EUROCHIP-3 WP7 DISCUSSION ON ALL FOCUS LIST (A) non-HR ...

EUROCHIP-3 WP7 DISCUSSION ON ALL FOCUS LIST(A) non-HR/(B) non-B mature 15.02.2011MINIMUM REQUIREMENT TOOLS- DIAGNOSTICS1.Di.04by who and whenMRD (minimal residual disease) in cytofluorimetrySpecialistLaboratory-biologist-evidencediscussion to evidenceproblemsHTA referencedone to identify residual diseaseNumerous studies suggesting differential outcome by MRD1-2 levelRequirement or diagnosis can be made by morphology. Required for stratification of therapyCentralization of samples in few laboratoriesStandardisation of technologyConclusions THIS WILL BE FINALISED DURING THE NEXT WP7 MEETING in JUNE 2011Alternatives do not exist - should be considered -may exist pending further researchAlternativeby who and whenevidencediscussion to evidenceproblemsHTA referenceIf applicableConclusions THIS WILL BE FINALISED DURING THE NEXT WP7 MEETING in JUNE 2011Alternatives do not exist - should be considered -may exist pending further research1

EUROCHIP-3 WP7 DISCUSSION ON ALL FOCUS LIST(A) non-HR/(B) non-B mature 15.02.2011ADDITIONAL TOOLS –Diagnostics1.Di.07by who and whenevidenceBrain MRI/CTRadiologistDone to assess brain toxicity or damagesBasic test level 1 evidence base literaturediscussion to evidenceproblemsHTA referenceTo detect possible CNS involvement - Not standard test for diseaseEthical concerns for CT; High MRI costConclusions THIS WILL BE FINALISED DURING THE NEXT WP7 MEETING in JUNE 2011Alternatives do not exist - should be considered -may exist pending further researchAlternativeby who and whenevidencediscussion to evidenceproblemsHTA referenceIf applicableConclusions THIS WILL BE FINALISED DURING THE NEXT WP7 MEETING in JUNE 2011Alternatives do not exist - should be considered -may exist pending further research2

EUROCHIP-3 WP7 DISCUSSION ON ALL FOCUS LIST(A) non-HR/(B) non-B mature 15.02.2011ADDITIONAL TOOLS –Diagnostics1.Di.09by who and whenevidencediscussion to evidenceproblemsHTA referencePCR-MRDSpecialist-Laboratory- biologistDone to detect molecular involvement or remissionNumerous studies suggesting differential by MRD 1 level• Flohr T, Schrauder A, Cazzaniga G et al. Minimal residual disease-directed riskstratification using real-time quantitative PCR analysis of immunoglobulin and T-cellreceptor gene rearrangements in the international multicenter trial AIEOP-BFM ALL 2000for childhood acute lymphoblastic leukemia. Leukemia 2008;22(4):771-82.• van der Velden VH, Hochhaus A, Cazzaniga G, et al. Detection of minimal residualdisease in hematologic malignancies by real-time quantitative PCR: principles,approaches, and laboratory aspects. Leukemia. 2003;17:1013-1034.• van Dongen JJ, Langerak AW, Bruggemann M, et al. Design and standardization of PCRprimers and protocols for detection of clonal immunoglobulin and T-cell receptor generecombinations in suspect lymphoproliferations: report of the BIOMED-2 ConcertedAction BMH4-CT98-3936. Leukemia. 2003;17:2257-2317.• Dworzak MN, Froschl G, Printz D, et al. Prognostic significance and modalities of flowcytometric minimal residual disease detection in childhood acute lymphoblastic leukemia.Blood. 2002;99:1952-1958.• Gaipa G, Basso G, Maglia O, et al. Drug-induced immunophenotypic modulation inchildhood ALL: implications for minimal residual disease detection. Leukemia.2005;19:49-56.• Ratei R, Karawajew L, Lacombe F, et al. Discriminant function analysis as decisionsupport system for the diagnosis of acute leukemia with a minimal four color screeningpanel and multiparameter flow cytometry immunophenotyping. Leukemia.2007;21:1204-1211.• Veltroni M, De Zen L, Sanzari MC, et al. Expression of CD58 in normal, regenerating andleukemic bone marrow B cells: implications for the detection of minimal residual diseasein acute lymphocytic leukemia. Haematologica. 2003;88:1245-1252.• Basso G, Veltroni M, Valsecchi MG, et al. Risk of relapse of childhood acutelymphoblastic leukemia is predicted by flow cytometric measurement of residual diseaseon day 15 bone marrow. J Clin Oncol. 2009 Nov 1;27(31):5168-74Required for stratification of therapy and to be sure of CR but not an absolute requirementfor diagnosis (Diagnosis can be made by morphology and immuno-cytochemistry)Standardisation of technology and methodology is required (not always available)Studies not availableConclusions THIS WILL BE FINALISED DURING THE NEXT WP7 MEETING in JUNE 2011Alternatives do not exist - should be considered -may exist pending further researchalternativeby who and whenevidencediscussion to evidenceproblemsHTA referenceTopic to be further investigatedConclusions this will be finalised during the next wp7 meeting in june 2011Alternatives do not exist - should be considered -may exist pending further research3

EUROCHIP-3 WP7 DISCUSSION ON ALL FOCUS LIST(A) non-HR/(B) non-B mature 15.02.2011MINIMUM REQUIREMENT TOOLS- Radiotherapy4.Ra.01by who and whenRadiotherapy only on specific demand (only HR or CNS+)(only HR or CNS+)evidence • Schrappe M, Reiter A, Ludwig WD, et al. Improved outcome in childhood acutelymphoblastic leukemia despite reduced use of anthracyclines and cranialradiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM StudyGroup. Blood. 2000;95:3310-3322.• Conter V, Schrappe M, Arico M, et al. Role of cranial radiotherapy for childhood T-cellacute lymphoblastic leukemia with high WBC count and good response to prednisone.Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Munster groups. J Clin Oncol. 1997;15:2786-2791.• Conter V, Arico M, Valsecchi MG, et al. Intensive BFM chemotherapy for childhoodALL: interim analysis of the AIEOP-ALL 91 study. Associazione Italiana EmatologiaOncologia Pediatrica. Haematologica. 1998;83:791-799.• Schrappe M, Reiter A, Henze G, et al. Prevention of CNS recurrence in childhood ALL:results with reduced radiotherapy combined with CNS-directed chemotherapy in fourconsecutive ALL-BFM trials. Klin Padiatr. 1998;210:192-199.discussion to evidenceproblemsHTA referenceAccess limited due to organizational aspects and linked to network activity limitationsConclusions THIS WILL BE FINALISED DURING THE NEXT WP7 MEETING in JUNE 2011Alternatives do not exist - should be considered -may exist pending further researchalternativeby who and whenevidencediscussion to evidenceproblemsHTA referenceStructural EU funds should be allocated to network-affiliated institutesConclusions THIS WILL BE FINALISED DURING THE NEXT WP7 MEETING in JUNE 2011Alternatives do not exist - should be considered -may exist pending further research4

EUROCHIP-3 WP7 DISCUSSION ON ALL FOCUS LIST(A) non-HR/(B) non-B mature 15.02.2011ADDITIONAL TOOLS – Medical Oncology5.On.14by who and whenevidencediscussion to evidenceproblemsHTA referencePeg - Asparaginasetherapy tooladministered by physician in a multidrug regimen specific for ALL cellsCost-effectiveness studies to be considered in relation to alternatives (see below)Conclusions THIS WILL BE FINALISED DURING THE NEXT WP7 MEETING in JUNE 2011Alternatives may exist and further investigation is requiredalternativesby who and whenevidenceL-Asparaginase L-Asi E.Coli, Erwinasemultidrug regimen specific for ALL cellskey in standard therapy - randomised evidence that optimal exposure improves outcome2 level references• Abuchowski A, Kazo GM, Verhoest CR, Jr., et al. Cancer therapy with chemically modifiedenzymes. I. Antitumor properties of polyethylene glycol-asparaginase conjugates. CancerBiochem Biophys. 1984;7:175-186.• Asselin BL, Whitin JC, Coppola DJ, Rupp IP, Sallan SE, Cohen HJ. Comparativepharmacokinetic studies of three asparaginase preparations. J Clin Oncol. 1993;11:1780-1786.• Muller HJ, Loning L, Horn A, et al. Pegylated asparaginase (Oncaspar) in children withALL: drug monitoring in reinduction according to the ALL/NHL-BFM 95 protocols. Br JHaematol. 2000;110:379-384.• Park YK, Abuchowski A, Davis S, Davis F. Pharmacology of Escherichia Coli-Lasparaginasepolyethylene glycol adduct. Anticancer Res. 1981;1:373-376.• Avramis VI, Sencer S, Periclou AP et al. A randomized comparison of native Escherichiacoli asparaginase and polyethylene glycol conjugated asparaginase for treatment ofchildren with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children'sCancer Group study. Blood 2002 Mar 15;99(6):1986-94. Erratum in: Blood 2002 Sep1;100(5):1531.• Rizzari C, Citterio M, Zucchetti M et al. A pharmacological study on pegylatedasparaginase used in front-line treatment of children with acute lymphoblastic leukemia.Haematologica. 2006 Jan;91(1):24-31.• Jarrar M, Gaynon PS, Periclou AP et al. Asparagine depletion after pegylated E. coliasparaginase treatment and induction outcome in children with acute lymphoblasticleukemia in first bone marrow relapse: a Children's Oncology Group study (CCG-1941).Pediatr Blood Cancer. 2006 Aug;47(2):141-6.• Wetzler M, Sanford BL, Kurtzberg J et al. Effective asparagine depletion with pegylatedasparaginase results in improved outcomes in adult acute lymphoblastic leukemia:Cancer and Leukemia Group B Study 9511. Blood 2007 May 15;109(10):4164-7.• Abshire TC, Pollock BH, Billett AL et al. Weekly polyethylene glycol conjugated L-asparaginase compared with biweekly dosing produces superior induction remissionrates in childhood relapsed acute lymphoblastic leukemia: a Pediatric Oncology GroupStudy. Blood 2000 Sep 1;96(5):1709-15.• Sallan SE, Hitchcock-Bryan S, Gelber R, Cassady JR, Frei E, 3rd, Nathan DG. Influence ofintensive asparaginase in the treatment of childhood non-T-cell acute lymphoblasticleukemia. Cancer Res. 1983;43:5601-5607.• Silverman LB, Gelber RD, Dalton VK, et al. Improved outcome for children with acutelymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood.5

EUROCHIP-3 WP7 DISCUSSION ON ALL FOCUS LIST(A) non-HR/(B) non-B mature 15.02.2011discussion to evidenceproblemsHTA reference2001;97:1211-1218.• Killander D, Dohlwitz A, Engstedt L, et al. Hypersensitive reactions and antibodyformation during L-asparaginase treatment of children and adults with acute leukemia.Cancer. 1976;37:220-228.• Evans WE, Tsiatis A, Rivera G, et al. Anaphylactoid reactions to Escherichia Coli andAsparaginasi da Erwinia in children with leukemia and lymphoma. Cancer.1982;49:1378-1383.• Muller HJ, Beier R, Loning L, et al. Pharmacokinetics of native Escherichia Coliasparaginase (Asparaginase medac) and hypersensitivity reactions in ALL-BFM 95reinduction treatment. Br J Haematol. 2001;114:794-799.• Muller HJ, Boos J. Use of L-asparaginase in childhood ALL. Crit Rev Oncol Hematol.1998;28:97-113.• Appel IM, Kazemier KM, Boos J et al. Pharmacokinetic, pharmacodynamic andintracellular effects of PEG-asparaginase in newly diagnosed childhood acutelymphoblastic leukemia: results from a single agent window study. Leukemia 2008Sep;22(9):1665-79.• Vieira Pinheiro JP, Wenner K, Escherich G et al. Serum asparaginase activities andasparagine concentrations in the cerebrospinal fluid after a single infusion of 2,500IU/m(2) PEG asparaginase in children with ALL treated according to protocol COALL-06-97. Pediatr Blood Cancer 2006 Jan;46(1):18-25.Cost-effectiveness studies to be considered in relation to Peg AsparaginasePancreatic- Allergic toxicity - coagulopathy(studies on vinase efficacy and cost efficacy to be included)Pending cost referenceConclusions THIS WILL BE FINALISED DURING THE NEXT WP7 MEETING in JUNE 2011Alternatives do not exist - should be considered -may exist pending further research6