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NPM1-Mutated AML: Prognosis & Therapeutic Implications

Explore a clinical case of NPM1-mutated acute myeloid leukemia with FLT3-ITD and DNMT3A mutations. Understand prognostic implications, treatment strategies, and the role of minimal residual disease monitoring.

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NPM1-Mutated AML: Prognosis & Therapeutic Implications

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  1. CLINICAL CASE 91 Xavier CalvoGonzález Department of Hematopathology Hospital Clínic de Barcelona October, 2013

  2. Clinical case • 56 year-old male • No relevant medical history August 2007: 2 weeks ago - Fever - Gingivitis - Skin lesions in trunk and extremities Physical examination: - PS 2 • Cervical and submandibular lymph nodes • Gingival hypertrophy • Hepatosplenomegaly • Papular and nodular skin lesions • Dorsal distal hypoesthesia of right food

  3. Clinical & laboratoryfeatures Laboratoryfeatures Hb 106 g/L WBC 121.1 x 109/L (N 1%, L 5%, Blasts 88%) Plt 58 x 109/L Biochemistry LDH 1033 IU/L; Cr 1.15 mg/dL AST 23 IU/L; ALT 56 IU/L; GGT 461 IU/L; AF 441 IU/L Viral serologies (HBV, HCV, HIV): negative Coagulation tests: PT 69%, aTTP 28 sec, FDP positive Abdominal and thoracic CT-scan Lymph node involvement in multiple territories: supraclavicular, axillary, mediastinic, retroperitoneal and para-aortic

  4. Peripheral blood smear

  5. Bone marrow aspirate

  6. MYELOPEROXIDASE

  7. NASDA

  8. ANBE

  9. Cerebrospinal fluid: blast cell infiltration

  10. granulocytes Plasma cell August 2007 Lymphocytes CD34+ Abnormal cells with intermediate-high FSC/SSC of immature myeloid origin (CD34 partial (30%) and CD117+) with monocytic differentiation and coexpression of CD7 and CD5

  11. Bone marrow August 2007 46, XY [20] FISH 11q23 LSI MLL: normal FISH 5p15.2 and 5q31: normal

  12. Wild-type Mutated ITD Exon 12 mutation of Nucleophosmin (NPM1): Positive FLT3 InternalTandemDuplication (FLT3-ITD): Positive RATIO mut/wt: 0.45 Size of mutated band: 90bp Wild-type DNMT3A mutations: Positive* R882H *It was known retrospectively

  13. Diagnosis & treatment NPM1-mutated AML (M5 subtype) with normal karyotype carrying FLT3-ITD and DNMT3A mutations IDICE:complete remission RELAPSE IDA-FLAGRefractory Mylotargprevioustocordblood HSCT  Refractory Exitus

  14. Discussion NPM1-mutated AML with NK • Therapeutic and prognostic implications of FLT3-ITD and/or DNMT3A • Minimal screening panel of mutations in AML-NK • Role of MRD

  15. NPM1mut: Prognostic relevance • NPM1mut: OS at 4 yrs: 60% vs 21% “other genotypes” • No difference in OS with AlloSCT • Triple negative: poor outcome 33% 4yrs Schlenk RF, NEJM 2008

  16. Prognostic impact of accompanying mutations in NPM1mut AML (I) The ratio of FLT3-ITD modulates prognosis on NPM1mut AML Threshold FLT3-ITD/FLT3-wt: 0.5 NPM1mut + High ratio: Higher relapse rate ( 79% vs 20% at 5yrs) Shorter OS (29% vs 47% at 5yrs) Survival benefit with AlloSCT in CR1 Pratcorona M, Blood 2013

  17. Prognostic impact of accompanying mutations in NPM1mut AML (II) Controversies about the prognostic impact of DNMT3A Within patients with NK-AML, DNMT3Amut had an unfavorable effect on OS, RFS, and CR rate in NPM1/FLT3-ITD high-risk but not in low-risk patients DNMT3Amut was significant within NPM1/FLT3-ITD low risk patients (not in high risk) CEBPA and DNMT3A : almost mutually exclusive (not evaluable) Thol F, JCO 2011 Renneville A, Leukemia 2012

  18. Prognostic impact of accompanying mutations in NPM1mut AML (III) Controversies about the prognostic impact of DNMT3A *No effect of DNMT3Amut on survival was found nor in the FLT3wt/NPM1mut NK-AML (like Thol et al) nor in FLT3-ITD/NPM1mut NK-AML (like Renneville et al) DNMT3Amut did not impact in NK-AML (in contrast to previous studies) Negative impact only in ELN-unfav NK-AML subset *Ribeiro T, Blood 2012 Gaidzik V, Blood 2013

  19. Prognostic impact of accompanying mutations in NPM1mut AML (IV) Patel J, NEJM 2012

  20. Therapeutic implications of gene mutations Benefit of high-dose vs. standard-dose daunorubicin in patients with NPM1/DNMT3A mutations or with MLL translocations Patel J, NEJM 2012

  21. Minimal screening panel of mutations European LeukemiaNet recommendations DNMT3A TET2 ASXL1 IDH 1/2 RUNX1 PHF6 MLL-PTD More clinical data is needed (controversies about prognosis or minimal clinical data) Potential role of specific treatments ( targeting epigenetic modifiers, FLT3 inhibitors, high dose daunorubicin,…) Döhner H, Blood 2010

  22. Minimal Residual Disease (MRD) NPM1 • NPM1isstable, even in thepresence of clonalevolution • Usedforearlydetection of relapse (increase of 1 log at any time) in a median time of 62 days • Earlydetection of relapsebasedon “molecular response” (lessthan 3 log decrease) • Pretreatmentlevels of NPM1 transcriptdidnotimpactevent free survival • No informationabout DNMT3A (future role of NGS) • FLT3-ITD isnot a goodmarker (presence of different clones at thesame time, acquisitionordisappearance at relapse)  Schnittger ASH 2012: stablebetweendiagnostic and relapsesamples in 86.3% FLT3-ITD and DNMT3A Krönke, JCO 2011

  23. Minimal Residual Disease (MRD) NPM1 • After double induction therapy: • RQ-PCR-negativity : CIR 6.5% 4 yr (OS: 90%) • RQ-PCR-positivity : CIR 53% 4 yr (OS: 51%) • After completion of consolidation therapy : • RQ-PCR-negativity : CIR 15.7% 4 yr • RQ-PCR-positivity : CIR 66.5% 4 yr • Early detection of relapse in patients exceeding more than 200 NPM1mut/104 ABL copies Krönke, JCO 2011

  24. Conclusions • Ratios of FLT3-ITD/FLT3-wt above 0.5 confer a worse prognosis to NPM1-mutated AMLs with normal karyotype • There is no consensus about the prognostic impact of DNMT3A mutation, but only one study supports the deleterious impact in the subset of patients with NPM1mut/FLT3wt AML with normal karyotype • Benefit of high-dose versus standard-dose daunorubicin in the subgroup of patients with NPM1/DNMT3A mutations or with MLL translocations • Nowadays the minimal screening panel of mutations for the normal cytogenetics AML must include: NPM1, CEBPA and FLT3-ITD. We have not enough clinical information to recommend the study of the mutational status of other genes (DNMT3A, TET2, IDH, RUNX1, ASXL1, ...) • NPM1 is well established as a MRD target. The MRD levels after induction or consolidation therapy will determine the outcome of the patients

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