Haematopoietic stem cell transplantation for treatment of relapsing-remitting multiple sclerosis in Sweden: an observational cohort study.

BACKGROUND: A growing evidence base supports the use of autologous haematopoietic stem cell transplantation (aHSCT) for treatment of relapsing-remitting multiple sclerosis (RRMS), but it has not yet been integrated into most national clinical guidelines. The objective of this study was to assess efficacy and safety when aHSCT is implemented in routine healthcare. METHODS: We assessed 231 patients and the final analysis included 174 RRMS patients who were treated with aHSCT in Sweden before 1 January 2020. Efficacy was evaluated by performing a retrospective analysis of prospectively collected data from the Swedish MS registry. Procedure-related safety was assessed by analysing data from electronic patient records covering a period of 100 days following aHSCT. RESULTS: With a median follow-up time of 5.5 (IQR: 3.4-7.5) years, the Kaplan-Meier estimate for no evidence of disease activity was 73% (95% CI 66% to 81%) at 5 years and 65% (95% CI 57% to 75%) at 10 years. Out of the 149 patients with baseline disability, 80 (54%) improved, 55 (37%) were stable and 14 (9%) deteriorated. The mean number of adverse events per patient was 1.7 (±SD: 1.5) for grade 3 events and 0.06 (±SD: 0.3) for grade 4 events. Febrile neutropenia was the most common adverse event, affecting 68% of patients. There was no treatment-related mortality. CONCLUSIONS: Treatment with aHSCT for RRMS is associated with freedom from disease activity in a majority of patients, with acceptable adverse events. This procedure should be considered a standard of care for patients with highly active RRMS.

Presence of MDSC associates with impaired antigen-specific T cell reactivity following COVID-19 vaccination in cirrhotic patients.

Background and aims: Cirrhosis entails high risk of serious infections and abated efficiency of vaccination, but the underlying mechanisms are only partially understood. This study aimed at characterizing innate and adaptive immune functions, including antigen-specific T cell responses to COVID-19 vaccination, in patients with compensated and decompensated cirrhosis. Methods: Immune phenotype and function in peripheral blood from 42 cirrhotic patients and 44 age-matched healthy controls were analysed after two doses of the mRNA-based COVID-19 vaccines [BNT162b2 (Pfizer BioNTech) or mRNA-1273 (Moderna)]. Results: Cirrhotic patients showed significantly reduced blood counts of antigen-presenting dendritic cells (DC) and high counts of monocytic myeloid-derived suppressor cells (M-MDSC) as compared to healthy controls. In addition, monocytic cells recovered from cirrhotic patients showed impaired expression of the antigen-presenting molecule HLA-DR and the co-stimulatory molecule CD86 upon Toll-like receptor (TLR) stimulation. These features were more prominent in patients with decompensated cirrhosis (Child-Pugh classes B & C). Interestingly, while patients with compensated cirrhosis (Child-Pugh class A) showed an inflammatory profile with myeloid cells producing the proinflammatory cytokines IL-6 and TNF, decompensated patients produced reduced levels of these cytokines. Cirrhotic patients, in particular those with more advanced end-stage liver disease, mounted reduced antigen-specific T cell reactivity to COVID-19 vaccination. Vaccine efficiency inversely correlated with levels of M-MDSC. Conclusion: These results implicate MDSC as mediators of immunosuppression, with ensuing deficiency of vaccine-specific T cell responses, in cirrhosis.

[Thrombotic thrombocytopenic purpura - a rare diagnosis]. / En sällsynt diagnos: trombotisk trombocytopen purpura (TTP).

Thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening thrombotic microangiopathy (TMA) characterized by a microangiopathic hemolytic anemia and severe thrombocytopenia, due to platelet consumption. Microthrombi form in small vessels, leading to organ ischemia, most commonly in the central nervous system (CNS). The pathophysiology of TTP is related to a deficiency of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), an enzyme that cleaves the von Willebrand multimer. In the absence of ADAMTS13, the von Willebrand multimer is unfolded into an elongated active form that causes platelet activation and aggregation in arterioles and capillaries. Acquired TTP is caused by autoantibodies against ADAMTS13.  The hemolytic anemia is typically DAT-negative and caused by shattering of erythrocytes when passing the microthrombi. Rapid recognition is crucial for the outcome and to initiate the appropriate treatment. It may take several days to get the test results for ADAMTS13 and when there is a high clinical probability for TTP, plasmapheresis must be initiated pending test results. PLASMIC score can be used in determining the probability of low ADAMTS13 in a hospitalized patient with thrombocytopenia and hemolysis to identify the patients that could benefit from early TTP-specific treatment.  First line treatment for acute TTP includes daily plasma exchange, steroids and rituximab. Caplacizumab is an anti-von-Willebrand factor-directed antibody fragment that targets the A1 domain of the von Willebrand factor, thereby inhibiting the interaction between von Willebrand factor multimers and platelets. The treatment has been shown to have beneficial effects when added to standard treatment, without having immunosuppressive effects.

Catch-up antibody responses and hybrid immunity in mRNA vaccinated patients at risk of severe COVID-19.

BACKGROUND: The immunogenicity of repeated vaccination and hybrid immunity in vulnerable patients remains unclear. METHODS: We studied the impact of iterative Covid-19 mRNA vaccination and hybrid immunity on antibody levels in immunosuppressed subjects. Patients with liver cirrhosis (n = 38), survivors of allogeneic haematopoietic stem cell transplantation (allo-HSCT) (n = 36) and patients with autoimmune liver disease (n = 14) along with healthy controls (n = 20) were monitored for SARS-CoV-2-S1 IgG after their 1st-3rd vaccine doses, 31 of whom became infected with the Omicron variant after the 2nd dose. Ten uninfected allo-HSCT recipients received an additional 4th vaccine dose. RESULTS: Unexpectedly, immunosuppressed patients achieved antibody levels in parity with controls after the 3rd vaccine dose. In all study cohorts, hybrid immunity (effect of vaccination and natural infection) resulted in approximately 10-fold higher antibody levels than vaccine-induced immunity alone. CONCLUSIONS: Three doses of the Covid-19 mRNA vaccine entailed high antibody concentrations even in immunocompromised individuals, and hybrid-immunity resulted further augmented levels than vaccination alone. Clinical trial registration: EudraCT 2021-000349-42.

Long-Term Immunity Against Tetanus and Diphtheria after Vaccination of Allogeneic Stem Cell Transplantation Recipients.

Revaccination against tetanus and diphtheria after allogeneic hematopoietic stem cell transplantation (HCT) is usually effective, but the duration of the immunity is unknown. We conducted this study to evaluate humoral immunity to tetanus and diphtheria in long-term survivors and to provide knowledge regarding the need for boosters. The median time from HCT to blood sampling was 14 years (range, 8 to 40 years). All patients had received at least 3 doses of vaccines against both tetanus and diphtheria, either monovalent or combination vaccines containing a full dose of the diphtheria toxoid component. In addition, 1 or more booster doses were administered to 21 of the 146 patients (14%). On enzyme-linked immunosorbent assay, levels <.1 IU/mL for diphtheria and <.01 IU/mL for tetanus were considered low or seronegative. Values between .01 and .5 IU/mL for tetanus and between .1 and 1.0 IU/mL for diphtheria were considered to represent partial protection, and levels >.5 and >1.0 IU/mL were considered high and protective, respectively. In all, 39% of patients were seronegative against diphtheria, 52% had some protection, and 9% had a high titer. In contrast, no patient had become seronegative to tetanus, 32% had "partial protection" against tetanus and 68% had a high titer. In multivariate analysis, active graft-versus-host-disease, sex, or time from sampling did not affect the probability of becoming seronegative or seropositive. Younger age was associated with lower antibody levels to tetanus toxoid, but age was not correlated with antibody levels against diphtheria toxoid. Tetanus immunity was maintained after vaccination in most long-term survivors, but immunity against diphtheria was poor, and boosters should be considered.

[Cohort study on the experiences of cancer diagnosis and treatment in Iceland in the year 2015-2019].

INTRODUCTION: In the coming years, an increase in the number of cancer cases can be expected in Iceland. It is important to gain more insight into the experiences of the diagnostic- and treatment phase among those diagnosed with cancer to improve quality of life and life expectancy. METHODS: The study included 4575 individuals diagnosed with cancer between 2015 and 2019 in Iceland, 18 years or older at the time. Participants answered an on-line questionnaire once between 2020 and 2021. RESULTS: A total of 1672 (37%) individuals responded to the questionnaire. The mean age at diagnosis was 59 years (±12). The majority of participants were informed on their cancer diagnosis during a doctor's appointment (67%), but a quarter (25%) received the information by telephone. A total of 77% of participants were satisfied with the diagnostic process, thereof relatively fewer women than men (73% vs. 83%) (p<0,001). Fewer of those who received the cancer diagnosis by telephone were pleased with the diagnostic process (62%) compared with those receiving information during a doctor's appointment (85%) (p<0,001). More women (58%) than men (33%) expressed the need for support regarding mental well-being from healthcare professionals during the diagnostic process (p<0.001). In 2015, 36% of participants started treatment more than month after diagnosis, compared with 51% in 2019. The need for various specific resources during treatment, e.g. physiotherapy, psychological services or nutritional counseling were regularly assessed among 20-30% of participants. CONCLUSION: A quarter of respondents diagnosed with cancer received information about the diagnosis over the phone instead of an interview. There is a suggestion that the time from diagnosis to the start of cancer treatment is increasing. It is necessary to assess whether it is possible to support individuals with cancer better during the diagnostic- and treatment phase based on their individual needs.

Impaired SARS-CoV-2-specific T-cell reactivity in patients with cirrhosis following mRNA COVID-19 vaccination.

Background & Aims: Cirrhosis entails elevated risk of COVID-19-associated mortality. This study determined T cell-mediated and antibody reactivity against the spike 1 (S1) protein of SARS-CoV-2 among 48 patients with cirrhosis and 39 healthy controls after mRNA COVID-19 vaccination. Methods: SARS-CoV-2-specific T-cell reactivity was measured by induced level of T cell-derived interferon-γ (IFN-γ) in blood cells stimulated ex vivo with multimeric peptides spanning the N-terminal portion of S1. S1-induced IFN-γ was quantified before and after the 1st and 2nd vaccination (BNT162b2, Pfizer-BioNTech or mRNA-1273, Moderna) alongside serum IgG against the receptor-binding domain (RBD) within S1 (anti-RBD-S1 IgG). Results: T-cell reactivity against S1 was reduced in patients with cirrhosis after the 1st (p <0.001 vs. controls) and 2nd (p <0.001) vaccination. Sixty-eight percent of patients lacked detectable S1-specific T-cell reactivity after the 1st vaccination vs. 19% in controls (odds ratio 0.11, 95% CI 0.03-0.48, p = 0.003) and 36% remained devoid of reactivity after the 2nd vaccination vs. 6% in controls (odds ratio 0.12, 95% CI 0.03-0.59, p = 0.009). T-cell reactivity in cirrhosis remained significantly impaired after correction for potential confounders in multivariable analysis. Advanced cirrhosis (Child-Pugh class B) was associated with absent or lower T-cell responses (p <0.05 vs. Child-Pugh class A). The deficiency of T-cell reactivity was paralleled by lower levels of anti-RBD-S1 IgG after the 1st (p <0.001 vs. controls) and 2nd (p <0.05) vaccination. Conclusions: Patients with cirrhosis show deficient T-cell reactivity against SARS-CoV-2 antigens along with diminished levels of anti-RBD-S1 IgG after dual COVID-19 vaccination, highlighting the need for vigilance and additional preventative measures. Clinical trial registration: EudraCT 2021-000349-42. Lay summary: T cells are a pivotal component in the defence against viruses. We show that patients with cirrhosis have impaired SARS-CoV-2-specific T-cell responses and lower antibody levels after mRNA vaccination against COVID-19 compared with healthy controls. Patients with more advanced liver disease exhibited particularly inferior vaccine responses. These results call for additional preventative measures in these patients.

Deficiency of SARS-CoV-2 T-cell responses after vaccination in long-term allo-HSCT survivors translates into abated humoral immunity.

Recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematological diseases are at risk of severe disease and death from COVID-19. To determine the safety and immunogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines, samples from 50 infection-naive allo-HSCT recipients (median, 92 months from transplantation, range, 7-340 months) and 39 healthy controls were analyzed for serum immunoglobulin G (IgG) against the receptor binding domain (RBD) within spike 1 (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; anti-RBD-S1 IgG) and for SARS-CoV-2-specific T-cell immunity, reflected by induction of T-cell-derived interferon-γ in whole blood stimulated ex vivo with 15-mer SI-spanning peptides with 11 amino acid overlap S1-spanning peptides. The rate of seroconversion was not significantly lower in allo-transplanted patients than in controls with 24% (12/50) and 6% (3/50) of patients remaining seronegative after the first and second vaccination, respectively. However, 58% of transplanted patients lacked T-cell responses against S1 peptides after 1 vaccination compared with 19% of controls (odds ratio [OR] 0.17; P = .009, Fisher's exact test) with a similar trend after the second vaccination where 28% of patients were devoid of detectable specific T-cell immunity, compared with 6% of controls (OR 0.18; P = .02, Fisher's exact test). Importantly, lack of T-cell reactivity to S1 peptides after vaccination heralded substandard levels (<100 BAU/mL) of anti-RBD-S1 IgG 5 to 6 months after the second vaccine dose (OR 8.2; P = .007, Fisher's exact test). We conclude that although allo-HSCT recipients achieve serum anti-RBD-S1 IgG against SARS-CoV-2 after 2 vaccinations, a deficiency of SARS-CoV-2-specific T-cell immunity may subsequently translate into insufficient humoral responses.

Vaccination against tick-borne encephalitis (TBE) after autologous and allogeneic stem cell transplantation.

INTRODUCTION: Our aim was to assess response and side effects of 4 doses of TBE vaccine to patients (pts) after allo- and autologous stem cell transplantation (SCT). PATIENTS: Included were 104 pts with leukaemia, myeloma and lymphoma, median age 61 yrs. METHODS: Vaccine (FSME-Immun®) was given at 9, 10, 12, and 21 months post-transplant. Serum samples were obtained before and after vaccinations. Healthy controls (n = 27) received 3 vaccinations. Assessments of TBE specific IgG antibodies were performed by Enzygnost anti-TBE ELISA test (Siemens, Sweden). RESULTS: Antibody levels (>12 U/mL; "seropositivity") were seen in 77% and 80% of pts after allo- and autoSCT; IgG levels; 89 vs 94 U/mL. Ongoing chronic GvHD and immunosuppression (n = 29) was associated with sero-negativity in the last sample (p = 0.007). All controls (n = 27) developed protective antibody levels. CONCLUSIONS: TBE vaccination was safe, and 4 doses starting 9 months post-SCT, induced seropositivity in a vast majority of pts.

Autologous haematopoietic stem cell transplantation compared with alemtuzumab for relapsing-remitting multiple sclerosis: an observational study.

OBJECTIVE: To compare outcomes after treatment with autologous haematopoietic stem cell transplantation (AHSCT) and alemtuzumab (ALZ) in patients with relapsing-remitting multiple sclerosis. METHODS: Patients treated with AHSCT (n=69) received a conditioning regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulinerG (6.0 mg/kg). Patients treated with ALZ (n=75) received a dose of 60 mg over 5 days, a repeated dose of 36 mg over 3 days after 1 year and then as needed. Follow-up visits with assessment of the expanded disability status scale score, adverse events and MR investigations were made at least yearly. RESULTS: The Kaplan-Meier estimates of the primary outcome measure 'no evidence of disease activity' was 88% for AHSCT and 37% for ALZ at 3 years, p<0.0001. The secondary endpoint of annualised relapse rate was 0.04 for AHSCT and 0.1 for ALZ, p=0.03. At last follow-up, the proportions of patients who improved, were stable or worsened were 57%/41%/1% (AHSCT) and 45%/43%/12% (ALZ), p=0.06 Adverse events grade three or higher were present in 48/69 patients treated with AHSCT and 0/75 treated with ALZ in the first 100 days after treatment initiation. The most common long-term adverse event was thyroid disease with Kaplan-Meier estimates at 3 years of 21% for AHSCT and 46% for ALZ, p=0.005. CONCLUSIONS: In this observational cohort study, treatment with AHSCT was associated with a higher likelihood of maintaining 'no evidence of disease activity'. Adverse events were more frequent with AHSCT in the first 100 days, but thereafter more common in patients treated with ALZ.

Humoral immunity to tetanus, diphtheria and polio in adults after treatment for hematological malignancies.

INTRODUCTION: After chemotherapy, children with acute lymphocytic leukemia lose immunity and need revaccination against tetanus and diphtheria. However, little is known about immunity in adult patients after treatment for hematological malignancies. In this study, we assessed serology levels against polio, diphtheria and tetanus in adult patients after conventional treatment for leukemia and lymphoma. PATIENTS: One hundred and four patients, age 61 (19-86) years, were included at a median of 18 (4-77) months after chemotherapy for acute leukemia (n = 24) or lymphoma (n = 80). Pre-treatment sera were available in 73 cases for a pre-versus post treatment comparison. Healthy, age- and sex matched controls were available for 47 pts. METHODS: Tetanus antibodies were quantified using ELISA, and antibody levels ≥0.01 IU/mL were considered protective. Diphtheria antibodies were analyzed using neutralization test (n = 60) or by ELISA (n = 44). In both tests values ≥0.01 IU/mL were considered protective. Antibodies against poliovirus serotype 1 and 3 were assessed by a neutralizing test. A microneutralization titer of ≥2 was considered protective. RESULTS: Tetanus: There were significantly more non-immune patients after treatment (24%), compared to before (12%), p = 0.02. Post-treatment antibody levels were significantly lower than pre-treatment levels (p = 0.02). Diphtheria: There was a trend, p = 0.06, towards more non-immune patients after treatment (21%) compared to before (27%). Antibody levels post treatment were lower than pre treatment levels (p = 0.03) and lower than controls (p = 0.01). Polio: There was no significant difference in the number of non-immune patients before vs after chemotherapy for either PV1 or PV3. Protective immunity against serotype 1 and 3 was preserved in 90 and 97%, respectively. CONCLUSIONS: After standard chemotherapy for leukemia and lymphoma a significant proportion of patients had impaired humoral immunity to diphtheria and tetanus. However, polio immunity was well preserved.

Vaccination of haemopoietic stem cell transplant recipients: guidelines of the 2017 European Conference on Infections in Leukaemia (ECIL 7).

Infection is a main concern after haemopoietic stem cell transplantation (HSCT) and a major cause of transplant-related mortality. Some of these infections are preventable by vaccination. Most HSCT recipients lose their immunity to various pathogens as soon as the first months after transplant, irrespective of the pre-transplant donor or recipient vaccinations. Vaccination with inactivated vaccines is safe after transplantation and is an effective way to reinstate protection from various pathogens (eg, influenza virus and Streptococcus pneumoniae), especially for pathogens whose risk of infection is increased by the transplant procedure. The response to vaccines in patients with transplants is usually lower than that in healthy individuals of the same age during the first months or years after transplant, but it improves over time to become close to normal 2-3 years after the procedure. However, because immunogenic vaccines have been found to induce a response in a substantial proportion of the patients as early as 3 months after transplant, we recommend to start crucial vaccinations with inactivated vaccines from 3 months after transplant, irrespectively of whether the patient has or has not developed graft-versus-host disease (GvHD) or received immunosuppressants. Patients with GvHD have higher risk of infection and are likely to benefit from vaccination. Another challenge is to provide HSCT recipients the same level of vaccine protection as healthy individuals of the same age in a given country. The use of live attenuated vaccines should be limited to specific situations because of the risk of vaccine-induced disease.

Vaccination of patients with haematological malignancies who did not have transplantations: guidelines from the 2017 European Conference on Infections in Leukaemia (ECIL 7).

Patients with haematological malignancies are at high risk of infection because of various mechanisms of humoral and cell-mediated immune deficiencies, which mainly depend on underlying disease and specific therapies. Some of these infections are vaccine preventable. However, these malignancies are different from each other, and the treatment approaches are diverse and rapidly evolving, so it is difficult to have a common programme for vaccination in a haematology ward. Additionally, because of insufficient training about the topic, vaccination is an area often neglected by haematologists, and influenced by cultural differences, even among health-care workers, in compliance to vaccines. Several issues are encountered when addressing vaccination in haematology: the small size of the cohorts that makes it difficult to show the clinical benefits of vaccination, the subsequent need to rely on biological parameters, their clinical pertinence not being established in immunocompromised patients, scarcity of clarity on the optimal timing of vaccination in complex treatment schedules, and the scarcity of data on long-term protection in patients receiving treatments. Moreover, the risk of vaccine-induced disease with live-attenuated vaccines strongly limits their use. Here we summarise guidelines for patients without transplantations, and address the issue by the haematological group-myeloid and lymphoid-of diseases, with a special consideration for children with acute leukaemia.