1. European Focus on MPN and MDS 2014
Leukemic Transformation in Myelofibrosis (MF):
Molecular Pathogenesis and Clinical Implications
Frank Stegelmann, MD
Prague, 2 May 2014
Department of Internal Medicine III
University Hospital of Ulm, Germany

2. Common Features of Classic MPN
JAK2mut ~60% ET PV
JAK2mut ~95%
Hemorrhage
Thrombosis
Secondary AML
(sAML)
JAK2mut ~60%
PMF
SMF
Primary / Secondary MF
Levine et al., ASH 2006 (modified)

3. Background and Introduction
Myelofibrosis (MF) is characterized by constitutional symptoms and poor prognosis; median survival ranges between 2-11 years
Leukemic transformation occurs in ~20% of pts; it represents the most common cause of death in MF
In MF and sAML, various genetic alterations were identified in recent years that involve cytokine signaling, RNA splicing, and epigenetic regulation
Though many questions are still unanswered, novel pathogenic and clinical aspects of MF will be summarized in the next minutes, with the focus on their role in leukemic transformation

4. Genetic Evolution of MPN
MPN in chronic phase
Blast Phase
>20% Blasts
in PB/BM
Tefferi and Vainchenker, J Clin Oncol 2011

5. Models of Leukemic Transformation1.
Accumulation of genetic events during the
course of the disease cause sAML over time 2.
MPN / sAML originates as a separate disease
from a common founder clone 3.
Separate founder clones are responsible for
the development of MPN / sAML as separate
diseases
Rampal et al., Curr Opin Hematol 2013

6. Clinical Risk Factors for Leukemic Transformation
DIPSS = Dynamic International Prognostic Scoring System
DIPSS
DIPSS-Plus
95% CI
Hazard Ratio p
15% of pts
Gangat et al., J Clin Oncol 2011

7. Clinical Risk Factors for Leukemic Transformation
Frequency of Leukemic Transformation in PMF: 7% (n=52)
Low risk: PLT >100/nL and
No unfavorable karyotype
High risk: PLT <100/nL or
Unfavorable karyotype
Unfavorable karyotype:
Trisomy 8, -5/5q, -7/7q, 12p-, inv(3),
Isochromosome(17q),
11q23 rearrangement,
Complex karyotype (≥ 3 aberrations)
5-year Risk: 6% (low) vs. 18% (high)
10-year Risk: 12% (low) vs. 31% (high)
Gangat et al., J Clin Oncol 2011

8. Frequent Mutations in PMF
TET2 (10%)
JAK-STAT activation
Epigenetic dysregulation
ASXL1 (22%)
Spliceosome mutation
SRSF2 (8%)
MPL (5%)
CBL (4%)
DNMT3A (6%)
EZH2 (5%)
JAK2 (59%)
IDH1/2 (3%)
Vannucchi et al., Leukemia 2013

9. Impact of Mutations on Leukemic Transformation
`Prognostic Detrimental Mutations´
EZH2
SRSF2
mut
mut
mut
ASXL1
IDH1/2
mut
Vannucchi et al., Leukemia 2013

10. Impact of Combinations of Detrimental Mutations
ASXL1 +/- IDH1/2 +/- SRSF2 +/- EZH2 mutation: High Molecular Risk
69%
24% 7%
Guglielmelli et al., Leukemia 2014

11. Novel Marker in MPN: Mutations of CALR
Klampfl et al., N Engl J Med 2013
Screening for JAK2mut + CALRmut + MPLmut  Clonality in ~95% of MF

12. `Triple Negativity´: Adverse Outcome in PMF
One Mutation (JAK2 or MPL or CALR) vs. Triple Negative (9%)
Tefferi et al., Leukemia 2014

13. CALRunmut + ASXL1mut: Adverse Outcome in PMF
Mutation Combinations of ASXL1 and CALR
17%
22%
61%
Tefferi et al., Leukemia 2014

14. Genetic Complexity of sAML
Milosevic and Kralovics, Int J Hematol 2013

15. Dismal Outcome by Conventional Treatment
Regimen
Survival Data
Best Supportive Care
1.5 – 2.5 months
Low-Intensity Treatment
(Ara-C, 5-Aza, JAK Inhibitors etc.)
2.9 – 8.0 months
Intensive Chemotherapy +/- Allogeneic Transplantation
3.9 – 47 months
Mesa et al., Blood 2005 (91 cases)
Tam et al., Blood 2008 (74 cases)
Thepot et al., Blood 2010 (54 cases)
Noor et al., Leuk Res 2011 (112 cases)
Kennedy et al., Blood 2013 (75 cases)

16. Summary and Outlook
Significant advances have been achieved in recent years regarding the molecular understanding of MF; biological and clinical impact of novel markers are under investigation
Some favorable and unfavorable genotypes (e.g. ASXL1+/CALR-) have already been identified that are of prognostic relevance
These data will likely be integrated into risk scores to improve prognostication of the individual risk of the patients in MF
However, the enormous genetic complexity of MF and sAML is a challenge for translation of molecular data into clinical practise; patient-tailored, targeted treatment approaches will be necessary to overcome dismal outcome of sAML