2007 Workshop of SH/EAHP. Session 5 Therapy-related myeloid neoplasms

Transcription

1 2007 Workshop of SH/EAHP Session 5 Therapy-related myeloid neoplasms

2 Classification: Key issues MDS vs. AML-M6 MDS vs. MDS/MPD Genetically defined entities Relevance of morphologic classification Clinical and pathologic associations with genetic lesions Residual primary disease

3 Therapy-related myeloid neoplasms Clinical syndrome occurring following exposure to chemotherapy and/or radiotherapy Latency dependent on the type of therapy, cumulative dose/dose intensity Heterogeneous morphologic presentation: spectrum t-mds and t-aml, t-mds/mpd Specific genetic lesions and their clinical correlates Poor survival

4 Therapy-related myeloid neoplasms Total number of cases 13 Cases submitted 10 Cases moved from other categories 3 Diagnosis agreement 13 Minor modifications 1

5 Morphologic and genetic subtypes of therapy-related myeloid neoplasms

6 Cases for presentation Case number Presenter Diagnosis 014 Jeremy Wallentine t-mds/aml 183 Marsha Kinney 057 Judith Ferry Acute erythroid leukemia, therapy related t-aml arising in donor marrow Persistent plasma cell myeloma 032 Ken Young t-mds/mpd 086 Mohammad Vasef 089 Russ Brynes t-aml with t(9;11)(9p22;q23); metastatic Ewing sarcoma t-aml with t(8;21)(q22;q22) and systemic mastocytosis 188 Carl Buckner t-aml with t(15;17)(q22;q21) 176 Chad Soupir t-mds/aml with t(9;22)(q34;q11.2)

7 CASE PRESENTATIONS

8 Morphologic and genetic subtypes of therapy-related myeloid neoplasms

9 Summarized cases Case number Submitter Submitter dx Panel dx 034 Penn t-mds/aml Agree 206 Fend t-aml Agree 040 Hoyer MDS possibly therapy related, α thalassemia CMML features, α thalassemia 156 Lott t-cmml Agree 144 Massey t-aml, concurrent CLL Agree

10 Case 034, Penn 61 yr old male with follicular lymphoma of the cheek dx in 1994, initially watch and wait; 1999 left neck mass treated with CHOP-R, received G-CSF; July, 2003 mediastinal mass on restaging (nl CBC, BM with erythroid hyperplasia); March-April 2004 developed axillary and cervical LN, Fludarabine: June 2004 hemolytic anemia; July 2005 eyebrow lymphoma, COP-R; January 2006 pancytopenia

11 Case 034, Penn

12 Case 034, Penn 10% blasts; CD34, CD117, HLA-DR, CD13, CD7, CD33-

13 Case 034, Penn Submitter dx: t-mds/aml Panel dx: agree

14 Case 034, Penn Case 014, Wallentine Case 183, Kinney Case 206, Fend 10% blasts

15 Case 206, Fend 53 year old treated for mediastinal precursor T lymphoblastic lymphoma 44 months after primary treatment presented with pancytopenia The following biopsy was taken six months after the diagnosis of therapy related MDS transforming to AML with erythroid differentiation Submitter dx: therapy-related AML, pure erythroid differentiation Panel dx: agree

16 Case 206, Fend

17 Therapy-related MDS: is blast count and degree of dysplasia clinically relevant? Singh et al studied 155 patients with therapy related MDS or AML 81 MDS (RA, RCMD, RCMD-RS, RAEB-1 and 2) 69 AML 5 MDS/MPD Patients were diagnosed according to WHO classification Singh et al, AJCP 2007;127:

18 Therapy-related MDS: is blast count and degree of dysplasia clinically relevant? WHO classification did not add clinically relevant information when applied to therapy related MDS/AML Singh et al, AJCP 2007;127:

19 t-mds and t-aml: need to subclassify? Only borderline difference in survival between t- MDS and t-aml (median survival 8.5 vs. 6.5 months) Singh et al, AJCP 2007;127:

20 t-mds and t-aml: impact of cytogenetics Relatively favorable survival of normal cytogenetic group Patients with >3 abnormalities show poor survival similar to poor cytogenetic risk group of IPSS Singh et al, AJCP 2007;127:

21 Case 040, Hoyer 58 year old male originally dx with AML with inv(16)(p13q22) in 1999; treated with induction chemotherapy followed by autologous SCT Two subsequent follow-up marrows with trilineage hematopoiesis and normal karyotype 2005 steadily declining counts with WBC 3.6x10 9 /L (35% monocytes), Hgb 11.4g/dL, platelets 62x10 9 /L, decreasing MCV to 74.5fL Submitter dx: MDS with multilineage dysplasia possibly due to previous therapy, acquired alpha thalassemia Panel dx: agree (features of CMML)

22 Case 040, Hoyer

23 Case 040, Hoyer

24 Acquired α thalassemia in myeloid malignancies α thalassemia clones in: 8% of MDS (both de novo and therapy related); a proportion showing full phenotype of α thalassemiamyelodysplastic syndrome (ATMDS) 2.5% CMPDs Mechanisms: Somatic mutations in ATRX, gene transactivating α globin expression Loss of terminal portion of 16p containing α globin genes Steensma et al Br J Haematol 2007;139:439 Gibbons et al Nature Genetics 2003;34:446 Steensma et al Blood 2004;103:1518

25 Case 156, Lott 49 year old female with long-standing h/o Wegener granulomatosis treated with methotrexate and Cytoxan September, 2006 presented with Hb 7.4g/dL platelets of 6k/cumm, absolute monocyte count 5.2k/cumm Submitter dx: t-mds/aml (t-cmml) Panel dx: agree

26 Case 156, Lott Get pb smear from flow

27 t-mds/aml in patients with no prior malignancy Received cytotoxic treatment for: Rheumatoid arthritis Behcet syndrome Polymyositis ITP Renal allografts More likely to present with t-mds vs. t-aml Longer latency interval More frequent involvement of chr. 5 and 7 than those with solid tumors Smith et al Blood 2003;102:43

28 Therapy related myeloid neoplasms other than t-mds/aml <5% of therapy-related myeloid neoplasms CML, a-cml, MDS/MPD unclassifiable Reported in both pediatric and adult populations Kim et al J Clin Pharm Ther 2006;31:401 Riaz et al Pediatr Blood Cancer 2007;49:1058 Singh et al Am J Clin Pathol 2007;127:197 Satake et al Genes Chr and Cancer 1997;20:60 Both alkylating agents, topoisomerase inhibitors and platinum-based therapies implicated

29 Case 144, Massey 58 year old female with h/o large cell lymphoma (1998) and CLL diagnosed in : treated with CHOP (1998), fludarabine (2001) and chlorambucil (2006) November, 2006 presentation with WBC 117k/ul with 29% blasts and 69% lymphocytes (persistent CLL), Hgb 10g/dL, platelets 144k/ul Submitter dx: Concurrent CLLwith t-aml Panel dx: agree

30 Case 144, Massey 45% blasts positive for CD34, CD33, CD117, HLA-DR, CD13, CD7, CD38 CD34

31 Case 144, Massey Karyotype: 45,XX,t(3;3)(q21;q26),-7, del(9)(p13), add(20)(q13.3) [12]/45, idem, del(5)(q13q33) [7] 3q21q26 syndrome/evi1 de novo and therapy related cases 2% AML, MDS, CML-BP Clinical features: nl/elevated platelet count, young age, rapid progression, poor response to therapy Bitter et al Blood 1985;66:1362 Jotterand-Bellomo et al Cancer Genet Cytogenet 1992; 59:138

32 3q21q26 syndrome/evi1 EVI1 identified at viral integration site leading to myeloid tumors in mice Block endomitosis leading to dysplastic hypolobated megakaryocytes Kilbey et al Br J Haematol 2005;130:902

33 Session 5: Therapy-related myeloid neoplasms Heterogeneity of clinical context Morphologic spectrum from MDS to AML with less emphasis on detailed subclassification (broad category of t-mds/aml) Entities defined by recurrent cytogenetic abnormalities Clinical and pathologic correlates with genetic lesions (Pedersen-Bjergaard et al Leukemia 2006;20:1943)

34 Pedersen- Bjergaard et al Leukemia 2006;20:1943