an RV detected in the 90 days before HCT. In univariable analysis, transplant factors including younger age, total body irradiation, umbilical cord blood transplantation, lymphocyte count <100/mm3, HCT comorbidity index score ≥3, and viral factors including symptomatic infection, human rhinovirus as a virus type, and symptomatic pretransplant upper respiratory tract infection were associated with fewer days alive and out of hospital. In multivariable analysis, transplant factors remained significant, but not viral factors. There was a higher incidence of progression to posttransplant LRTI with the same pretransplant RV if the last positive PCR before HCT was ≤30 days compared with >30 days (P = .007). CONCLUSIONS: In the setting of recommending HCT delay for high-risk RVs, symptomatic upper respiratory tract infection, including human rhinovirus infections, may lead to increased duration of hospitalization and early progression to LRTI when transplantation is performed within 30 days of the last positive PCR test.

Breakthrough COVID-19 in vaccinated patients with hematologic malignancies: results from the EPICOVIDEHA survey.

Limited data are available on breakthrough COVID-19 in patients with hematologic malignancy (HM) after anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Adult patients with HM, ≥1 dose of anti-SARS-CoV-2 vaccine, and breakthrough COVID-19 between January 2021 and March 2022 were analyzed. A total of 1548 cases were included, mainly lymphoid malignancies (1181 cases, 76%). After viral sequencing in 753 cases (49%), the Omicron variant was prevalent (517, 68.7%). Most of the patients received ≤2 vaccine doses before COVID-19 (1419, 91%), mostly mRNA-based (1377, 89%). Overall, 906 patients (59%) received COVID-19-specific treatment. After 30-day follow-up from COVID-19 diagnosis, 143 patients (9%) died. The mortality rate in patients with the Omicron variant was 7.9%, comparable to other variants, with a significantly lower 30-day mortality rate than in the prevaccine era (31%). In the univariable analysis, older age (P < .001), active HM (P < .001), and severe and critical COVID-19 (P = .007 and P < .001, respectively) were associated with mortality. Conversely, patients receiving monoclonal antibodies, even for severe or critical COVID-19, had a lower mortality rate (P < .001). In the multivariable model, older age, active disease, critical COVID-19, and 2-3 comorbidities were correlated with a higher mortality, whereas monoclonal antibody administration, alone (P < .001) or combined with antivirals (P = .009), was protective. Although mortality is significantly lower than in the prevaccination era, breakthrough COVID-19 in HM is still associated with considerable mortality. Death rate was lower in patients who received monoclonal antibodies, alone or in combination with antivirals.

Pneumocystis jirovecii pneumonia in intensive care units: a multicenter study by ESGCIP and EFISG.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic, life-threatening disease commonly affecting immunocompromised patients. The distribution of predisposing diseases or conditions in critically ill patients admitted to intensive care unit (ICU) and subjected to diagnostic work-up for PJP has seldom been explored. MATERIALS AND METHODS: The primary objective of the study was to describe the characteristics of ICU patients subjected to diagnostic workup for PJP. The secondary objectives were: (i) to assess demographic and clinical variables associated with PJP; (ii) to assess the performance of Pneumocystis PCR on respiratory specimens and serum BDG for the diagnosis of PJP; (iii) to describe 30-day and 90-day mortality in the study population. RESULTS: Overall, 600 patients were included in the study, of whom 115 had presumptive/proven PJP (19.2%). Only 8.8% of ICU patients subjected to diagnostic workup for PJP had HIV infection, whereas hematological malignancy, solid tumor, inflammatory diseases, and solid organ transplants were present in 23.2%, 16.2%, 15.5%, and 10.0% of tested patients, respectively. In multivariable analysis, AIDS (odds ratio [OR] 3.31; 95% confidence interval [CI] 1.13-9.64, p = 0.029), non-Hodgkin lymphoma (OR 3.71; 95% CI 1.23-11.18, p = 0.020), vasculitis (OR 5.95; 95% CI 1.07-33.22, p = 0.042), metastatic solid tumor (OR 4.31; 95% CI 1.76-10.53, p = 0.001), and bilateral ground glass on CT scan (OR 2.19; 95% CI 1.01-4.78, p = 0.048) were associated with PJP, whereas an inverse association was observed for increasing lymphocyte cell count (OR 0.64; 95% CI 0.42-1.00, p = 0.049). For the diagnosis of PJP, higher positive predictive value (PPV) was observed when both respiratory Pneumocystis PCR and serum BDG were positive compared to individual assay positivity (72% for the combination vs. 63% for PCR and 39% for BDG). Cumulative 30-day mortality and 90-day mortality in patients with presumptive/proven PJP were 52% and 67%, respectively. CONCLUSION: PJP in critically ill patients admitted to ICU is nowadays most encountered in non-HIV patients. Serum BDG when used in combination with respiratory Pneumocystis PCR could help improve the certainty of PJP diagnosis.

Decreased invasive fungal disease but no impact on overall survival by posaconazole compared to fluconazole prophylaxis: a retrospective cohort study in patients receiving induction therapy for acute myeloid leukaemia/myelodysplastic syndromes.

OBJECTIVE: Posaconazole prophylaxis during induction chemotherapy for acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) has been shown to significantly decrease the incidence of invasive fungal disease (IFD) and increase overall survival in a trial setting, but only small real-life studies have been published. METHODS: This was a retrospective cohort study including consecutive patients with AML/MDS treated with intensive induction chemotherapy; 176 patients received fluconazole prophylaxis 2008-2011 and 107 patients received posaconazole prophylaxis 2011-2013. Only proven and probable IFD according to the revised EORTC/MSG criteria were included in the analysis. RESULTS: The two cohorts were well matched without significant differences in patient characteristics. At day 100, patients receiving posaconazole had a significantly lower incidence of total IFD (0.9% vs. 10.8%, P < 0.01), invasive aspergillosis (0% vs. 5.7%, P = 0.02) and invasive candidiasis (0% vs. 4.0%, P < 0.05). There was no significant difference in overall survival, neither at day 100 (87% in the posaconazole group vs. 85% in the fluconazole group) nor at end of follow-up (78% vs. 77%). CONCLUSIONS: Posaconazole prophylaxis decreased the incidence of IFD but did not improve short-term overall survival. Improved treatment efficacy of manifest IFD is likely to explain the lack of survival benefit.

The mortality of COVID-19 in CML patients from 2020 until 2022: results from the EPICOVIDEHA survey.

Since the beginning of the COVID-19 pandemic, there has been an overall improvement in patient mortality. However, haematological malignancy patients continue to experience significant impacts from COVID-19, including high rates of hospitalization, intensive care unit (ICU) admissions, and mortality. In comparison to other haematological malignancy patients, individuals with chronic myeloid leukemia (CML) generally have better prognosis. This study, conducted using a large haematological malignancy patient database (EPICOVIDEHA), demonstrated that the majority of CML patients experienced mild infections. The decline in severe and critical infections over the years can largely be attributed to the widespread administration of vaccinations and the positive response they elicited. Notably, the mortality rate among CML patients was low and exhibited a downward trend in subsequent years. Importantly, our analysis provided confirmation of the effectiveness of vaccinations in CML patients.

Decoding the historical tale: COVID-19 impact on haematological malignancy patients-EPICOVIDEHA insights from 2020 to 2022.

Background: The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced. Methods: The EPICOVIDEHA registry (National Clinical Trials Identifier, NCT04733729) gathers COVID-19 data from hematological malignancy patients since the pandemic's start worldwide. It spans various global locations, allowing comprehensive analysis over the first three years (2020-2022). Findings: The EPICOVIDEHA registry collected data from January 2020 to December 2022, involving 8767 COVID-19 cases in hematological malignancy patients from 152 centers across 41 countries, with 42% being female. Over this period, there was a significant reduction in critical infections and an overall decrease in mortality from 29% to 4%. However, hospitalization, particularly in the ICU, remained associated with higher mortality rates. Factors contributing to increased mortality included age, multiple comorbidities, active malignancy at COVID-19 onset, pulmonary symptoms, and hospitalization. On the positive side, vaccination with one to two doses or three or more doses, as well as encountering COVID-19 in 2022, were associated with improved survival. Interpretation: Patients with hematological malignancies still face elevated risks, despite reductions in critical infections and overall mortality rates over time. Hospitalization, especially in ICUs, remains a significant concern. The study underscores the importance of vaccination and the timing of COVID-19 exposure in 2022 for enhanced survival in this patient group. Ongoing monitoring and targeted interventions are essential to support this vulnerable population, emphasizing the critical role of timely diagnosis and prompt treatment in preventing severe COVID-19 cases. Funding: Not applicable.

Outcome of COVID-19 in allogeneic stem cell transplant recipients: Results from the EPICOVIDEHA registry.

Background: The outcome of COVID-19 in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is almost uniformely considered poor. The aim of present study was to retrospectively analyse the outcome and risk factors for mortality in a large series of patients who developed COVID-19 infection after an allogeneic HSCT. Methods: This multicenter retrospective study promoted by the European Hematology Association - Infections in Hematology Study Working Group, included 326 adult HSCT patients who had COVID-19 between January 2020 and March 2022. Results: The median time from HSCT to the diagnosis of COVID-19 was 268 days (IQR 86-713; range 0-185 days). COVID-19 severity was mild in 21% of the patients, severe in 39% and critical in 16% of the patients. In multivariable analysis factors associated with a higher risk of mortality were, age above 50 years, presence of 3 or more comorbidities, active hematologic disease at time of COVID-19 infection, development of COVID-19 within 12 months of HSCT, and severe/critical infections. Overall mortality rate was 21% (n=68): COVID-19 was the main or secondary cause of death in 16% of the patients (n=53). Conclusions: Mortality in HSCT recipients who develop COVID-19 is high and largely dependent on age, comorbidities, active hematologic disease, timing from transplant and severity of the infection.

Impact of SARS-CoV-2 vaccination and monoclonal antibodies on outcome post-CD19-directed CAR T-cell therapy: an EPICOVIDEHA survey.

Patients with previous CD19-directed chimeric antigen receptor (CAR) T-cell therapy have a prolonged vulnerability to viral infections. Coronavirus disease 2019 (COVID-19) has a great impact and has previously been shown to cause high mortality in this population. Until now, real-world data on the impact of vaccination and treatment on patients with COVID-19 after CD19-directed CAR T-cell therapy are lacking. Therefore, this multicenter, retrospective study was conducted with data from the EPICOVIDEHA survey. Sixty-four patients were identified. The overall mortality caused by COVID-19 was 31%. Patients infected with the Omicron variant had a significantly lower risk of death due to COVID-19 compared with patients infected with previous variants (7% vs 58% [P = .012]). Twenty-six patients were vaccinated at the time of the COVID-19 diagnosis. Two vaccinations showed a marked but unsignificant reduction in the risk of COVID-19-caused mortality (33.3% vs 14.2% [P = .379]). In addition, the course of the disease appears milder with less frequent intensive care unit admissions (39% vs 14% [P = .054]) and a shorter duration of hospitalization (7 vs 27.5 days [P = .022]). Of the available treatment options, only monoclonal antibodies seemed to be effective at reducing mortality from 32% to 0% (P = .036). We conclude that survival rates of CAR T-cell recipients with COVID-19 improved over time and that the combination of prior vaccination and monoclonal antibody treatment significantly reduces their risk of death. This trial was registered at www.clinicaltrials.gov as #NCT04733729.

Outcomes of SARS-CoV-2 infection in Ph-neg chronic myeloproliferative neoplasms: results from the EPICOVIDEHA registry.

Background: Patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPN) typically incur high rates of infections and both drugs and comorbidities may modulate infection risk. Objectives: The present study aims to assess the effect of immunosuppressive agents on clinical outcomes of MPN patients affected by the coronavirus disease 2019 (COVID-19). Design: This is an observational study. Methods: We specifically searched and analyzed MPN patients collected by EPICOVIDEHA online registry, which includes individuals with hematological malignancies diagnosed with COVID-19 since February 2020. Results: Overall, 398 patients with MPN were observed for a median of 76 days [interquartile range (IQR): 19-197] after detection of SARS-CoV2 infection. Median age was 69 years (IQR: 58-77) and 183 individuals (46%) had myelofibrosis (MF). Overall, 121 patients (30%) of the whole cohort received immunosuppressive therapies including steroids, immunomodulatory drugs, or JAK inhibitors. Hospitalization and consecutive admission to intensive care unit was required in 216 (54%) and 53 patients (13%), respectively. Risk factors for hospital admission were identified by multivariable logistic regression and include exposure to immunosuppressive therapies [odds ratio (OR): 2.186; 95% confidence interval (CI): 1.357-3.519], age ⩾70 years, and comorbidities. The fatality rate was 22% overall and the risk of death was independently increased by age ⩾70 years [hazard ratio (HR): 2.191; 95% CI: 1.363-3.521], previous comorbidities, and exposure to immunosuppressive therapies before the infection (HR: 2.143; 95% CI: 1.363-3.521). Conclusion: COVID-19 infection led to a particularly dismal outcome in MPN patients receiving immunosuppressive agents or reporting multiple comorbidities. Therefore, specific preventive strategies need to be tailored for such individuals. Plain language summary: EPICOVIDEHA registry reports inferior outcomes of COVID-19 in patients with Philadelphia-negative chronic myeloproliferative neoplasms receiving immunosuppressive therapies. Patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPN) incur high rates of infections during the course of their disease.The present study was aimed at assessing which patient characteristics predicted a worse outcome of SARS-COV-2 infection in individuals with MPN.To pursue this objective, the researchers analyzed the data collected by EPICOVIDEHA, an international online registry, which includes individuals with hematological malignancies diagnosed with COVID-19 since February 2020.The database provided clinical data of 398 patients with MPN incurring COVID-19:Patients were mostly elderly (median age was 69 years);Forty-six percent of them were affected by myelofibrosis, which is the most severe MPN;Moreover, 32% were receiving immunosuppressive therapies (JAK inhibitors, such as ruxolitinib, steroids, or immunomodulatory IMID drugs, such as thalidomide) before COVID-19.Hospitalization was required in 54% of the patients, and the risk of being hospitalized for severe COVID-19 was independently predicted byOlder age;Comorbidities;Exposure to immunosuppressive therapies.Overall, 22% of MPN patients deceased soon after COVID-19 and the risk of death was independently increased over twofold byOlder age;Comorbidities;Exposure to immunosuppressive therapies before the infection.In conclusion, COVID-19 infection led to a particularly dismal outcome in MPN patients receiving immunosuppressive agents, including JAK inhibitors, or reporting multiple comorbidities. Therefore, specific preventive strategies need to be tailored for such individuals.

B-cell malignancies treated with targeted drugs and SARS-CoV-2 infection: A European Hematology Association Survey (EPICOVIDEHA).

Patients with lymphoproliferative diseases (LPD) are vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we describe and analyze the outcome of 366 adult patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin Lymphoma (NHL) treated with targeted drugs and laboratory-confirmed COVID-19 diagnosed between February 2020 and January 2022. Median follow-up was 70.5 days (IQR 0-609). Most used targeted drugs were Bruton-kinase inhibitors (BKIs) (N= 201, 55%), anti-CD20 other than rituximab (N=61, 16%), BCL2 inhibitors (N=33, 9%) and lenalidomide (N=28, 8%).Only 16.2% of the patients were vaccinated with 2 or more doses of vaccine at the onset of COVID-19. Mortality was 24% (89/366) on day 30 and 36%(134/366) on the last day of follow-up. Age >75 years (p<0.001, HR 1.036), active malignancy (p<0.001, HR 2.215), severe COVID-19 (p=0.017, HR 2.270) and admission to ICU (p<0.001, HR 5.751) were risk factors for mortality at last day of follow up. There was no difference in OS rates in NHL vs CLL patients (p=0.306), nor in patients treated with or without BKIs (p=0.151). Mortality in ICU was 66% (CLL 61%, NHL 76%). Overall mortality rate decreased according to vaccination status, being 39% in unvaccinated patients, 32% and 26% in those having received one or two doses, respectively, and 20% in patients with a booster dose (p=0.245). Overall mortality rate dropped from 41% during the first semester of 2020 to 25% at the last semester of 2021. These results show increased severity and mortality from COVID-19 in LPDs patients treated with targeted drugs.

Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial.

BACKGROUND: Patients with immunocompromised disorders have mainly been excluded from clinical trials of vaccination against COVID-19. Thus, the aim of this prospective clinical trial was to investigate safety and efficacy of BNT162b2 mRNA vaccination in five selected groups of immunocompromised patients and healthy controls. METHODS: 539 study subjects (449 patients and 90 controls) were included. The patients had either primary (n=90), or secondary immunodeficiency disorders due to human immunodeficiency virus infection (n=90), allogeneic hematopoietic stem cell transplantation/CAR T cell therapy (n=90), solid organ transplantation (SOT) (n=89), or chronic lymphocytic leukemia (CLL) (n=90). The primary endpoint was seroconversion rate two weeks after the second dose. The secondary endpoints were safety and documented SARS-CoV-2 infection. FINDINGS: Adverse events were generally mild, but one case of fatal suspected unexpected serious adverse reaction occurred. 72.2% of the immunocompromised patients seroconverted compared to 100% of the controls (p=0.004). Lowest seroconversion rates were found in the SOT (43.4%) and CLL (63.3%) patient groups with observed negative impact of treatment with mycophenolate mofetil and ibrutinib, respectively. INTERPRETATION: The results showed that the mRNA BNT162b2 vaccine was safe in immunocompromised patients. Rate of seroconversion was substantially lower than in healthy controls, with a wide range of rates and antibody titres among predefined patient groups and subgroups. This clinical trial highlights the need for additional vaccine doses in certain immunocompromised patient groups to improve immunity. FUNDING: Knut and Alice Wallenberg Foundation, the Swedish Research Council, Nordstjernan AB, Region Stockholm, Karolinska Institutet, and organizations for PID/CLL-patients in Sweden.

Immune modulation to prevent antibody-mediated rejection after allogeneic hematopoietic stem cell transplantation.

It has been shown that antibodies to donor CD34+/VEGFR-2+ stem cells or antibodies against mismatched HLA are associated with graft rejection after hematopoietic stem cell transplantation (HSCT). CD34/VEGFR-2 positive stem cells have been implicated to play a major role in engraftment after HSCT. In this study we treated four patients with an imminent risk of antibody-mediated rejection with immune modulation, i.e. plasma exchange, intravenous immunoglobulin (IVIG), and rituximab before HSCT. Three of the patients had been previously transplanted and rejected their initial grafts after 12 months, 1 month, and less than 1 month, respectively. The fourth patient was not transplanted previously but had HLA directed antibodies present against the graft. During the immune modulatory treatment we followed the pattern of antibodies in sera using FACS and microcytotoxicity assay. We could show that two patients had antibodies against donor CD34+/VEGFR-2+ cells while the other two had antibodies directed against HLA. All four patients tolerated the immune modulatory regimen without any side effects. In this preliminary study we show that immune modulatory treatment may be used to reduce antibody levels and to prevent rejection after HSCT. In two of the three patients which experienced previous rejections and had detectable anti-HLA or anti-CD34+/VEGFR-2+ antibodies, immune modulation resulted in engraftment. In the fourth patient with known anti-HLA-class I antibodies, the treatment also resulted in engraftment. Our results encourage further studies regarding this treatment regimen.

Novel antibodies to the donor stem cell population CD34+/VEGFR-2+ are associated with rejection after hematopoietic stem cell transplantation.

BACKGROUND: Reconstitution of hematopoiesis after hematopoietic stem cell transplantation (HSCT) occurs through a reservoir of donor CD34+ HSC. CD34+/VEGFR-2+ is a primitive, quiescent subpopulation of HSC known to generate hematopoietic or endothelial progeny in vitro and in vivo. We hypothesized that donor-specific antibodies to the CD34+/VEGFR-2+ stem cells may be associated with rejection after HSCT. METHODS: We studied 30 patients without and 11 with rejections after HSCT and 20 nontransplanted healthy individuals. Ninety-three sera taken pre and posttransplantation from patients receiving HSCT were studied for the presence of donor CD34+/VEGFR-2+ cell-specific antibodies. RESULTS: We provide evidence that significantly higher numbers of patients with rejections 9/11 (81%), whereas 1/30 (3%) (P=0.001) without rejections had antibodies against donor CD34+/VEGFR-2+ cells, but not CD34-/VEGFR-2- cells. In eight transplantations, antibodies against donor CD34+/VEGFR-2+ cells were detected already before transplantation. Purified IgG fractions from patients with rejections but not controls significantly decreased the ability of these cells to form hematopoietic and endothelial colonies. In multivariate analysis, antibodies against CD34+/VEGFR-2+ cells proved to be the most significant risk factor for rejection. CONCLUSIONS: These novel findings document a high rate of rejections in patients with donor-specific antibodies to CD34+/VEGFR-2+ HSC. These antibodies may significantly and commonly contribute to HSCT rejections.

The TNFd4 allele is correlated to moderate-to-severe acute graft-versus-host disease after allogeneic stem cell transplantation.

Certain cytokine gene polymorphisms may be associated with severe acute graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. The present study analysed 196 patients and their donors for TNF-308, TNFd, IL-10-1064 and IL-10-1082 gene polymorphisms. Serum analysis of tumour necrosis factor-alpha (TNF-alpha) and interleukin 10 (IL-10) levels during conditioning therapy was also performed. Among patients with sibling donors, the TNFd allele 4 was significantly correlated with acute GVHD grades II-IV (P < 0.01). Acute GVHD grades II-IV were more common among patients homozygous for the IL-10-1064 allele 13 (P = 0.02). Patients homozygous for the TNF-308 allele (AA) correlated with higher TNF-alpha serum levels during conditioning (P = 0.02).

Graft-versus-host disease is associated with a lower relapse incidence after hematopoietic stem cell transplantation in patients with acute lymphoblastic leukemia.

To determine the graft-versus-leukemia effect after hematopoietic stem cell transplantation (HSCT), we studied 199 patients with acute lymphoblastic leukemia who underwent transplantation at Huddinge University Hospital between 1981 and 2001. Seventy-four patients were in first complete remission (CR1), and 125 were in later stages of the disease. Most patients had an HLA-identical sibling donor. Conditioning consisted mainly of total body irradiation and cyclophosphamide, and graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. Acute GVHD developed in 143 patients and chronic GVHD in 67. The 5-year probability of relapse and relapse-free survival (RFS) were 32% and 49%, respectively, in patients in CR1, as compared with 53% and 33% in those with more advanced disease. In the multivariate risk factor analysis of relapse, we found that the absence of chronic GVHD (P<.001), absence of herpes simplex virus infection after HSCT (P=.003), combination prophylaxis with methotrexate and cyclosporine (P=.01), and >6 weeks from the diagnosis to CR (P=.025) were independent risk factors for relapse after HSCT. Factors associated with a better relapse-free survival were chronic GVHD (P<.001), ABO blood group mismatch (P=.006), younger patient age (P=.01), and an HLA-matched donor (P=.01). The association between herpes simplex virus infection and a low frequency of relapse is a new observation and may indicate that viral antigens play a role in the induction of an antileukemic effect.