MDS

Question 1

What are some low risk MDS genetic defining events?

Answer 1

MDS w/5q deletion
MDS w/SF3B1 mutation
These are both low blast/low risk MDS

Question 2

What is a high risk MDS genetic defining event?

Answer 2

MDS with biallelic TP53 mutations.

Question 3

What are some high risk cytogenetic abnormalities with MDS?

Answer 3

Think anything with chromosome 3 is bad. Inv3, del3q, t(3q), del7

Question 4

What are some good risk MDS cytogenetic abnormalities? Very good risk? If you don’t remember all of these it’s okay, more so important to know the high risk ones.

Answer 4

Good risk-del 5q, del 12p, del 20q
Very good risk: -Y, del 11q

Question 5

What MDS mutation is associated with a good prognosis and is the only one for this?

Answer 5

SF3B1 mutation

Question 6

When treating a MDS patient who has anemia with a ESA agent, what level predicts for response?

Answer 6

If they have a level of less than 200 they are the most likely to get a response and also between 200-500 a moderate response, but anything more than this they will not get a response.

Question 7

What is Luspatercept approved for in MDS? Remember there are two separate indications.

Answer 7

It is approved for the treatment of very low, low, and intermediate risk MDS w/o del 5q with ringed sideroblasts greater than or equal to 15% or RS greater than or equal to 5% with a SF3B1 mutation. They can also have one cytogenetic abnormality. ALSO, the other indication is you can use it for low/intermediate risk patients without prior ESA who are transfusion dependent.

Question 8

When using Luspatercept in MDS what signaling is affected and how?

Answer 8

It decreases SMAD2 and SMAD3 signaling (normally when this pathway is active it inhibits RBC maturation).

Question 9

What is the approval for Lenalidomide for MDS?

Answer 9

Patients with very low, low, or intermediate risk disease with 5q del +/- one other cytogenetic abnormality (except deletion 7) with EPO less than or equal to 500 or greater than 500.

Question 10

What is the mechanism of action of Lenalidomide in MDS?

Answer 10

It modulates E3 ubiqutin ligase cereblon activity, this in turn alters the degradation of casein kinase 1 which increases Wnt/B-catenin signaling

Question 11

What is the only medication that is associated with a survival benefit in high risk MDS besides transplant?

Answer 11

Azacitidine

Question 12

Remember to yourself, what defines high risk MDS, in terms of blast count, platelet, and Hgb?

Answer 12

Marrow Blast Count>10%
Hgb less than 8
Platelet Count less than 50K

Question 13

What are the treatment options for high risk MDS who are not eligible for transplant?

Answer 13

Azacitidine +/- Venetoclax (preferred), Decitabine +/- Venetoclax, Oral decitabine in combination with cedazuridine. If they have a IDH1 mutation a Cat 2B rec is Ivosidenib +/-Aza or Olutasidenib + Azacitidine.

Question 14

All high risk patients with MDS should be pushed for what?

Answer 14

Transplant unless there are contraindications.

Question 15

What HLA product can be overexpressed in hypoplastic MDS and what is a treatment option?

Answer 15

HLA-DR2 and HLA-DR15
Tx-Cyclosporine and horse ATG, can also add Eltrombopag
Other assoc features: STAT3, PNH clone

Question 16

What cytogenetic features in MDS warrant aggressive treatment and not observation?

Answer 16

t(8;21), t(15;17), inv 16, t(9;11), t(6;9), inv 3, mutated NPM1, CEBPA in frame bZIP mutation, NUP98 rearrangement, other KMT2A rearrangements, other MECOM rearrangement

Question 17

What is Imetelstat approved for in MDS?

Answer 17

It is approved for patients with low to intermediate risk 1 MDS who have required 4 or more blood transfusions over the past 2 months or for patients who are resistant to ESAs.

Question 18

When using Ivosedinib alone in low risk MDS, what is this approved for? What about in high risk MDS?

Answer 18

You can use it for patients who have low risk MDS with IDH1 mutation in those who have failed an HMA after 4-6 cycles. High risk MDS: those with IDH1 mutation that have relapsed/refractory disease. But keep in mind you can use this alone or in combination with Azacitidine in the upfront setting.

Question 19

What mutations are associated with t-MDS in terms of alkylating agents and topoisomerase inhibitors?

Answer 19

Alkylating agents: -5 and -7 chromosome
Topoisomerase inhibitors: t(9;11), t(8;21), t(3;21)

Question 20

What aklylating chemotherapy agents are associated with t-MDS?

Answer 20

Aklylating agents-Cyclophosphamide, Cisplatin, Carboplatin, Dacarbazine, Bendamustine, Nitrogen Mustard, Chlorambucil

Question 21

What topoisomerase inhibitors are assoc with t-MDS and more commonly overt AML? What is the key differentiation here vs using alkylating agents?

Answer 21

Etoposide and Doxorubincin. Please note that with these agents patients often develop AML 1-3 years after without antecedent MDS. Usually with Alkylating agents it takes longer and they develop MDS before transforming to AML.

Question 22

What are some options according to NCCN for intermediate, high, and very high risk MDS patients who are transplant candidates?

Answer 22

Patients can go for upfront alloSCT, Azacitidine plus Ivosedenib (IDH1 mutation) followed by allo, clinical trial followed by allo transplant. You can also combine Azacitidine or Decitabine with Venetoclax. Oral Decitabine w/Cedazuridine, Azacitidine, or Decitabine alone for those who aren’t candidates for alloSCT. High intensity chemo is an option as well!

Question 23

What is the indication for using Imeltestat in very low, low, and intermediate risk MDS?

Answer 23

You can use it for patients who lack del 5q but have ringed sideroblasts greater than or equal to 15% or RS greater than or equal to 5% w/SF3B1 mutation and EPO level greater than 500 +/- one other cytogenetic mutation. Remember in this scenario the preferred option is Luspatercept.