Introduction: Is it time to revisit classification of Thalassemia Syndromes?

Transcription

1 1st International Working Group on Thalassemia: Introduction: Is it time to revisit classification of Thalassemia Syndromes? CAMPUS OF HEMATOLOGY "Franco e Piera Cutino" A.O.R. "Villa Sofia - V. Cervello" Palermo (Italy) Prof. Aurelio Maggio

2 DEFINITION OF THALASSEMIA SYNDROMES Thalassemia syndromes (TS) are currently classified as transfusion dependent (TDT) and non transfusion depedent (NTDT). TDT comprises patients who require regular transfusions for survival. They commonly need at least 7 ml/kg/month of packed red blood cells. The main clinical phenotypes falling under this classification are beta-thalassemia major patients (TM) and severe forms of hemoglobin e/beta-thalassemia. NTDT is a term used to label patients who do not require lifelong regular transfusions for survival, although they may require occasional or even frequent transfusions in certain clinical settings and usually for defined periods of time. the main clinical phenotypes falling under this classification are beta-thalassemia intermedia (TI), mild/moderate forms of hemoglobin e/beta-thalassemia, and hemoglobin h disease.

3 SURVIVAL IN THALASSEMIA SYNDROMES Recent survival studies both in Western and Eastern countries showed that life expectancy of TDT is similar to that of NTDT patients. Vitrano et al. Br. J. Haematol Rajaeefard et al. Epidemiol. Health 2015

4 THALASSEMIA SYNDROMES SURVIVAL PROBABILITY IS IMPROVING WORLDWIDE IRAN* TAIWAN ** PAKISTAN *** ITALY **** *Rajaeefard A, Hajipour M, Tabatabaee HR, Hassanzadeh J, Rezaeian S, Moradi Z, Sharafi M, Shafiee M, Semati A, Safaei S, Soltani M. Analysis of survival data in thalassemia patients in Shiraz, Iran. Epidemiol Health Jul 7;37:e doi: /epih/e **Wu HP, Lin CL, Chang Y, et al. Survival and complication rates in patients with thalassemia major in Taiwan. Pediatr Blood Cancer Jan;64(1): doi: /pbc ***For kind concession of Dr. Saqib Hussain Ansari, National Institute of Blood Disease & Bone Marrow Transplantation, Karachi (Pakistan): 1996: data from HBB Karachi, 2006: data from BTIHS, Karachi ****Vitrano A, Calvaruso G, Lai E, et al. The era of comparable life expectancy between thalassaemia major and intermedia: Is it time to revisit the majorintermedia dichotomy? Br J Haematol Jan;176(1): doi: /bjh

5 RELATIONSHIP BETWEEN CURRENT CLASSIFICATION AND SEVERITY OF THALASSEMIA SYNDROMES If current classification (TDT/NTDT) predicts clinical severity of Thalassemia Syndromes (TS), then two well separated classes of risk or of phenotype severity should be apparent in the thalassemia population

6 DOES CURRENT THALASSEMIA SYNDROMES CLASSIFICATION FIT WITH TWO CLASSES OF SURVIVAL RISK? Focusing on clinical severity indicators of 1547 patients (1332 TDT and 215 with NTDT), a cluster analysis was performed to explore if the current thalassemia syndromes classification fits with two classes of risk, regardless if the patients had TDT or NTDT. The following Indicators of Phenotype Severity (IPhS) were selected: 1) age at first transfusion, years; 2) age at starting chelation, years; 3) transfusion therapy (yes/no); 4) mean serum ferritin levels, ng/ml; 5) number of complications. (Vitrano A. et al., Abstract submitted to ASH 2017)

7 PRELIMINAR DATA ON CLUSTER ANALYSIS Cluster identifies a cohort of patients with the same phenotype profile independently from the diagnosis of TDT or NTDT Cluster analysis was applied at these indicators with the task of grouping a set of statistical units in such a way that units in the same group (cluster) will be more similar to each other than to those in other clusters. If current classification fits with clinical severity of thalassemia syndromes, only two well separated classes of risk matching TDT and NTDT should be identified. (Vitrano A. et al., Abstract submitted to ASH 2017)

8 RESULTS FROM PRELIMINAR DATA ON CLUSTER ANALYSIS Cluster analysis suggests that the classes of risk for TDT and NTDT may not fit with such current classification of thalassemia syndromes. Indeed, some patients are detected in the same area of the clusters, independently from the diagnosis of TDT or NTDT (Vitrano A. et al., Abstract submitted to ASH 2017). A B

9 RESULTS FROM PRELIMINAR DATA ON CLUSTER ANALYSIS (Vitrano A. et al., Abstract submitted to ASH 2017)

10 INTERPRETATION OF CLUSTER ANALYSIS Is this the effect of conventional and optimal treatment able to improve the phenotype severity of patients with TDT (and lack for NTDT)? Is the effect of a continuum phenotype with different Classes of Risk ( as in Myelodisplasia,i.e Class I, II, III) from NTDT to TDT? In any of the two cases, this issue will merit consideration.

11 RATIONALE FOR CONSTITUTING AN INTERNATIONAL WORKING GROUP ON THALASSEMIA SYNDROMES Therefore to address these issues different opinion leaders coming from different worldwide countries have been invited to join the I International Working Group!

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13 KUNLE ADEKILE KUWAIT

14 SAQIB HUSSAIN ANSARI PAKISTAN

15 YESIM AYDINOK TURKEY

16 ITALY CATERINA BORGNA PIGNATTI

17 SUISSE MARIE CHARLOTTE BOUE SSEAU

18 MARIA DOMENICA CAPPELLINI ITALY

19 MARINA CAVAZZANA FRANCE

20 ADRIANA CECI ITALY

21 LAKHMIR S. CHAWLA USA

22 SOTEROULA CHRISTOU CIPRO

23 ALAN R. COHEN USA

24 SHAHINA DAAR OMAN

25 VITO DI MARCO ITALY

26 AMAL EL-BESHLAWY EGYPT

27 ALDO FILOSA ITALY

28 GIANLUCA FORNI ITALY

29 SUTHAT FUCHAROEN THAILAND

30 OLIVIER HERMINE FRANCE

31 HISHAMSHAH IBRAHIM MALAYSIA

32 MEHRAN KARIMI IRAN

33 ANTONIS KATTAMIS GREECE

34 PAOLO MOI ITALY

35 KHALED MUSALLAM LEBANON

36 ALESSIA PEPE ITALY

37 ANTONIO PIGA ITALY

38 JOHN PORTER UK

39 ELIEZER RACHMILEWITZ ISRAEL

40 PAOLO RICCHI ITALY

41 FARRUKH SHAH KSA

42 ALOK SRIVASTAVA INDIA

43 TIM ST PIERRE AUSTRALIA

44 ALI TAHER LEBANON

45 PAUL TELFER UK

46 ELLIOTT VICHINSKY USA

47 VIP VIPRAKASIT THAILAND

48 MAHMOUD YASSIN QATAR

49 ISSUES THAT IT WILL BE ADDRESSED BY THE IWG DURING PANEL DISCUSSION (September 15,2017) Interactive discussions, on September 15,2017, about the progress, in different countries, on transfusion management, antiviral treatment, chelation and MRI availability, will help the IWG to reach a shared consensus on this issue: 1. Is the current management of TS in term of access to transfusions, antiviral treatments, chelation, MRI and survival improving worldwide?

50 WORLDWIDE SITUATION PRELIMINARY DATA COLLECTION Nation: Topic Antiviral Treatment NTDT Chelation Treatment MRI Indicator Not Evidence (=0) Evidence (=1) High Evidence (=2) Accessibility Results Management Survival (vs TDT) Accessibility Results Accessibility Impact on survival Data about Worldwide situation will be: Collected during discussions Reviewed with all discussants Used for submitting a paper on worldwide situation

51 ISSUES THAT IT WILL BE ADDRESSED BY THE IWG DURING PANEL DISCUSSION (September 16,2017) 2. Which is the quality/grade (Guayatt et al.,2008) of evidence for the currently used criteria to differentiate TDT versus NTDT at initial diagnosis: Age of diagnosis (<2 vs >2 years old) Hemoglobin level (<7 vs >7 g/dl) Growth failure (<3 percentile) Hemoglobin electrophoresis results

52 ISSUES THAT IT WILL BE ADDRESSED BY THE IWG DURING PANEL DISCUSSION (September 16,2017) 3 Do the IWG recommend others as more relevant for differentiating TDT versus NTDT at initial diagnosis? i.e. - Age of transfusions >6 years or <6 years - Starting chelation treatment >4 years or <4years OR Do they think that TDT and NTDT, at the onset, could be considered as an unique TS with needing of periodical clinical and therapeutical reevaluations?

53 ISSUES THAT IT WILL BE ADDRESSED BY THE IWG DURING PANEL DISCUSSION (September 16,2017) 4. Which could be Indexes of Phenotype Severity (IPhS) for TS, independently if patient has TDT or NTDT? It should be noted that a similar exercise has been recently conducted by Cappellini and colleagues (EJIM 2016) who developed a scoring system for NTDT. We can use this as a starting model to go through the same exercise for all thalassemia phenotypes.

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55 POSSIBLE INDICATORS OF PHENOTYPE SEVERITY FOR THALASSEMIA SYNDROMES (TS) Age Sex Diagnosis Age at diagnosis Age at first trasfusion Age at first chelation Hb pre-trasfusion Trasfusion status Hemoglobin Platelets Iron overload ALT AST Blood requirement Mean ferritin Ejection fraction Cardiac T2* (MRI) Heart failure Arrhythmias Pericarditis Thrombosis Hepatitis B/C Bilirubin (indirect) Gallbladder Cyrrhosis Anti-HCV HCV-RNA Other liver diseases Splenomegaly Splenectomy Renal PHT Leg ulcers Diabetes mellitus Hypoparathyroidism Hypogonadism Hypotiroidism Adrenal Insufficiency Growth hormone deficiency Final eight<3 percentile on standardized charts Osteopenia Osteoporosis Sketal deformity Bone pain Pathologic fractures Dental malocclusion Otitis media Chronic sinusitis Extramedullary hematopoiesis Cancer Infections Lung complications Causes ofdeath Status (dead/alive)

56 ISSUES THAT IT WILL BE ADDRESSED BY THE IWG DURING PANEL DISCUSSION (September 16,2017) Bibliography for IWG participants on this issues is available at site:

57 ISSUES THAT IT WILL BE ADDRESSED BY THE IWG Publications The opportunity to submit to a top haematological journal, with the name of all IWG participants, the results of this I IWG meeting will be pursued. Particularly, it would be nice to submit: Current management of TS worldwide Consensus of criteria on diagnosis at the onset and on indicators of phenotype severity in TS

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59 ACKNOWLEDGEMENTS MAJOR SPONSOR: OTHER SPONSOR: FRANCO AND PIERA CUTINO FOUNDATION: COLLAGE spa: STAFF:

60 WELCOME TO PALERMO

61 WELCOME TO PALERMO