Diagnosis and management of newly diagnosed childhood autoimmune haemolytic anaemia. Recommendations from the Red Cell Study Group of the Paediatric Haemato-Oncology Italian Association

Autoimmune haemolytic anaemia is an uncommon disorder to which paediatric haematology centres take a variety of diagnostic and therapeutic approaches. The Red Cell Working Group of the Italian Association of Paediatric Onco-haematology (Associazione Italiana di Ematologia ed Oncologia Pediatrica, AIEOP) developed this document in order to collate expert opinions on the management of newly diagnosed childhood autoimmune haemolytic anaemia.The diagnostic process includes the direct and indirect antiglobulin tests; recommendations are given regarding further diagnostic tests, specifically in the cases that the direct and indirect antiglobulin tests are negative. Clear-cut definitions of clinical response are stated. Specific recommendations for treatment include: dosage of steroid therapy and tapering modality for warm autoimmune haemolytic anaemia; the choice of rituximab as first-line therapy for the rare primary transfusion-dependent cold autoimmune haemolytic anaemia; the indications for supportive therapy; the need for switching to second-line therapy. Each statement is provided with a score expressing the level of appropriateness and the agreement among participants

Monitoring oral iron therapy in children with iron deficiency anemia: an observational, prospective, multicenter study of AIEOP patients (Associazione Italiana Emato-Oncologia Pediatrica)

Oral ferrous salts are standard treatment for children with iron deficiency anemia (IDA). The objective of our study was to monitor oral iron therapy in children, aged 3 months-12 years, with IDA. We prospectively collected clinical and hematological data of children with IDA, from 15 AIEOP (Associazione Italiana di Ematologia ed. Oncologia Pediatrica) centers. Response was measured by the increase of Hb from baseline. Of the 107 analyzed patients, 18 received ferrous gluconate/sulfate 2 mg/kg (ferrous 2), 7 ferrous gluconate/sulfate 4 mg/kg (ferrous 4), 7 ferric iron salts 2 mg/kg (ferric), 62 bis-glycinate iron 0.45 mg/kg (glycinate), and 13 liposomal iron 0.7-1.4 mg/kg (liposomal). Increase in reticulocytes was evident at 3 days, while Hb increase appeared at 2 weeks. Gain of Hb at 2 and 8 weeks revealed a higher median increase in both ferrous 2 and ferrous 4 groups. Gastro-intestinal side effects were reported in 16% (ferrous 2), 14% (ferrous 4), 6% (glycinate), and 0 (ferric and liposomal) patients. The reticulocyte counts significantly increased after 3 days from the start of oral iron supplementation. Bis-glycinate iron formulation had a good efficacy/safety profile and offers an acceptable alternative to ferrous iron preparations

Retrospective And Prospective Study Of Childhood Autoimmune Hemolytic Anemia. A Preliminary Report From The Red Cell Working Group Of The Paediatric Hemato-Oncology Italian Associations (Aieop)

Autoimmune hemolytic anemia (AIHA) is an uncommon disease of childhood caused by the premature destruction of erythrocytes by autoantibodies. In this rare disease both diagnostic criteria and therapeutic approaches are not well standardized. The Red Cell Working Group of the Pediatric Italian Hematogy and Oncology Association (AIEOP) developed specific recommendations to help Physicians for AIHA management. The document is available on the AIEOP website since November 1st 2013. The Italian Pediatric AIHA Group began an observational, retrospective and prospective study in order to monitor the management of children with AIHA diagnosed from 2010 to 2018, and to assess whether the availability of AIEOP recommendations had an impact on the clinical management of such patients in AIEOP Centers. We collected a national cohort of 159 children with AIHA from 21 AIEOP Centers; 48 patients were diagnosed before November 2013 and 111 patients after that date. Gender was 56% males and 44% females; median age at diagnosis was 47 months, with 11.9% under 12 months of age; 8.2% of children were born prematurely and 3.9% showed congenital malformations. 23.2 % of patients had a familiar history of immunological, hematological or oncological diseases. The median hemoglobin level at diagnosis was 6.1 gr/dL. Table 1 reports the distribution of our cases, according to the different type of autoantibodies. The comparison between the retrospective and prospective study did not reveal significative differences in clinical and biological presentation. The cold IgM forms were mainly post infective (38.4%) or primary forms (53.8%), only one patient had a secondary form due to a primitive immunodeficiency. These patients did not develop other diseases during follow up (median follow up: 28,6 months). The preliminary results of treatment and follow up of the 146 patients with warm antibody AIHA revealed the following: The treatment with conventional dose of steroids (median dose 2 mg/Kg, range 0.7- 3.5 mg/Kg) was started in 94.4% of patients, in 53% of cases on the same day of diagnosis. A high number of children used additional treatment: red blood cell transfusions (51.4%), high dose Prednisolone (59.7%), high dose i.v. Immunoglobulin (49.7%) and Plasma Exchange (1.4%). 9.5% of patients, with poor responsive disease, needed alternative drugs during the first four weeks of therapy. Response criteria were so defined: a complete response was defined as the achievement of an Hb concentration greater than or equal to the lower normal limit for age with no signs of haemolysis, i.e. normal reticulocyte count and bilirubine concentration. A partial response was defined as an increase of Hb >2 g/dL without the Hb concentration reaching a normal value for the patient age and no response as an increase of Hb< 2 g/dL and/or dependence on transfusion. A complete response was reached by 62.5%, 79.3%, 85.1% at 3, 4, 6 weeks respectively. 14.9% of patients had either a partial response or a resistant disease at 6 weeks. IgG/IgG+C3d positivity was a negative prognostic factor, as compared to positivity to C3d only, with the need of a second line treatment (prevalently Mabthera or Mycophenolate Mofetil) in 31.7% vs 0, respectively (p 0.009). Currently 6.1% of the patients were lost to follow up, 1.3% died, 55,8% are in Complete Response without events and 21.9% of the patients are still on treatment . At the last follow up, in the whole "cohort" of warm AIHA, 58% have a Primary form, 15.7% an isolated post infective form and 27.7% a Secondary form (56% Evans Syndrome). The management of the patients diagnosed after November 2013 was mostly in agreement with our recommendations, whose comprehensive therapeutic algorithm is reported in table 2, with prolonged steroid tapering in order to extend the treatment for at least 6 months. The most important difference between the retrospective and prospective study was the duration of first line treatment: 6 months or more, for steroid dependence, in 71.6% of patients in the prospective study versus 52.3% of the retrospective (p 0.031) and, more importantly, the percentage of relapsed patients: 8.3% in the prospective study versus 29.8% of the retrospective (p 0.001), these data need a longer follow up (median follow up: 24 months in the prospective study versus 63 in the retrospective

Retrospective and Prospective Study of Childhood Autoimmune Hemolytic Anemia. a Preliminary Report from the Red Cell Working Group of the Paediatric Hemato-Oncology Italian Associations (AIEOP)

Autoimmune hemolytic anemia (AIHA) is an uncommon disease of childhood caused by the premature destruction of erythrocytes by autoantibodies. In this rare disease both diagnostic criteria and therapeutic approaches are not well standardized. The Red Cell Working Group of the Pediatric Italian Hematogy and Oncology Association (AIEOP) developed specific recommendations to help Physicians for AIHA management. The document is available on the AIEOP website since November 1st 2013. The Italian Pediatric AIHA Group began an observational, retrospective and prospective study in order to monitor the management of children with AIHA diagnosed from 2010 to 2018, and to assess whether the availability of AIEOP recommendations had an impact on the clinical management of such patients in AIEOP Centers. We collected a national cohort of 159 children with AIHA from 21 AIEOP Centers; 48 patients were diagnosed before November 2013 and 111 patients after that date. Gender was 56% males and 44% females; median age at diagnosis was 47 months, with 11.9% under 12 months of age; 8.2% of children were born prematurely and 3.9% showed congenital malformations. 23.2 % of patients had a familiar history of immunological, hematological or oncological diseases. The median hemoglobin level at diagnosis was 6.1 gr/dL. Table 1 reports the distribution of our cases, according to the different type of autoantibodies. The comparison between the retrospective and prospective study did not reveal significative differences in clinical and biological presentation. The cold IgM forms were mainly post infective (38.4%) or primary forms (53.8%), only one patient had a secondary form due to a primitive immunodeficiency. These patients did not develop other diseases during follow up (median follow up: 28,6 months). The preliminary results of treatment and follow up of the 146 patients with warm antibody AIHA revealed the following: The treatment with conventional dose of steroids (median dose 2 mg/Kg, range 0.7- 3.5 mg/Kg) was started in 94.4% of patients, in 53% of cases on the same day of diagnosis. A high number of children used additional treatment: red blood cell transfusions (51.4%), high dose Prednisolone (59.7%), high dose i.v. Immunoglobulin (49.7%) and Plasma Exchange (1.4%). 9.5% of patients, with poor responsive disease, needed alternative drugs during the first four weeks of therapy. Response criteria were so defined: a complete response was defined as the achievement of an Hb concentration greater than or equal to the lower normal limit for age with no signs of haemolysis, i.e. normal reticulocyte count and bilirubine concentration. A partial response was defined as an increase of Hb >2 g/dL without the Hb concentration reaching a normal value for the patient age and no response as an increase of Hb< 2 g/dL and/or dependence on transfusion. A complete response was reached by 62.5%, 79.3%, 85.1% at 3, 4, 6 weeks respectively. 14.9% of patients had either a partial response or a resistant disease at 6 weeks. IgG/IgG+C3d positivity was a negative prognostic factor, as compared to positivity to C3d only, with the need of a second line treatment (prevalently Mabthera or Mycophenolate Mofetil) in 31.7% vs 0, respectively (p 0.009). Currently 6.1% of the patients were lost to follow up, 1.3% died, 55,8% are in Complete Response without events and 21.9% of the patients are still on treatment . At the last follow up, in the whole "cohort" of warm AIHA, 58% have a Primary form, 15.7% an isolated post infective form and 27.7% a Secondary form (56% Evans Syndrome). The management of the patients diagnosed after November 2013 was mostly in agreement with our recommendations, whose comprehensive therapeutic algorithm is reported in table 2, with prolonged steroid tapering in order to extend the treatment for at least 6 months. The most important difference between the retrospective and prospective study was the duration of first line treatment: 6 months or more, for steroid dependence, in 71.6% of patients in the prospective study versus 52.3% of the retrospective (p 0.031) and, more importantly, the percentage of relapsed patients: 8.3% in the prospective study versus 29.8% of the retrospective (p 0.001), these data need a longer follow up (median follow up: 24 months in the prospective study versus 63 in the retrospective

Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP)

Acquired aplastic anemia (AA) is a rare heterogeneous disease characterized by pancytopenia and hypoplastic bone marrow. The incidence is 2-3/million inhabitants/year, in Europe, but higher in East Asia. Survival in severe aplastic anemia (SAA) has markedly improved in the past 2 decades because of advances in hematopoietic stem cell transplantation, immunosuppressive and biologic drugs, and supportive care. In SAA hematopoietic stem cell transplant (HSCT) from a matched sibling donor (MSD) is the treatment of choice. If a MSD is not available, the options include immunosuppressive therapy (IST) or unrelated donor HSCT. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of pediatric patients with AA. A preliminary, evidence-based document issued by a group of pediatric hematologists was discussed, modified and approved during a series of "Consensus Conferences" according to procedures previously validated by the AIEOP Board. The guidelines highlight the importance of referring pediatric patients with AA to pediatric centers with long experience in diagnosis, differential diagnosis, management, supportive care and follow-up of AA

Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP)

Acquired aplastic anemia (AA) is a rare heterogeneous disease characterized by pancytopenia and hypoplastic bone marrow. The incidence is 2-3/million inhabitants/year, in Europe, but higher in East Asia. Survival in severe aplastic anemia (SAA) has markedly improved in the past 2 decades because of advances in hematopoietic stem cell transplantation, immunosuppressive and biologic drugs, and supportive care. In SAA hematopoietic stem cell transplant (HSCT) from a matched sibling donor (MSD) is the treatment of choice. If a MSD is not available, the options include immunosuppressive therapy (IST) or unrelated donor HSCT. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of pediatric patients with AA. A preliminary, evidence-based document issued by a group of pediatric hematologists was discussed, modified and approved during a series of "Consensus Conferences" according to procedures previously validated by the AIEOP Board. The guidelines highlight the importance of referring pediatric patients with AA to pediatric centers with long experience in diagnosis, differential diagnosis, management, supportive care and follow-up of AA