Hematologic Malignancy Part I - Srinakharinwirot University€¦ · •Disseminated intravascular coagulopathy ACUTE < 3 weeks. 6 Gum hypertrophy. Risk factor •Irradiation •Occupational
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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.
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