Work Disability and Return to Work After Treatment for Acute Lymphoblastic Leukemia: A Danish Nationwide Cohort Study.

Purpose: Most adult patients diagnosed with acute lymphoblastic leukemia (ALL) are below retirement age. The overall survival of patients with ALL has improved with implementation of high intensity pediatric-inspired treatment protocols. However, this treatment comes with a risk of long-term complications, which could affect the ability to work. The aim of this study was to investigate the risk of disability pension (DP) and return to work (RTW) for patients with ALL. Patients and Methods: Patients aged 18-60 years diagnosed with ALL between 2005 and 2019 were identified in the Danish National Acute Leukemia Registry. Each patient was matched with five comparators from the general population on birth year, sex, and Charlson Comorbidity Index. The Aalen-Johansen estimator was used to calculate the cumulative risk of DP for patients and comparators from index date (defined as 1 year after diagnosis) with competing events (transplantation or relapse, death, retirement pension, or early retirement pension). Differences in cumulative incidences were calculated using Gray's test. RTW was calculated as proportions one, three, and five years after the index date for patients holding a job before diagnosis. Results: A total of 154 patients with ALL and 770 matched comparators were included. The 5-year cumulative risk of DP was increased fivefold for patients with ALL compared with the general population. RTW was 41.7%, 65.7%, and 60.7% one, three, and five years after the index date, respectively. Conclusion: The risk of DP in patients with ALL increased significantly compared with the general population. Five years after the index date, RTW was 60.7% for patients with ALL.

Successful use of interferon alfa-2a for persistent parvovirus B19 infection.

Human infection with parvovirus B19 causes a range of clinical manifestations, including benign erythema infectiosum in children, arthralgias in adults, aplastic crisis in patients with bone marrow failure, and potentially fatal congenital hydrops fetalis. Persistent parvovirus B19 infection is a rare disease presentation mostly seen in adult women or immunocompromised individuals. Treatment options include corticosteroids and intravenous immunoglobulin; however, viral clearance is difficult to obtain and rarely maintained. In this Grand Round, we report the case of a 43-year-old man with persistent parvovirus B19 infection and anaemia, who was refractory to standard treatment regimens, and whom we successfully treated with pegylated interferon alfa-2a. Initial treatment led to viral clearance and remission of anaemia, although secondary recurrence of virus required treatment extension. Despite extensive genetic and immunological evaluations, no underlying primary or secondary immunodeficiency was identified in the patient. We propose interferon alfa-2a as a treatment option for persistent parvovirus B19 infection and advocate long-term follow-up of patients and potentially repeated treatment.

A survey on thromboprophylaxis and coagulation assessment in children and young adults with acute lymphoblastic leukaemia (ALL) in the Nordic and Baltic countries: Different practices of assessment and management.

Patients undergoing treatment for acute lymphoblastic leukaemia (ALL) are at risk of coagulopathy, especially thromboembolism. We conducted a survey on practices in the assessment and management of coagulopathy during the new ALLTogether protocol in 29 (17 paediatric, 12 adult) Nordic and Baltic cancer centres. While 92% of adult centres used thromboprophylaxis with low-molecular-weight heparin, no paediatric centre did. Almost all providers performed baseline coagulation studies, but only 59% continued the assessment. Fibrinogen replacement was conducted in 59%, and antithrombin replacement in 28% of the centres. The survey highlights the need for guidelines in the management of coagulopathy during ALL therapy.

Salvage Therapy in Early Relapse of T-Lymphoblastic Leukemia/Lymphoma Using Daratumumab/Nelarabine Combination: Two Consecutive Cases.

Treatment of early relapses of T lymphoblastic leukemia/lymphoma is often unsuccessful. We tested an experimental regimen containing daratumumab and nelarabine in two young patients with early relapses of T lymphoblastic lymphoma and T-ALL, respectively. Both patients achieved a deep complete remission. Combining daratumumab with chemotherapy may have a role in relapsing T lymphoblastic leukemia/lymphoma.

SARS-CoV-2 infection among patients with haematological disorders: Severity and one-month outcome in 66 Danish patients in a nationwide cohort study.

OBJECTIVES: Patients with haematological disorders may be particularly vulnerable to respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, this is unknown. METHODS: We conducted a prospective, nationwide study including 66 patients in follow-up at Danish haematology departments with a malignant or non-malignant haematological disorder and with verified SARS-CoV-2 infection. Outcomes were intensive care unit (ICU) admission and one-month survival rate. RESULTS: Mean age was 66.7 years, 60.6% were males, 90.9% had comorbidity, and 13.6% had a BMI ≥ 30. The most frequent diagnoses were chronic lymphocytic leukaemia/lymphoma (47.0%), multiple myeloma (16.7%) and acute leukaemia/myelodysplastic syndrome (AL/MDS) (12.1%). Treatment for the haematological disease was ongoing in 59.1% of cases. Neutropenia was present in 6.5%, lymphopenia in 46.6% and hypogammaglobulinaemia in 26.3%. The SARS-CoV-2 infection was mild in 50.0%, severe in 36.4% and critical in 13.6%. After one month, 21.2% had been admitted to ICU, and 24.2% died. Mortality was highest in older patients, patients with severe/critical SARS-CoV-2 infection, high comorbidity score or high performance status score, purine analogue treatment and with AL/MDS. Although older patients and patients with comorbidities had the highest mortality rates, mortality was considerable among all haematological patients. CONCLUSION: Haematological patients with SARS-CoV-2 infection has a severe clinical course.

Addressing the room for improvement in management of acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is highly curable. To achieve high cure rates, targeted therapy with retinoic acid (ATRA) must be started promptly at time of suspected diagnosis. Early death rates (EDRs, ≤30 days from diagnosis) differ markedly in patients treated on clinical trials compared to the general population. OBJECTIVES AND METHODS: We used the comprehensive Danish National Acute Leukemia Registry (DNLR) to investigate the incidence, treatment, EDR, and long-term clinical outcome in APL between 2000 and 2014. RESULTS: Twenty-two of 41 deaths occurring in 122 APL patients were EDs which were primarily caused by intracranial hemorrhage, disseminated intravascular coagulation (DIC), sepsis, and multiorgan failure. The overall EDR was 18.0%, whereas clinical trial participants had an EDR of 6.7%. Fifteen patients recruited to the NCRI AML17 APL trial from 2010 to 2013 were younger and had decreased mortality (HR 0.18, CI 0.04-0.86, P = 0.02) compared to contemporarily treated patients (n = 15) not recruited to a clinical trial. Performance status, leukemia origin, and Sanz-score were independent prognostic variables. CONCLUSIONS: The very low EDR for on-trial patients is not observed in the general cohort of APL patients. Diagnostic awareness emerges as the greatest clinical challenge in management of APL.

Stringent or nonstringent complete remission and prognosis in acute myeloid leukemia: a Danish population-based study.

Stringent complete remission (sCR) of acute myeloid leukemia is defined as normal hematopoiesis after therapy. Less sCR, including non-sCR, was introduced as insufficient blood platelet, neutrophil, or erythrocyte recovery. These latter characteristics were defined retrospectively as postremission transfusion dependency and were suggested to be of prognostic value. In the present report, we evaluated the prognostic impact of achieving sCR and non-sCR in the Danish National Acute Leukaemia Registry, including 769 patients registered with classical CR (ie, <5% blasts in the postinduction bone marrow analysis). Individual patients were classified as having sCR (n = 360; 46.8%) or non-sCR (n = 409; 53.2%) based on data from our national laboratory and transfusion databases. Survival analysis revealed that patients achieving sCR had superior overall survival (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.10-1.64) as well as relapse-free survival (HR, 1.25; 95% CI, 1.03-1.51) compared with those with non-sCR after adjusting for covariates. Cox regression analysis regarding the impact of the stringent criteria for blood cell recovery identified these as significant and independent variables. In conclusion, this real-life register study supports the international criteria for response evaluation on prognosis and, most importantly, documents each of the 3 lineage recovery criteria as contributing independently.

Serologic response to a 23-valent pneumococcal vaccine administered prior to autologous stem cell transplantation in patients with multiple myeloma.

Patients with multiple myeloma are known to have an increased risk of infections with Streptococcus pneumoniae and vaccination is recommended. We retrospectively investigated the response of a 23-valent polysaccharide-based pneumococcal vaccine in 60 patients with multiple myeloma administered prior to autologous stem cell transplantation (ASCT). Specific antibody titers were measured before and after vaccination. Disease stage was evaluated and associated to the response. We found that 33% of the patients responded to the vaccine. There was a statistic significant association between response to the vaccine and disease stage (p = 0.01). We conclude that vaccination against S. pneumoniae prior to ASCT is reasonable at least in patients responding well to induction therapy, but still it is important to be aware that the response is frequently poor and the duration of it is unknown.

Sepsis in acute myeloid leukaemia patients receiving high-dose chemotherapy: no impact of chitotriosidase and mannose-binding lectin polymorphisms.

Infections after chemotherapy often cause significant morbidity in patients with acute myeloid leukaemia (AML). Chitotriosidase (CHIT) and mannose-binding lectin (MBL) are part of the innate immune system. Polymorphism in the CHIT-coding gene (CHIT1) may be associated with Gram-negative sepsis in children with AML, and polymorphism in the MBL-coding gene (MBL2) seems to modify the risk of infections in several patient groups. The purpose of this study was to investigate the possible associations between polymorphisms in CHIT1, MBL2 and sepsis in adult patients treated with high-dose chemotherapy for AML. We included 190 patients treated with 526 cycles of chemotherapy. The follow-up period was 6 months from the diagnosis of AML. Prophylactic antibiotics were not used. We identified 604 febrile episodes with 246 episodes of sepsis. Thirty-two patients (17%) either died from infection or infection was a major concomitant factor for death. No significant associations between CHIT1 polymorphism and sepsis (P = 0.85) or death caused by sepsis (P = 0.14) were found. Furthermore, no significant associations between MBL2 polymorphism and sepsis (P = 0.76) or death caused by sepsis (P = 0.24) were observed. The severe and long-lasting neutropenia and mucositis after chemotherapy may explain why the MBL system does not protect against sepsis in patients with AML. Replacement therapy with recombinant MBL is not likely to decrease the risk of sepsis in patients with AML.

Infectious complications after chemotherapy and stem cell transplantation in multiple myeloma: implications of Fc gamma receptor and myeloperoxidase promoter polymorphisms.

Multiple myeloma is associated with a high risk of infections. We hypothesized that Fc gamma receptor (FCGR) and myeloperoxidase (MPO) promoter gene polymorphisms influence the risk of infections after induction chemotherapy (IC) and autologous stem cell transplantation (ASCT). Retrospectively, we analysed 136 patient courses of IC and 113 procedures of ASCT. Genetic analyses were made with PCR techniques on genomic DNA. The incidence rate ratio of sepsis during ASCT in patients homozygous for the G-129MPO promoter type was 0.30 (95% CI: 0.09-0.96). The G-463AMPO promoter polymorphism was not associated with the risk of infections. The polymorphisms of FCGR2A, FCGR3A and FCGR3B were not convincingly associated with infections. The NA1 variant of FCGR3B was strongly skewed with other risk factors, and the results in IC and ASCT were conflicting. Further studies of the G-129AMPO promoter as a potential risk modifier for infections are relevant.

Rapid single-step methods for detection of two immune defence gene polymorphisms: the myeloperoxidase (MPO) G-129A and the Fc gamma receptor 2A (FCGR2A) H/R131.

Polymorphisms of immune defence genes may act as disease modifiers and are studied by many researchers. A conclusive analysis of the impact of genetic variations typically requires a large number of sample specimens, and in retrospective studies this may include samples of reduced quality, e.g. formalin-fixed paraffin-embedded tissue specimens. Here we describe two new single-step methods for rapid and sensitive analysis of: 1. The G-129A myeloperoxidase (MPO) promoter polymorphism, which affects the amount of myeloperoxidase in neutrophils. 2. The Fc gamma receptor 2A (FCGR2A)-H/R131 polymorphism, which is critical to the binding of IgG2 immune complexes to phagocytes.

Chemotherapy-related infections in patients with multiple myeloma: associations with mannan-binding lectin genotypes.

OBJECTIVES: To study a possible association between mannan-binding lectin genotypes and severe infections in patients with multiple myeloma receiving moderate strength induction chemotherapy. METHODS: Chemotherapy-related infections were identified retrospectively using clinical records and database files. Mannan-binding lectin genotypes were identified with polymerase chain reaction on stored samples of stem cells or formalin-fixed paraffin-embedded bone marrow biopsies. RESULTS: We included 138 myeloma patients. In five patients, data were incomplete, and 133 patients were analysed. Eighty-eight patients were homozygous for wild-type MBL2 (AA) and forty-five patients were heterozygous or homozygous for variant genotypes (AO/OO). A total of 390 chemotherapy cycles were reviewed. Common Toxicity Criteria grades 3 and 4 infections in general were seen in relation to 104 cycles and were not more common in patient with variant MBL2 (P = 0.90). Septicaemia was seen after 10% of chemotherapy cycles in AA patients vs. 15% in AO/OO patients (P = 0.15). In multi-variate analyses, we found indication of a reduced risk of septicaemia in AA patients [OR 0.27 (0.08-0.90), P = 0.03], after first chemotherapy cycle, but reduction of the risk including all cycles was not significant. A similar trend was seen for grades 3 and 4 infections in general. CONCLUSIONS: During induction chemotherapy in patients with multiple myeloma, a general protective effect of wild-type MBL2 against chemotherapy-related infections was not apparent in this study. However, we found indications of a reduced occurrence of septicaemia in patients with wild-type compared with variant MBL2. Further studies in larger cohorts of patients are relevant.