Patient with MF has Increasing B lasts but Not Y et AML What to D o John Mascarenhas MD Myeloproliferative Disorders Program Tisch Cancer Institute Division of HematologyOncology ID: 225670
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Case Study: Patient with MF has Increasing Blasts, but Not Yet AML -- What to Do?
John Mascarenhas, MDMyeloproliferative Disorders ProgramTisch Cancer Institute, Division of Hematology/Oncology Mount Sinai School of Medicine New York, New York Slide2
Co-Presenters
Jeffrey C. Bryan,
PharmD
,
RPh
Clinical Pharmacy Specialist, Leukemia
Division of Pharmacy, University of Texas
MD Anderson Cancer CenterHouston, TX
Otitolola Arterbery, MSN, RN, OCN
Clinical Nurse
MD Anderson Cancer Center
Houston, TXSlide3
Evolution of Myeloproliferative Neoplasms (MPNs) to Acute Myeloid Leukemia
In general, MPNs are chronic diseases, but some patients have clinical signs of disease progression Leukemic transformation is a major complication1 Median survival, 3-6 months Not meaningfully altered with induction chemotherapyFor patients with myelofibrosis (MF), AML is the most common cause of death
2
1.
Rampal
R,
Mascarenhas
J. Curr Opin Hematol. 2014;21:65-71; 2.
Cervantes, et al.
Blood
. 2009;113(13):
2895-901
.Slide4
Patient Case Study: Michael G. 54-year old man, diagnosed with JAK2V617F mutation-positive primary myelofibrosis (DIPSS Int-1 risk), was treated with hydroxyurea to manage spleen discomfort. Four years later (2011), spleen size had increased to 8 cm below the left costal margin. He had fatigue and weakness, drenching night sweats, and 3 episodes of unexplained fever in the past 2 months.Slide5
Patient Case Study: Michael G. Re-assessed as DIPSS Int-2 [4 risk factors, constitutional symptoms (1), Hb <10 g/dL
(2), blood blasts 2% (1 [ie, ≥1%]]. Switched from HU to JAK inhibitor therapy (ruxolitinib) and has done well, with reduced splenomegaly and improvement in constitutional and spleen related symptoms. Slide6
Case Study (cont.): Michael G. At a recent visit (1.5 years later), he complained of profound fatigue and weakness and unintentional weight loss. Hematologic values: WBC 24.5 x 10
9/L; Hb 10.5 g/dL; platelets 75 x 109/L Increased myeloid forms on the peripheral blood smear. 12% blasts by manual count; confirmed by flow cytometry to be myeloblasts. Bone marrow biopsy Distorted marrow architectureImmunohistochemical staining confirmed presence of
myeloblasts. Slide7
Case Study (cont.): Michael G. Q: Does
this patient have post-MF AML?YesNoMaybeSlide8
Case Study (cont.): Michael G. Q: Does
this patient have post-MF AML?YesNoMaybeThis patient has 12% peripheral blasts – Accelerated phase, but not yet blast phase (AML)Slide9
Criteria for Leukemic Transformationof MPNs Mesa RA, et
al. Leuk Res 2007; 31:737–740.MPN Disease Phase
Definition 1Leukemic transformation (blast phase [MPN-BP])
≥20% blasts in peripheral blood or bone marrow
Accelerated phase (MPN-AP)
No consensus; ≥10% to <20% blasts widely considered
to be in AP
Various degrees of pancytopeniaSlide10
Caring for the Patient with Progressing MFIncreased need/frequency of:Supportive care to manage symptoms caused by low levels of blood cells (bone marrow ‘burns out’)
Medications may include:Erythropoietin (EPO) to increase red blood cells (RBCs)Granulocyte colony-stimulating factor (G-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) to increase white blood cells (WBCs)Systemic antibiotics and antiviral drugs to fight infections that the patient’s own WBCs cannot adequately fight on their ownTransfusions to add RBC or platelets if the response to medications is insufficientSlide11
Caring for the Patient with Progressing MFIncreased need/frequency of (cont.):Monitoring and surveillance by lab visits, office visits, phone calls to patient – hematology, symptoms, performance status
Multidisciplinary care (eg, dietary changes, counseling, support programs, in-patient care if hospitalized)Patient education (eg, resources on advanced-stage MF; medication changes, HSCT) Slide12
Q: Within 10 years of PMF diagnosis, what percentage of patients will
develop leukemic transformation (MF-BP)?A. 1%B. 5%C. 10%D. 20%E. 50%Slide13
Q: Within 10 years of PMF diagnosis, what percentage of patients will
develop leukemic transformation (MF-BP)?A. 1%B. 5%C. 10%D. 20%E. 50%Slide14
Rate of Transformation from an MPN to Acute Myeloid Leukemia
MPN Subtype at Diagnosis10-year Leukemic Transformation Rate*Essential thrombocythemia (ET)
1%Polycythemia
vera
(PV)
4%
Primary
myelofibrosis
(PMF)
20%
Rampal
,
Mascarenhas
.
Curr
Opin
Hematol
.
2014;21:65-71
*From time of MPN diagnosisSlide15
Comparison of Blast Transformation Rates Among MPNs (N=826)
Tefferi A et al. Blood. 2014; 124(16): 2507–2513. Slide16
Risk Factors for Leukemic Transformationin Patients with MPNs
PV - Age >70 years or prior exposure to P-32, busulfan, or pipobroman1ET - Anemia or platelet >1000 x 109/L2
MFLeukocytes >30 x 109/L or abnormal karyotype
3
PB blasts ≥3% or platelet count < 100
x
10
9/L4Time to development of hemoglobin <10 g/
dL
, leukocytes >30
x
10
9
/L, platelets <150
x
10
9
/L
5
BM blasts >10% or high-risk karyotype
6
Splenectomy, platelet count <100
x
10
9
/L, PB blasts
≥1%
7
BM blasts >10%, platelet count <50
x
10
9
/L, chromosome 17 abnormalities (define MF-AP as a necessary step to MF-BP)
8
Monosomal
karyotype
9
Triple-negative mutational status 10,11
1.
Gangat
N
,
et al.
Leukemia
2007;
21:270–6; 2.
Finazzi
G,
et
al.
Blood
2005
;
105:2664–670; 3.
Dupriez
B,
et
al
.
Blood
1996;88:1013–8; 4. Huang
J,
et
al.
Cancer
2008;
112:2726–32; 5. Morel
P,
et
al
.
Blood
2010;115:4350–5; 6.
Quintas-Cardama
A,
et
al.
Clin
Lymphoma Myeloma
Leuk
2013;
13:315–8
;
e2; 7.
Barosi
G,
et al.
Blood
1998;
91:3630–6; 8. Tam
CS,
et
al.
Blood
2008
;
112:1628–37; 9. Vaidya
R,
et
al.
Blood
2011
;
117:5612–5615; 10.
Tefferi
A et al.
Blood.
2014; 124(16):
2507–13; 11. Rumi
E et al.
Blood
2014;124:1062-9.Slide17
Effect of Driver Mutations on Incidence of Leukemic Transformation in PMF
Rumi E et al. Blood 2014;124:1062-1069.Slide18
Case Study (cont.): Michael G. Based on the finding of 10% blasts, our patient’s MF is in the ‘accelerated phase
’ (MF-AP), and not yet full transformation into acute leukemia (MF-BP; defined as at least 20% blasts). His JAK2V617F allele burden increased to 45%; also showed an aberration of chromosome 9p, and an acquired a TET2 mutation (an epigenetic modifier).
Q: Does this new genetic information change whether or not his disease in blast phase?
Yes
No
Slide19
Case Study (cont.): Michael G. Q: Does this new genetic information change whether or not his disease in blast phase?
YesNoPatient’s profile is still consistent with accelerated phase (defined by up to 20% blasts, not by cytogenetic or mutational status – although some karyotypes may be indicative of poorer prognosis)
The process of leukemic transformation is thought to arise from the accumulation of additional genetic events in addition to mutations in the JAK-STAT pathway. Additional mutations are often seen in accelerated phase.Slide20
Additional Mutations Are Often Seen in MF-AP and MF-BP
The number of chromosomal abnormalities differs between chronic phase MF, MF- AP, and post-MF AML (MF-BP)Klampfi T, et al. Blood 2011;118:167-76.Slide21
Spectrum of Mutations in MPN-BPand De-novo AML
Rampal
, Mascarenhas.
Curr
Opin
Hematol. 2014;21:65-71.Slide22
Possible Mechanisms of MPN Evolutionto AML (BP)1,2
An MPN with wt JAK2 may develop JAK2 mutation JAK2V617F mutations are not always retained2
1.
Rampal
,
Mascarenhas
.
Curr
Opin
Hematol
.
2014;21:65-71.
2. Tam CS et al.
Blood
. 2008;112
: 1628-37.Slide23
Q: This 60-yr-old patient with PMF is taking ruxolitinib to manage his splenomegaly and constitutional symptoms. He has progressed to accelerated phase, but not yet blast phase.
What would you do?Continue on ruxolitinibDiscontinue ruxolitinib immediately and proceed directly to allogeneic hematopoietic stem cell transplantSwitch from ruxolitinib to low-intensity AML therapy (eg, azacitidine, low-dose ara
-C)Induction chemotherapy for de novo AML
Clinical trial
Supportive care only
Case Study (
cont.
): Michael G. Slide24
Q: This 60-yr-old patient with PMF is taking ruxolitinib to manage his splenomegaly and constitutional symptoms. He has progressed to accelerated phase, but not yet blast phase.
What would you do?Continue on ruxolitinibDiscontinue ruxolitinib immediately and proceed directly to allogeneic hematopoietic stem cell transplantSwitch from ruxolitinib to low-intensity AML therapy (eg, azacitidine, low-dose ara
-C)Induction chemotherapy for de novo AML
Clinical trial
Supportive care only
Case Study (
cont.
): Michael G. Slide25
Combination Strategies: Ruxolitinib and DNA Methyltransferase Inhibitor in PMF Patients with Elevated Blasts
Combination evaluated in 3 symptomatic patients with cytopenias and elevated blast* counts Median age 80 years (range: 60 – 88)All had JAK2
V617F mutation2 had PMF and 1 had
post-ET MF
Clinical
trials
are investigating combinations of:
2
Ruxolitinib
and
azacitidine
in patients with Int-2 or high-risk MF requiring therapy (NCT01787487).
Ruxolitinib
and
decitabine
in patients with MPN-AP/MPN-BP (NCT02076191)
Tabbaroki A et al.
Leukemia
& Lymphoma
, 2014; Early Online:
1–3;
2. Mascarenhas J. Best Prac Res Clin Haematol. 2014;
27:197-208
. Slide26
There is no ‘standard of care’ and treatment options are very limited. Patients with severe or advanced MF may be treated with bone marrow transplantation (HSCT). This is currently the only treatment with the potential to cure MF transformed to leukemia.1
Leukemia treatments may be given with the aim of achieving a favorable response that allows completion of HSCT2Treatment Options for MF-AP or MF-BP1. Alchalby H, et al.
Biol Blood Marrow Transplant. 2014 Feb;20(2):279-81;
2.
Cervantes F
.
Blood.
2014;124(17):2635-42. Slide27
Median Survival by Treatment Strategyfor MPN-BP
Mesa, 2005Tam, 2008Kennedy, 2013Passamonti, 2005
Noor, 2011Thepot, 2010
Entire cohort
2.7
mo
5
mo
6.6
mo
2.9
mo
4.6
mo
-
Induction chemotherapy
3.9
mo
6
mo
9.4
mo
b
5.6
mo
6
mo
-
Induction chemotherapy and HSCT
-
-
47
mo
-
10.5
mo
Low-intensity therapy (
eg
, JAK2
inhibitor, DNA
hypomethylating
agent)
a
2.9
mo
7
mo
6.6
mo
-
-
8
mo
Supportive
therapy
2.1
mo
1.5
mo
-
2.5
mo
1.9
mo
-
a
Category also includes alkylating agents, vincristine, low-dose
cytarabine
,
gemtuzumab
.B Includes only those MPN-BP patients who achieved CR/Cri
Reviewed in
Rampal
,
Mascarenhas
.
Curr
Opin
Hematol
.
2014;21:65-71. Mesa
RA
,
et al.
Blood
2005
;
105:973–7;
Tam CS,
et
al.
Blood
2008
;
112:1628–37;
Kennedy JA,
et
al.
Blood
2013;
121:2725–33;
Passamonti
F,
et
al.
Cancer
2005;
104:1032–6;
Noor SJ,
et
al.
Leuk
Res
2011
; 35:608–13;
Thepot
S,
et
al.
Blood
2010;
116:3735–42.Slide28
Starting a New Oral Medication: Pharmacy Perspectives
Chemotherapy drugs (like those used for AML) may be prescribed for MF patients who are in BP (and sometimes in AP)Understand the planned treatment transition strategy/ timing to ensure medications are available as neededScreen for possible drug-drug interactions based on patient’s medication recordDiscuss treatment costs, including the patient’s responsibility; identify assistance program if neededPatient education
How to take the medicationDrug-specific side effects that might develop, what to do, and how to report How to prevent, minimize, or relieve side effects
Importance of compliance/adherence to treatment schedule
Safe handlingSlide29
A Change in Therapy: Considerations for Stopping Ruxolitinib Therapy
Consider tapering the dose of ruxolitinib gradually rather than stopping abruptly. After discontinuing ruxolitinib, MF symptoms generally return to pretreatment levels over a period of ~1 week.Some patients have experienced: fever, respiratory distress, hypotension, DIC, or multi-organ failureEvaluate and treat intercurrent illness and consider restarting or increasing the dose of ruxolitinib
Jakafi
prescribing information, 2014.Slide30
Michael’s MF is risk stratified as Int-2 risk (DIPSS; median survival, 1.5 years), as well classified as MPN-AP At 60 years of age, induction chemotherapy followed by HSCT is a viable option (if a donor is available and his comorbidity index is appropriate ). In the absence of a viable HSCT approach, enrollment in a clinical trial of a novel therapeutic approach should be considered. He still appears to be benefitting from ruxolitinib with respect to spleen reduction and symptom management; he will continue while exploring clinical trial or HSCT options
Gradually taper off ruxolitinib immediately prior to induction chemotherapy or HSCT conditioning therapy Case Study (cont.): Michael G. Slide31
ConclusionsThis patient’s case illustrates a major unmet need – treatment of patients with MF-AP or MF-BPPrognosis is poor, no medical therapy has been adequately evaluated in prospective study to demonstrate improved outcomes.
Selected MPN-BP patients who are transplant eligible (with an available donor) and have chemotherapy responsive disease, can have significant improvement in survival if HSCT is completed.1,2 The effect of ruxolitinib prior to HSCT is being investigated.3,4Enrollment in clinical trial should always be considered when available1. Kennedy JA, et al. Blood.
2013;121:2725-33; 2. Alchalby H, et al. Biol
Blood Marrow Transplant
.
2014;20:279-81;
3.
Jaekel N, et al. Bone Marrow Transplant. 2014;49:179-84; 4. Stubig
T,
et al.
Leukemia
2014;28:1736-64
. Slide32
ConclusionsRecently, treatment response criteria were proposed for use in clinical trials in patients with MPN-BP1While JAK inhibitors are effective in improving splenomegaly-related and cytokine-mediated symptoms, therapies that can alleviate cytopenias and decrease BM and PB blasts are
needed 1. Mascarenhas J, et al. Leuk Res. 2012;36: 1500–4;