Acute Myeloid Leukemia Flashcards by Ned Jones

Medications that are RF’s for therapy-related AML

Topoisomerase inhibitors
Alkylating agents

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Variables used to classify AML

cytogenetics (chromosomal translocations) + molecular characteristics

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Signs/symptoms

bruising/bleeding, constitutional symptoms (fever, fatigue), DOE.

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diagnostic criteria

Blasts (of myeloid lineage) from marrow OR peripheral blood >*20% OR presence of specific chromosomal abnormalities (t(15;17), t(8;21), inv(16), t(16;16))

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general treatment approach

induction therapy (tumor debulking) –> BMB for response assessment –> await for counts to recover –> repeat BMB –> consolidation therapy –> maintenance therapy (for some types)

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management of patient with aplastic marrow following induction therapy

await count recovery and consider growth factor support. Then repeat BMB.

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when do you evaluate for CR

7 to 10 days after completion of induction chemotherapy (demonstrate adequate elimination of leukemia cells) + then repeat again after cell line recovery to document remission status

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definition of morphologic CR

marrow blasts less than 5%, no auer rods, no persistence of extramedullary disease

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definition of cytogenetic CR

normal cytogenetics in patients who had abnormal cytogenetics

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definition of incomplete CR (CRi)

CR with persistence of cytopenia (usually thrombocytopenia)

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Selection of consolidation therapy depends…

Depends on favorable vs intermediate vs. poor risk AML but usually cytarabine (standard vs. intermediate vs. high dose)

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treatment options for relapse

ASCT
Clinical trial followed by ASCT
Salvage chemotherapy followed by ASCT
Supportive care

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classic AML patient in terms of age and demographic

Male in his mid 60s (male predominance)

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What does a myeloblast look like?

Immature cells with large nuclei, usually with prominent nucleoli, and a variable amount of pale blue cytoplasm (sometimes with faint granulation) after staining with Wright Giemsa

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Image of myeloblast

https://www.google.com/search?q=myeloblast&sxsrf=ALeKk003-G0eW2csR836edRbQJjlGnBsFw:1601909565760&source=lnms&tbm=isch&sa=X&ved=2ahUKEwj6kISV2p3sAhUPUa0KHRxkDY4Q_AUoAXoECBkQAw&biw=1117&bih=509#imgrc=RWwfVxY1u9X22M

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Bone marrow appearance in AML

usually hypercellular due to a partial or almost total replacement of the normal cellular components of the marrow by immature or undifferentiated cells, although AML can sometimes present with a hypocellular marrow.

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What is the general basic science goal of diagnosis in AML?

To determine that clonal population of cells is of myeloid origin

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What is a myeloblast?

Unipotent stem cell which differentiates into the effectors of the granulocyte series.

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Typical regimen for induction chemo

7-day continuous infusion of cytarabine along with anthracycline treatment on days 1 to 3 (so-called “7+3” regimens),
AND targeted agent if leukemia has specific mutation

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Cure rate after induction chemo

60 to 80 percent of younger adults achieve a CR with such regimens, but only about one-third of patients overall are ultimately cured of AML.

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Management of patient who doesn’t achieve CR after induction chemo

Second, shorter course of remission induction therapy

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How is response to therapy classified?

1) Complete remission (CR)
2) Complete remission (CRi) with incomplete recovery of normal neutrophil or platelet counts
3) Partial remission (PR)
4) Resistant disease (sometimes called refractory)

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What is the goal of post remission therapy?

Eliminate residual, undetectable disease and achieve long-term disease control and cure

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What is consolidation therapy in general?

intensive treatment that follows soon after the attainment of CR

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what is HiDAC therapy?

infusions of high dose cytarabine

Options for consolidation therapy in AML

1) one or more courses of chemotherapy (usually infusions of high dose cytarabine, so-called HiDAC therapy) 2) autologous hematopoietic cell transplantation (HCT) 3) allogeneic HCT. - Depending on medical fitness and whether transplant candidate

Which type of transplant is preferred in AMl and WHY?

- allogeneic HCT - Induces an important graft-versus-leukemia effect that is not provided by other approaches but is complicated by short- and long-term toxicities)

Role of maintenance therapy in AML

Not necessary for most types of AML, certain categories of AML may benefit from maintenance therapy following recovery from consolidation therapy.

Labs in AML

Leukopenia or leukocytosis + retic normal or decreased + variable degree of normocytic anemia + variable degree of thrombocytopenia.

When is BMB typically performed

7 to 10 days after completion of induction chemotherapy to demonstrate adequate elimination of leukemia cells. Repeated after recovery of neutrophils and platelets to document remission status. The first marrow after induction therapy may be inconclusive and lead to a repeat marrow examination 7 to 10 days later.

Age cutoff typically used to differentiate management

What is a chimeric oncogene?

oncogene formed by chromosomal translocation, which generates a fusion oncogene

CBC in AML

neutropenia thrombocytopenia Can see leukocytosis (due to circulating blasts)

Clinical features of leukostasis in AML

respiratory and/or neurologic distress in AML patient + myeloblasts >50K

TLS labs

Hyperkalemia Hyperphosphatemia Hyperuricemia hypocalcemia

Risk categories of AML

Favorable Intermediate Poor/Adverse

Post-remission therapy means

Two phases: consolidation and maintenance therapy

Options for consolidation in AML

HiDAC Autologous HCT Allogeneic HCT

HiDAC is

High dose cytarabine

Preferred consolidation therapy for patients with intermediate or unfavorable prognosis AML

HCT

Preferred transplant type for patients with intermediate or unfavorable prognosis AML + why

Allogeneic (induces graft-versus-leukemia effect

Induction therapy for AML if prior history of MDS

vyxeos

vyxeos is

daunorubicin and cytarabine

Ven-FLAG regimen

Venetoclax Fludarabine Ara-C Cytarabine G-CSF

NPM1 risk category (with FLT3)

Mutated without FLT3 = favorable Mutated with FLT3 = intermediate Wild type = poor

Relapsed AML options

1) Second allograft 2) salvage chemo 3) glasdegib 4) clofarabine 5) targeted agents 6) clinical trial

Targets of molecular therapies in AML

IDH1 FLT3

FLT3 inhibitor drug

midostaurin giltertinib

when to do BMB after induction therapy

Controversial -- same say 7 days, others say wait until ANC of 0, which makes more sense to me

when BMB is repeated

typically 14 days after counts start recovering

management of residual disease found on BMB after induction therapy

typically repeat induction

when consolidation is typically started

day 28

IDH inhibitors

Enasidenib and ivosidenib

5 year survival

30%

Survival depends highly on

1) age 2) performance status 3) cytogenetics

what are topoisomerase inhibitors

anthracyclines etoposide

Cell surface markers that are negative in APL (board question)

CD34 and HLA-DR (confirm)

RUNX1 -- favorable or unfavorable

unfavorable

-5, -7, inv(3), complex cytogenetics -- favorable or unfavorable

unfavorable

CEBPA --- Bialleliic, dual mutant - favorable or unfavorable

Favorable

t(15;17) -- risk stratification

Favorable

Inv(16) or t(8;21) -- favorable or unfavorable

Favorable

KIT mutation -- favorable or unfavorable

Generally unfavorable

general prognosis of APML

do very well with ATRA based therapy

lower intensity treatment options for less fit patients

LDAC (low dose cytarabine) HMA (hypomethylating agents) Targeted agents

what are the hypomethylating agents

azacitidine decitidine

FDA approved treatment for therapy-related AML

CPX-351 (vyxeos)

FDA approved treatment for CBF-AML

intensive chemo + gemtuzumab

transplant timing for unfavorable

ASAP (immediately after induction or more realistically after 1-2 HIDAC cycles)

New maintenance therapy that will likely become standard of care

Oral azacitidine

monoclonal AB approved for AML + indication

- Gemtuzumab - intermediate but most benefit is in favorable risk w/ CEBPA

Relapse risk is predicated now on...

MRD

What are the MRD categories?

MRD-negative MRD-positive

Hallmark genetic feature of therapy-related AML

MLL rearrangement

Most common drugs causing therapy-related AML

Topoisomerase inhibitors Alkylating agents

Preferred induction regimen at UMass

Mitoxantrone + cytarabine

consolidation for AML

IF moderate or high risk -- allo transplant Favorable risk -- HIDAC

FDA approved maintenance treatment of AML

Oral azacitidine

Molecular targets for AML

IDH1 or IDH2, FLT3, CD22

IDH1 or IDH2 targeted agents

ivosidenib, enosidib

FLT3 targeted agents

midostaurin, gitleritinib

Prognostic significance of therapy-related AML

- confers worse prognosis (higher likelihood of high risk genetic features)

schedule for 7+3 regimen

seven-day continuous infusion of cytarabine along with anthracycline treatment on days 1 to 3 (so-called "7+3" regimens),

Favorable gene abnormalities

1) t(8;21) 2) inv(16) 3) t(16;16) 4) Mutated NPM1 without FLT3 5) Biallelic mutated CEBPA IDH2 (confim)

Blast immunophenotype in AML

CD34+

Why DAH happens in induction therapy with AML

blasts invade lung, when killed by chemo, they cause alveolar inflammation and hemorrhaging

Management of patient with CRi and not able to be taken to transplant

HMA

management of cerebellar toxicity with HiDAC

Discontinuation of HiDAC. Never rechallenge.

timeframe of therapy related AML after treatment with topoisomerase inhibitors

1-3 years after exposure

Difference between topoisomerase inhibitor therapy-related AML and alkylating agent-associated therapy-related AML

topoisomerase inhibitor - rarely preceded by MDS + shorter latency period

Clinical features of therapy related AML

- rapidly progressive leukemia + high white blood cell counts

Markers expressed by AML M7 (megakaryocytic AML)

CD41 and CD61

marker associated with erythroid leukemia

CD235a

markers associated with monocytic leukemia

CD11c, CD14 and CD64

risk stratification system used in AML

European LeukemiaNet (ELN) risk stratification system

Classification of cytogenetics

Favorable Intermediate Adverse

Significance of low FLT3-ITD

low allelic ratio

intermediate risk genetic abnormalities

1) mutated NPM1 and FLT3-ITD (High) 2) Wild-type NPM1 without FLT3-ITD or with FLT3-ITD (low) 3) t(9;11) 4) cytogenetic abnormalities not classified as favorable or adverse

adverse genetic abnormalities

t(6;9) t(v;11q23.3) t(9;22) inversion(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2) -5 or del(5q); -7; -17/abn(17p) monosomal karyotype wild-type NPM1 and FLT3-ITD (High) mutated RUNX1 Mutated ASXL1* Mutated TP53

Caveat about RUNX1 or ASXL1 mutation classification

- should not be used as an adverse prognostic marker if they co-occur with favorable-risk AML subtypes

Hypoplasia definition with response assessemnt

Cellularity less than 20% of which residual blasts are less than 5%

Extramedullary manifestation of acute leukemia is referred to as? Term for skin manifestation?

1) Myeloid sarcomas 2) leukemia cutis

Management of myeloid sarcomas

- systemic chemotherapy with 3+7 regimen (considered manifestations of systemic disease)

Allo conditioning regimens per boards

- IV busulfan + cyclophosphamide - IV busulfan + fludarabine

normal cytogenetics risk stratification

intermediate risk

Risk factors for cerebellar toxicity with high-dose Ara-C

elderly + renal dysfunction

management of pregnant patient diagnosed with AML

3+7 (38% risk of fetal demise) but can't treat pregnant mother otherwise

what are the myeloid lineage markers

CD13 and CD33

Gene defect implicated in therapy related AML due to topoisomerase inhibitors

MLL rearrangement

Latency period for therapy related AML with topoisomerase inhibitors

1-3 years

Latency period for therapy related AML from alkylating agents

3-5 years

Giltertinib target

FLT3 positive

7 + 3 dosing + schedule

200 mg/m2 continuous infusion cytarabine for 7 days OR daily + idarubicin 12 mg/m2 or daunorubicin 60-90 mg/m2 x 3 days

How is gemtuzumab administered for CD33 positive patients?

single dose on day 1 of 7+3

consolidation for favorable risk

Hi-DAC (3 gm/m2 BID) x 3-4 cycles, TIW x 4 doses

consolidation for therapy related AML

Allo-transplant (carries poor prognosis)

Favorable mutation in AML

NPM1 mutation (think of scene)

Advantages and disadvantages of umbilical cord blood for transplants

*Single cord transplants have stem cells so can't be used in patients with higher BMI. - single cord is associated with better OS as compared to double cord

what are standard and high doses of daunorubicin

45 mg/m2 = standard dose 90 mg/m2 = high dose

When is high dose daunorubicin indicated for?

- No benefit in patients above age 65.

highest risk mutation in AML

P53

Blast cutoff in AML

Greater than 10% + recurrent genetic abnormalities

Other favorable mutations for AML

bZIP AMl1-ETO CBFB-MYH11

AML Maintenance for patients who are transplant ineligible

oral azacitadine

Cytogenetic abnormalities conferring poor prognosis and warranting transplant

1) inv (3) 2) t(6;9) 3) del(5q) 4) del(7p) 5) chromosome 17 abnormalities 6) complex karyotype

Clinical features of AML with myelodysplasia-related changes (AML-MRC)

AML + multilineage dysplasia + MDS related cytogenetic changes

What cytogenetics are seen in MDS?

Deletion chromosome 7 and 5

Treatment of AML with myelodysplasia-related changes

liposomal daunorubicin and cytarabine (vyxaneos)