MDS

Question 1

What are the characteristics of del(5q)?

What is used to treat it? (Dose + Response rate)

Answer 1

Normal platelet count or thrombocytosis w/ atypical megakaryocytes (hypolobulated)
Macrocytic anemia w/ erythroid hypoplasia
Mild leukopenia/neutropenia
Low blast count
Isolated del(5q)

Lenalidomide 10mg PO daily, given 21/28d; Response rate of 57% for transfusion independence and cytogenetic response (CR+PR) of 57%. Has some utility in non-del(5q) with ~25% response rate. Development of resistance associated with TP53 mutation.

Question 2

What two mutations are very good risk in MDS IPSS-R?

Answer 2

del(11q) and del(Y)

Question 3

What cytogenetic abnormalities are “Good” in IPSS-R?

Answer 3

Normal, del(5q), del(12p), del(20q)

Question 4

What cytogenetic abnormalities are very poor in IPSS-R?

Answer 4

Complex >3 abnormalities

Question 5

What cytogenetic abnormalities are poor in IPSS-R?

Answer 5

Complex 3 abnormalities, -7, inv(3)/t(3q)/del(3q)

Question 6

What cytogenetic abnormalities are intermediate in IPSS-R?

Hint: major route abnormalities CML are ALMOST the same…

Answer 6

del(7q), [+8, +19, i(17q)], any other single or double independent clones

The brackets are the classic CML major route abnormalities.

Question 7

What is the mechanism of action of Luspatercept? How frequently is it dosed?

Answer 7

Erythroid maturation (not production) agent.

• Neutralizes select TGF-B- superfamily ligands to intercept/inhibit SMAD 2/3 signalling
• The reduction in SMAD signaling leads to enhanced erythroid maturation.

BELIEVE trial in Beta- thal, MEDALIST in MDS

It is dosed q3weekly, both indications start at 1mg/kg, but beta-thal only goes up to 1.25mg/kg

MDS can be dosed at 1mg/kg-> 1.33mg/kg -> 1.75mg/kg

Fatigue, Nausea and Diarrhea are common AEs

Question 8

What clinical and laboratory parameters predict response to ESA in MDS?

Answer 8

1. low transfusion requirement (< 2 units/month)
2. low endogenous pretreatment plasma EPO level (< 500 U/L), but ideally <200U/L
3. < 10% bone marrow blasts
4. low/intermediate-1 (int-1) risk International Prognostic Scoring System (IPSS).

*not FDA approved

Question 9

What is the controversy for Romiplostim in MDS?

Answer 9

The trial examining this was halted early for concern of increased transformation to AML. Further investigation of this study showed there was no increased transformation risk, but been hesitancy in the field since this finding. Generally contraindicated with>5% blasts. Otherwise use at own peril.

Question 10

What drugs cause macrocytosis?

Answer 10

Chemotherapy:
Methotrexate, Hydroxyurea, Azathioprine, 6MP, Imatinib

Antibiotics:
Septra

Anti-seizure:
Phenytoin, Valproate

Anti-viral:
Lamivudine, Zidovudine

Question 11

What are the components of the IPSS-R?

Answer 11

BM Blast %
Cytogenetics
Hb
Plt
Neutrophils

Question 12

Which MDS patients benefit from up-front alloHSCT

Answer 12

1) Intermediate-2, High-risk, or IPSS-R Intermediate, High or Very High Risk
2) Delay lower risk to failure of HMAs or progression to higher-risk

Question 13

CMML Diagnostic Criteria:

Answer 13

Major:

1. Absolute monocytosis >1.0 and accounting for >10% of WBC differential x3 months
2. Not meeting WHO criteria for CML, PV, ET, MF
3. Blasts (and their equivalents) account for <20% of differential
4. Dysplasia involving at-least 1 myeloid lineage

Minor:
A clonal marker is found, or exclusion of reactive causes of monocytosis

Diagnosis:
Either all 4 major, or first 3 major and minor criteria. If the minor criteria is used you MUST exclude all other fusion genes (PDGFRA-FIP1L1, PDGFRB, FGFR, PCM1-JAK2)

Stages:
CMML0: <2% blasts plus promonocytes in peripheral blood and <5% blasts in bone marrow
CMML1: 2 to 4% blasts plus promonocytes in peripheral blood and 5 to 9 percent blasts in BM
CMML2: 5 to 19% blasts plus promonocytes in peripheral blood and 10 to 19%blasts in BM or any Auer rods

Question 14

Define Idiopathic cytopenia of undetermined significance:

Answer 14

Cytopenia in one or more blood lineages that remain unexplained despite appropriate evaluation, as described separately.

●No evidence of clonal hematopoiesis (CH); if a leukemia-associated mutation is detected, the variant allele frequency (VAF) should be <2 percent.

●No other evidence of a hematologic malignancy, according to World Health Organization (WHO) criteria.

Question 15

Define Clonal cytopenias of undetermined significance:

Answer 15

●Unexplained, clinically meaningful cytopenias

●CH is detected with ≥2 percent VAF of a leukemia-associated gene

●No other evidence of a hematologic malignancy, as described above

Question 16

Define Clonal Hematopoiesis of Indeterminate Potential

Answer 16

●VAF ≥2 percent of an acquired mutation of a leukemia-associated gene; the most common mutations affect DNMT3A, TET2, and/or ASXL1.

●Normal peripheral blood counts. The diagnosis of CHIP specifically excludes patients with clinically significant cytopenias; such patients should instead be diagnosed with clonal cytopenia of uncertain significance (CCUS).

●No clinical or pathologic evidence for a World Health Organization (WHO)-defined hematologic malignancy.

Higher over-all mortality, and CVD

Question 17

What are the MDS/MPN overlap syndromes?

Answer 17

1. CMML
2. MDS/MPN-RS-T (Essentially ET + MDS; has typically JAK2/CALR/MPL and SF3B1)
3. JMML
4. Atypical CML (Peripheral blood leukocytosis due to increased numbers of neutrophils and their precursors comprising ≥10% of leukocytes, Dysgranulopoiesis, No or minimal absolute basophilia; basophils usually <2% of leukocytes, No or minimal absolute monocytosis; monocytes <10% of leukocytes, Hypercellular bone marrow with granulocytic proliferation and granulocytic dysplasia, with or without dysplasia in the erythroid and megakaryocytic lineages, <20% blasts in the blood and bone marrow, No evidence of PDGFRA, PDGFRB, or FGFR1 rearrangement, or PCM1-JAK2, Not meeting WHO criteria for BCR-ABL1+ CML, PMF, PV, or ET*)

Question 18

When correcting B12 deficiency how long does count recovery take for:

Reticulocytes
Anemia
Macrocytosis
Neurologic recovery

Answer 18

Within hours; peak reticulocyte count within 1 week.
Within 1 week
2-3 months
3-12 months. May be permanent

Question 19

Bone marrow findings in copper deficiency?

Answer 19

Bone marrow aspirate may show dysplasia in the erythroid precursors such as large size, nuclear multilobulation, and nuclear budding as well as the presence of ring sideroblasts. Unlike myelodysplastic syndrome, the bone marrow aspirate in copper deficiency characteristically shows cytoplasmic vacuoles within erythroid and myeloid precursors.