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Therapy-Related AML/MDS With A Philadelphia Chromosome

Chad P. Soupir MD and Robert P. Hasserjian MD.Massachusetts General Hospital

2 November 2007

HARVARDMEDICAL SCHOOL

CASE ID# 176

Initial PresentationHPI:

• 43 year old male presented in December 2002 with fatigue and 20 lb weight loss since July 2002.

PAST MEDICAL HISTORY: • Mild psoriasis.

MEDICATIONS: None.

FAMILY HISTORY: • Father died of lung cancer. • Mother has history of diabetes mellitus type II.• Brother has history of TTP.

PHYSICAL EXAM: Unremarkable


Initial PresentationADMISSION LABORATORY FINDINGS:• WBC 19.1 x 109/L

• 54% neutrophils, 4% myelocytes, 1% metamyelocytes, 19% lymphocytes, 2% monocytes, 2% eosinophils, 17% blasts, and 1% promonocytes

• Hgb 9.4 g/dL• Platelets 341 x 109/L

Pathology:Bone Marrow Biopsy Performed


December 2002

Figure 1 (200x)

December 2002

Figure 2 (400X)

Diagnostic Marrow Findings

• Aspirate differential56% myeloid precursors 2% erythroid precursors 7% lymphocytes2% monocytes1% eosinophils, 0% basophils 1% plasma cells4% promyelocytes 27% blasts

~20% of all cells are positive for nonspecific esterase.

~ 25% of blast cells are positive for myeloperoxidase.

December 2002 (400x)


Flow Cytometry

• CD33+, CD13+, HLA-DR+, CD117+/-, TdT+/-,CD34-, MPO-, CD4dim+, CD7dim+ myeloblasts(23% of total events).


47,XY,+21[5]/46,XY[14] Figure 3

December 2002

Diagnosis: WHO Classification

ACUTE MYELOID LEUKEMIA NOT OTHERWISE CATEGORIZED:ACUTE MYELOMONOCYTIC LEUKEMIA (FAB M4)


Treatment and Response

Jan2003

Feb March April May June July Dec Jan2004

Induction:Study protocol CALGB 19808.

Complete remission

Consolidation: 1 cyclehigh dose of etoposide & high dose cytarabine

Bone marrow harvest

Admitted for high-dose busulfan, etoposide, &autologous transplant

Laboratory (July to Dec 2003): WBC: 1.5-5.5 x 109/LHgb: 8.8-13.1 g/dLPlatelets: 39-89 x 109/L

Feb

Day 100 s/p transplant Trilineage hematopoiesis. No evidence of acute leukemia

Cytogenetics: XY[20]


January 2004HPI:

• Patient reported increased fatigue and leg weakness.

LABORATORY FINDINGS:• WBC 10.0 x 109/L

• 66% neutrophils, 8% myelocytes, 1% metamyelocytes, 2% promyelocytes, 10% lymphocytes, 3% monocytes, 0% basophils, and 10% blasts.

• 12 nRBCs/100 WBC

• Hgb 7.9 g/dL• Platelets 106 x 109/L


January 2004 Pathology• Bone Marrow Biopsy:

• Limited sample• Multilineage dysplasia noted with 12% blasts.• Flow cytometry showed 4% myeloblasts• Cytogenetics attempted but no metaphases for analysis.

• Clinically followed over next few months.• Peripheral blood counts remained low, but stable.

• Repeat biopsy in April 2004


April 2004 PathologyWBC: 7.6 x 109/L • 88% neutrophils, 3% myelocytes, 3% metamyelocytes,

4% lymphocytes, 0% basophils, 2% Blasts• 4 nucleated RBC/100 WBC.

April 2004: Figure 4

Fig. 5Fig. 4b


Hgb: 8.8 g/dLPlatelets: 58 x 109/L

April 2004

Figure 6 (40x)

April 2004

Figure 7 (100x)

April 2004

Figure 9 (1000x)

Diagnostic Marrow Findings• Aspirate differential

73% myeloid precursors 16% erythroid precursors 1% lymphocytes0% basophils 1% promyelocytes 9% blasts

The blast count vary in areas ranging from 5 to 15%.

April 2004 (1000x)


Flow Cytometry• CD33+, CD13+, HLA-DR+, CD117+, TdT-,

CD34-, MPO+/-, CD4-, CD7- myeloblasts (6% of total events).


April 2004

46,XY,der(1)inv(1)(p13q42)del(1)(q43),t(9;22)(q34;q11.2)[15]/46,XY[5]

Figure 10)

ish der(9)(ABL+,BCR+),der(22)(BCR+,ABL+)

MetaphaseFISH

Clinical CourseTwo weeks after bone marrow biopsy

presented with worsening fatigue.

LABORATORY FINDINGS:• WBC 86.3 x 109/L

• 48% blasts• Hgb 7.0 g/dL• Platelets 66 x 109/L


Therapy-related AML / MDS with Philadelphia chromosome.


Diagnosis: WHO Classification

Treatment

• Admitted for re-induction with intrathecal methotrexate, steroids, idarubicin and cytarabine.

• Gleevec started two weeks after re-induction.

• Died at day 39.


• Late-occurring Philadelphia chromosome is rare in MDS and AML– Cytogenetic progression of an existing myeloid

neoplasm– Therapy-related AML/MDS


Philadelphia Chromosome in Therapy-related AML/MDS

• Pedersen-Bjergaard et al. (1997) literature review: • Identified 8 cases of AML with Philadelphia chromosome

following DNA topoisomerase II inhibitors• 2 following treatment for Hodgkin lymphoma• 6 following treatment for myeloid neoplasms• Some of these appear to represent relapsed AML with t(9;22)

acquisition

• 4 of 20 Ph+AML patients in a multi-institutional series presented as secondary leukemia (Soupir et al. 2007)

• 2/4 were karyotypically distinct from original leukemia, consistent with t-AML/MDS

• In 1 case, the t(9;22) represented a secondary change in relapsed disease

• In 1 case the relationship of the secondary leukemia to the original leukemia was indeterminate



• Univariate and multivariate analysis of published cases of t-AML/MDS with balanced chromosome aberrations (Andersen et al. 1998)– 8.5% patients (N=328) with t-MDS/AML with balanced

translocations following treatment with DNA topoisomerase II inhibitors had a t(9:22)

– However, only 0.12% of all leukemias exhibiting t(9;22) are secondary Ph+ AML (Soupir et al. 2007).



Conclusion

• The difference in karyotype and morphology between the original AML and secondary AML in this case favor t-AML/MDS rather than acquisition of t(9;22) in relapsed AML.– BCR-ABL FISH attempted on original AML (biopsy

block and aspirate smear) was unsuccessful.– Thus, a pre-existing Ph+ clone in the patient’s original

leukemia cannot be entirely excluded.


Bibliography

1. Andersen, Mette Klarskov, Bertil Johansson, Severin Olesen Larsen, Jens Pederson-Bjergaard. Chromosomal abnormalities in secondary MDS and AML. Relationship to drugs and radiation with specific emphasis on the blanced rearrangements. Haematoligca 1998: 83: 483-488.

2. Han, Jin-Yeong and Karl S. Theil. The Philadelphia chromosome as a secondary abnormality in inv(3)(q21q26) acute myeloid leukemia at diagnosis: confirmation of p190 BCR-ABL mRNA by real-time quantitative polymerase chain reaction. Cancer Genetics and Cytogenetics 2006; 165; 70-74

3. Najfeld V, Geller M, Troy K, Scalise A. Acquisition of the Ph chromosome and BCR-ABL fusion product in AML-M2 and t(8;21) leukemia: cytogenetic and FISH evidence for a late event. Leukemia 1998;12:517–9.

4. Nawata, Ryohei, Kenji Shinohara, Tetsuya Yamada, Toru Takahashi, Kensaku Katsuki, Koumei Takeda, Naoko Kameda, Koichi Ariyoshi, Itsuro Ota, and Kazuhiko Muraki. Morphological and cytogenetic changes in therapy-related leukemia developed in a t(8;21)-acute myeloid leukemia (M2) patient: sequential cytogenetic and molecular analyses. International Journal of Hematology 2000 Jun;71(4):353-8.

5. Pederson-Bjergaard J, Brondum-Nielsen K, Karle H, Johansson B. Chemotherapy-related—late occurring—Philadelphia chromosome in AML, ALL and CML: similar events related to treatment with DNA topoisomerase II inhibitors? Leukemia. 1997;11:1571-1574.

6. Soupir CP, Vergilio JA, Dal Cin P, Muzikansky A, Kantarjian HM, Jones DM and Hasserjian RP. Philadelphia chromosome-positive acute myeloid leukemia: a rare aggressive leukemia withclinicopathologic features distinct from chronic myeloid leukemia in myeloid blast crisis. American Journal of Clinical Pathology. 2007 Apr;127(4):642-50.


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Therapy-Related AML/MDS With A Philadelphia Chromosomepathol/HematopathologyWorkshop/login_successful... · Philadelphia Chromosome in Therapy-related AML/MDS. Conclusion • The