The choice of new treatments in autoimmune hemolytic anemia: how to pick from the basket?

Autoimmune hemolytic anemia (AIHA) is defined by increased erythrocyte turnover mediated by autoimmune mechanisms. While corticosteroids remain first-line therapy in most cases of warm-antibody AIHA, cold agglutinin disease is treated by targeting the underlying clonal B-cell proliferation or the classical complement activation pathway. Several new established or investigational drugs and treatment regimens have appeared during the last 1-2 decades, resulting in an improvement of therapy options but also raising challenges on how to select the best treatment in individual patients. In severe warm-antibody AIHA, there is evidence for the upfront addition of rituximab to prednisolone in the first line. Novel agents targeting B-cells, extravascular hemolysis, or removing IgG will offer further options in the acute and relapsed/refractory settings. In cold agglutinin disease, the development of complement inhibitors and B-cell targeting agents makes it possible to individualize therapy, based on the disease profile and patient characteristics. For most AIHAs, the optimal treatment remains to be found, and there is still a need for more evidence-based therapies. Therefore, prospective clinical trials should be encouraged.

Vaccinations in hematological patients in the era of target therapies: Lesson learnt from SARS-CoV-2.

Novel targeting agents for hematologic diseases often exert on- or off-target immunomodulatory effects, possibly impacting on response to anti-SARS-CoV-2 vaccinations and other vaccines. Agents that primarily affect B cells, particularly anti-CD20 monoclonal antibodies (MoAbs), Bruton tyrosine kinase inhibitors, and anti-CD19 chimeric antigen T-cells, have the strongest impact on seroconversion. JAK2, BCL-2 inhibitors and hypomethylating agents may hamper immunity but show a less prominent effect on humoral response to vaccines. Conversely, vaccine efficacy seems not impaired by anti-myeloma agents such as proteasome inhibitors and immunomodulatory agents, although lower seroconversion rates are observed with anti-CD38 and anti-BCMA MoAbs. Complement inhibitors for complement-mediated hematologic diseases and immunosuppressants used in aplastic anemia do not generally affect seroconversion rate, but the extent of the immune response is reduced under steroids or anti-thymocyte globulin. Vaccination is recommended prior to treatment or as far as possible from anti-CD20 MoAb (at least 6 months). No clearcut indications for interrupting continuous treatment emerged, and booster doses significantly improved seroconversion. Cellular immune response appeared preserved in several settings.

Autoimmune hemolytic anemia during pregnancy and puerperium: an international multicenter experience.

Relapsing or occurring de novo autoimmune hemolytic anemia (AIHA) during pregnancy or puerperium is a poorly described condition. Here, we report 45 pregnancies in 33 women evaluated at 12 centers from 1997 to 2022. Among the 20 women diagnosed with AIHA before pregnancy, 10 had a relapse. An additional 13 patients developed de novo AIHA during gestation/puerperium (2 patients had AIHA relapse during a second pregnancy). Among 24 hemolytic events, anemia was uniformly severe (median Hb, 6.4 g/dL; range, 3.1-8.7) and required treatment in all cases (96% steroids ± intravenous immunoglobulin, IVIG, 58% transfusions). Response was achieved in all patients and was complete in 65% of the cases. Antithrombotic prophylaxis was administered to 8 patients (33%). After delivery, rituximab was administered to 4 patients, and cyclosporine was added to 1 patient. The rate of maternal complications, including premature rupture of membranes, placental detachment, and preeclampsia, was 15%. Early miscarriages occurred in 13% of the pregnancies. Fetal adverse events (22% of cases) included respiratory distress, fetal growth restriction, preterm birth, AIHA of the newborn, and 2 perinatal deaths. In conclusion, the occurrence of AIHA does not preclude the ability to carry out a healthy pregnancy, provided close monitoring, prompt therapy, and awareness of potential maternal and fetal complications.

Vaccinations in hematological patients in the era of target therapies: Lesson learnt from SARS-CoV-2

Novel targeting agents for hematologic diseases often exert on- or off-target immunomodulatory effects, possibly impacting on response to anti-SARS-CoV-2 vaccinations and other vaccines. Agents that primarily affect B cells, particularly anti-CD20 MoAbs, Bruton tyrosine kinase inhibitors, and anti-CD19 chimeric antigen T-cells, have the strongest impact on seroconversion. JAK2, bcl 2 inhibitors and hypomethylating agents may hamper immunity but show a less prominent effect on humoral response to vaccines. Conversely, vaccine efficacy seems not impaired by anti-myeloma agents such as proteasome inhibitors and immunomodulatory agents, but lower seroconversion rates are observed with anti-CD38 and anti-BCMA MoAbs. Complement inhibitors for complement-mediated hematologic diseases and immunosuppressants used in aplastic anemia do not generally affect seroconversion rate, but the extent of the immune response is reduced under steroids or anti-thymocyte globulin. Vaccination is recommended prior to treatment or as far as possible from anti-CD20 MoAb (at least 6 months). No clearcut indications for interrupting continuous treatment emerged, and booster doses significantly improve seroconversion. Cellular immune response appeared preserved in several settings.

Pulmonary embolism in a patient with eltrombopag-treated aplastic anaemia and paroxysmal nocturnal haemoglobinuria clone during COVID-19 pneumonia.

Thrombosis in patients with thrombocytopenia has several risk factors, both disease-related and treatment-associated. Recently, COVID-19 infection was recognized as an additional risk factor, further complicating the delicate balance between thrombosis and bleeding in these patients. Here we describe the case of a patient with aplastic anaemia on eltrombopag who developed pulmonary embolism during COVID-19 pneumonia, despite receiving oral anticoagulation with edoxaban. Notably, he was also carrying a large paroxysmal nocturnal haemoglobinuria clone, although without evidence of haemolysis. The presented case recapitulates some of the open questions in thrombotic risk management of cytopenic patients, such as the management of thrombopoietin receptor agonists and the choice of anticoagulation in PNH, while also accounting for the additional thrombotic risk linked to COVID-19.

Seroconversion to mRNA SARS-CoV-2 vaccines in patients with autoimmune cytopenias and bone marrow failures.

Data concerning the efficacy of SARS-CoV-2 vaccines in patients with non-oncological hematologic conditions are lacking. These include autoimmune cytopenias (autoimmune hemolytic anemia AIHA, immune thrombocytopenia ITP, and autoimmune neutropenia), and bone marrow failure syndromes (aplastic anemia, low risk myelodysplastic syndromes, and paroxysmal nocturnal hemoglobinuria). These conditions may relapse/reactivate after COVID-19 infection and vaccine. Moreover, they are mainly handled with immunosuppressive drugs that may hamper the response to vaccine. In this study, we prospectively evaluated the rate of seroconversion after mRNA SARS-CoV-2 vaccines in patients with autoimmune cytopenias or bone marrow failure syndrome after 2 ± 1 months from the last vaccine dose. Overall, 149 patients were tested and 135 (91%) seroconverted. The highest proportion of non-responders was observed in Evans syndrome (association of ITP and AIHA) and warm AIHA patients (p = 0.001), in those with lower levels of baseline serum IgG (p = 0.008), and in patients on active therapy with steroids (p = 0.03) who also had lower anti-Spike titers. The latter were inversely related with age, and a positively with lymphocyte counts. Additionally, patients who had received rituximab within 12 months from vaccination showed higher rates of non-response (p = 0.03) as compared to those treated before. Contrarily, cyclosporine alone, complement inhibitors, and bone marrow stimulating agents had no detrimental effect on seroconversion. These data suggest maintaining high vigilance and adherence to preventive/protective measures in this population since a proportion of cases may not respond or exhibit low anti-Spike titers.

Seroconversion to mRNA SARS-CoV-2 Vaccines in Hematologic Patients.

Hematologic patients show lower responses to SARS-CoV-2 vaccines, but predictors of seroconversion are lacking. In this prospective cohort study, hematologic patients undergoing SARS-CoV-2 mRNA vaccination at a single center in Milan, Italy, were sampled for anti-Spike and anti-Nucleocapsid IgG titer at 5 ± 1 weeks and at 3 months from the second vaccine dose. Patients (N = 393) received either BNT162b2 (Pfizer-BioNTech, 48%) or MRNA-1273 (Moderna, 52%), and 284 (72%) seroconverted and 100% persisted at 3 months. Non-response was higher in chronic lymphocytic leukemia (CLL) and lymphoma patients, and in those treated with small molecules and monoclonal antibodies. In myeloid neoplasms, lower responses were detected in patients with acute myeloid leukemia treated with venetoclax plus hypomethylating agents and in patients with myelofibrosis receiving ruxolitinib. Multivariable analysis showed that seroconversion was favorably associated with a diagnosis other than indolent lymphoma/CLL [OR 8.5 (95% CI 4.1-17.6)], lack of B-cell-depleting therapy [OR 3.15 (1.7-5.9)], and IgG levels within the normal range [OR 2.2 (1.2-4.2)]. We developed a simple algorithm according to these 3 risk factors [(A) diagnosis of indolent lymphoma/CLL, (B) B-cell-depleting treatment, and (C) low IgG] to predict non-response. IgG levels and treatment may be modifiable risk factors and should be considered for timing of vaccine administration.

Secondary Hemophagocytic Lymphohistiocytosis and Autoimmune Cytopenias: Case Description and Review of the Literature.

Hemophagocytic lymphohistocytosis (HLH) is a rare hyperinflammatory condition which may be primary or secondary to many diseases, including hematologic malignancies. Due to its life-threatening evolution, a timely diagnosis is paramount but challenging, since it relies on non-specific clinical and laboratory criteria. The latter are often altered in other diseases, including autoimmune cytopenias (AIC), which in turn can be secondary to infections, systemic autoimmune or lymphoproliferative disorders. In the present article, we describe two patients presenting at the emergency department with acute AICs subsequently diagnosed as HLH with underlying diffuse large B cell lymphoma. We discuss the diagnostic challenges in the differential diagnosis of acute cytopenias in the internal medicine setting, providing a literature review of secondary HLH and AIC.

Complement Mediated Hemolytic Anemias in the COVID-19 Era: Case Series and Review of the Literature

The complex pathophysiologic interplay between SARS-CoV-2 infection and complement activation is the subject of active investigation. It is clinically mirrored by the occurrence of exacerbations of complement mediated diseases during COVID-19 infection. These include complement-mediated hemolytic anemias such as paroxysmal nocturnal hemoglobinuria (PNH), autoimmune hemolytic anemia (AIHA), particularly cold agglutinin disease (CAD), and hemolytic uremic syndrome (HUS). All these conditions may benefit from complement inhibitors that are also under study for COVID-19 disease. Hemolytic exacerbations in these conditions may occur upon several triggers including infections and vaccines and may require transfusions, treatment with complement inhibitors and/or immunosuppressors (i.e., steroids and rituximab for AIHA), and result in thrombotic complications. In this manuscript we describe four patients (2 with PNH and 2 with CAD) who experienced hemolytic flares after either COVID-19 infection or SARS-Cov2 vaccine and provide a review of the most recent literature. We report that most episodes occurred within the first 10 days after COVID-19 infection/vaccination and suggest laboratory monitoring (Hb and LDH levels) in that period. Moreover, in our experience and in the literature, hemolytic exacerbations occurring during COVID-19 infection were more severe, required greater therapeutic intervention, and carried more complications including fatalities, as compared to those developing after SARS-CoV-2 vaccine, suggesting the importance of vaccinating this patient population. Patient education remains pivotal to promptly recognize signs/symptoms of hemolytic flares and to refer to medical attention. Treatment choice should be based on the severity of the hemolytic exacerbation as well as of that of COVID-19 infection. Therapies include transfusions, complement inhibitor initiation/additional dose in the case of PNH, steroids/rituximab in patients with CAD and warm type AIHA, plasma exchange, hemodialysis and complement inhibitor in the case of atypical HUS. Finally, anti-thrombotic prophylaxis should be always considered in these settings, provided safe platelet counts.

Are Patients With Autoimmune Cytopenias at Higher Risk of COVID-19 Pneumonia? The Experience of a Reference Center in Northern Italy and Review of the Literature.

During COVID-19 pandemic the care of onco-hematologic and autoimmune patients has raised the question whether they are at higher risk of infection and/or worse outcome. Here, we describe the clinical course of COVID-19 pneumonia in patients with autoimmune cytopenias (AIC) regularly followed at a reference center in Northern Italy. The study period started from COVID-19 outbreak (February 22, 2020) until the time of writing. Moreover, we provide a review of the literature, showing that most cases reported so far are AIC developed during or secondary to COVID-19 infection. At variance, data about AIC pre-existing to COVID infection are scanty. The 4 patients here described (2 autoimmune hemolytic anemias, AIHA, 1 Evans syndrome, and 1 immune thrombocytopenia) with COVID-19 pneumonia belong to a large cohort of 500 AIC patients, making this study nearly population-based. The observed frequency (4/501; 0.7%) is only slightly superior to that of the general population admitted to hospital/intensive care unit (0.28/0.03%, respectively) in Lombardy in the same period of observation. All cases occurred between March 21 and 25, whilst no more AIC were recorded later on. Although different in intensity of care needed, all patients recovered from COVID-19 pneumonia, with apparently no detrimental effect of previous/current immunomodulatory treatments. AIHA relapse occurred in two patients, but promptly responded to therapy. With limitations due to sample size, these results suggest a favorable outcome and a lower-than-expected incidence of COVID-19 pneumonia in patients with previously diagnosed AIC, and allow speculating that immunomodulatory drugs used for AIC may play a beneficial rather than a harmful effect on COVID-19 infection.