Download Patient with MF has Increasing

Case Study:
Patient with MF has Increasing Blasts,
but Not Yet AML -- What to Do?
John Mascarenhas, MD
Myeloproliferative Disorders Program
Tisch Cancer Institute, Division of Hematology/Oncology
Mount Sinai School of Medicine
New York, New York
Co-Presenters
Jeffrey C. Bryan, PharmD, RPh
Clinical Pharmacy Specialist, Leukemia
Division of Pharmacy, University of Texas
MD Anderson Cancer Center
Houston, TX
Otitolola Arterbery, MSN, RN, OCN
Clinical Nurse
MD Anderson Cancer Center
Houston, TX
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 chemotherapy
• For patients with myelofibrosis (MF), AML is the
most common cause of death2
1. Rampal R, Mascarenhas J. Curr Opin Hematol. 2014;21:65-71; 2. Cervantes, et al. Blood. 2009;113(13):2895-901.
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.
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.
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 109/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 architecture
– Immunohistochemical staining confirmed presence of
myeloblasts.
Case Study (cont.): Michael G.
Q: Does this patient have post-MF AML?
A. Yes
B. No
C. Maybe
Case Study (cont.): Michael G.
Q: Does this patient have post-MF AML?
A. Yes
B. No
C. Maybe
This patient has 12% peripheral blasts
– Accelerated phase, but not yet blast
phase (AML)
Criteria for Leukemic Transformation
of MPNs
MPN Disease Phase
Definition 1
Leukemic transformation (blast • ≥20% blasts in peripheral blood or
phase [MPN-BP])
bone marrow
Accelerated phase (MPN-AP)
Mesa RA, et al. Leuk Res 2007; 31:737–740.
• No consensus; ≥10% to <20% blasts
widely considered to be in AP
• Various degrees of pancytopenia
Caring for the Patient with Progressing MF
Increased 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 own
– Transfusions to add RBC or platelets if the response to
medications is insufficient
Caring for the Patient with Progressing MF
Increased 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)
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%
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%
Rate of Transformation from an MPN to
Acute Myeloid Leukemia
MPN Subtype at Diagnosis
10-year Leukemic
Transformation Rate*
Essential thrombocythemia (ET)
1%
Polycythemia vera (PV)
4%
Primary myelofibrosis (PMF)
20%
*From time of MPN diagnosis
Rampal, Mascarenhas. Curr Opin Hematol. 2014;21:65-71
Comparison of Blast Transformation Rates
Among MPNs (N=826)
Tefferi A et al. Blood. 2014; 124(16): 2507–2513.
Risk Factors for Leukemic Transformation
in Patients with MPNs
• PV - Age >70 years or prior exposure to P-32, busulfan, or pipobroman1
• ET - Anemia or platelet >1000 x 109/L2
• MF
– Leukocytes >30 x 109/L or abnormal karyotype 3
– PB blasts ≥3% or platelet count < 100 x 109/L4
– Time to development of hemoglobin <10 g/dL, leukocytes >30 x 109/L,
platelets <150 x 109/L5
– BM blasts >10% or high-risk karyotype6
– Splenectomy, platelet count <100 x 109/L, PB blasts ≥1% 7
– BM blasts >10%, platelet count <50 x 109/L, chromosome 17 abnormalities
(define MF-AP as a necessary step to MF-BP) 8
– Monosomal karyotype9
– 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.
Effect of Driver Mutations on Incidence of
Leukemic Transformation in PMF
Rumi E et al. Blood 2014;124:1062-1069.
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?
A. Yes
B. No
Case Study (cont.): Michael G.
Q: Does this new genetic information change whether or
not his disease in blast phase?
A. Yes
B. No
 Patient’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.
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.
Spectrum of Mutations in MPN-BP
and De-novo AML
Rampal, Mascarenhas. Curr Opin Hematol. 2014;21:65-71.
Possible Mechanisms of MPN Evolution
to 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.
Case Study (cont.): Michael G.
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?
A.
Continue on ruxolitinib
B.
Discontinue ruxolitinib immediately and proceed directly to
allogeneic hematopoietic stem cell transplant
C.
Switch from ruxolitinib to low-intensity AML therapy (eg,
azacitidine, low-dose ara-C)
D. Induction chemotherapy for de novo AML
E.
Clinical trial
F.
Supportive care only
Case Study (cont.): Michael G.
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?
A.
Continue on ruxolitinib
B.
Discontinue ruxolitinib immediately and proceed directly to
allogeneic hematopoietic stem cell transplant
C.
Switch from ruxolitinib to low-intensity AML therapy (eg,
azacitidine, low-dose ara-C)
D. Induction chemotherapy for de novo AML
E.
Clinical trial
F.
Supportive care only
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 mutation
– 2 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.
Treatment Options for MF-AP or MF-BP
• 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 HSCT2
1. Alchalby H, et al. Biol Blood Marrow Transplant. 2014 Feb;20(2):279-81;
2. Cervantes F. Blood. 2014;124(17):2635-42.
Median Survival by Treatment Strategy
for MPN-BP
Mesa,
2005
Tam,
2008
Kennedy,
2013
Passamonti,
2005
Noor,
2011
Thepot,
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
B Includes
also includes alkylating agents, vincristine, low-dose cytarabine, gemtuzumab.
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.
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 needed
• Screen for possible drug-drug interactions based on patient’s
medication record
• Discuss treatment costs, including the patient’s responsibility;
identify assistance program if needed
• Patient education
– How to take the medication
– Drug-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 handling
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 failure
• Evaluate and treat intercurrent illness and consider
restarting or increasing the dose of ruxolitinib
Jakafi prescribing information, 2014.
Case Study (cont.): Michael G.
• 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
Conclusions
• This patient’s case illustrates a major unmet need – treatment
of patients with MF-AP or MF-BP
• Prognosis 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.3,4
• Enrollment in clinical trial should always be considered when
available
1. 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.
Conclusions
• Recently, treatment response criteria were
proposed for use in clinical trials in patients
with MPN-BP1
• While 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;