Post on 11-Jan-2016
description
Acute Leukemia: Treatment
HistoricalGeneral Principles (AML)APLALL Cases
Acute Leukemia: TreatmentHistorical
Prior to modern chemotherapy (1960s), average survival with acute leukemia ~ 2 months
General PrinciplesIndividualized and risk adapted
Major supportive care component due to natural history of the disease and due to treatment toxicity
Treatment with curative intent involves sequential remission Induction and post-remission phases
General PrinciplesIndividualized and risk adapted
Individualized risk/benefit analysis. Since conventional leukemia treatment is associated with significant toxicity and mortality (10-40%), based on age, comorbidities, disease biology etc., not all patients should be treated aggressively.
General PrinciplesIndividualized and risk adapted
Whereas even 10 years ago all patients treated aggressively were treated identically (overkill), due to a better molecular understanding of disease biology, and better prognostication (largely molecular and cytogenetic) the intensity of treatment (and hence the toxicity) is now tailored to the individual case).
General PrinciplesMajor supportive care component
Protean signs and symptoms
Patients may present with or develop during treatment
life-threatening opportunistic infections (neutropenia)septic shock, respiratory failure etc.
severe bleeding, often life threatening (thrombocytopenia +/- coagulopathy)
neurological symptoms (CNS infiltration or bleeding)etc.
General Principles
Treatment with curative intent involves sequential remission Induction and post-remission
phases
Treatment of AML
Remission-Induction Post-remission
RefractoryCR Cure
Relapse
Death Death
Treatment of AML
Remission-Induction Post-remission
RefractoryCR Cure
Relapse
Death Death
Chemotherapy x 2(3)
Allotransplant
Long-term follow-up (with assessment of minimal residual disease)
Maintenance treatment?
Chemotherapy x 1
Why Post-remission treatment?
CR: > 60-70%
Long-Term Survival (>3 years): ~15%
> 50% of patients relapse
< 5% Marrow Blasts in Normocellular Marrow
Normal Peripheral Blood Counts
No Extramedullary Disease
CompleteRemission
Minimal Residual Disease (MRD)
Post-remission Treatment
Cure
Relapse
~109 cells
Pre-treatment
~1012 cells
Treatment of AML
Remission-InductionPrognostic factors (who gets treated?)Drugs
Remission-InductionPrognostic factors before therapy
Age (>60 unfavourable; median 68)Secondary leukemia (unfavourable)Comorbidities (unfavourable)Cytogenetics
FavourableIntermediatePoor risk
Otherelevated LDHpresentation LKC
Interrelated
Induction chemotherapySupportive careClinical trialNo treatment
Drugs
Cytosine Arabinoside, Cytarabine, Ara-CS-phase-specific cytotoxic antimetaboliteMetabolized intracellularly into Ara-CTP DNA damage due to inhibition of -DNA polymerase, inhibition of DNA repair, and incorporation into DNA.
Anthracycline (Daunorubicin, Mitoxantrone, Idarubicin)DNA intercalation, inhibiting DNA synthesis and DNA-dependent RNA synthesis. Cytotoxic activity cell cycle phase non-specific, but maximal in S-phase.
Drugs
EtoposideCytotoxic topoisomerase II inhibitor, inhibiting
DNA synthesis. Affects mainly the S and G2 phases
Remission?
Induction Chemotherapy
CRAllotransplant
Observation
? Maintenance
ConsolidationChemotherapy x 2
Prognostic factors after therapyAge (>60 unfavourable; median 68)Comorbidities Cytogenetics
FavourableIntermediatePoor risk
OtherTime to CRNumber of blasts on day 14-16MRD
Prognostic factors after therapyAge (>60 unfavourable; median 68)Comorbidities Cytogenetics
FavourableIntermediatePoor risk
OtherTime to CRNumber of blasts on day 14-16MRD
pp 4075-4083
17del(5q)/-5, -7, abn 3q
abn 9q, 11q, 20q, 21q, 17p,
complex karyotypes (>= 5 unrelated abn), t(6;9), t(9;22)
30del(5q)/-5, -7/del(7q), abn 3q
abn 9q, 11q, 20q, 21q, 17p,
t(6;9), t(9;22), complex karyotypes (>= 3 unrelated abn)
Unfavourable
Poor
62Normal, 11q23 abn, +8, del(9q), del(7q), +21, +22, all others
46Normal, +8, +6, -Y, del(12p)Intermediate
Indeterminate
Standard
21inv(16)/t(16:16)/del (16q)
t(15;17), t(8:21) +/- other aberrations
20inv(16)/t(16:16)/del (16q)t(15;17) +/- other aberrations; t(8:21) without del(9q) or complex karyotypes
Favourable
Good
%MRC AML 10%SWOG/ECOG Risk Status
Proportions of different cytogenetic subtypes in each age group
Bacher, U. et al. (2005) Haematologica 90: 1502-1510
1: 21-30 years2: 31-40 years3: 41-50 years4: 51-60 years5: 61-70 years
Bacher, U. et al. (2005) Haematologica 90: 1502-1510
Slovak, M. L. et al. Blood 2000;96:4075-4083
So who gets transplanted ?
(Who gets observed?)
Blood, 2003 v102, 1232-1240
Allogeneic compared with autologous stem cell transplantation in the treatment ofpatients younger than 46 years with acute myeloid leukemia (AML) in firstcomplete remission (CR1): an intention-to-treat analysis of theEORTC/GIMEMAAML-10 trialStefan Suciu, Franco Mandelli, Theo de Witte, Robert Zittoun, Eugenio Gallo, Boris Labar, Gennaro De Rosa, Amine Belhabri,Rosario Giustolisi, Richard Delarue, Vincenzo Liso, Salvatore Mirto, Giuseppe Leone, Jean-Henri Bourhis, Giuseppe Fioritoni,Ulrich Jehn, Sergio Amadori, Paola Fazi, Anne Hagemeijer, and Roel Willemze, for the EORTC and GIMEMA Leukemia Groups
Autologous BMT in CR1 identical to chemotherapy alone…
Allogeneic BMT vs. Autologous BMT
Allogeneic BMT vs. chemotherapy alone
DFS from CR according to donor availability
Good Risk
Suciu, S. et al. Blood 2003;102:1232-1240
Allo BMT?
Good Risk… NO
DFS from CR according to donor availability
Bad Risk
Suciu, S. et al. Blood 2003;102:1232-1240
Allo BMT?
Bad Risk… YES
DFS from CR according to donor availability
Intermediate Risk
Suciu, S. et al. Blood 2003;102:1232-1240
DFS from CR according to donor availability in 3 age groups
15-25 years 26-35 years 36-45 years
Suciu, S. et al. Blood 2003;102:1232-1240
Allo BMT?
Intermediate Risk… Maybe
How to further stratify intermediate risk group?
46 %Normal, +8, +6, -Y, del(12p)
Intermediate
Indeterminate
Standard
46 %Normal, +8, +6, -Y, del(12p)
Intermediate
Indeterminate
Standard
~1/3
15-25 years 26-35 years 36-45 years
1. Age
…alloBMT cut-off 35-40 years?
Suciu, S. et al. Blood 2003;102:1232-1240
2. Presence of specific mutations
2.i FLT3 mutations
i. FLT3/ITD - “internal tandem duplication” in JM domain - activating - associated with high LKC - ~20-25%
ii. FLT3/TKD - activating point mutation - second tyrosine kinase domain of FLT3 - ~7-10%
iii. FLT3-JM-PM - activating point mutation in JM domain - ~2%
pp 1752-1759
316899Unknown
.51741923abn(3q)
.01722830-7
.02001616-5
.005001919del(5q)
.00003214344Complex
867379Adverse
.71721012+22
.728215374+8
.00500181811q23
.11021820del(7q)
.00013496185281Normal
30132302434Intermediate
.003733942inv(16)
.0004966167t(8;21)
.002374984133t(15;17)
2458184242Favourable
P%FLT3/ITD+FLT3/ITD+FLT3/ITD-TotalCytogenetics
Suciu, S. et al. Blood 2003;102:1232-1240
316899Unknown
.51741923abn(3q)
.01722830-7
.02001616-5
.005001919del(5q)
.00003214344Complex
867379Adverse
.71721012+22
.728215374+8
.00500181811q23
.11021820del(7q)
.00013496185281Normal
30132302434Intermediate
.003733942inv(16)
.0004966167t(8;21)
.002374984133t(15;17)
2458184242Favourable
P%FLT3/ITD+FLT3/ITD+FLT3/ITD-TotalCytogenetics
Suciu, S. et al. Blood 2003;102:1232-1240
<.00132%44%41%OS
<.00123%39%35%EFS
<.00130%46%42%DFS
<.00164%44%49%RR
Outcome at 5 y
.411%9%10%RD
.0411%7%8%ID
.0578%84%82%CR
227627854No. of patients
PFLT3/ITD+FLT3/ITD-Total
Kottaridis, P. D. et al. Blood 2001;98:1752-1759
Kottaridis, P. D. et al. Blood 2001;98:1752-1759
Kottaridis, P. D. et al. Blood 2001;98:1752-1759
Should FLT3/ITD status define alloBMT?
2.ii. MLL partial tandem duplications
- partial internal tandem duplication usually involving exons 2-6 or 2-8- ~10 of AML with normal cytogenetics- ~ 90% of AML with +(11)
No difference in presentation features
No difference in CR rate
Remission duration PTD-positive (n = 16) vs. PTD-negative (n = 158) AML with normal cytogenetics
Dohner, K. et al. J Clin Oncol; 20:3254-3261 2002
Overall survival PTD-positive (n = 18) vs. PTD-negative (n = 203) AML with normal cytogenetics
Dohner, K. et al. J Clin Oncol; 20:3254-3261 2002
2.iii. Nucleophosmin mutations
- ~50-60% normal cytogenetics
pp 3733-3739
Kaplan-Meier analysis of AML with normal karyotype bearing mutated or WT NPM1
Schnittger, S. et al. Blood 2005;106:3733-3739
2.iv. otherCEBP
-~ 15-20% of normal cytogenetics- confers favourable prognosis
RAS- ~ 10% of normal cytogenetics- neutral
KIT- ~ 1%- unknown
3. Overexpression of specific genes
3.i. ERG (ETS - Related Gene)
- overexpression ~25% normal cytogenetics
4. otherCEBP
-~ 15-20% of normal cytogenetics- confers favourable prognosis
RAS- ~ 10% of normal cytogenetics- neutral
KIT- ~ 1%- unknown
4. otherCEBP
-~ 15-20% of normal cytogenetics- confers favourable prognosis
RAS- ~ 10% of normal cytogenetics- neutral
KIT- ~ 1%- unknown
Outcome of patients grouped by ETS-related gene (ERG) expression into quartile 4 (Q4), the uppermost quartile, and quartiles 1 to 3 (Q1-3), the lower quartiles
Marcucci, G. et al. J Clin Oncol; 23:9234-9242 2005
3.ii. BAALC (Brain And Acute Leukemia, Cytoplasmic)
Figure 2. Kaplan-Meier analysis of OS, EFS, and DFS for de novo AML patients with normal cytogenetics
Combinatorial analysis?
Distribution of additional mutations in the NPM1-mutated group
Schnittger, S. et al. Blood 2005;106:3733-3739
Mrozek, K. et al. Blood 2007;109:431-448
Kaplan-Meier analysis of AML with normal karyotype and different NPM1 and FLT3-ITD status
NPM- FLT3/ITD-
NPM+ FLT3/ITD-
NPM- FLT3/ITD+
NPM+ FLT3/ITD+
Schnittger, S. et al. Blood 2005;106:3733-3739
Kaplan-Meier analysis of AML with normal karyotype and different NPM1 and FLT3-TKD status
NPM- FLT3/TKD-
NPM+ FLT3/TKD-
NPM- FLT3/TKD+
NPM+ FLT3/TKD+
Schnittger, S. et al. Blood 2005;106:3733-3739
Mrozek, K. et al. Blood 2007;109:431-448
Induction Chemotherapy
CRAllotransplant
Observation
ConsolidationChemotherapy x 2(3)
? Maintenance
Chemo
Prognostic factors after therapyAge (>60 unfavourable; median 68)Comorbidities Cytogenetics
FavourableIntermediatePoor risk
OtherTime to CRNumber of blasts on day 14-16MRD
Monitoring MRDStratification parameterDetection of impending relapse
Multiparameter flow cytometryDetect low frequency aberrant immunophenotype
Quantitative PCRDetect translocation-specific transcripts
t(15;17)inv(16)t(8;21)
Detect expression of leukemia associated genesWT1EVI1
usually expressed as log reduction from diagnosis
Induction Chemotherapy
CRAllotransplant
Observation
? Maintenance Chemo
ConsolidationChemotherapy x 2(3)
Maintenance Chemotherapy ?
No accepted role in NA in non-M3 AML(but of key importance in APL and ALL)
Acute Leukemia: Treatment
HistoricalGeneral Principles (AML)APLALL Cases
Acute Leukemia: Treatment
HistoricalGeneral Principles (AML)APLALL Cases
APL
While all of the “general principles” apply, APL has several unique features
- most curable AML- most progress in outcome in last 15 years of all AMLs
DNR + ATRA
DNR
Tallman, M. et al., (2002) Blood,100:4298-4302North American Intergroup
Overall Survival
APL
- most “deadly” up front due to life-threateningcoagulopathyhemorrhagethrombosisretinoic acid syndrome
APL
- 10 - 15% of adult AML- median age ~ 40 years- no increase in incidence with age- increased incidence among Hispanics, Philipinos
APL
Prognostic factors- t(15;17) confers good prognosis- presence of additional cytogenetic abnormalities does not alter this risk- simultaneous presence of “bad risk” or complex abnormalities do not confer bad risk in the presence of t(15;17) - RAR fusion partner PZLF-RAR confers poor drug response- WBC count >10 bil/L (likely have FLT3/ITD mutation)
- Platelet count <40 bil/L- CD56 +ve
Treatment- unique sensitivity to all-trans retinoic acid (ATRA) and arsenic trioxide
- LKC < 10,000: start ATRA day 0 and daunorubicin day 5
- LKC > 10,000: start ATRA and daunorubicin simultaneously
Treatment
- typically no role for alloBMT
- maintenance:LKC < 10 bil/L, ATRA x 1 – 2 yearsLKC > 10 bil/L, ATRA + 6-mercaptopurine +
methotrexate x 2 years- only AML in which autoBMT in CR2 as good as alloBMT
Treatment
MRD assessment - following induction, usually PCR +ve
- following final consolidation, >95% PCR -ve (PCR +vity at this point very bad)- following completion of consolidation chemo, MRD assessment every 3 months for 2-3 years- if -ve PCR becomes +ve, chance of overt relapse within 1 year > 95%
Acute Leukemia: Treatment
HistoricalGeneral Principles (AML)APLALL Cases
Acute Leukemia: Treatment
HistoricalGeneral Principles (AML)APLALL Cases
ALL
While all of the “general principles” apply, ALL has several unique features
Adverse prognostic factors:Age > 35 years> 4 weeks to CRLKC > 30 bil/L (B lineage)LKC > 100 bil/L (T lineage)Cytogenetics Ph+ t(9;22) (30 % adults)
translocations involving MLL, mychypodiploidy (mostly pediatric)
ALL
Distinct biologylymphadenopathy, splenomegaly much more likelymediastinal mass commonCNS disease much more common
ALL
Treatment of adult ALL is much more complicated than that of AML:
- more drugs doxorubicincytarabinemethotrexatevincristine/vinblastineL-asparaginasecorticosteroids6-mercaptopurine
- prophylactic CNS treatment intrathecal chemo + XRT
- treatment lasts several years in 3 week cycles of alternating drugs, and with periodic CNS treatment, and periodic dose intensification
ALL
In adults, alloBMT currently restricted to Ph+ cases and to those with 11q23 abnormalities
Acute Leukemia: Treatment
HistoricalGeneral Principles (AML)APLALL Cases