Hematologic Malignancy Part I

Nisa Makruasi, MDDivision of Hematology, Department of Medicine,

HRH Princess Maha Chakri Sirindhon Medical Center,Srinakharinwirot University

Outlines

• Leukemia: AML, ALL• MPNs: CML, PV, ET, PF• Lymphoid neoplasm: NHL, HD, CLL/SLL• Plasma cell dyscrasia

Leukemia

Pathogenesis

Molecular alteration

Loss of cell cycle control-P 53 dysfunction

-P15,16 CDK gene methylation

Autonomous cell proliferation-Activating mutations:Flt3,Ras,

C-kit

-Inactivating mutation :NF-1

-Autocrine loops

Escape from apoptosis

Increased self renewal-Catenin mutations

-Activation of Wnt, activated RTK

Differentiation block-Fusion transcription factors-Retinoic acid reception, PML-RAR-MLL fusions

Dissemination-TNF secretion-Increased selectin

AKT pathway, P 53 mutations, Bcl 2 overexpression

Acute lekemia: clinical

• BM failure • Hyperleukocytosis

• Leukemic infiltration :gum, brain, skin, bone

• Tumor lysis syndrome • Disseminated intravascular coagulopathy

ACUTE < 3 weeks

6

Gum hypertrophy

Risk factor

• Irradiation• Occupational chemicals eg. benzyne• Chemotherapeutic agents (especially

alkylating agents, topoisomerase II inh)• Immunosuppression• Prior myeloproliferative neoplasm• Prior myelodysplasia

AML following alkylating agents exposure

• Typically 5- 10 yrs latency period• Associated with antecedent

myelodysplastic phase • Monosomies or deletions of the long arm

of chromosomes 5 and 7

Topoisomerase II-induced AML

• Shorter latency period of 1 -3 yrs• Less often preceded by myelodysplastic

phase• Usually shows monocytic differentiation• Balanced 11q23 translocation with

partners (6;11), (9;11), or (11;19)

FAB classification• M0: AML with minimal differentiation (MPO<3%)

• M1: AML without maturation (MPO≥3%, <10% maturation beyond blast stage)

• M2: AML with maturation (MPO≥3%, >10% maturation beyond blast stage)

• M3: Acute promyelocytic leukemia (≥30%blasts+hypergranular promyelocytes, strongly MPO or Sudan black B positive; microgranularvariant(M3v) inconspicuous granules, 15% of APL)

• M4: Acute myelomonocytic leukemia (>20% monocytes, NSE positive)

• M4eos: Acute myelomonocytic leukemia with eosinophilia (abnormal marrow eosinophils associated with inv(16) or t(16;16) )

• M5: Acute monocytic leukemia (M5a poorly differentiated; monoblastic, M5b differentiated promonocytes, monocytes; strongly NSE positive)

• M6: Acute erythroleukemia (Erythroblasts≥50%, dyserythropoiesis, glycophorinA+)

• M7: Acute megakaryocytic leukemia (Associated with marrow fibrosis, CD41 or CD61 often positive)

MyeloblastMonoblast

WHO 2008 Classification of AML

• Acute myeloid leukemia with recurrent genetic abnormalities

– AML with t(8;21)(q22;q22); RUNX1-RUNX1T1

– AML with inv (16) (p13.1;q22) or t (16;16) (p13.1;q22); CBFB-MYH11

– Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARA

– AML with t(9;11)(p22;q23); MLLT3-MLL– AML with t(6;9)(p23;q34); DEK-NUP214

– AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1

– AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1

– AML with mutated NPM1 – AML with mutated CEBPA

• Acute myeloid leukemia with myelodysplasia-related changes

• Therapy-related myeloid neoplasms

WHO Classification of AML

• Acute myeloid leukemia, not otherwise specified

– AML with minimal differentiation

– AML without maturation

– AML with maturation

– Acute myelomonocytic leukemia

– Acute monoblastic/monocytic leukemia

– Acute erythroid leukemia

• Pure erythroid leukemia

• Erythroleukemia, erythroid/myeloid

– Acute megakaryoblastic leukemia

– Acute basophilic leukemia

– Acute panmyelosis with myelofibrosis

• Myeloid sarcoma

• Myeloid proliferations related to Down syndrome – Transient abnormal myelopoiesis

– Myeloid leukemia associated with Down syndrome

Prognosis • Age > 55-60 yrs• Number of WBC at diagnosis• Denovo or secondary AML• Cytogenetic risk– Good risk– Intermdeiate risk– Adverse risk

• Molecular risk– FLT3-ITD, NPM1, WT1, C-kit, MLL-PTD

• Chemotherapy resistance• Poor performance status

Cytogenetic risk• Good cytogenetic

– t(15;17)(q22;q12~21)/PML-RARA– t(8;21)(q22;q22)/RUNX1-RUNX1T1– inv(16)(p13q22)/t(16;16)(p13;q22)/CBFB-MYH1

• Intermediate cytogenetic– Entities not classified as favorable or adverse

• Adverse cytogenetic– abn(3q) <excluding t(3;5)(q21~25;q31~35)>– inv(3)(q21;q26)/t(3;3)(q21;q26)/EVI-1 expression– add (5q), del(5q), -5– -7, add(7q)– t(6;11)(q27;q23), t(10;11)(p11~13;q23), t(9;22)(q34;q11), -17– abn(17p) with other changes– Complex (>3 unrelated abnormalities)

CBF

Adapted from ASH2009

ASH2009

ASH2009

New Prognostic Markers in AML

¨ MDR-1 or FLT3 mutation (FLT3-ITDs): positive

¨ Kit mutation in CBF: positive

¨ MLL-PTD (MLL gene- partial tandem duplication) mutation: positive

¨ BAALC (Brain and acute leukemia, cytoplasmic): positive

¨ ERG (ETS- related gene) overexpression: positive

NPM1 (nucleophosmin)or CEBPA (CCAAT enhancer binding protein-α ) :positive

MayoClin Proc,Feb2006

CONCLUSIONS

Conclusion: molecular risk

• Good risk– CEBPA mutant (biallelic, FLT3-ITD-)–WT1 wild type– CBF + c-kit mutation poor prognosis than

no mutation• Adverse risk– FLT3-ITD–MLL-PTD

Adapted from ASH2009

Gene mutation with favorable risk

Gene mutaion with unfavorable risk

NPM1+ C-kitFTL3-ITD- MLL-PTD

FLT3-ITD+WT1

MiRNA with unfavorable risk: BEME•BAALC, ERG overexpression, MN1, EVI-1

ASH 2008

Investigation

• BMA, BMBx• Chromosome (G-banding)• FISH (Fluorescent insitu hybridization)• Molecular genetic• Flow cytometry for acute leukemia panel

Immunophenotypes

Treatment

• M3 or non-M3• Specific treatment: induction, post remission• Supportive treatment: blood transfusion,

blood chemistry (BUN, Cr, E’lyte), G-CSF (no benefit in induction)

• Emergency condition: hyperleukocytosis, CNS involvement

Standard Treatment

• Induction: Daunorubicin 45mg/m2/d (3) plus Cytarabine 100mg/m2/d (7): CR (< 60y)= 60-80%, CR (> 60y)= 40-60%

• Induction: Gemtuzumab (GO) plus DNR and Cytarabineclofarabine, laromustine, rapamycin, tipifarnib

• Post- remisson therapy: Chemotherapy (HiDAC) or BMT

Induction(Age <55-60 yrs)

• Standard induction (3+7 regimen): CALGB• RR ~60-80%• Dose: Ara-C 100 mg/m2 X 7 days• Idarubicin 12 mg/m2 X 3 days• RR: Idarubicin = Mitoxantrone,

Idarubicin > Doxorubicin

ECOG trial; Daonorubicin Age< 60 yrs

• DNR 45 mg/m2 VS 90 mg/m2 : CR rate 57% VS 72% (sig.)

• Survival rate in DNR 90 mg > 45 mg in favorable + intermediate risk, no sig. in unfavorable risk

MRC study

• GO (Gemtuzumab ozogamicin) induction• 7+3 VS 7+3+GO– CR เทา่กนั

– DFS at 3 yrs 40% VS 51% (sig. 0.008)

Induction(Age >60 yrs)

• 3+7 regimen CR 40-60 %• HOVON study: Age >60 yrs– DNR 45 mg/m2 VS 90 mg/m2– CR 54 % VS 64 % (p=0.002)– No sig. in survival

New agents• Clofarabine: Age>65 yrs, N=44 , 11 (25%)

unfavorable risk– ORR 56%, CR 44%– Unfavorable risk: ORR 36%, CR 27%

• Laromustine• Rapamycin• Tipifarnib (Farnesyltransferase inhibitor)– Poor risk elderly, CR 14%, PR 9%, median

survival of CR = 18 mos– Tipifarnib+Etoposide in elderly: CR 25%,

median survival 22 mos

New agents

• Hypomethylating agent in elderly– Decitabine 20 mg/m2 IV X 5 days• ORR 25%, CR 24%, CCyR 15%• Median OS 7.7 mos, median EFS 5.8 mos

– Azacitidine 75 mg/m2 OD VS best supportive care VS low dose Ara-C VS intensive CMT• Median F/U 20 mos• 2 yrs OS azacitidine VS 3 others gr: 50 %

VS 16%

Post remission treatment• After induction: repeat BM at week 3-4– Complete hematologic response (CHR)– Morphology CR– Chromosome normal (if CS normal: no benefit)– RQ-PCR: Wilm tumor 1, flow for MRD 103-104

CR

1. Post remission chemotherapy or2. Stem cell transplantation( Depent on cytogenetic + molecular base)

Indication for all-SCT (young adults) AML in CR 1 (adapted from ASH 2009)

HLA-MRD MUD/Haplo/Cord•Favorable, all except•C-kit

NoPossible

NoPossible

•Intermediate, all except•NPM1 +/ FLT3-ITD-

Yes

Possible

Possible

No•Unfavorable Yes Yes

•t(8;21) + add กบัตวัอื3น controversy•ASH2009; MRC, CALGB: add/no add …good prognosis in western, asian controversial•SWOG/ECOG: t(8;21) lacking del 9q favorable risk

Allo-HSCT conditioning regimen (Age<50-55 yrs)

• Full myeloablative: Age 35-40 yrs– TRM at day 100; 21-26.8%– Grade 4 AGVHD 30-35%, CGVHD extensive 30-35%, VOD

27-28%– MD anderson: IV bulsulfan; TRM < oral– AML, CML from Canada

• Bulsulfan 130 mg/m2 + Fludarabine IV• AGVHD 2-4: 14%, AGVHD 3-4: 3%, CGVHD 54%, 34% NRM (4%≤45 yrs ,

6% >45 yrs)• RIC

– Low dose bulsulfan V/fludarabine– Fludarabine/melphalan

• Non-myeloablative• Fludarabine/2 Gy TBI (JCO, June 2010)• Age 60 yrs, AGVHD gr4: 5%, gr 3: 9%, gr 2: 38%)

Autologous SCT

• Low TRM< 5%; center experience• Benefit in intermediate, good risk (best)• No benefit in poor risk, FLT3-ITD+• AuSCT compare intensive post remission

chemotherpy– DFS AuSCT > chemo; relapse น้อยกวา่

– Transplant center; prefer AuSCT; use PBSCT (decrease contaminate); check MRD

• MRD– Flow for MRD detect 1 cell in 103-104

–WT1 RQ-PCR detect 1 cell AML in 103-106

• Decrease 2 log reduction relapse 43%• Decrease < 2 log reduction relapse 73%

AlgorithmAge <55-60 yrs

Induction 3+7 regimens; CR 60-80%

CR1

salvage/second induction

Yes No

Post remission therapy

Post remission therapy

Good cytogenetic Intermediate

Adverse cytogenetic

C-kit mutation

Yes No

Possible-HLA-MRD-MUD/haplo/cord

HIDAC 3 g/m2 q 12 hr X 3 days X 4 cycles

Donor

Yes No

MRDMUDHaploCord

Y: MRD HLAPossible: MUD/haplo/cord

Relapse with CR2

AuSCT

CMT

Suggested treatment strategy for older AML (Age>55 yrs), ASH2009

Diagnosis: AML(antecendent MDS, CS analysis, PF, HLA typing)

Poor-risk cytogenetics Normal

Novel agent-based Tx. Induction Tx.

No CRCR with donor (sibling, MUD, cord blood)

No CR

Investigational Tx. Or investigational transplant regimen

Investigational Tx. Or investigational transplant regimen

Hyperleukocytosis• Hyperviscosity-cellular component• พบใน AML > CML > ALL > CLL• มกัพบวา่ blast > 100,000/mm3

• S&S – Respiratory: dyspnea, hypoxemia– CNS: headache, confusion, tinnitus, papilledema, ataxia,

stupor, CNS hemorrhage• Management

– Rapidly decrease WBC count: Leukapharesis, chemotherapy– Hydration, Allopurinol– Avoid RBC transfusion ในระยะแรก เพื3อไมเ่พิ3ม viscosity– Platelet transfusion to prevent bleeding

APL

• Acute promyelocytic leukemia (M3); abnormal promyelocyte

• 5-15% of adult AML• Fusion gene PML-RARA, t(15;17)– 15q22:PML gene, 17q21 RARa gene– Disruption of normal differentiation

• Variant APL: t(5;17), t(11;17), dup 17

PML RARA in APL

Frohling SandDohner H.NEngl JMed2008;359:722-734

PML/RAR-α & Acute Promyelocytic Leukemia

t(15;17) in APL

PML-RARa: Inh. RARA interacting prot e.g.retinoid X receptor and native PML protein(tumor suppressor gene >>>inh.differentiation at promyelocyte

APL

• Prior poor prognosis of AML due to death from bleeding

• Since……ATRA >>>>cure rate ~80-90% of CR patient

Mechanism of coagulopathy in APL

• DIC

• Excessive fibrinolysis (primary hyperfibrinolysis) from express UPA, tPA, Annexin II (enhance plasmin generation)

• Proteolysis: leukemic blast release proteolyticenz. (elastase, chymotrypsin)

Unfavorable risk of APL; ASH 2006

• Age > 60 yrs• WBC >10,000• Platelet <40,000• Variant APL: No response to ATRA

(PLZF, STAT5b)

Diagnosis• PBS + BMA– Hypergranular: abnormal promyelocyte, faggot

(multiple auer rods)– Hypogranular: M3V (monocytoid nuclei, dumb-bell

shaped nuclei)• Molecular confirm PML-RARA– RT-PCR for PML-RARA (gold standard forDx)

• Flow cytometry: CD13+, CD34-/+dim, CD117-/+dim, HLA-DR-/+dim

• Chromosome: t(15;17)(q22;q12) PML-RARA, t(5;17)(q35;q21) NPM1-RARA, t(11;17)(q23;q21) PLZF-RARA, t(11;17)(q13;q21) NUMA-RARA, dup17(q21.3q23)STAT5b

APL

Multiple auer rod = faggot

Abnormal promyelocyteswith hypergranulation

Microgranular varient: Dumb-bell

Confirmation of diagnosis

Blood.2005;105:3019-3025

Mechanism of ATRA

Wintrobe’s hematology, 12 th edition

CoR RA

RA CoR

Proliferation

APL: treatment

• Specific treatment: induction, consolidation, maintenance– All-trans retinoic acid– Arsenic acid– Chemotherapy

• Supportive treatment– Hemorrhage– DIC– Differentiation syndrome

Drug

Arsenic• Oxidantdirectbinding

nuclearbodyaggregationpoly-Ubiquitination byRNF4>>>proteasome>>>degradation

• apoptosis

Retinoicacid• PML/RARA• activation• proliferation

differentiation

Lossselfrenewal

P53activation

activation

degradation

RA

Transcriptionalrepresser

PML PML

CoRR

Activationordegradation

NRx activationtranscription,butfailtodegradePML/RARANRx terminaldiff,maintainedself-renewal

• PMLNBSactivateP53signaling• RA+arsenic 97.5%survival• RA+chemo84.5%survival

• RA+arsenic:non-overlappingdegradationpathway

• ArsenictargetbothPML/RARAfordegradation&PMLforaggregation

SynergisticPML/RARAdegration

EnhancedPMLaggregationNBformation

PartnerrecruitmentSynergisticP53activation

Cure

PML

RA

AS

PML

PML PML

AS

AS

Induction regimens

• ATRA + anthracycline-base CMT cure rate 70-95%

• GIMEMA 1997– ATRA 45 mg/m2/day devided bid (resolved

coagulopathy) day 1 until CR– Idarubicin 12 mg/m2/day day 2,4,6,8– CR ~95%

• GAMLOG 2000; benefit in high risk gr, add high dose Ara-C (CR~92%)

Evaluation after induction

• Complete hematologic response at 4-6 wks (morphologic CR)

• Criteria (needs 3/3)– ANC >1,000– Platelet >100,000– Blast + atypical promyelocytes <5%

• If no morphologic CR >>>continue ATRA until day 40-50

Supportive treatment• Keep platelet ≥ 30,000-50,000• Fibrinogen 100-150 mg/dL• Avoid intervention (CVP, LP, intensive

procedure)

• Lab: CBC 2-3 times/day, fibrinogen,coag 2 times/day until no coagulopathy

• Question: benefit of heparin, transamine, anticoagulant

Differentiation syndromeATRA administration

Differentiation of abnormal promyelocytes

Release Capthepsin G (from primary granule)

Increase capillary permeabilityUnexplained fever

Weight gainPleural effusion, pericardial effusion

HypotensionFluid retention

Respiratory distressCardiac and renal failure

Differentiation syndrome

• Risk Factors– Initial WBC at diagnosis > 10,000 in patient who

treatment with ATRA/ATO• Treatment

– Stop ATRA– Give dexamethasone 10 mg IV q 12 hrs– ±Diuretic drug (ARF, hemodialysis, mechanical

ventilator)

Risk classification for relapse at Dx.

• Low risk: WBC <10,000, plt>40,000• Intermediate risk: WBC ≤10,000, plt≤40,000

• High risk: WBC >10,000, plt ≤40,000

Consolidation

• Anthracycline base– Daunorubicin 25 mg/m2/day D1-D4 or– Idarubicin 12 mg/m2//day D1-D4 or– Mitoxantrone 10 mg/m2/day D1-D3

• + ATRA 45 mg/m2/day X 15 days

• Low/intermediate risk: 2-3 cycles• High risk: 2-3 cycles; GIMEMA APL2000

add intermediate dose Ara-C 1 g/m2/day D1-D4

Maintenance Therapy

• After consolidation evaluate CBC, BM, CS, Molecular CR (FISH for PML-RARA: detect 1 leukemic cell 103-104, RT-PCR for PML-RARA)

• Benefit in RCT 2 trial: North americanintergroup, European APL 93

Maintenance Therapy

PCR negative• Maintaenance Tx• ATRA 45 mg/m2/day X 15

days q 3 months• + MTX 15 mg/m2 weekly dose• + 6-MP 50 mg/m2/day• Duration 2 yrs• Monitor molecular; especially

initial WBC >10,000 (cost-effective)– Intermediate risk q 3-6 mos– High risk q 3 mos– Duration 2-3 yrs

PCR positive• Salvage Tx• ATO-based regimen• And/or• Allo SCT (if donor และ

PCR+ aafter salvage)• Or• AutoSCT (salvage แล้วได้

CR)

Refractory/Relapsed APL• Morphologic not CR after ATRA 40-50 days• ATO: remission rate ~72-93%• Mechanism– Direct degradation of PML-RARA

>>>differentitation– Apoptosis: ATO release cytochrome C from

mitochrondia + caspase activation >>apoptosis

• Induction Tx: dose 0.15 mg/kg until BM clear leukemic cell (max 60 days)

• Consolidation: ATO 25 days; start 3 wks after BM remission

Refractory/Relapsed APL• ATRA+ATO: small trial; no benefit• IT MTX weekly dose X 4 doses or alternate

MTX/Ara-C: CNS prophylaxis in relapsed APL• CNS relapse(isolated)– ATO สามารถผา่น CNS ได้– RT if space-occupying chloroma– IT MTX 2 times/wk until cell clear then weekly

dose X 4 weeks then monitor q 4-6 mos• AutoSCT– Consolidation if molecular CR2– More outcome; 5-yr DFS 70-80%– Conditioning regimens: High dose Ara-C

Others induction regimens• ATO+ATRA– Not tolerate anthracycline (heart dz, older adults,

refusal chemo, maximum dose of anthracycline)– If initial WBC >10,000: idarubicin 2-3 dose to

control WBC– CR ~90-94%, 5-yr OS ~85-91%

• ATO (single agent): CR ~85-91%, 5-yr OS ~ 86-91%

• ATRA + ATO +chemo or GO (in high risk or develop WBC >10,000 while tx): CR ~90%, OS 85%

ASH2008

Conclusion APL Tx(adapted from ASH2008)

ALL

• Classification• Prognosis marker• Emergency condition• Treatment

Introduction• Most common leukemia in children (23% of cancer

Dx in children < 15 yrs)• 20% of adult leukemia• Children CR rate 97-99% , 5-yr EFS 75-86% (Pui et

al,2008,2009)• Adults CR 65-90%, 5-yr survival rates 25-50%

(Gokbuget and Hoezler,2009)• Less favorable prognosis for adults:

– Higher frequency poor-risk prognostic Fx( disease biology, comorbidities, (older age, impair ability to tolerate intensive multiagent CMT) )

– Difference in treatment regimens– Treatment compliance

FAB morphological classification

• ALL, L1: small size, cytoplasm น้อย, nucleoli ไมช่ดัเจน หรือไมมี่เลย

• ALL, L2: large size, cytoplasm มากตดิสฟีา้ออ่น ไมมี่ granule มี nuleoi เดน่ชดัเจน มกัมีขนาดเลก็

• ALL, L3: large size, Burkitt’s cell

• Contained little prognostic or therapeutic information that might help to guide treatment choice

Classification of B-ALL

TdT CD19 CD10 CD20 Cytoµ SurfaceIgPro-B + + - - - -Pre-Pre B(commonALL)

+ + + - - -

PreB + + + +/- + -EarlyB(Burkitt)

- + + + - +

TdT CD7

CD2 CD5 CD1 CD3 Cy CD3 CD4/CD8

Prothymocyte + + + - - - + -/-

ImmatureThy

+ + + + - - + -/-

Common Thy + + + + + +/- + +/+

Mature Thy - + + + - + + CD4 orCD8+

Mature T cell - + + + - + + CD4 orCD8+

Classification of T-lineage ALL

Evaluation• PBS, BM study• Flow cytometry for ALL• FISH: t(4;11), t(9;22), t(12,21), t(1,19)• Molecular: HOX11, NOTCH1 in T ALL• HLA math• Seromarker• Blood chemistry• CXR• Stool examination

Unfavorable prognosis• Age > 55 yrs (OS 34-57% in age < 30 yrs,

15-17% in age > 50 yrs)• High WBC at diagnosis– B-ALL: WBC >30,000-50,000; OS 19-29%– T-ALL: WBC > 100,000; increase risk of CNS

involvement• Cytogenetic– Good risk: t(12;21) _มกัพบในเดก็, hyperdiploidy

&hypertriploidy– Poor risk: t(9;22), t(1;19) resistance to chemo,

hypodiploidy, t(4;11), t(8;14)(q24.1;q32)

Unfavorable prognosis• T-ALL subtype (ASH2006)– Thymic T-ALL (LFS 63%), Early T-ALL (LFS

25%), Mature T-ALL (LFS 28%)• Pro-B ALL (suggest BMT in CR1)• Molecular– NOTCH1 in T-ALL consensus เรื3อง prognosis – FBXW7 mutation– TLX1 (HOX11) oncogene expression; if positive

median 7 yr death 12% VS 44%• MRD post induction >10-4

• Delayed achieving remission > 4 weeks

Treatment

• Specific treatment: induction, post remission, CNS prophylaxis

• Emergency condition: tumor lysissyndrome, CNS involvement

• Supportive care: tumor lysis syndrome

Specific Treatment

• Induction: ALL protocol• Post remission: maintenance Tx, SCT• CNS prophylaxis: CNS radiation

(neurotoxicity, cognitive repair), IT MTX+Ara-C X 6 cycles

Algorithm: Ph neg ALLInduction: ALL protocol

Evaluate at 4-6 wksNo CR CR by MRD (RT-PCR)

HyperCVAD/MTX-Ara-C

Age<60 yrs Age>60 yrs

SCT* Maintenance Tx

Yes donor No donor

Autologous SCT(experience; must

F/U RQ-PCR)

Age <40 yrs(mean age 28 yrs)No comorbidities, Good ECOG-MA (TBI base)

Age >40-55 yrs(mean age 45 yrs)• RIC

*Prefer SCT in CR1 in standard, poor risk (ECOG 2993)

Criteria CR (international working group) need 3/3

• Normal physical examination• Complete hematologic response– ANC ≥ 1,000, Platelet ≥ 100,000– PBS: no abnormal cells– Independence from red cell transfusion

• BM criteria: cellularity normocellular to hypercellular, blast<5%

RIC in Ph neg ALL

• MRC trial• Age 40-55 yrs– Less GVL– CR 52%–Minimal survival – OS 27%

• Age > 55 yrs– 2-yr survival 22%

ASH2009

LALA-87 trial; Age > 50 yrs

• AlloSCT in high risk ตวัที3มีผลตอ่ outcome ได้แก่

BCR-ABL+, older age, high WBC, delayed CR >>>outcome ดีกวา่ทํา ASCT or CMT

• ASCT DFS เหมือนกนั

• CMT

ASH2009

LALA-94 high risk ALL

• AlloSCT DFS 45%• *ASCT DFS 18%• *CMT

• * if no donor• No benefit of ASCT

ASH2009

MRC + ECOG; Age < 50 yrs• Ph neg>>>induction CMT 2 months

– Donor: alloSCT; OS 53%– No Donor: ASCT/consolidation+mainenance; OS 45%

• Ph pos>>>after induction>>>MUD• High risk (age>35 yrs, WBC ≥ 100,000 in T-ALL,

≥30,000 in B-ALL)– AlloSCT vs no AlloSCT: OS 41% vs 35% (p=0.2) no

sig. in high risk pt older age have high TRM• Standard risk

– AlloSCT vs no AlloSCT: OS 62% vs 52% (p=0.02)• ***standard risk: benefit from alloSCT• AlloSCT decrease relapsed rate

ASH2009

RIC (EBMT)CR1 CR2/3 More advance dz

• 3 yr-OS 52% 27% 20% • ทําในคนไข้ที3แก่กวา่ NRM 22% 32% (MA)• Leukemia free 38% 37%

survival• OS ไมต่า่งกนั แต ่population น้อย

ASH2009

Others prognostic factors

• Poor prognosis in young adults (18-20 yrs)• Dose intensity of MTX ในเดก็มากกวา่ในผู้ใหญ่ สว่น

vincristin, steroid ไมต่า่งกนั

• Good cytogenetic: t(11;21) พบในเดก็มากกวา่

Clinical trials

• Υ-secretase inhibitors: Nelarabine in T-ALL

• Clofarabine: T-ALL, B-ALL• Epratuzumab: antiCD22

Algorithm: Ph pos ALL

•No CNS involvement•TKI + hyperCVAD/MTX+Ara-C(IM 400-800 mg/day)+IT MTX or

•CNS involvementDasatinib + hyperCVAD

Age>60 yrs Age < 60 yrs

•No CNS involvementIM 800mg + Pred *45 days then IM maintenance

•CNS involvementDasatinib + Pred * 28 days

IM + ALLprotocal or

No CR in 2 mos

No CRin 2 mos

Change TKI

CRMolecular CR

Post remission• IM alone (chemo intolerate)

IM add on chemotherapy

• IM add ± BMT /ได้ benefit กวา่ไม ่add IM• IM + no BMT: OS 20%• IM + BMT:OS 51%• ถ้าไมทํ่า BMT กินแต ่IM อยา่งเดียว จะ relapse

IM add on chemotherapy

• IM + chemo: CR≥ 90%, >50% PCR neg• Advantage of HyperCVAD: ให้ครั Pงเดียว

• Advantage of ALL protocol: use in age> 55 yrs (hyperCVAD intolerate)

• Disadvantage of ALL protocol: sequential dose หลงัให้ยามี FN ทําให้

inadequate chemo เกิด delayed CR

GIMEMA• Elderly patient: Age >60 yrs• 45 days induction: IM 800 mg/day + pred• IM maintenance until relapse or excessive

toxicity• All patients: CR, no deaths in CR• Median remission duration 8 mos• Median survival from diagnosis 20 mos• Relapse ~50% at 1 yrs• Toxicity ต่Qา , improve DFS• Prior Supportive Tx: no CR, OS < 1mo• IM alone OS ~ 1 yr (57-74%)

Younger patients

• IM 400-500 mg/day + chemo (hyperCVAD, ALL protocol)

• CR ~90%• OS 36-76%

Dasatinib add on chemotherapy

• CR ~90%, molecular remission 28-72%• Regimens– HyperCVAD + Dasatinib d1-14– Elderly patients: Dasatinib + steroid

Dasatinib monotherapy induction

• Age ≥ 18 yrs• Regimen– 70 mg bid X 12 wks– 4 weeks แรก add Prednisolone

• CR ทกุคน, short F/U

Compare BMTAlloSCT RIC ASCTTBI/Cy Decrease TRM

aGVHD gr.2-443.2%CGVHD 65.6%

Role in pre-imatinib era

High TRM from infection, GVHD

เกิด CGVHD จะได้

benefit เมื3อเทียบกบัคนที3ไมไ่มมี่

Inferior กวา่

alloSCT

Ph+ALL: Post remission therapy

Donor eligible No donor eligible

AlloSCT AutoSCT(experience)

CMT + TKI

Post alloSCTMRD+•Continue IM

•6-MP+ low dose MTX + IM •**IFN-α+IM

**OS ดีกวา่ IM alone แต ่

small population

Post Allo SCT in Ph+ALL

• IM มี role ในคนไข้ที3ไมไ่ด้ MRD neg หลงัทํา 3 months

• MRD + (RQ-PCR) at 3 months >>>>>DLI + IM maintenance

Ph+ALL: CNS prophylaxis

• IT MTX ± Ara-C ± Steroids• Cranial radiation

Relapsed/refractory ALL Ph+

• ถ้าเคยได้ IM มาก่อน สงสยั resistant หรือไม่

• Prefer Dasatinib + hyperCVAD

Tumor lysis syndrome

• Risk factors– Type of tumor: rapid proliferative neoplasm

eg. ALL, lymphoblastic lymphoma, small non-cleaved lymphoma (Burkitt, Burkitt-like), CLL treated by Fludarabine/Cladribine

– High tumor mass: bulky mass, high LDH– Preexisting hyperuricemia or renal

insufficiency– Post chemotherapy

Tumor lysis syndrome• Diagnosis– Hyperuricemia, hyperphosphatemia,

hyperkalemia, hypocalcemia, acute renal failure(from uric acid nephropathy)

• Management– Hydration with 0.9% NSS for diuresis– Allopurinol 300-600 mg/day– Urine alkalinization with NaHCO3– Hemodialysis prompt available– F/U blood chemistry

Chronic lymphocytic leukemia• B-CLL: clonal expansion of mature, long lived,

B lymphocytes• Identical to SLL• Clinical: leukemic (blood & marrow), nodal dz.• Richter transformation (10%): rapid increase in

lymphadenopathy, extranodal involve, splenomegaly, worsening B symptoms, increase LDH

• 30% of all leukemia in Western• 5% of all leukemia in Asia (T-cell predominate)• Median age 60-65 yrs, men > women

Clinical presentation• Asymptomatic: most common• B symptoms (fever, night sweats,

sig.weakness, weight loss) 20%• Lymphadenopathy• Hepatosplenomegaly• Related to marrow replacement• Autoimmune complication• Recurrent bacterial infections (from

hypogammaglobulinemia)

Physical Examination

• Peripheral lymphadenopathy• Hepatomegaly (20% of case)• Splenomegaly (30-40% of case)

***Organomegaly may range from mild to massive

Laboratory features• PBS: small mature lymphocyte, smudge cells

(commonly present), basket cells• Anemia, thrombocytopenia (1/3 of pt, usually mild in

degree)• DCT + (25% at diagnosis)• AIHA (10-25%)• ITP (15-20%)• Neutropenia (reflection of marrow involvement by

CLL)• Hypogammaglobulinemia (hallmark of this disorger)• BM: normocellular or hypercellular, at least 30%

lymphocytes (nodular, interstitial or diffuse pattern)

CLL

-CD20+dim-CD23+-CD5+-CD10--Cyclin D1-

Diagnostic criteria

• Absolute lymphocytosis >5,000• Mature lymphocytes in PBS• Marrow involvement with small

lymphocyte at least 30% (nodular, interstitial, or diffuse pattern)

• Flow cytometry compatible with CLL (CD5+, CD10-, CD20wk, CD23+)

CritetiaCriteria NCIcriteria IWCLLcriteriaLymphocyte ≥ 5,000ofB-

lymphocytes≥1B-cellmarker(CD19,20,23)andCD5+

≥10,000+Bphenotype orBMinvolvementIf<10,000ต้องมี Bphenotype+BMinvolvement

Atypicalcell(prolymphocyte)

<55% Notstate

Durationoflymphocytosis

Notrequired Notstate

BMlymphocyte ≥30% >30%

Clinical staging systemBinet classification

Stage Definition Patients(%) Risk groupA Hb≥10gldl, plt≥100,000

<3 enlarged LN area60 Low

B Hb≥10gldl, plt≥100,000,≤3 enlarged LN area

30 Intermediate

C Hb<10 and/or plt<100,000, any number of enlarged LN area

10 High

Adapted from ASH-SAP 2010

Clinical staging systemRai classification

Stage Definition Patients(%) Median OS (yrs)

0 Lymphocytosis only 30 101 Lymphadenopathy 25 5-72 Hepatomegaly or

splenomegaly±lymphadenopathy

25

3 Stage 0-2, with Hb <11 10 1-34 Stage 0-3, with plt

<100,00010

Adapted from ASH-SAP 2010

Poor prognostic marker• Chromosome: del 17p13 > del 11q22 > trisomy 12

&normal karyotype> 13q14 ( good prog.)• ZAP-70 expression• CD38 expression• Unmutate IgVH (median OS 8 yrs), mutate (median

OS 20 yrs; good prog.)• Lymphocyte doubling times < 6 mos• Increase thymidine kinase• Increase B2M (>3.5 PFS 13 mos, <3.5 PFS 75mos)• MRD pos (MRD neg after Tx longer response duration

& OS)• Absolute lymphocyte count (>30,000 PFS 17 mos,

<30,000 PFS 88 mos)

Chromosome

• del 17p13 (median survival2-3 yrs)• del 11q22 (median survival 6-7 yrs)• trisomy 12 &normal karyotype (median

survival 9 yrs)• 13q14 (median survival 11 yrs; good

prog.)

Binet A or Rai 0 (ASH2009)• High risk: del17p13 โดยไมส่นใจวา่

mutated/unmutated IgVHF/U q 3-6 months

• Intermediate risk: del11q22 and/or unmutated IgVHF/U q 6-12 months

• Low risk: no del17p13 or del11q22 + mutated IgVHF/U annual

Indication for treatment in early stage (NCI-96), Rai stage 0-II

• Symptoms: weight loss ≥10% within previous 6 mos, extreme fatigue (ECOG PS ≥2), fever >38 for ≥2 wks without evidence of infection, night sweat ≥1 moswithout evidence of infection

• Marrow failure• Autoimmune anemia and/or thrombocytopenia poorly

responsive to steroid Tx.• Massive (>6 cm below LCM) or progressive splenomegaly• Massive nodes or cluster (>10 cm in longest dimeter) or

progressive lymphadenopathy• Progressive lymphocytosis with increase≥50% over a 2

mos period or and anticipated doubling time < 6mos)• Marked hypogammaglobulinemia or development of

monoclonal protein in absence of any of above criteria is not indication for treatment

Algorithm for 1o and 20 line therapy of CLL (adapted from ASH2009)

Stage Fitness Molecular cytogenetics

First line TxStandard Alternatives

AsymptomaticBinet A-B or Rai 0-II

Irrelevant

Irrelevant None Only in trials: Tx inhigh risk pts.

Binet C or RaiIII-IV, or

symptomatic dz(any stage)

Go Go •No del 17p•Del 17p

•FCR•FCR, A or FA then AlloSCT

•BR, FR, FA, FCA

SlowGo

•No del 17p•Del 17p

•CLB•A?

CLB+R, CLB+GA101, B, dose reduced F or FC or FCR

CLB: Chlorambucil, B: Bendamustine, GA101: novel anti CD20Ab

Chemotherapy in CLL

• Single agent– Cytostatic agents: Chlorambucil,

Fludarabine, Cladribine, Bendamustine–Monoclonal Ab: antiCD52

• Combination CMT– Fludarabine/Cyclophosphamide

Chemoimmunotherapy

• Combination Rituximab– FCR, CFAR, BR

• Combination Alemtuzumab– FA, FCA, AR

• Combination Lumiliximab (antiCD23)– L-FCR

• Novel agents in combination with chemoimmunotherapy– Oblimerson (anti Bcl 2) add to FC

Treatment in relapsed disease (adapted from ASH2009)

Relapse Fitness Molecular cytogenetic

Standard Alternatives

Early (<1 yr)=refractory dz

Go Go •No del(17p)

•Del 17p

•A or FA then AlloSCT

•A or FA then AlloSCT

•BR, Flavopiridol, Len•Flavopiridol,Len

Slow Go

•No del(17p)•Del 17p

•A•A

•BR, B, Len•Len

Late (>1 yr) Go Go Repeat first lineSlow

Go

Relapsed/refractory CLL

• Mitoxantrone VS FC• CR 50% (MRD neg 10 case)

ASH 2009

Untreated progressive CLL

• Cladribine VS Cladribine/cyclophos VS Cladribine/Cyclophos/MitoxantroneCR 21% VS 29% VS 36%

• No difference in OR, PFS, OS• Grade 3/4 neutropenia C (20%), CC (32%),

CCM (38%)• >>>>cladribine combination: no offer in first

line CLL

ASH 2009

Indication for SCT (ASH2009)

• Younger pt who fail to response or progressive within 12 mos or relapse < 12 mos after fludarabine based regimen

• Relapse shortly within 24 mos after purine analogue combination Tx or Tx of similar efficacy (ie.ASCT)

• Patient with 17p-/P53 del/mutation requiring Tx.