Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3049-3049

Abstract: Driver mutations of JAK2, CALR and MPL are found in 〉 90% of adults with BCR-ABL1-negative myeloproliferative neoplasms (MPN). In children, the presence of clonal markers ranges between 22 and 40%, and inherited forms of MPD, such as familial erythrocytosis (FE) and hereditary thrombocytosis (HT), are common. Data on the mutational spectrum and biology of childhood MPD are limited. The aims of this study were: a) to evaluate the ability of a next-generation sequencing (NGS)-based 44-gene analysis to better characterize wild type (WT) MPD, and b) to identify non-canonical and/or non-driver mutations in children and adolescents with MPD. Eighty patients (pts) aged ≤20 years (yrs) at diagnosis of MPD, observed between June 1980 and September 2015, were first investigated with standardized methods for driver mutations of MPN (JAK, MPL, CALR), for genes involved in FE (HRE, EpoR, HIF2α, HIF1α, VHL, PHD1-3, STAT5, LNK, TET2) and HT (THPO, MPL, LNK and TET2). Then, a 44-gene panel providing diagnostic information in myeloid malignancies and in rare inherited erythrocytosis/thrombocytosis (JAK2, CALR, MPL, ASXL1, CBL, C-Kit, CSF3R, CUX1, DNMT3A, ETNK1, EZH2, IDH1, IDH2, IKZF1, KRAS, LNK, NFE2, NRAS, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1, ZRSR2, BPGM, EGLN1 (PHD2), EPAS1 (HIF2A), EPOR, GATA1, GELSOLIN, HBA1, HBA2, HBB, JAK2,MPL, RUNX1, SH2B3, SRC, THPO, VHL, WAS) was employed to better characterize these diseases. Sequencing analyses of DNA from mononuclear peripheral blood cells were performed in 57/80 pts. Eighty pts (M 41, F 39; median age at diagnosis: 149/12 yrs, range 3 months-1911/12 yrs), investigated by standardized methods, were retrospectively classified according to the WHO 2016 criteria as follows: 35 essential thrombocythemia (ET) (10 JAK2V617F, 2 CALR type1, 6 CALR type2, 1 CALR atypical, 16 WT), 9 polycythemia vera (PV) (4 JAK2V617F, 5 WT) and 3 primary myelofibrosis (PMF) (1 JAK2V617F, 2 WT). Twenty-three pts with MPLS505N or MPLV501A mutations and 10 pts with HIF mutations (3 pts) and/or anamnestic criteria of FE (7 WT) were considered HT and FE, respectively. The NGS-based 44-gene panel was applied to 57 MPD pts (11 JAK2V617F, 6 CALR, 12 MPLS505N, 2 MPLV501A, 3 HIF2α and 23 WT). According to the WHO 2016 criteria, 27 pts were ET, 14 HT, 8 FE, 7 PV and 1 PMF. By using the NGS panel, clonal markers were found in 12/23 (52%) pts with MPN WT: HBB and PDH2 in 2 FE, MPLW515_P518 〉 KT in 1 ET pt and non-driver mutations in 9 pts (7 ET, 1 PF and 1 PV). Furthermore, two non-canonical driver mutations, MPLC322G and JAK2G301R were identified in 1 CALR type2 ET and in 1 JAK2V617FPV, respectively. An additional MPLV501M mutation was found in 1 MPLS505N HT. Taken together, among the 57 pts 18 (32%) had one (11/18=68%) or two (7/18=39%) non-driver mutations. Eight of the 34 pts (23.5%) with a clonal marker had additional non-driver mutations, that was single in 6 pts. Within the familial MPD, a single non-driver mutation was found in 3/8 FE pts (37.5%), while no mutations were detected in HT pts. Considering the functional classification of non-driver mutations, we found mutations in signaling (CBL, LNK/SH2B3, CSF3R, KIT, SETBP1) and splicing (U2AF1, ZRSR2) genes in ET and PMF pts, and mutations of epigenetic regulation genes (TET2, ASXL1, DNMT3A) in PV, FE and ET pts (Table 1). The co-occurrence of driver and non-driver mutations in the same individual is illustrated in the circos plot (Figure 1). The use of a NGS-based 44-gene panel in acquired and familial pediatric MPD enabled to identify driver and non-driver mutations, not otherwise detected by conventional methods, with a substantial proportion of MPD pts (81%) showing mutations in the genes analyzed. Interestingly, we found additional neoplastic mutations in some pts with FE. Although the utilized NGS-based panel proved useful to better characterize children and adolescents with MPD, 19% of our pts still remain without any identified clonal marker. Further targeted NGS and whole genome sequencing may enable to better define MPD children without molecular markers. Disclosures Malaspina: Sapienza University, Rome: Other: Resident in Hematology. Foà:ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; NOVARTIS: Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-118102

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 33-34

Abstract: Immune thrombocytopenic purpura (ITP) is one of the most common hemorrhagic disorders in childhood, often caused by an acute self-limiting event. However, 30% of these children develop chronic ITP. Identification of the underlying causes in ITP is an important challenge. Inherited thrombocytopenia (IT) is a rare, underdiagnosed disease, included among the chronic platelet disorders. Next-Generation-Sequencing (NGS) could be an efficient way of discovering potential IT-associated mutations in children with chronic ITP. The purpose of this retrospective study was to investigate children with chronic ITP using a targeted NGS, in order to identify IT-associated mutations. Between June 2017 and April 2020, mutational screening by a targeted NGS was performed on 19 children, either with a familial history of IT [4 unrelated patients (pts)], or with chronic ITP (15 pts), after all other causes of thrombocytopenia were excluded. Nineteen relatives were also investigated. This study was carried out in collaboration with the Laboratory of Genetics, IRCCS Burlo Garofolo in Trieste, that developed a targeted NGS method for the simultaneous analysis of 28 IT genes. The cost of the NGS tests were supported by the public healthcare service. We retrospectively divided our cohort of 19 pts, into three subgroups: Group I included 4 unrelated pts with familial IT; Group II consisted of 6 pts with chronic ITP and a clinical history and/or laboratory features associated with familial IT; and, Group III included 9 pts with chronic ITP refractory to several treatments (Table 1). The median age at the initial diagnosis of thrombocytopenia was lower in Group I than in Groups II and III (19/12 years vs 1310/12 years and 9 years, respectively, p=0.33). The median time between the diagnosis of thrombocytopenia, and the time of the study, was shorter in Group I compared to Groups II and III (11.7 months vs 45.3 and 51.7 months, respectively, p=0.16). Median platelet count at the disease onset was lower in Group III than in Groups I and II (21 x 109/L vs 99 x 109/L and 38 x 109/L, respectively, p=0.28). The median MPV values were 12.5 fL, 9.85 fL and 8.8 fL in Groups II, III, and I respectively. Bleeding symptoms requiring treatment were present at diagnosis in 1/6 (16%) and in 5/9 (55%) children of Groups II and III, respectively. Genetic variants, usually detected in IT, were found in heterozygosity in all children in Groups I and II, and in 7/9 (78%) in Group III. Two out of 4, 2/6 and 2/9 children in Groups I, II, and III, respectively, presented ≥2 variants. Among the 4 children of Group I, ANKDR26 variant was found in 2 pts, together with GP1BA and NBEAL2 (pt#1) and TUBB1 (pt#2). ANKDR26 variant was also recorded as a single mutation in their relatives. Two different variants involving GP1BA (c.98T & gt;A and c.515C & lt;T) were detected in the remaining 2 children of Group I and in their relatives. Pt #4 with GP1BA c.515C & gt;T mutation with mild macrothrombocytopenia had relatives with a previous diagnosis of monoallelic Bernard-Souliers syndrome. As shown in table 1, ABCG8, ACTN1, ETV6, GP1BA, MYH9, SLFN14, or WAS variants, found in combination in 2 pts (pt#5, pt#8), were also detected in the children in Group II, as well as, at least one of the relatives (for a total of 7 cases). ABCG5, ABCG8, ETV6, FLNA, GP1BA, NBEAL2, or SLFN14 were found as variants in patients of Group III. The peripheral blood smear evaluation confirmed the diagnosis of grey platelet syndrome with two NBEAL2 mutations in pt #16. SLFN14, as a single variant, was associated with macrothrombocytopenia in one pt (#10). Three pts (#5, #6, #17), with variants of ABCG8 had hypercholesterolemia. In the cohort of pts with chronic ITP, 4 (#12, #13, #14, #15) had relatives with thrombocytopenia, and 2 (#11, #13) had a familial history of hematological malignancies. Segregation analysis in families, and functional studies to evaluate the pathogenic role of the variants reported, are still in progress. The clinical significance of IT-associated mutations in chronic ITP is uncertain, and yet to be clarified. However, our experience has shown that an in-depth clinical history, and accurate peripheral blood smear examinations, are important to better characterize chronic ITP in children. A targeted NGS method for the simultaneous analysis of different IT genes, has demonstrated to be an effective approach to explore in-depth the IT-associated mutations in children with chronic ITP, refractory to treatment. Table 1. Disclosures Giona: Novartis: Research Funding; Takeda: Speakers Bureau; Sanofi Genzyme: Research Funding, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-138651

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1041-1041

Abstract: The knowledge of Langerhans Cell Histiocytosis (LCH) is based on pediatric studies. Adults with LCH are usually treated with pediatric protocols. In 2001, guidelines for adults with LCH (GIMEMA LCH 2001) were proposed, in order to standardize the diagnostic and therapeutic approaches for this category of patients. The aims of this retrospective study are: a) to evaluate the role of a multidisciplinary assessment in adults with LCH, according to the GIMEMA LCH 2001 guidelines, and b) to analyze the results obtained with the GIMEMA LCH 2001 guidelines and those obtained with pediatric protocols. Pts aged 〉 18 years with a diagnosis of LCH (S-100+, CD1a+, CD207+) managed at our Institution since 1985 to 2018 were considered. As diagnostic and treatment approaches, two different strategies were used over time: the GIMEMA LCH 2001 guidelines and the pediatric protocols. The GIMEMA LCH 2001 guidelines included a multidisciplinary diagnostic work-up with complete odontostomatologic, pulmonary and endocrinologic assessments; treatment strategy consisted of: wait and see or local therapy in unifocal single system (SS), indomethacin in bone multifocal SS and vinblastine combined with low-dose prednisone (PDN) in multi-system (MS), PDN in pulmonary honey-combing disease (PHCD) and cladribine in central nervous system involvement. DAL-HX 83 and 90, LCH-I and LCH II were the pediatric protocols utilized over time. Response to treatment was defined as complete (CR) or intermediate (IR). Persistence of the symptoms and/or appearance of new lesions were defined no response (NR). Progression was considered the appearance of symptoms and/or new lesions after initial response. One-hundred-thirty-one LCH pts (females 72, males 59) with a median age at diagnosis of 36 years (range 18 - 71) were considered. Median follow up was 43 months (range 12 - 330). One-hundred-seven patients were managed according to the GIMEMA LCH 2001 guidelines, 16 of them previously treated with a pediatric protocol. Pulmonary and/or oral involvements were identified in 31/107 (29%) and 12/107 (11%) patients, respectively, 5/16 (31%) and 3/16 (19%), respectively, of previously treated asymptomatic patients. Ninety-one newly diagnosed patients (median age at diagnosis: 36 years) were treated according to the GIMEMA LCH 2001 guidelines and 40 (median age at diagnosis: 33 years) were managed with pediatric protocols. All patients treated with the GIMEMA LCH 2001 were evaluable for response. In particular, all patients with SS-LCH achieved a response (100%), that was complete in 20/26 (76.9%) unifocal-SS and in 10/14 (71.4%) multifocal-SS. All but one patient with MS-LCH reached a response that was complete in 22/45 (48.9%). Of 6 pts with PHCD, 5 had a IR and one a CR. No pt presented CNS involvement at initial diagnosis. Thirty-nine of 40 pts managed with pediatric protocols were evaluable for response. All 13 pts with SS-LCH had a response that was complete in 6 (46.1%). Among 26 patients with MS-LCH, 3 of them with organ risk involvement achieved a response, that was complete in 1, while among 23 patients without organ risk, 12 (52.2%), 8 (34.8%) and 3 (13%) had a CR, IR and NR, respectively. Overall, 12 patients were lost to follow-up. Disease progression was recorded in 47/95 pts (49.5%) after a median time of 19 months (range: 6-147 months). The progression-free survival at 43 months was significantly better for patients treated according to the GIMEMA LCH 2001 guidelines compared to those managed with pediatric protocols, 67% (IC95% 53.14 - 80.86%) vs 48% (IC95% 31.37 - 64.63%), respectively (p 0.005). Overall, 7 deaths were recorded, 5 in patients treated with the pediatric protocols. The overall survival at 43 months, was similar in patients managed with the GIMEMA LCH 2001 guidelines and in those treated with pediatric protocols (97.9%, CI 95%: 93.75% - 100% and 97.3%, (IC95% 91.96% - 100%). BRAF V600E mutation was found in 13/35 (37%) evaluable cases. No differences in response and outcome between BRAFV600E-mutated patients and those not-mutated were found. Our experience in a large cohort of LCH adults shows that a multidisciplinary approach is useful in identifying organ involvement in adults, including those asymptomatic. This is critical for an adequate treatment. Moreover, guidelines specific for adults with LCH proved efficacy in improving the outcome in this category of patients. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-129707

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Acta Haematologica, S. Karger AG, Vol. 142, No. 3 ( 2019), p. 185-186

Type of Medium: Online Resource

ISSN: 0001-5792 , 1421-9662

URL: Article

DOI: 10.1159/000497137

Language: English

Publisher: S. Karger AG

Publication Date: 2019

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detail.hit.zdb_id: 80008-9

In: Acta Haematologica, S. Karger AG, Vol. 145, No. 1 ( 2022), p. 84-88

Abstract: Myeloid sarcoma (MS) is a very rare disease in both adults and children. Prognosis is poor in adults; in the pediatric age, the prognostic impact of extramedullary disease is controversial. Systemic therapy represents the mainstay of treatment even in isolated MS, but a comparison between different induction regimens is very limited in the literature. To date, it is still not clear if induction treatment should differ from that of other acute myeloid leukemias and stem cell transplant is considered for consolidation in both leukemic patients and in those with isolated disease. Our study describes a retrospective series of 13 cases of MS (adults and children), diagnosed and treated at our institute over 18 years. We report the results of immunophenotypic, cytogenetic and molecular studies, therapeutic approaches, and outcome, in order to establish the best strategy for patients’ workup.

Type of Medium: Online Resource

ISSN: 0001-5792 , 1421-9662

URL: Article

DOI: 10.1159/000517389

Language: English

Publisher: S. Karger AG

Publication Date: 2022

detail.hit.zdb_id: 1481888-7

detail.hit.zdb_id: 80008-9

In: Blood, American Society of Hematology, Vol. 119, No. 10 ( 2012-03-08), p. 2219-2227

Abstract: Sixty-four patients 〈 20 years of age, investigated for a suspicion of Philadelphia-negative myeloproliferative disease (MPD), were retrospectively evaluated to characterize the different forms and to examine the treatments used and long-term outcome. JAK2 mutations, endogenous erythroid colony growth, and clonality were investigated in 51 children. Mutations of thrombopoietin, the thrombopoietin receptor (MPL), and the erythropoietin receptor and mutations of other genes involved in the pathogenesis of MPD were investigated in JAK2 wild-type patients. Based on our criteria for childhood MPD, we identified 34 patients with sporadic thrombocythemia (ST), 16 with hereditary thrombocytosis (HT), 11 with sporadic polycythemia (SP), and 3 with hereditary polycythemia (HP). JAK2V617F mutations were present in 47.5% of ST and in no HT. The MPLS505A mutation was detected in 15/16 HT patients and in no ST (P 〈 .00001). The JAK2V617F mutation occurred in 27% of SP patients diagnosed according to the Polycythemia Vera Study Group or World Health Organization 2001 criteria. Children with ST received more cytoreductive drugs than those with HT (P = .0006). After a median follow-up of 124 months, no patient had developed leukemia or myelofibrosis and 5% had thrombosis; the miscarriage rate in thrombocythemic patients was 14%. The low complication rate in our population suggests that children with MPD may be managed by tailored approaches.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2011-08-371328

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 5121-5121

Abstract: Background. Hematologic and, to a lesser extent, molecular relapsed/refractory in adult acute lymphoblastic leukemia (R/R ALL) is associated with a poor outcome, with low rates of subsequent complete remission (CR) and short survival. Blinatumomab has shown to be effective in both settings. Aims and methods. In this retrospective, single center study we aimed at: 1) evaluating the efficacy of blinatumomab in both hematologic and molecular R/R patients enrolled in clinical trials and in a real life setting; 2) identifying predictive factors impacting on overall and disease free-survival (OS and DFS), and 3) establishing the feasibility and the role of a subsequent allogenic stem cell transplantation (HSCT). Thirty-six adult patients (≥18 years) in hematologic or molecular R/R ALL were treated with blinatumomab between January 2012 and March 2017. Blinatumomab was administered either in the context of a clinical trial (Blast, MT103-211, Tower, Alcantara), in a compassionate use program or according to AIFA (Agenzia Italiana del Farmaco) guidelines. Blinatumomab was administered as continuous infusion for 4 weeks, followed by a 2-week wash out. A stepwise dose of 9 µg/day during the first week of cycle 1 followed by 28 µg/day thereafter, was administered for hematologic R/R cases and a flat dose of 15 µg /m2/day for molecular R/R patients. Patients who witnessed a response received up to 4 additional cycles or underwent a HSCT; patients showing after 1 cycle an increase in the blast count or of minimal residual disease levels, discontinued treatment. Results. Thirty-six patients were analyzed: 21 (58.4%) were in hematologic R/R and 15 (41.6%) in molecular R/R. Four patients had high-risk genetic features (2 BCR/ABL1 and 2 MLL/AF4). Thirteen patient were treated in the context of a clinical trial. All patients received at least one cycle of blinatumomab. At the end of the first cycle, among the 21 hematologic R/R pts, 14 (67%) achieved a CR and 10/14 (71%) also a CMR, while in the molecular R/R group 12/15 (80%) achieved a CMR. As expected, the rate of CMR was significantly higher in the molecular R/R cases as opposed to hematologic R/R (80% vs 52%, p=0.05). Notably, all 4 patients treated for a primary refractory disease, achieved a CR and CMR after the first cycle as opposed to hematologic relapsed cases (p=0.08). With a median follow-up of 33.9 months (range 1-89), the overall OS and DFS at 3 years are 34% and 42.5%, respectively. OS was significantly better for molecular R/R cases than for hematologic R/R cases (54.2% vs 26.1%, p=0.05), while no significant differences were observed in DFS. OS and DFS are 100%, respectively, for refractory cases. Median OS is 6.75 months for hematological R/R, while it is not reached for molecular R/R. Median DFS is 26 months for both groups. Predictive factors for non-response were the status of disease prior to blinatumomab (hematologic vs molecular R/R) and primary refractoriness. A better, though not significant, outcome was observed for patients treated in first rather than in subsequent relapse, and in cases without molecular aberrations (p=0.07, p=0.09). Overall, 14 patients - 9 with molecular and 5 with hematologic R/R at enrollment - underwent a HSCT: 8 are in continuous CR (median follow-up: 17 months, range 5-73). Among the 22 patients who did not receive a HSCT, including 16 molecular and 6 hematologic R/R at enrollment), 7 are in continuous CR (median follow-up: 51 months, range 10-89). Due to the small sample size, we cannot define the role of transplant; transplant-related mortality (TRM) was observed in 3/14 (21.4%). Treatment was well tolerated: the most common adverse events were pyrexia (55%), infectious events (33.3%) and neurotoxicity (19.4%); hematologic toxicity was rare and more frequent in hematologic R/R. Conclusions. Treatment with blinatumomab was safe and effective. As expected, patients treated in molecular R/R had better survival rates than hematologic R/R patients. Despite the small number, all primary refractory patients responded to blinatumomab, suggesting that in these cases immunotherapeutic strategies can be extremely effective, irrespective of a chemo-insensitive disease. HSCT did not impact on OS and DFS, possibly due to the small number of the cohort. Finally, no differences in terms of adverse events, DFS or OS were observed between patients treated in the context of a clinical trial or in a real-life setting. Disclosures Chiaretti: Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Foà:Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-128156

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1889-1889

Abstract: Abstract 1889 Poster Board I-912 Introduction: MPD rarely occur in children and published data of pediatric patients (pts) are limited. In adults, current diagnostic criteria are those of the WHO2008 and the therapeutic options are supported by controlled studies. From our experience, we suggested that the biological markers show a clinical relevance in Ph- MPD children and may influence their management. Patients and methods: We retrospectively analyzed 65 pts aged ≤20 years (yrs) at diagnosis (dx) with Ph-negative MPD, observed between December 1981 and March 2009. Dx was performed according to the PVSG or WHO criteria. Since 2002, 52/65 pts were studied for JAK2 mutations, polycytemia rubra vera-1 (PRV-1) RNA expression, thrombopoietin (TPO) and its receptor (c-MPL) mutations, erythropoietin receptor (EPO-r) gene mutations, spontaneous endogenous erythroid colony (EECs) growth, clonality on female pts. Results: Thirty-nine females and 26 males with a median age at dx of 14 yrs were classified as follow: 34 (52%) essential thrombocythemia (ET), 16 (24.5%) familial thrombocythemia (FT), 11 (17%) polycythemia vera (PV), 3 (4.5%) familial polycythemia (FP) and 1 idiopathic myelofibrosis (IM). Clinical and biological data, treatment and outcome are reported. Pts with familial disease were younger than those with the sporadic form (p 〈 .05). Hematocrit (Hct) values were higher in ET than in FT pts (p .0047). Fifty pts underwent a bone marrow aspirate and biopsy (15 FT and FP children were excluded). No chromosome abnormalities were found. Overt fibrosis was present in 1 pt. Symptoms at dx were recorded in 21/64 pts (33%) and splenomegaly was present in 13/64 (20%), more frequently in sporadic disease pts. The JAK2V617F mutation was found in 47.5% of ET and 27% of PV. Clonal myelopoiesis was present in 7/11 (63.5%) ET and 2/3 PV females. None of the FT and FP pts showed JAK2V617F mutations or clonality. EECs grew in 58% of ET, in 42% of FT and in 40% of PV. PRV-1 RNA overexpression was found in 29/44 pts (66%). No EECs growth or EPO-r gene mutation was found in FP pts. The median EPO level was 5 mU/ml (1.1–16.4) in polycythemic pts. MPLS505A mutations were detected in15/16 FT pts and a novel HIF2A mutation in 1 FP pt. Treatment was modified during follow-up (f-up): 15 children did not undergo any treatment and 16 pts received more than one cytoreductive drugs. Phlebothomies were carried out in 9 polycythemic pts. Overall, 26 pts were treated with different cytoreductive drugs (hydroxyurea, interferone-alpha, anagrelide and pipobroman). Because of the persistently higher platelet (PLT) count, ET children needed more cytoreductive drugs than FT pts (p .0006). Anti-platelet agents were used in 40 pts and stopped in 30. No hemorrhagic events were recorded; 3 pts (5%) developed thromboses. Eight pts had 11 pregnancies (4 abortions: 2 spontaneous). Five pts showed progressive splenomegaly, 2 (1 PV and 1 ET, untreated) of them developed IM. Two pts developed a cancer. All pts are alive after a median f-up of 10 yrs. Conclusions: This represents the largest reported series of pediatric MPD. A broad familial work-up combined to molecular analyses allowed us to characterize the MPD disorders in our pediatric population, to plan suitable treatments and to better manage their disease. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.1889.1889

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: American Journal of Hematology, Wiley, Vol. 96, No. 3 ( 2021-03), p. 292-301

Abstract: Adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) represent a unique patient population with specific characteristics and needs. Growing evidences suggest that pediatric‐inspired approaches improve the outcome in AYA. These results prompted the design of a pediatric AIEOP‐BFM ALL 2000‐based regimen ‐ the GIMEMA LAL‐1308 protocol ‐ for newly diagnosed AYA (range 18‐35 years) with Philadelphia negative (Ph‐) ALL. The protocol included minimal residual disease (MRD) analysis at two different time‐points (TP), that is, at the end of induction IA and consolidation IB, and a modulation in post‐consolidation intensity according to MRD. Seventy‐six patients were eligible between September 2010 and October 2014. The regimen was well tolerated, with 2.7% induction deaths and no deaths in the post‐consolidation phase. The complete response (CR) rate was 92%; the 48‐month overall survival (OS) and disease‐free survival (DFS) were 60.3% and 60.4%. Both OS and DFS were significantly better in T‐ALL than B‐ALL. A molecular MRD 〈 10 −3 at TP1 was associated with a significantly better OS and DFS (77% vs 39% and 71.9% vs 34.4%, respectively);similar results were documented at TP2 (OS and DFS 74.5% vs 30.6% and 71.5% vs 25.7%, respectively). The LAL‐1308 results were compared to those from similar historic AYA populations undergoing the two previous GIMEMA LAL‐2000 and LAL‐0904 protocols. Both OS and DFS improved significantly compared to the two previous protocols. These results indicate that this pediatric‐inspired and MRD‐oriented protocol is feasible and effective for Ph‐ AYA ALL patients, and underline the prognostic value of MRD determinations at specific TPs.

Type of Medium: Online Resource

ISSN: 0361-8609 , 1096-8652

URL: Issue

URL: Article

DOI: 10.1002/ajh.v96.3

DOI: 10.1002/ajh.26066

Language: English

Publisher: Wiley

Publication Date: 2021

detail.hit.zdb_id: 1492749-4

In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 4949-4949

Abstract: Several associated thrombophilic abnormalities have been reported in adults with Bcr-Abl negative chronic myeloproliferative disorders (MPD), mostly essential thrombocythemia (ET) and polycythemia vera (PV), but sporadic data are available in younger patients (pts). In order to define coagulation abnormalities in very young pts, we evaluated thrombophilic parameters in MPD pts aged & lt;20 years (yrs) at diagnosis. Prothrombin time (PT), activated partial thromboplastin time (aPTT), lupus anticoagulant (KCT and dRVVT), functional protein C (PC), free protein S (PS) antigen, functional antithrombin (AT), homocysteine (HCY), factor V Leiden (FVL) mutation, factor II (FII) G20210A mutation and methylentethrahydrofolate reductase (MTHFR) C677T polymorphism were investigated. Thirty-two MPD pts (16 males and 16 females) with a median age of 166/12 yrs (range: 3mo-1911/12 yrs) diagnosed at the study Institution between March 1980 and February 2005 were tested after informed consent of pts or parents. Twenty-five had a diagnosis of ET (7 familial forms) and 5 had PV, according to the criteria of the PV Study Group; in 2, a diagnosis of MPD with thrombocytosis and erythrocytosis was made. Cytogenetic and molecular studies were normal in all cases. At diagnosis, median platelet count for ET and MPD pts was 1,184 x 109/L (range 611–2,640); median hematocrit level for PV and MPD pts was 54% (range 52–72%). Among the ET cohort, 6 asymptomatic pts received no treatment, 4 were treated with aspirin alone and 15 received cytoreductive therapy. PV and MPD pts were phlebotomized to maintain a hematocrit level & lt;50%. Median interval between diagnosis and the time of the study was 8.8 yrs (range: 1 mo – 24 yrs ). No thrombotic events occurred. Four female ET became pregnant and had 4 children, 1 of them being affected by familial thrombocythemia. At the time of the coagulation study, median platelet count for ET and MPD pts was 695 x 109/L (range 325–1,120); the median hematocrit level for those with PV and MPD was 53% (range 52–60.5%). Increased PT and aPTT ratios (n.v. & lt;1.14 and & lt;1.16) were observed in 8/32 (20%) and 16/32 (50%) pts, combined in 7. KCT ratio (n.v. & lt;1.31) was increased in 4/31 (13%) pts, while the dRVVT ratio was normal in 31/31 tested pts. Functional PC and free PS levels were decreased in 3/30 (10%) and 3/31 (10%) tested pts, respectively. AT levels were normal in all pts (32/32). An increased HCY level was found in 1 PV pt. Of the 27 pts investigated for FVL, FII G20210A mutations and MTHFR C677T polymorphism, 1 ET pt was heterozygous for both the FVL and FII G20210A mutations, 1 ET pt was heterozygous for both MTHFR C677T polymorphism and FII G20210A mutation. One ET pt showed an isolated FII G20210A mutation. Screening for the C677T polymorphism in the MTHFR gene revealed that 18 pts (66.5%) were heterozygous, 15 of them affected by ET (7 with the familial form). In our MPD population of children and young adults, the frequencies of heterozygosis of FII G20210A mutation (3/27 pts = 11%) and MTHFR C677T polymorphism (66.5%) were higher than those reported in the normal population (about 2.5% and 45%, respectively). Larger multicenter studies are required to further extend these observations.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V106.11.4949.4949

Language: English

Publisher: American Society of Hematology

Publication Date: 2005

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7