mpn transformation to mds and amlaihemato.cluster013.ovh.net/aih/documents/cours des... · leukemic...

MPN transformation to MDS and AML

Lionel AdèsHopital Saint Louis , Paris University

Background

• BCR-ABL negative myeloproliferative neoplasms (MPN) with blast-

phase are considered as very poor prognosis diseases

• Median overall survival between 3 to 6 months

• Limited therapeutic option

• Frequently excluded from clinical trials

Web of Science 2019

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Keywords : Myeloproliferative

Web of Science 2019

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Keywords : Myeloproliferative & Transformation

Leukemic evolution in PV : A Long term issue

Causes of deaths< 60 years

n = 35

60 years

n = 54

All patients

n = 89

Leukemic events 18 (51%) 8 (15%) 26 (29%)

Vascular events 2 (6%) 17 (31%) 19 (21%)

Solid tumors 5 (14%) 8 (15%) 13 (15%)

Unrelated 8 (23%) 8 (15%) 16 (18%)

Unknown 2 (6%) 13 (24%) 15 (17%)

Median follow-up: 11.4 years

Kiladjian et al. 2003

Survival after MDS/AML transformation

Median Survival 3-6 mo

Magnus Björkholm, JCO 2011

Therapy-related MDS/AML in PV

• Predictive factor of MDS/AML evolution

Finazzi et al, Blood. 2005, 105(7):2664-70

Older Age Longer disease duration Previous hemorrhagic eventTreatment with >1 cytoreductive drugP32 BusulphanPipobroman

HU was not associated with increased risk of BT

Evolution to AML/MDSof PV treated with HU or Pipibroman

10 years 15 years 20 years

Total cohort 9.8% 24% 34%

HU (ITT) 6.6% 16.5% 24%

Pipo (ITT) 13% 34% 52%

Kiladjian, JCO 2010

Genetic events associated with leukemic transformation

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Karyotypic Associated With Increased Risk of AML

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Reference MPN type abnormalities

Dupriez, 1996 MMF Abnormal

Tam, 2009 MMF Chromosome 17 anormalité

Vaidya, 2011 MMF Monosomal Karyotype

Gangat, 2011

(DIPSS-Plus)

MMF Complex+8-7/7q-i(17q)-5/5q-12p-Inv(3)11q23

Quintas-Cardama ,2013 MMF del17p, 5, 7, and/or complex

Tefferi, 2013 PV/ET Abnormal Karyotype

Genomic analysis of leukemic transformation of myeloproliferative neoplasms

Raajit Rampala et al. PNAS 2014

Somatic TP53 mutations are common in post-MPN AML but

not in chronic-phase MPN

• The association of JAK2 allelic burden and transformation is not consistent in PV

– Increased risk of AML in PV if JAK2 mutant allele burden >50%.

– JAK2V617F allele burden (>50%) was associated with MF transformation but not leukemogenesis.

• In ET, no difference in LT in JAK2 mutated or unmutated patients

Passamonti et al. Leukemia 2010Malak, Blood Cells Mol Dis 2012Barbui T, J Clin Oncol 2011

JAK2V617F presence is not a prerequisite for Leukemicevolution and additional genetic events are required

Pronostic implications of the JAK2V617F or its allelicburden : PV/ET

Pronostic implications of the JAK2V617F or its allelic burden : MF

Barosi, Plos 2013

The accumulation of mutated alleles in the

JAK2V617F clone or the selective acquisition of a

proliferative advantage in the wt clone are two

relevant routes to BT in PMF

JAK2 Variants Associated With the Transformation of Myeloproliferative Neoplasms

Verstovsek S. Cancer 2019

2154 MPD & BT PatientsJAK2 (non exon 12, non V617F) sequence variants wereidentified in 114 (5.3%).

A JAK2 variant in addition to JAK2V617F (n = 13) in myelofibrosis was associatedwith an increased cumulative risk of transformation into AML

Mutations influencing Transformationin MF at diagnosis

EZH2ASXL1

IDH1/2SRSF2

Vannucchi, Leukemia 2013

Samples from the European cohort, collected at time of diagnosis, wereanalyzed for mutations in ASXL1, SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL and JAK2

Distinct mutational spectrum in post-MPN AML segregated by JAK2V617F mutational status

JAK2V617F mutated JAK2 WT

TP53

(44%)

CALR (43%)

ASXL1

(44%)

ASXL1

(38%)

IDH2

(44%)

SRSF2

(29%)

… but no differences in survivalbetween patients with mutations in JAK2 or CALR or patients wild-

type for both

Raajit Rampala et al. PNAS 2014

NO TP53 in JAK2-wild type post-MPN AML

En Résumé

GENE Predit la TA Present à la TA

ASXL1 OUI OUI

IDH ½ OUI OUI

EZHZ2 OUI OUI

SRSF2 OUI OUI

TP53 OUI

TET2 OUI

JAK2 non Exon 12 non V617F OUI

Role of High dose CxT & Transplant

Chemotherapy and Transplant

• The only curative option

• Can be offer to a very limited number of patients due to

–Age

–Co-morbidities

–Absence of CR at transplant

High dose Chemotherapy

retrospective review of 75 patients with MPN-BP treated according to a uniform treatmentstrategy

James A. Kennedy, Blood 2013

50%




38%




22%

High dose Chemotherapy & Transplant

Intensive Chemo and CR and NO transplantVs No Chemo

Intensive Group : Transplant vs No tranplant


Impact of mutations on prognosis of AML secondary to myeloproliferative neoplasms

• Institut Paoli Calmettes - CRCM

• N=73 patients

• Conventional clinical factors (age, karyotype, ELN2017 prognostic classification, treatments received, treatments response, Allo-SCT...) failed to predict the patients outcome.

Venton et al. Am J Hematol. 2018;93:330–338.

Chemotherapy for post-myelofibrosis acute myeloidleukemia: eradication of the leukemic clone but not the MPN clone

Emmanuelle Verger and Jean-Jacques Kiladjian Leuk Lymph 2017

Role of Hypomethylating agents

Increased number of differentially

methylated regions at transformation

compared to chronicPhase

Cristina Pérez Haematologica 2013

Aberrant DNA methylation profile of chronic and transformedclassic Philadelphia-negative myeloproliferative neoplasms

Chronic Phase BT

• 54 patients included in the ATU program of AZA in transformed MPN in 17 centers, and having completed 1 cycle of AZA

• Initial MPN diagnosed according to the classical criteria used at the time of first observation

• CMML were excluded

• Response assessed according to IWG-AML 2003 criteria and IWG 2006 MDS criteria

Thepot et al. Blood 2011

Characteristics of the initial MPN

All PV ET PMF MPNu P-value

n 54 21 21 7 5

Median age 69.5 66 71 73 71 NS

M/F 34/20 12/9 13/8 5/2 4/1 NS

Jak2

V617F

59% 86% 56% 29% 25% 0.023

HU 63% 76% 67% 17% 60% NS

AML/MDS 26/28 13/8 10/11 3/4 0/5 NS

Mediantime to transformation (mo)

71 154 70 19 19 <10-3


Response

Global ORR 52 %

Global CR 22%


Primary MPN ET (n=8)

PV (n=3)

JAK 2 V617F mutation (n=5)

Wild type (n=2)

Median time before transformation

11 years (range 2-22)

OMS at transformation AML : n=3

RAEB-2 : n=6

RAEB-1 : n =2

11 patients (20%) had recurrence of thrombocytosis or polycythemia

(ie feature of initial MPD, before transformation)

After a median number of 3 cycles of AZA

P=0.055

Restoration of MPN features after AZA

Similar Results with Decitabine

• 21 patients with MPN-AML• ORR 30%• median overall survival was significantly higher in responder (10.5 vs 4 months).

Badar, Leur Res 2015

Prolonged administration of DAC in AML/MDS

Patients with TP53 mutations had favorable clinical responsesand robust mutation clearance after receiving serial 10-day courses of decitabine

Welsh et al. NEJM 2016

Any role in MPN BT ?

Ruxolitinib

Ruxolitinib as single Agent

• Phase 2 study

• ruxolitinib in patients with relapsed or refractory leukemias

• Ruxolitinib 25 mg x2/d for 4 weeks

• Twelve patients had JAK2V617F mutation.

• Three of 18 patients BT after MPN showed a significantresponse:– 2 achieved CR

– and one achieved a CRi

Alireza Eghtedar, Blood 2012

LIMITED ANTI LEUKEMIC EFFECT

Phase I/II study Decitabine-Ruxolitinib

• MD Anderson experience

• Decitabine 20 mg/m2/d x 5 days

• Ruxolitinib (10-50 mg BID) starting day 1

• 14 pts with AML following MPN were enrolled

• 4 CR/CRi + 1 leukemia free state

• No DLT

Prithviraj Bose, ASH 2016

Ruxolitinib + Chemotherapy

Cluzeau et al, BJH 2015

Table 1: Patient, disease, treatment characteristics and outcome after treatment

UPN age/sex BP of Cytogenetics Induction

chemotherapy Ruxolitinib in induction

Outcome after

induction

Consolidation chemotherapy

Ruxolitinib in consolidation

Toxicity during

treatment

Allo-HSCT

Overall outcome

1 52/M post ET

secondary MF MCK IDA12+AraC200 10 mg x 2/d CR IDA9 + LDAC 10 mg x 2/d No No

Early relapse,

death

2 46/M ET MCK IDA12+AraC200 10 mg x 2/d PR IDA9 + LDAC 10 mg x 2/d No Yes Persistent

CR at 5 mo

3 54/M ET +X IDA12+AraC200 10 mg x 2/d CR IDA9 + LDAC 10 mg x 2/d No Yes Persistent

CR at 10 mo

4 52/M PV Normal DNR60+AraC200 10 mg x 2/d Death NR 10 mg x 2/d

Intestinal

occlusive syndrome

NR Death in

aplasia

5 60/M post PV

secondary MF CK IDA12+AraC200 10 mg x 2/d Death NR 10 mg x 2/d

Intestinal occlusive

syndrome

NR Death in aplasia

6 60/F post PV

secondary MF

del(20q)

del(7q) DNR60+AraC200 20 mg x 2/d PR LDAC 5 mg x 2/d No Yes

On going

Allo-HSCT

ALR-C = acute leukemia response - complete; ALR-P = acute leukemia response - partial; AraC = cytarabine; BP = blast phase; CK = complex karyotype; CR = complete response; DNR = daunorubicin; ET = essential thrombocytosis; F = female; IDA = idarubicin; M = male; MCK = mosomal complex karyotype; MF = myelofibrosis; mo = months; NR = not relevant; PV = polycythemia vera; LDAC = low dose cytarabine.

Any promising Drug?

CPX-351 vs 3+7 : LAM MRC du sujet agé (60-75 ans)

J. Lancet et al. J Clin Oncol 2018

Un avantage en Survie Particulièrement marqué chez les patients greffés


Enasidenib 100 mg/jour (LAM R/R IDH2m)

Stein et al. , Blood 2019

Des réponses en monothérapie Associées à des réponses moléculaires

N=214

ORR 38.8%

CR/Cri/CRp 29%

Delai pour la réponse 1.9 mois

Survie 8.8 mois

EFS 4.7 mois


Conclusion

• Evolution to leukemia could be the first cause of deaths in the

long-term in properly managed MPN patients

• Evolution to leukemia is part of the natural history of MPN, but

this risk can clearly be enhanced by medicines like alkylating

agents

• → Non-leukemogenic drugs should be favored to treat

patients <60 years

Conclusion

• Very limited therapeutic option in BT

• SCT is the only curative option

• HMA might have some efficacy

• Other options remain to be evaluated in clinical trials.

Aknowledgement

• Marie Sebert

• Sylvain Thepot

• JJ Kiladjian

• B Cassinat

• S Giraudier

• P Fenaux

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