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

Acute Leukemia: Treatment Historical Prior to modern chemotherapy (1960s), average survival with acute leukemia ~ 2 months

General Principles Individualized 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 Principles Individualized 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 Principles Individualized 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 Principles Major 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 Refractory CRCure Relapse Death

Treatment of AML Remission-Induction Post-remission Refractory CRCure Relapse 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 Complete Remission Minimal Residual Disease (MRD) Post-remission Treatment Cure Relapse ~10 9 cells Pre-treatment ~10 12 cells

Treatment of AML Remission-Induction Prognostic factors (who gets treated?) Drugs

Remission-Induction Prognostic factors before therapy Age (>60 unfavourable; median 68) Secondary leukemia (unfavourable) Comorbidities (unfavourable) Cytogenetics Favourable Intermediate Poor risk Other elevated LDH presentation LKC Interrelated

Induction chemotherapy Supportive care Clinical trial No treatment

Drugs Cytosine Arabinoside, Cytarabine, Ara-C S-phase-specific cytotoxic antimetabolite Metabolized 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 Etoposide Cytotoxic topoisomerase II inhibitor, inhibiting DNA synthesis. Affects mainly the S and G2 phases

Remission?

Induction Chemotherapy CR Allotransplant Observation ? Maintenance Consolidation Chemotherapy x 2

Prognostic factors after therapy Age (>60 unfavourable; median 68) Comorbidities Cytogenetics Favourable Intermediate Poor risk Other Time to CR Number of blasts on day MRD

Prognostic factors after therapy Age (>60 unfavourable; median 68) Comorbidities Cytogenetics Favourable Intermediate Poor risk Other Time to CR Number of blasts on day MRD

pp

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:

1: years 2: years 3: years 4: years 5: years Bacher, U. et al. (2005) Haematologica 90:

Slovak, M. L. et al. Blood 2000;96:

So who gets transplanted ? (Who gets observed?)

Blood, 2003 v102, Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial Stefan 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:

Allo BMT? Good Risk… NO

DFS from CR according to donor availability Bad Risk Suciu, S. et al. Blood 2003;102:

Allo BMT? Bad Risk… YES

DFS from CR according to donor availability Intermediate Risk Suciu, S. et al. Blood 2003;102:

DFS from CR according to donor availability in 3 age groups years26-35 years36-45 years Suciu, S. et al. Blood 2003;102:

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 years26-35 years36-45 years 1.Age …alloBMT cut-off years? Suciu, S. et al. Blood 2003;102:

2. Presence of specific mutations

2.iFLT3 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

316899Unknown abn(3q) del(5q) Complex Adverse q del(7q) Normal Intermediate inv(16) t(8;21) t(15;17) Favourable P%FLT3/ITD+FLT3/ITD+FLT3/ITD-TotalCytogenetics Suciu, S. et al. Blood 2003;102:

316899Unknown abn(3q) del(5q) Complex Adverse q del(7q) Normal Intermediate inv(16) t(8;21) t(15;17) Favourable P%FLT3/ITD+FLT3/ITD+FLT3/ITD-TotalCytogenetics Suciu, S. et al. Blood 2003;102:

<.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 No. of patients PFLT3/ITD+FLT3/ITD-Total Kottaridis, P. D. et al. Blood 2001;98:

Should FLT3/ITD status define alloBMT?

2.ii.MLL partial tandem duplications - partial internal tandem duplication usually involving exons 2-6 or ~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:

Overall survival PTD-positive (n = 18) vs. PTD-negative (n = 203) AML with normal cytogenetics Dohner, K. et al. J Clin Oncol; 20:

2.iii.Nucleophosmin mutations - ~50-60% normal cytogenetics

pp

Kaplan-Meier analysis of AML with normal karyotype bearing mutated or WT NPM1 Schnittger, S. et al. Blood 2005;106:

2.iv.other CEBP  -  ~ 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.other CEBP  -  ~ 15-20% of normal cytogenetics - confers favourable prognosis RAS - ~ 10% of normal cytogenetics - neutral KIT - ~ 1% - unknown

4.other CEBP  -  ~ 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:

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:

Mrozek, K. et al. Blood 2007;109:

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:

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:

Mrozek, K. et al. Blood 2007;109:

Induction Chemotherapy CR Allotransplant Observation Consolidation Chemotherapy x 2(3) ? Maintenance Chemo

Prognostic factors after therapy Age (>60 unfavourable; median 68) Comorbidities Cytogenetics Favourable Intermediate Poor risk Other Time to CR Number of blasts on day MRD

Monitoring MRD Stratification parameter Detection of impending relapse Multiparameter flow cytometry Detect low frequency aberrant immunophenotype Quantitative PCR Detect translocation-specific transcripts t(15;17) inv(16) t(8;21) Detect expression of leukemia associated genes WT1 EVI1 usually expressed as log reduction from diagnosis

Induction Chemotherapy CR Allotransplant Observation ? Maintenance Chemo Consolidation Chemotherapy 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 Historical General Principles (AML) APL ALL Cases

Acute Leukemia: Treatment Historical General Principles (AML) APL ALL 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: North American Intergroup Overall Survival

APL - most “deadly” up front due to life-threatening coagulopathy hemorrhage thrombosis retinoic acid syndrome

APL % 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 drugresponse - 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 years LKC > 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 Historical General Principles (AML) APL ALL Cases

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

ALL While all of the “general principles” apply, ALL has several unique features Adverse prognostic factors: Age > 35 years > 4 weeks to CR LKC > 30 bil/L (B lineage) LKC > 100 bil/L (T lineage) CytogeneticsPh+ t(9;22) (30 % adults) translocations involving MLL, myc hypodiploidy (mostly pediatric)

ALL Distinct biology lymphadenopathy, splenomegaly much more likely mediastinal mass common CNS disease much more common

ALL Treatment of adult ALL is much more complicated than that of AML: - more drugsdoxorubicin cytarabine methotrexate vincristine/vinblastine L-asparaginase corticosteroids 6-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 Historical General Principles (AML) APL ALL Cases