MPN Flashcards
Treatment for symptomatic PMF
- Ruxolitinib
- Peginterferon alfa-2a
- Hydroxyurea, if cytoreduction would be symptomatically beneficial
- Pacritinib (if platelets < 50 x 109/L)
- Momelotinib (category 2B)
If asymptomatic, monitor for signs and symptoms of disease progression every _____
3-6 months
Evaluation for allogeneic HCT is recommended for
- Patients with low platelet counts
- Complex cytogenetics
Treatment for Higher Risk PMF, Plt >50, with symptomatic splenomegaly and/or constitutional symptoms
ALWAYS ASSESS IF TRANSPLANT CANDIDATE
- Ruxolitinib (category 1)
- Fedratinib (category 1)
Others:
* Momelotinib
* Pacritinib (category 2B)
Treatment for Higher Risk PMF, Plt <50
ALWAYS ASSESS IF TRANSPLANT CANDIDATE
- Pacritinib (category 1)
Other recommended regimen:
Momelotinib (category 2B)
MANAGEMENT OF MF-ASSOCIATED ANEMIA
Symptomatic splenomegaly and/or constitutional symptoms currently controlled on a JAK inhibitor
Preferred regimen
* Clinical trial
Other recommended regimens
* Ruxolitinib combination
Add luspatercept-aamt
Add erythropoiesis-stimulating agents (ESAs) (if serum EPO < 500 mU/mL)
Add danazol (category 2B)
Useful in certain circumstances
* Change to momelotinib
* Change to pacritinib
MANAGEMENT OF MF-ASSOCIATED ANEMIA
Symptomatic splenomegaly and/or constitutional symptoms currently not controlled
Preferred regimens
* Clinical trial
* Momelotinib
Other recommended regimens:
* Pacritinib
* Ruxolitinib combination
Add luspatercept-aamt
Add erythropoiesis-stimulating agents (ESAs) (if serum EPO < 500 mU/mL)
Add danazol (category 2B)
MANAGEMENT OF MF-ASSOCIATED ANEMIA
Anemia and no symptomatic splenomegaly and/or constitutional symptoms
Preferred regimen
* Clinical trial
Other recommended regimens
* Luspatercept-aamt
* ESAs (if serum EPO <500 mU/mL)
* Danazol
* Momelotinib (category 2B)
* Pacritinib (category 2B)
Useful for del(5q)
Lenalidomide + prednisone
Medication that requires prostate cancer screening and monitoring of LFTs as well as the use of concomitant medications such as statins are recommended over concerns for increased risk of rhabdomyolysis
Danazol
DYNAMIC INTERNATIONAL PROGNOSTIC SCORING SYSTEM (DIPSS)
- Age
- White blood cell count
- Hemoglobin, g/dL ≥10 <10
- Peripheral blood blast, %
- Constitutional symptoms
Low 0
Intermediate-1 (INT-1) 1 or 2
Intermediate-2 (INT-2) 3 or 4
High 5 or 6
DIPSS-PLUS
- DIPSS low-risk 0
- DIPSS intermediate-risk 1 (INT-1) 1
- DIPSS intermediate-risk 2 (INT-2) 2
- DIPSS high-risk 3
- Platelets < 100 x 109/L 1
- Transfusion need 1
- Unfavorable karyotype 1
Low 0
Intermediate-1 (INT-1) 1
Intermediate-2 (INT-2) 2 or 3
High 4 to 6
Unfavorable karyotype (in DIPSS Plus)
- Complex karyotype
- Sole o ttwo abnormalities that include
- trisomy 8
- 7/7q-
- i(17q)
- -5/5q-
- 12p-
- inv(3),
- 11q23 rearrangement
MUTATION-ENHANCED IPSS (MIPSS-70) FOR PATIENTS WITH PMF AGE ≤70 YEARS
- Hemoglobin < 10 g/dL 1
- Leukocytes >25 x 109/L 2
- Platelets < 100 x 109/L 2
- Circulating blasts ≥2% 1
- Bone marrow fibrosis grade ≥ 2 1
- Constitutional symptoms 1
- CALR type-1 unmutated genotype 1
- High-molecular-risk (HMR) mutations 1
- ≥2 HMR mutations 2
High-molecular-risk (HMR) mutations
- ASXL1
- EZH2
- SRSF2
- IDH1/2
SEAI
MUTATION AND KARYOTYPE-ENHANCED IPSS
(MIPSS-70+ VERSION 2.0) FOR PATIENTS WITH PMF
- Severe anemia (Hemoglobin < 8 g/dL in women and < 9 g/dL in men) 2
- Moderate anemia (Hemoglobin 8–9.9 g/dL in women and 9–10.9 g/dL in men) 1
- Circulating blasts ≥2% 1
- Constitutional symptoms 2
- Absence of CALR type 1 mutation 2
- HMR mutations
- ≥2 HMR mutations 3
- Unfavorable karyotype 3
- Very-high-risk (VHR) karyotype 4
Very low 0
Low 1–2
Intermediate 3–4
High 5–8
Very high ≥9
Unfavorable karyotype (in MIPSS-70+ Version 2.0)
- Any abnormal karyotype other than normal karyotype
- Sole abnormalities of:
- 20q-
- 13q-
- +9
- chromosome 1 translocation/duplication,
- -Y or sex chromosome abnormality other than –Y
VHR karyotype:
- Single/multiple abnormalities of −7
- i(17q)
- inv(3)/3q21
- 12p−/12p11.2
- 11q−/11q23
- Other autosomal trisomies not including + 8/+9 (eg, +21, +19)
MYELOFIBROSIS SECONDARY TO PV AND ET-PROGNOSTIC MODEL (MYSEC-PM)
- Age at diagnosis 0.15 per patient’s year of age
- Hemoglobin < 11 g/dL 2
- Circulating blasts ≥3% 2
- Absence of CALR type 1 mutation 2
- Platelets < 150 x 109/L 1 Constitutional symptoms 1
Low <11
Intermediate-1 (INT-1) ≥11 and <14
Intermediate-2 (INT-2) ≥14 and <16
High ≥16
POLYCYTHEMIA VERA
Low-risk:
High-risk:
Low-risk
* Age < 60 years and no prior history of thrombosis
High-risk
* Age ≥ 60 years and/or prior history of thrombosis
TREATMENT FOR LOW-RISK POLYCYTHEMIA VERA
- Manage cardiovascular risk factors
- Aspirin (81–100 mg/day)
- Phlebotomy (to maintain hematocrit < 45%)
Aspirin twice daily may be considered for patients with refractory symptoms
TREATMENT FOR HIGH-RISK POLYCYTHEMIA VERA
In addition to Aspirin, Phlebotomy
Preferred regimens:
* Hydroxyurea
* Ropeginterferon alfa-2b-njft
Other recommended regimen:
* Peginterferon alfa-2a
Useful in certain circumstances:
* Ruxolitinib
FDA approved for the treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea.
Have activity after inadequate response or loss of response to other agents besides hydroxyurea
Ruxolitinib
MIPSS-PV
- Thrombosis history 1
- Leukocyte count ≥15x109/L 1
- Age >67 2
- Adverse mutations (SRSF2) 3
Low 0–1
Intermediate 2–3
High ≥4
ESSENTIAL THROMBOCYTHEMIA
Very-low-risk
Low-risk
Intermediate-risk
High-risk
Very-low-risk
* Age ≤60 years, no JAK2 mutation, no prior history
of thrombosis
Low-risk
* Age ≤60 years, with JAK2 mutation, no prior
history of thrombosis
Intermediate-risk
* Age ˃60 years, no JAK2 mutation, no prior history
of thrombosis
High-risk
* History of thrombosis at any age or age >60 years
with JAK2 mutation
TREATMENT FOR VERY-LOW-RISK OR LOW-RISK OR INTERMEDIATE-RISK ESSENTIAL THROMBOCYTHEMIA
- Manage cardiovascular risk factors
- Aspirin (81–100 nmg/day) for patientsb with vasomotor/microvascular disturbances
TREATMENT FOR HIGH-RISK ESSENTIAL THROMBOCYTHEMIA
In addition to Aspirin
Hydroxyurea
Other recommended regimens for cytoreductive therapy:
* Peginterferon alfa-2a
* Anagrelide
Can be considered for patients in need of cytoreductive therapy who are younger or pregnant or who defer hydroxyurea
Peginterferon alfa-2a
Used in emergent situations, eg, severe thrombocytosis-related neurologic complications
Plateletpheresis
MIPSS-ET
- Male sex 1
- Leukocyte count ≥11 x 109/L 1
- Adverse mutations (SRSF2, SF3B1, U2AF1, TP53) 2
- Age >60 4
Low 0–1
Intermediate 2–5
High ≥6
Treatment for Accelerated/ blast phase MPN
MPN-accelerated phase (blasts 10%– 19% in peripheral
blood or bone marrow)
MPN blast phase (blasts ≥20% in peripheral blood or bone marrow)
HCT
Treatment for Accelerated/ blast phase MPN
Not a candidate for transplant
- Clinical trial
- HMA ± JAK inhibitors
- HMA + venetoclaxd
- Low-intensity chemotherapy
CRITERIA
PMF, early/prefibrotic stage (pre-PMF)
Major criteria
1. Bone marrow biopsy showing megakaryocytic proliferation and atypia, bone marrow fibrosis grade < 2, increased age-adjusted bone marrow cellularity, granulocytic proliferation, and (often) decreased erythropoiesis
2. JAK2, CALR, or MPL mutation or presence of another clonal marker or absence of reactive bone marrow reticulin fibrosis
3. Diagnostic criteria for BCR::ABL1-positive CML, PV, ET, myelodysplastic syndromes, or other myeloid neoplasms are not met
Minor criteria
* Anemia not attributed to a comorbid condition
* Leukocytosis ≥11 x 109/L
* Palpable splenomegaly
* LDH level above the above reference range
The diagnosis of pre-PMF or overt PMF requires all 3 major criteria and at least 1 minor criterion confirmed in 2 consecutive determinations
PMF, overt fibrotic stage
Major criteria
1. Bone marrow biopsy showing megakaryocytic proliferation and atypia, accompanied by reticulin and/or collagen fibrosis grades 2 or 3
2. JAK2, CALR, or MPL mutation or presence of another clonal marker or absence of reactive myelofibrosis
3. Diagnostic criteria for ET, PV, BCR::ABL1-positive CML, myelodysplastic syndrome, or other myeloid neoplasms are not met
Minor criteria
* Anemia not attributed to a comorbid condition
* Leukocytosis ≥ 11 x 109/L
* Palpable splenomegaly
* LDH level above the above reference range
* Leukoerythroblastosis
The diagnosis of pre-PMF or overt PMF requires all 3 major criteria and at least 1 minor criterion confirmed in 2 consecutive determinations
Morphology of megakaryocytes in PMF:
- Small to giant megakaryocytes with a prevalence of severe maturation defects (cloud-like, hypolobulated, and hyperchromatic nuclei)
- Presence of abnormal large dense clusters (mostly >6 megakaryocytes lying strictly adjacent)
CRITERIA
PV
Major criteria
1. Elevated hemoglobin concentration or elevated hematocrit or increased red blood cell mass
2. Bone marrow biopsy showing age-adjusted hypercellularity with trilineage proliferation (panmyelosis), including prominent erythroid, granulocytic, and increase in pleomorphic, mature megakaryocytes without atypia
3. Presence of JAK2 V617F or JAK2 exon 12 mutation
Minor criterion
* Subnormal serum erythropoietin level
The diagnosis of PV requires either all 3 major criteria or the first 2 major criteria plus the minor criterion
Diagnostic thresholds for PV:
Hemoglobin:
Hematocrit:
Red blood cell mass:
Hemoglobin: >16.5 g/dL in men and >16.0 g/dL in women
Hematocrit: >49% in men and** >48%** in women
Red blood cell mass: >25% above mean normal predicted value
A bone marrow biopsy may not be required in patients with
- Sustained absolute erythrocytosis (hemoglobin concentrations of >18.5 g/dL in men or >16.5 g/dL in women and hematocrit values of >55.5% in men or >49.5% in women) and
- Presence of a JAK2 V617F or JAK2 exon 12 mutation
CRITERIA
ET
Major criteria
1. Platelet count ≥450 × 109/L
2. Bone marrow biopsy showing proliferation mainly of the megakaryocytic lineage, with increased numbers of enlarged, mature megakaryocytes with hyperlobulated staghorn-like nuclei, infrequently dense clusters; no significant increase or left shift in neutrophil granulopoiesis or erythropoiesis; no relevant bone marrow fibrosis
3. Diagnostic criteria for BCR::ABL1-positive CML, PV, PMF, or other myeloid neoplasms are not met
4. JAK2, CALR, or MPL mutation
Minor criteria
* Presence of a clonal marker or absence of evidence of reactive thrombocytosis
The diagnosis of ET requires either all major criteria or the first 3 major criteria plus the minor criteria
Reactive causes of thrombocytosis
- Iron deficiency
- Chronic infection
- Chronic inflammatory disease
- Medication
- Neoplasia
- History of splenectomy
Symptom response requires ____% reduction in the MPN-SAF TSS.
≥50%
Iron chelation could be considered for patients who have received > ______ transfusions and/or ferritin ______ ng/mL in patients with lower-risk
MF.
> 20 transfusions and/or
Ferritin >2500 ng/mL
However, the role of iron chelation remains unclear.
Consider this vaccine for patients on, or prior to, treatment with a JAK inhibitor
Recombinant (killed) zoster vaccine
Used in MPN-associated bone pain due to their efficacy in the treatment of growth-factor–related bone pain
Loratadine and nonsteroidal anti-inflammatory drugs (NSAIDs) (naproxen)
All females with PV should maintain hematocrit, ideally, below the gestational range:
- < 41% trimester 1
- < 38% trimester 2
- < 39% trimester 3
Definition of High-Risk Pregnancy in PV or ET
- Previous venous and/or arterial thrombosis with/without pregnancy
- Previous hemorrhage due to PV or ET
- Previous pregnancy complications:
- Unexplained death of a morphologically normal fetus ≥ 10 weeks of gestation. Premature delivery of a morphologically normal fetus at < 34 weeks of gestation due to:
◊ Severe preeclampsia or eclampsia defined according to standard criteria
◊ Recognized features of placental insufficiency - ≥3 unexplained consecutive miscarriages at < 10 weeks of gestation, without anatomic, hormonal, or chromosomal abnormalities
- Unexplained intrauterine growth restriction
- Significant antepartum or postpartum hemorrhage
Recommendations for the Management of High-Risk Pregnancy
Treatment to start (continue) when pregnancy test is positive, and pregnancy is considered high risk:
* Low-dose aspirin daily
* Prophylactic LMWH throughout pregnancy and for 6 weeks postpartum
* Cytoreductive therapy with interferon or peginterferon alfa-2a
PV and ET
Complete response is defined as:
- Hematocrit less than 45% without phlebotomy
- Platelet count ≤400 x 109/L
- WBC count ≤10 x 109/L
- No disease-related symptoms
Partial response is defined as hematocrit less than 45% without phlebotomy or response in three or more of other criteria.
