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Chronic Leukemia Flashcards

1
Q

philadelphia chromosome

A

excession mature neutrophil production
t(9;22) promotes fusion of 2 genes, BCR-ABL. protein p210 ->upregulated TK activity->promotes continuous cell cycling, inh apoptosis, inc mature neutrophil proliferation

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2
Q

CML - hematologic response

A

nml peripheral, WBC <450k, no immature cells

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3
Q

CML - cytogenetic response

A

complete: BMBx 0% Ph+ cells
partial: BMBx 1-34% Ph+ cells
Major = CR +PR
Minor = 35-95% Ph+ cells

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4
Q

CML - molecular response

A

complete: negative BCR-ABL by RT-PCR
major: cytogenetic remission with 3 log or greater reduction in BCR-ABL by RT-PCR

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5
Q

CML - tx goals

A 
#1 maintain chronic phase - sustained cytogentic / molecular remission
#2 prevent progression to accelerate/ blast
#3 minimize toxicity of chronic tx
#4 cure (only proven alloHSCT)
#4 if accelerated/blast - induce 2nd chronic phase
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6
Q

CML - imatinib - phase III iris trial

A

1st trial - 100% hematologic response
yr 4,5,6,7,8 tox is less than tx during yr 1,2,3 (paradigm shift)
8yr OS: 85% (if CML related OS: 93%)

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7
Q

imatanib AE’s

A

hematologic (neutropenia, anemia, thrombocytopenia), LFTs

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8
Q

CML - nilotinib vs imatinib

A

24 mo MMR (primary): 71% N 300bid, 66% N 400bid, 44% I 400qd
12 mo CCyR: 87%, 85%, 77%
Progression to AP/BC: <1%, 1.8%, 4.6%

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9
Q

nilotinib 300mg bid AE’s

A

neutropenia (12%), thrombocytopenia (10%), anemia (3%), Rash (1%), t bili (4%), ALT (4%), AST (1%), lipase (6%), dec phos (5%)

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10
Q

CML - dasatinib vs imatinib

A

24 mo CCyR: 86% d 100qd vs 82% i 400qd

24 mo MMR: 64 vs 46%

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11
Q

CML - bosutinib vs imatinib

A

12 mo CCyR: 70 b vs 68 i%
12 mo MMR: 41 vs 27%
dz progression: 3 vs 10%

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12
Q

imatinib ADME keys

A

400mg qd
take with food
inhibits 3A4 / 2D6
metabolism: 3A4

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13
Q

dasatinib ADME keys

A

100mg qd
with or without food (avoid acid reducers)
metabolism: maybe 3A4

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14
Q

nilotinib ADME keys

A 
300mg bid
empty stomach
metabolism 3A4
inhibits 3A4, 2C8, 2C9, 2D6
induces 2B6, 2C8, 2C9
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15
Q

bosutinib ADME keys

A

500mg daily
take with food
metabolism: 3A, P-gp

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16
Q

ponatinib ADME keys

A

45md daily
with or without food
metabolism: 3A, P-gp

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17
Q

mechanisms of resistance to TKI’s

A 
#1 bcr-abl gene amplification / overexpression
#2 mutation in the kinase domain (cell growth dependent of bcr-abl for 1 and 2)
#3 secondary genetic alterations (cell growth independent of bcr-abl activity, clonal evolution)
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18
Q

TKI point mutations

A

T315I R to imatinib, dasatinib, nilotinib

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19
Q

CML - 2nd line tx

A 
#1 dose escalation of i
#2 2nd gen TKI (d, n, b)
#3 3rd gen TKI (p)
#4 omacetaxine
#5 alloHSCT
#6 clinical trial
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20
Q

CML - 2nd line dasatinib (data very similar for nilotinib)

A

chronic phase: 91% CHemR, 49% CCyR, 59% major CyR
accelerated phase: 63, 24, 34
blast crisis: 35, 32, 39

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21
Q

CML - salvage - 2 prior TKI’s - bosutinib

A

28.5mo median f/u: CHemR 73%, CCyR 24%, MMR 15%

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22
Q

CML - ponatinib - phase I - T315I mutation (made NEJM)

A

CHemR 100%, MCyR 92%, CCyR 75%, MMR 67%

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23
Q

CML - ponatinib - phase II

A

majorCyR 70%

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24
Q

CML - salvage - omacetaxine - T315I mutation

A

1.25 mg/m2 subQ bid x14day each 28day cycle (maintenace 7 day q28d)
CHR 77%, MajCyR 23%, CCyR 16%
median PFS 7.7 mo

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25
Q

omacetaxine ADRs

A

gIII/IV

thrombocyto 76%, neutrop 44%, anemia 39%, pancytop 21%, leukop18%, infx 8%, fatigue 5%

26
Q

CML -salvage- omacetaxine - 2 prior TKIs

A

CP: OS 34 mo, MCyR 20%, CCyR 10%, CHR 69%
AP: 16 mo, 27, 0, 24%

27
Q

CML - AP tx

A 
#1 imatinib or other TKI (less response than if in chronic phase)
#2 alloHSCT (much less common)
28
Q

CML - blast crisis tx

A 
#1 disappointing results with TKI's
#2 induction chemo and/or TKI then alloHSCT: VAC CR 58%, OS 7mo, hyperCVAD
#3 lymphoid blast more responsive than myeloid
#4 consider alloHSCT if 2nd chronic phase
29
Q

CML - NCCN - 1st line

A

may use any TKI except ponatinib

30
Q

CLL: monoclonal B-cell

A

monoclonal b-cell detectable several yrs prior to CLL dx, similar antigen phenotype to CLL, 41 of 45pt had this screening positive

31
Q

CLL: cytogenetics - poor risk (these effect initial regimen selection)

A

del 11q (OS: 79 mo), del 17p (OS: 32 mo)

32
Q

CLL: somatic point mutations

A

TP53 15%, MYD88 10%, ATM 9%, NOTCH1 4%, etc, ect, ect

33
Q

CLL: dz course

A

indolent, OS 1-20 yrs, OS dependent on stage of dz (Rai stage IV 3-4 yrs), richter’s transformation (<5%)

34
Q

CLL: goals of tx

A 
#1 reserved for stage III-IV or those with clinical sx
#2 cytogenetics
#3 age
35
Q

CLL: front line without del 11q or del 17p

A

age >70: generally one/two drug, lighter chemo
chlorabm+/-R, BR, Cyclophos+pred+/-R, alemtuz, Flu+/-R, R, cladribine, lenalid
age <70: FCR, FR, PCR, BR

36
Q

CLL: second line without del 11q or del 17p: if short response 18-36 mo

A

age >70: reduced dose FCR or PCR, BR, mpR, chloramb+/-R, ofat, alemtuzR, dose dense R
age <70: FCR, PCR, BR, RCHOP, RhyperCVAD, RdaEPOCH, OFAR, ofat, alemtuzR, mpR

37
Q

CLL: 1st line: elderly, frail

A

chlorambucil +/- rituximab
rituximab
pulse steroids

38
Q

CLL: FCR

A

fludarabine 25mg/m2 x3d
cyclophos 250mg/m2 x3d
ritux 375mg/m2 wk1 then 500mg/m2
q28d x6 cycles

39
Q

CLL: FCR vs FC - front line

A

PFS: 51.8 vs 32.8 mo
CR: 44 vs 22
OS at 3yr: 87 vs 83
even thought CLL cells are not bound well by rituximab

40
Q

CLL: bendamustine 100mg/m2 d1-2 vs chlorambucil d1-15 - front line

A

CR 31 vs 2
RR 68 vs 31
median PFS: 21.6 vs 8.3 mos

41
Q

CLL: bendamustine 90mg/m2 d1-2 +ritux - front line

A 
RR: 88
CR: 23
median EFS: 34 mo
27 mo OS: 91%
centers moving toward this regimen from fludarabine for front line
42
Q

CLL: bendamustine ADR

A

leukop 30, thromboc 22, neutrop 20, anemia 20, allergic rxn 2, infx 2

43
Q

CLL: del 17p - 1st line

A

FCR, FR, alemtuz+/-R

44
Q

CLL: del 17p - 2nd line

A

R-CHOP, R-hyperCVAD, ofatumumab, mpR, alemtuzumabR

45
Q

CLL: del 11q : age <70 1st line

A

FCR, BR, PCR

46
Q

CLL: del 11q : age >70 1st line

A

reduced dose FCR, BR, chlorambucil +/-R, cyclophos +pred +/-R, alemtuz, R, lenalidomide

47
Q

CLL: del 11q : age <70 2nd line

A

FCR, PCR, BR, flu+alemtuz, RCHOP, RhyperCVAD, RdaEPOCH, OFAR, alemR, lenalidR, ofatumumab, mpR

48
Q

CLL: del 11q : age >70 2nd line

A

reduced dose FCR, reduced dose PCR, BR, mpR, chlorambucilR, alemR, lenalidR, ofatumumab, R

49
Q

CLL: relapsed CLL: FCR vs FC

A

PFS 30.6 vs 20.6mo
OS not reached vs 52 mo
RR 70 vs 58

50
Q

CLL: relapsed CLL: bendamustine-R

A

RR 59%
CR 9%
OS 34mo

51
Q

CLL: relapsed CLL: ofatumumab (third line)

A

RR 47%
median PFS 5.5mo
median OS 16.3mo

52
Q

ofatumumab MOA

A

binds to CD20 at a different epitope than rituximab (binds better in CLL cells than rituximab); more infusion rxn’s than ritux

53
Q

CLL supportive care - recurrent infxs

A 
#antimicrobials as appropriate
#IVIG  is IgG 500
54
Q

CLL supportive care - antibiotic px

A

give if purine analogue or alemtuzumab

HSV, PJP
for alemtuz CMV monitoring OR valganciclovir for 2 months after (gancic if viral load inc)

55
Q

CLL supportive care - autoimmune cytopenias

A

AIHA, fludarabine associated AIHA (stop, tx, avoid subsequent flu), ITP (eval BMBx for causes, tx: steroids, ritux, ivig, csa, splenectomy, eltrom, romiplos), pure red blood cell aplasia (eval parvovirus B19)

56
Q

CLL supportive care - immunizations

A

influenza q1yr, pneumococcal q5yr, avoid ALL live vaccines including herpes zoster

57
Q

CLL supportive care - blood pdt support

A

irradiate all blood pdts, follow institutional guideline

58
Q

CLL supportive care - TLS

A

std precautions

59
Q

CLL supportive care - thromboprophylaxis

A

if lenalidomide: ASA 81mg if plts >50k

60
Q

CLL supportive care - tumor flare rxns

A 
for lenalidomide pts
#painful lymph node enlargement (local inflammation at tx initiation), also could be spleen enlargement, low-grade fever, rash
#tx: steroids (pred 25-50 qd x5-10d, antihistamines for rash or pruritis
#px: in bulky LN >5cm pred 20mg qd x5-7d with rapid taper
61
Q

CLL: OFAR regimen

A

oxaliplatin 25mg/m2 d1-4, fludarabine 30mg/m2 d2-3, cytarabine 1gm/m2 d2-3, rituximab d3 1st cycle then d1
q4wks x6

BCOP (32 decks)

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