Acute Leukemia: Treatment Historical General Principles (AML) APL ALL Cases

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


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.


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


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


Bad Risk


Allo BMT?

Bad Risk… YES


Intermediate Risk


DFS from CR according to donor availability in 3 age groups

15-25 years 26-35 years 36-45 years


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?


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


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


<.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



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



KIT- ~ 1%- unknown

4. otherCEBP



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


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+


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+


Mrozek, K. et al. Blood 2007;109:431-448


CRAllotransplant

Observation

ConsolidationChemotherapy x 2(3)

? Maintenance

Chemo




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


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)





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%





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



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Acute Leukemia: Treatment Historical General Principles (AML) APL ALL Cases

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