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CMML Is there anything new?

CMML Is there anything new?. Mark Drummond Beatson Oncology Centre Glasgow. CMML Update. Background Diagnosis Prognosis Treatment. “ A Disorder lost in Classification….”. FAB Group 1. 1982. Myelodysplastic Syndrome. FAB Group 2. 1994. CMML-MD vs CMML-MP*. WHO 3. 2001.

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CMML Is there anything new?

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  1. CMMLIs there anything new? Mark Drummond Beatson Oncology Centre Glasgow

  2. CMML Update • Background • Diagnosis • Prognosis • Treatment

  3. “ A Disorder lost in Classification….” FAB Group1 1982 Myelodysplastic Syndrome FAB Group2 1994 CMML-MD vs CMML-MP* WHO3 2001 MDS / MPD WHO4 2008 CMML-1 / CMML-2** 1984 Blood, 63. ** BM Blasts <10% or 10-20% * WCC > 13 x 109/L 1Bennet et al, 1982; BJH, 51, 189-1999: 2Bennet et al, 1994; BJH, 87, 746-754: 3Vardiman et al, WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 2001: : 4Vardiman et al, WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 2008.

  4. WHO 2008 • PB monocytosis >1.0 x 109/L (usually >10% of leucocytes) • Absence of BCR-ABL • No rearrangement of PDGFRA or PDGFRB (exclude in eosinophilia) • <20% blasts in Blood and Marrow (includes myeloblasts, monoblasts and promonocytes) • Dysplasia in 1 or more myeloid lineage

  5. Demographics • Incidence: WHO ≈ 4 / 100,000 (WHO 2008) 0.46 / 100,000 (Thames Cancer Registry*) 0.7 / 100,000 (www.hmrn.org) 270 – 420 cases p.a. in UK • Age: WHO 65 – 75 years (WHO 2008) 76 years (www.hmrn.org) *Haematologica 2006; 91:1400-1404.

  6. A Spectrum of Disease? AML M4 or M5 (30%)* • CMML – MDS • 60%* • Cytopaenias • Median OS 16-31 months • CMML – MPD • 40%* • Leucocytosis • Organomegaly • Karyotypic evolution • Median OS 11-17 months WCC < 13 x 109/L FAB, 1994 • CMML – 2 (15%)* • Median OS 15 months** • CMML – 1 (85%)* • Median OS 20 months** *Such et al, 2013, Blood, Prepublished online 31.1.2013. ** Germing et al, 2007, Haematologica, 92, 974 – 977.

  7. Diagnosis

  8. Diagnostics • Lots of morphological variables, therefore very heterogeneous • Reactive vs. clonal monocytosis: Elderly patients, co-morbidities, other reasons for cytopaenias & monocytosis. • Monocytes difficult to assess in marrow (asp & trephine); granulocytic hyperplasia is striking • CMML vs. AML: overlapping morphology & flow. Transforming CMML –mixed picture. Blasts generally CD34 negative.

  9. Monocyte / Monoblast Morphology Monoblast Promonocyte Immature Monocyte AML (≥ 20%) CMML IWGM-MDS: Haematologica 2009; 94 (7): 994-999.

  10. Morphology X 100, oil Immersion

  11. Flow Cytometry is Helpful…. Monoblast Promonocyte Immature Monocyte CMML Reduced HLA-DR Aberrant CD56 Aberrant CD2 *Xu et al, Am J Path, 2005; 124 (5): 799-806.**Kern et al, LeukLymp, 2011; 52(1); 92-100

  12. 83% 99% Aberrant Markers Common • CD56 expressed in ≈ 80% CMML (40% AMoL) • Nice technique for PB • Very promiscuous antigen - caution • May be induced in reactive states &/or G-CSF / GM-CSF administration

  13. Trephine Histology • Hypercellular • Granulocytic Hyperplasia • Excess monocytes; best appreciated with ICC (e.g. CD68) • Variable reticulin fibrosis • May detect other causes of monocytosis or additional pathology (e.g. SM-AHNMD)

  14. Diagnosis: Summary • Cytology (blood +/- marrow) crucial • Flow useful to confirm abnormal monocytes & maturational stage • Trephine confirms myeloproliferative aspects • Genetic testing: cytogenetics (non-specific, abnormal in 30%), role of mutation analysis in future.

  15. Molecular Abnormalities

  16. TET2 Mutations Most common abnormality in CMML ≈ 50% of cases mutated Loss of protein function tumour suppressor role ? Found in CD34+ cells and T-cells Prognostic impact controversial

  17. Molecular Heterogeneity in CMML TET2 ≈ 50% ? outcome Epigenetic Regulation MPD phenotype, poor outcome ASXL1 ≈ 40% EZH2 ≈ 10% Poor outcome JAK2 V617F ≈ 10% MPD phenotype Signalling Pathways CBL ≈ 20% MPD phenotype, disease progression KRAS / NRAS ≈ 30% SRSF2 ≈ 50% mRNA Splicing 93% of CMML has one or more mutations in these genes RUNX1 ≈ 20% Transcription IDH2 ≈ 10% Metabolism

  18. Prognosis

  19. “ A Disorder lost in Prognostication….” 1997 IPSS WCC >12 x 109 excluded2 Dusseldorf Registry1 1992 Düsseldorf Score IPSS-R 2012 2011 Cytogenetic Risk Score WCC >12 x 109 excluded5 Spanish MDS Registry4 213 CMML pts3 Spanish MDS Registry6 2013 2002 MD Anderson Score CPSS 1Aul et al, Leukaemia 1992, 6, 52-59; 2Greenberg et al, Blood, 1997, 89 (6) 2079;3Onida et al, Blood 2002, 90 (3), 840; 4Such et al, Haematologica 2011, 96 (3), 375; 5Greenberg et al, Blood 2012, 120 (12), 2454; 6Such et al, Blood 2013 epub ahead of print

  20. Cytogenetic Risk Classification in CMML • 414 pts from Spanish registry (1980-2008) • 110 (27%) had abnormal karyotype • 3 Cytogenetic Risk categories identified: • LOW RISK (78%): Normal, or isolated loss of Y • NORMAL RISK (9%): All other • HIGH RISK (12%): Trisomy 8, abnormalities of chr7, or complex 5yr OS 35% 26% 4% Such et al, Haematologica 2011, 96 (3)

  21. CMML-Specific Prognostic Scoring System (CPSS) Such et al, Blood 2013 epub ahead of print

  22. CMML-Specific Prognostic Scoring System (CPSS) Median OS Low (41%): 72 Months Int-1 (29%): 31 Months Int-2 (26%): 13 months High (4%): 5 months Such et al, Blood 2013 epub ahead of print

  23. Treatment

  24. Patient / Doctor Treatment Goals in CMML Watch & wait Palliation Supportive Care Hydroxycarbamide LD Ara C Steroids HD chemo for sAML Disease Modification ? Demethylating Agents ? Experimental therapies Cure Allo SCT (+/- HD chemo pre-transplant)

  25. MS 20 months. p<0.0001 AML – 27%, ns MS 9 months, p<0.001 AML – 38%, ns Wattel et al, Blood 1996; 2480 - 2487

  26. Palliation / LD Chemo / HD Chemo • LD ARA-C • No studies specific to CMML, some reponses reported • Cytoreductive: use in extramedullary disease, pts with poor response to hydroxy • Prednisilone • Symptomatic control; skin and pleural effusions. • HD Chemo • No role in isolation • Pre allo SCT (1 or 2 cycles) • ‘intensive’ palliation?

  27. Palliation Transfusion support Hydroxycarbamide LD Ara C Steroids Cure Allo SCT (+/- HD chemo pre-transplant) Patient / Doctor Treatment Goals in CMML Disease Modification ? Demethylating Agents ? Experimental therapies

  28. ≈ 85-90% of patients are >65 www.hmrn.org

  29. Treatment Patterns Spanish Registry (414 pts, 1980 – 2008)1 • Supportive care (100%) • ESA (42%) • HC (16%) • AML-type Intensive Chemo (6%) • Allo SCT (<1%) • No Demethylating agents used French Transplant Registry2 • 73 allos done 1992 – 2009 • approx 1.5 % of all cases of CMML transplanted based on incidence of 0.47 / 100,000 p.a.3 1Such et al, Haematologica 2011, 96 (3); 2Park et al, EJH 2013; 3Drummond 2013, Back of an envelope, based on incidence

  30. Transplant Outcome: 1992-2009 73 pts 1992 – 2009 Median age 53 43 RIC / 30 MA; 41 sibling / 32 VUD Multivariate analysis Splenomegaly at transplant (HR 0.48) Transplant pre 2004 (HR 0.42) ?cytogenetic risk groups 1/3rd: Cured 1/3rd: TRM 1/3rd: Relapse Park et al, 2013, EJH; epub ahead of print.

  31. Palliation Transfusion support Hydroxycarbamide LD Ara C Steroids Cure Allo SCT (+/- HD chemo pre-transplant) Patient / Doctor Treatment Goals in CMML Disease Modification ? Demethylating Agents ? Experimental therapies

  32. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study Prof Pierre Fenaux MD a, Prof Ghulam J Mufti MD b, Prof Eva Hellstrom-Lindberg MD c, Valeria Santini MD d, Carlo Finelli MD e, Aristoteles Giagounidis MD f, Robert Schoch MD g, Norbert Gattermann MD h, Guillermo Sanz MD i, Prof Alan List MD j, Prof Steven D Gore MD k, John F Seymour MBBS l, Prof John M Bennett MD m, Prof John Byrd MD n, Jay Backstrom MD o, Linda Zimmerman BSN o, David McKenzie MS o, CL Beach PharmD o, Lewis R Silverman MD p, for the International Vidaza High-Risk MDS Survival Study Group AZA 001 Study. Fenaux et al 2009. The Lancet Oncology, 10;3:223-232 24.5 months V 15.0 months. Median FU 21.1 months

  33. SMC Advice Sept 2011 Azacitidine is recommended as a treatment option for adults who are not eligible for HSC and have: • Int-2 or HR MDS according to IPSS • CMML with 10-29% marrow blasts and without myeloproliferative disorder* • AML with 20-30% marrow blasts andmulti-lineage dysplasia, according to the WHO classification. • CMML in AZA001 study had WCC <13 x 109/l* • Identical to EMEA licensed indications • (approved by NICE 2010 on back of pt access scheme. Approved by FDA in 2004; EMEA 2009).

  34. Azacytidine in CMML: does it work? • Europe: Registration Study (2009) • AZA001 trial • 11 pts with CMML; not separately reported • USA: Registration Studies (2004) • 3 studies (CALGB 9221, 8921, 8421) • Total of 19 patients with CMML • ORR (CR + PR, MDS criteria): 15.8%

  35. Summary of Studies of Demethylating Agents in CMML In order: 2011 Costa et al, Cancer 117, 2690-2696; 2012 Thorpe et al, Leuk Res, 36, 1071-1073; 2007 Aribi et al, Cancer 109, 713-717; 2008 Wijermanset al, Leuk Res 32, 587-591; 2011 Braun et al, Blood 118, 3824-3830.

  36. A phase 2 study of azacitidine in chronic myelomonocytic leukaemia (CMML) • Supported by the NCRI Haematological Oncology MDS Subgroup • Sponsored by Leeds Teaching Hospitals NHS Trust • EudraCT Number: 2008-006349-23

  37. Recruitment & Treatment • 32 patients recruited (11 centres) Jan 2010 - August 2010 • Median age 70 (57 – 85); 67% male • 2 pts received <1 cycle • 14 pts < intended 6 cycles (most progressed) • 16 pts≥ 6 cycles Drummond et al, abstract 0869, EHA 2012

  38. Results Drummond et al, abstract 0869, EHA 2012

  39. Results • 20 patients transfusion dependent at diagnosis; 6 became transfusion independent • 5/7 pts on Hydroxycarbamide were able to stop this drug • Only 1/5 patients with skin lesions at outset demonstrated resolution • Median duration of responses 7.5 months Drummond et al, abstract 0869, EHA 2012

  40. Drummond et al, abstract 0869, EHA 2012

  41. Conclusions… “ Clinically meaningful responses (including CR, GR, and PR) were limited (10-17% depending on response criteria).” 3 patients continue on drug (>cycle 18). Support for Phase 3 trial: await oral aza? Implications for MDS Guidelines. Drummond et al, abstract 0869, EHA 2012

  42. BCSH MDS Guidelines (Draft): Management of CMML Recommendations: • Supportive care +/- hydroxycarbamide as required is recommended for most patients (Grade 1B). • Azacitidine is licensed for non-proliferative CMML-2 and can reasonably be recommended. Hypomethylating agents are unlicensed for proliferative disease (WCC ≥ 13 x 109/L) and as such their routine use is not recommended (Grade 2C). • Allo-SCT with or without preceding AML-type chemotherapy should be considered for selected patients (Grade 2B). • Patients requiring treatment should be considered for any appropriate clinical trial. Drummond & Bowen 2012

  43. Summary • Diagnosis may be challenging • New molecular markers • New CMML-specific prognostic score • Transplant curative in ≈ 30% but applicable to very few patients • Efficacy of azacitidine modest; not a universal treatment.

  44. AcknowledgementsLeeds CRU and Cellgene UK for CMML201 SupportDavid Bowen & Alex Szubert (statistician) LeedsParticipating Centres in CMML201 and MDS NCRN Trials SubgroupAllyson Doig (Flow Cytometry)

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