RIC: è l’ora delle raccomandazioni?

1. Convegno Regionale SIE Senigallia, 23-24 ottobre 2008 Delegazione Regionale Marche RIC: è l’ora delle raccomandazioni? Monia Marchetti Comitato Linee-Guida Società Italiana di Ematologia Unità di Ematologia, Ospedale C. Massaia, Asti

2. Strumenti Decisionali • Revisioni sistematiche • Q-TWiST analysis • Linee-guida • Consensus Conference • Analisi decisionali

3. Systematic Reviews

4. Revisioni Sistematiche (1) • IGEV • Immunoglobulin prophylaxis in hematological malignancies and hematopoietic stem cell transplantation. Raanani P et al. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD006501. • PROFILASSI ANTIFUNGINA • Antifungal prophylaxis in cancer patients after chemotherapy or hematopoietic stem-cell transplantation: systematic review and meta-analysis Robensthok et al, J Clin Oncol. 2007 Dec 1;25(34):5471-89. • Fluconazole versus itraconazole for antifungal prophylaxis in neutropenic patients with haematological malignancies: a meta-analysis of randomised-controlled trials. Vardakas KZ et al. Br J Haematol. 2005 Oct;131(1):22-8 • Evidence-based review of antifungal prophylaxis in neutropenic patients with haematological malignancies. Glasmaker & Prentice. J Antimicrob Chemother. 2005 Sep;56 Suppl 1:i23-i32 • BK • Prevention and management of BK-virus associated haemorrhagic cystitis in children following haematopoietic stem cell transplantation--a systematic review and evidence-based guidance for clinical management. Harkensee et al. Br J Haematol. 2008 Sep;142(5):717-31. • GF MIELOIDI • Meta-analysis: effect of prophylactic hematopoietic colony-stimulating factors on mortality and outcomes of infection. Sung L et al. Ann Intern Med. 2007 Sep 18;147(6):400-11. • Meta-analysis of randomized controlled trials of prophylactic granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor after autologous and allogeneic stem cell transplantation. Dekker A et al. J Clin Oncol. 2006 Nov 20;24(33):5207-15.

5. Revisioni Sistematiche (2) • PROFILASSI VOD • Use of prophylactic anticoagulation and the risk of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation: a systematic review and meta-analysis. Imran H et al. Bone Marrow Transplant. 2006 Apr;37(7):677-86. • FONTE DI STAMINALI • Individual patient data meta-analysis of allogeneic peripheral blood stem cell transplant vs bone marrow transplant in the management of hematological malignancies: indirect assessment of the effect of day 11 methotrexate administration.Bensinger W & SC Trialists’ Collaborative Group. Bone Marrow Transplant. 2006 Oct;38(8):539-46 J Clin Oncol. 2005 Aug 1;23(22):5074-87. • Survival after HLA-identical allogeneic peripheral blood stem cell and bone marrow transplantation for hematologic malignancies: meta-analysis of randomized controlled trials. Horan JT et al. Bone Marrow Transplant. 2003 Aug;32(3):293-8. • TRASFUSIONI PIASTRINICHE • Prophylactic platelet transfusion for haemorrhage after chemotherapy and stem cell transplantation. Stanworth SJ et al. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD004269.

6. Revisioni Sistematiche (3) • GVHD • Corticosteroids for preventing graft-versus-host disease after allogeneic myeloablative stem cell transplantation. Quellman S, et al. Cochrane Database Syst Rev. 2008 Jul 16;(3):CD004885 Leukemia. 2008 Sep;22(9):1801-3 • The effect of hematopoietic growth factors on the risk of graft-vs-host disease after allogeneic hematopoietic stem cell transplantation: a meta-analysis. Ho VT et al. Bone Marrow Transplant. 2003 Oct;32(8):771-5. • Profilassi antifungina • Antifungal prophylaxis in cancer patients after chemotherapy or hematopoietic stem-cell transplantation: systematic review and meta-analysis Robensthok et al, J Clin Oncol. 2007 Dec 1;25(34):5471-89. • Antifungal prophylaxis for severely neutropenic chemotherapy recipients: a meta analysis of randomized-controlled clinical trials. Bow EJ et al. Cancer. 2002 Jun 15;94(12):3230-46.

7. Revisioni sistematiche ASBMT • The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in adults: an evidence-based review. Biol Blood Marrow Transplant. 2006 Jan;12(1):1-30. • The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in children: an evidence-based review. Biol Blood Marrow Transplant. 2005 Nov;11(11):823-61 • The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myeloid leukemia in children: an evidence-based review. Biol Blood Marrow Transplant. 2007 Jan;13(1):1-25. • The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myelogenous leukemia in adults: an evidence-based review. Biol Blood Marrow Transplant. 2008 Feb;14(2):137-80. • The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of multiple myeloma: an evidence-based review. Biol Blood Marrow Transplant. 2003 Jan;9(1):4-37. • The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of diffuse large cell B-cell non-Hodgkin's lymphoma: an evidence-based review. Biol Blood Marrow Transplant. 2001;7(6):308-31.

8. STUDIES OF SCT FOR MDS USING REDUCED-INTENSITY CONDITIONING (I ) REFERENCE REGIMEN No AGE (MEDIAN) DISEASE DONOR TYPE NRM% FULL COHORT NRM% MDS SUBGROUP OUTCOME ENTIRE COHORT % OUTCOME MDS SUBGROUP % MARTINO 2006 R 1997-2001 FluTBI 2 Gy 215 27-72 (56) MDS MRD 22 (3 YR) ND 3 YR OS 41 3 YR PFS 33 REL INC 3 YR 45 ND LIM 2006 P 1999-2004 Flu+Bu+ Campath 75 19-68 (52) MDS T-AML MUD 3 YR 30 ND OS 3 YR 43 DFS 3 YR 41 ND LAPORT 2008 R 1998-2004 FluTBI 2 Gy 65 MDS 42-72 (60) sMDS 46-73 (56) MDS sMDS MRD MUD ND DE NOVO MDS NRM AT 3 YEARS 40% sMDS NRM AT 3 YEARS 31% ND MEDIAN FOLLOW-UP 47 MONTHS de NOVO MDS OS AT 3 YEARS 23% RFS AT 3 YEARS 20% RELAPSE AT 3 YEARS 40% T-NOVO MDS OS AT 3 YEARS 27% RFS AT 3 YEARS 29% RELAPSE AT 3 YEARS 40% HALLEMEIER 2006 P 1995-2002 TBI (550 cGy)/EDX 51 19-70 (44) MDS T-AML MRD MUD ND 3 YR RA 29 RAEB 47 ND OS 3 YR RA 46 RAEB 33 RELAPSE RISK 3 YR RA 53 RAEB 13 SIE systematic reviews

9. I believe !! Slow-down: the evidence is not complete! Clinical Guidelines

10. Levels of evidence • 1++ High quality meta­analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias • 1+ Well conducted meta­analyses, systematic reviews of RCTs, or RCTs with a low risk of bias • 1- Meta­analyses, systematic reviews or RCTs, or RCTs with a high risk of bias • 2++ High quality systematic reviews of case­control or cohort studies or High quality case­control or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal • 2+ Well conducted case­control or cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal • 2- Case­control or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the relationship is not causal • 3 Non­analytic studies, eg case reports, case series • 4 Expert opinion

11. REDUCED INTENSITY CONDITIONING STUDIES REFERENCE TYPE OF STUDY SIGN GRADING MARTINO 2006 RETROSPECTIVE 1997-2001 3 LIM 2006 PROSPECTIVE 1999-2004 2- LAPORT 2008 RETROSPECTIVE 1998-2004 2- HALLEMEIER 2006 PROSPECTIVE 1995-2002 2 VALCARCEL 2008 PROSPECTIVE 1998-2005 2 HO 2004 PROSPECTIVE (nd) 2- PARKER 2002 RETROSPECTIVE 1993-2000 3 CHO 2007 RETROSPECTIVE 2002-2005 2- SOLOMON 2005 RETROSPECTIVE 1997-2004 3 TAURO 2005 RETROSPECTIVE 1998-2004 3 CHAN 2003 PROSPECTIVE 2000-2003 2- RIC in MDS: levels of evidence (full papers)

12. SIGN grading • A • At least one meta­analysis, systematic review, or RCT rated as 1 + + and directly applicable to the target population or • A systematic review of RCTs or a body of evidence consisting principally of studies rated as 1 + directly applicable to the target population and demonstrating overall consistency of results • B • A body of evidence including studies rated as 2 + + directly applicable to the target population and demonstrating overall consistency of results or • Extrapolated evidence from studies rated as 1 + + or 1 + • C • A body of evidence including studies rated as 2 + directly applicable to the target population and demonstrating overall consistency of results or • Extrapolated evidence from studies rated as 2 + + • D • Evidence level 3 or 4 or • Extrapolated evidence from studies rated as 2 +

13. NCCN grading

15. General, Procedure & Follow-up • ECOG • Recommended guidelines for the management of autologous and allogeneic bone marrow transplantation. A report from the Eastern Cooperative Oncology Group (ECOG) Ann Intern Med. 1994 Jan 15;120(2):143-58 Gestione staminali • Screening and prevention practices for long-term survivors: • European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation Biol Blood Marrow Transplant. 2006 Feb;12(2):138-51. Bone Marrow Transplant. 2006 Feb;37(3):249-61

16. Supportive care • Profilassi e trattamento CMV • EBMT (Bone Marrow Transplant. 2004 Jun;33(11):1075-81) • [Consensus document from GESITRA-SEIMC on the prevention and treatment of cytomegalovirus infection in transplanted patients]- Torre-Cisneros et al. Enferm Infecc Microbiol Clin. 2005 Aug-Sep;23(7):424-37. • Mucosite • Generica - International Society of Oncology Cancer. 2007 Mar 1;109(5):820-31. • Fattori di crescita • Use of G-CSF in matched sibling donor pediatric allogeneic transplantation: a consensus statement from the Children's Oncology Group (COG) Transplant Discipline Committee and Pediatric Blood and Marrow Transplant Consortium (PBMTC) Executive Committee. Grupp SA et al. Pediatr Blood Cancer. 2006 Apr;46(4):414-21. • Complicanze infettive • AGIHO working party - German Society Hematology Oncology (Ann Hematol. 2003 Oct;82 Suppl 2:S175-85 ) • CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation (Cytotherapy. 2001;3(1):41-54. ) • Prevenzione (incl. profilassi) anti-infettiva • CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation Biol Blood Marrow Transplant. 2001;7 Suppl:19S-22S.; Clin Infect Dis. 2001 Jul 15;33(2):139-44. ) + ASH (Hematology Am Soc Hematol Educ Program. 2001:392-421 ) • Profilassi antibatterica - AGIHO working party - German Society Hematology Oncology (Ann Oncol. 2005 Aug;16(8):1381-90 ) • Vaccinazioni dopo il trapianto – • GETH (Spagna) Med Clin (Barc). 1998 Feb 7;110(4):146-55. • EBMT - Bone Marrow Transplant. 2005 Apr;35(8):737-46

17. Indications for Transplantation • Raccomandazioni specifiche all’interno di linee-guida di: • NCCN • SIE • BSH • ESMO • EBMT • ASBMT

18. “OUGHT” statements (such as Guidelines) rarely can be constructed uniquely and directlyfrom “IS” statements (such as Research Evidence). David Hume

19. Consensus Conference

20. Consensus • Perché? • “Views of a grup have greater validity and reliability than the judgment of an individual” • Quando? • Confronto tra rischi e benefici • Conferma dell’applicabilità dei dati • Conferma della fattibilità (disponibilità di tecnologia e/o expertise, costi) • Definizione della validità di traslazioni a sottogruppi • Giudizio di confronto indiretto tra trattamenti • Come? • Metodi strutturati (Delphi, NomGrTch, RAND-UCLA, CC)

21. Consensus Conferences Meetings that bring togeather a wide variety of participants (several non-physicians) who are charged with developing a mutually acceptable consensus statement to answer specific, pre-defined questions about the topic • CLL • Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. Dreger, Corradini et al. CLL working pary EBMT. Leukemia. 2007 Jan;21(1):12-7 • DLBCL • International Consensus Conference on High-Dose Therapy with Hematopoietic Stem Cell Transplantation in Aggressive Non-Hodgkin's Lymphomas: report of the jury. Shipp MA et al. J Clin Oncol. 1999 Jan;17(1):423-9. Ann Oncol. 1999 Jan;10(1):13- 9 • Mieloma Mutiplo • The role of high-dose chemotherapy and stem-cell transplantation in patients with multiple myeloma: a practice guideline of the Cancer Care Ontario Practice Guidelines Initiative. Ann Intern Med. 2002 Apr 16;136(8):619-29.

22. Q-TWiST analysis

23. TWiST (Time wo Symptoms or Toxicity) ASCT x DLBCL (CR1) Mounier et al Blood 2000

24. Q-TWiST

25. Decision Analysis

26. Modello decisionale MDS

27. Modello decisionale AML Sung et al, Cancer 2003

28. Analisi Decisionali (1) • Indicazioni al Trapianto (alloSCT) • A decision analysis of allogeneic bone marrow transplantation for the MYELODYSPLASTIC SYNDROMES: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Cutler CS et al. Blood. 2004 Jul 15;104(2):579-85 • Treatment options for patients with ACUTE MYELOID LEUKEMIA with a matched sibling donor: a decision analysis. Sung L et al. Cancer. 2003 Feb 1;97(3):592-600. • Bone marrow transplantation versus periodic prophylactic blood transfusion in sickle cell patients at high risk of ischemic stroke: a decision analysis. Nietert PJ et al. Blood. 2000 May 15;95(10):3057-64. • Allogenic bone marrow transplantation or chemotherapy for patients with ACUTE MYELOID LEUKEMIA in first complete remission: a decision analysis approach. Hertenstein B et al. Ann Hematol. 1996 Apr;72(4):223-30. • Unrelated donor bone marrow transplantation for CML: a decision analysis. Lee SJ et al. Ann Intern Med. 1997 Dec 15;127(12):1080-8. • An introduction to clinical decision analysis: bone marrow transplantation for aplastic anemia. Buchanan JG. Aust N Z J Med. 1983 Oct;13(5):451-6.

29. Analisi Decisionali (2) • Profilassi con pavilizumab (Ped) • Palivizumab prophylaxis to prevent respiratory syncytial virus mortality after pediatric bone marrow transplantation: a decision analysis model. Thomas. J Pediatr Hematol Oncol. 2007 Apr;29(4):227-32. • Bonifica dentale • A decision analysis: the dental management of patients prior to hematology cytotoxic therapy or hematopoietic stem cell transplantation. Elad et al. Oral Oncol. 2008 Jan;44(1):37-42. Epub 2007 Feb 16. • Biopsia cute x sospetta GVHD • Role of skin biopsy to confirm suspected acute graft-vs-host disease: results of decision analysis. Arch Dermatol. 2006 Feb;142(2):175-82.

30. American Society for Bone Marrow Transplantation

31. ASBMT • Guidelines • Es: recommended timing x consultation • Policy Statements (short list of recommend) • SC therapy for AML • Evidence-based Reviews (EB guidelines – SIGN) • Jones R et al. ASBMT policy statement regarding the methodology of evidence-based reviews in evaluating the role of blood and marrow transplantation in the treatment of selected diseases. American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2000;6(5):524-5. Updated in 2005 • Theresa Hanh: ALL adults; ALL children; AML adults (2008); AML chidlren; MM (2003); DLBCL (2001)

32. ASBMT – Recomm. Timing for Transplant Consultation (1)

33. ASBMT – Recomm. Timing for Transplant Consultation (2)

34. Società Italiana di Ematologia

35. Linee-guida SIE 1 membro GITMO

36. Reduced-intensity SC Transplantation

37. Problemi metodologici EBM • Stratificazione per rischio di malattia ma anche per comorbidità • RIC vs non-RIC richiede stratificazione dei pazienti sia per le analisi retrospettive che per gli studi prospettici • HCT-CI (Comorbidity Index) sviluppato x AML e MDS (Sorror JCO 2007): è’ l’unico score? Ci sono score di severità di malattia (WPSS…) con cui bilanciarlo? • Studi retrospettivi • Confronti multipli • RIC vs no SCT • RIC vs no RIC • RIC vs ASCT • Endpoint multipli • TRM • Qualità di vita

38. Competing risks

39. Raccomandazioni EBMT • Bacigalupo A.Third EBMT/AMGEN Workshop on reduced-intensity conditioning allogeneic haemopoietic stem cell transplants (RIC-HSCT), and panel consensus. Bone Marrow Transplant. 2004 Apr;33(7):691-6.

40. Raccomandazioni SIE • Indolent NHL • 2005: Myeloabl <45 yrs • DLBCL • 2006: >50 yrs • MM • 2004: still experimental • AML • 2008 (in press): RACC: >55 yrs & no severe comorb • MDS • 2001: no evidence for rec • (2008): >50 yrs & no severe comorb • HL • (2008): RACC

41. Raccomandazioni ASBMT • Indolent NHL • DLBCL • 2001: dati inadeguati x racc: arruolare in studi clinici comparativi • MM • 2003: no possibile formul racc al RIC • AML • 2007: RIC equivalente ma pochi dati x formul racc: dipende dalle caratterist del paz • MDS • HL

42. Conclusioni

43. Abbiamo bisogno di raccomandazioni x il RIC? • Abbiamo bisogno di raccomandazioni? • RIC = oltre un terzo degli alloSCT EBMT • Profonda eterogeneità tra centri • TRM molto limitata • Di quali raccomandazioni abbiamo bisogno? • RIT vs non HD therapy • RIT vs Myeloablative SCT • RIT vs ASCT

44. Possiamo formulare raccomandazioni? (1) • Systematic methods were used to search for evidence & the criteria for selecting the evidence are clearly described • The quality of evidence is graded • GRADE: Systematic and explicit consideration of study design, study quality, consistency, and directness of evidence in judgments about quality of evidence • GRADE: Explicit consideration of imprecise or sparse data, reporting bias, strength of association, evidence of a dose-response gradient, and plausible confounding • GRADE: Overall quality of evidence needs to be based on the lowest quality of evidence for any of the outcomes that are critical to making a decision • There is an explicit link between the supporting evidence and the recommendations

45. Possiamo formulare raccomandazioni? (2) • The methods used for formulating the recommendations are clearly described • GRADE: Clarifies each of these explicit & sequential judgments and reduces risks of introducing errors or bias that can arise when they are made implicitly • The health benefits, side effects, and risks have been considered in formulating the recommendations • GRADE: Explicit judgments about which outcomes are critical, which ones are important but not critical, and which ones are unimportant and can be ignored. • GRADE: Explicit consideration of trade-offs between important benefits and harms, the quality of evidence for these, translation of evidence into specific circumstances, and certainty of baseline risks • GRADE: Explicit consideration of whether the health benefits are worth the costs needs to be performed after first considering whether there are net health benefits

46. Possiamo formulare raccomandazioni? (3) • The guideline has been externally reviewed by experts prior to its publication • A procedure for updating the guideline is provided • Development, validation and application • GRADE: International collaboration across wide range of organizations in development and evaluation

47. CONCLUSIONI (1) • E’ necessario formulare raccomandazioni al RIC • I metodi EBM per sviluppare raccomandazioni al RIC possono essere applicati, ma con limiti derivanti dalla qualità dell’evidenza • Metodi alternativi (analisi decisionali, consensus conference) possono supportare raccomandazioni provvisorie, in attesa di maggiore evidenza • Le linee-guida SIE più recenti hanno infatti incluso raccomandazioni esplicite all’impiego del RIC

48. CONCLUSIONI (2) • L’arruolamento dei pazienti in registri e studi clinici diventa quindi indispensabile • Favorire lo sviluppo di strumenti per stratificare la comorbidità e per misurare la qualità di vita • Il progetto Linee-Guida della SIES potrebbe avvalersi di updates SCT-specifici GITMO

50. Indolent NHL -SIE 2005 “Myeloablative allogeneic SCT should be reserved to very selected patients <45 years old” [grade D] HL - SIE 2008 “RIC recommended” MDS -SIE 2001 “No recommendations may be given at present on the use of allo-SCT with regimens of low- intensity conditioning; the EP, however, consider this a promising approach” MDS -SIE 2008 … myeloablative conditioning regimen if younger than 50 years and without comorbidities… Ongoing discussion: reduced-intensity for SCT candidates older than 50 and/or with IPSS low/INT1? MM -SIE 2004 “The use of reduced-intensity or non-myeloablative conditioning regimens is still experimental and should be performed in the context of approved clinical trials” DLBCL - SIE 2006 “Younger patients (<50 ys) who are candidates to allogeneic SCT should receive myeloablative conditioning. Patients aged over 50 yrs should receive reduced-intensity conditioning.”[grade D] Fludarabine-containing regimens should be empolyed for reduced-intensity allogeneic SCT. “[grade C] SIE racc RIT