chronic lymphocytic leukemia current and future...
TRANSCRIPT
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C. Reinhardt Medical Clinic I, Hematology/Oncology
CECAD, Research Area C Clinical and Molecular Oncology
Chronic Lymphocytic Leukemia -
Current and future therapeutic options
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- What is CLL?
- Diagnostic tools - Prognostic scores
- Treatment of CLL
- Science becomes medicine (novel therapeutic approaches)
CLL - a brief recapitulation
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The blood smear reveals essential hints leading to the diagnosis
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CLL is a disease of the elderly !! a minority of patients qualifies for toxic therapy"
• Most&frequent&leukemia&in&the&Western&hemisphere.&• Median&age&at&diagnosis:&72&years1&
• Elderly&pa>ents&may&have&comorbidi>es&&
1.&Ries&LAG,&et#al.&SEER&Cancer&Sta>s>cs&Review,&1975–2005.&2.&Yancik&R,&Cancer&1997;&80:1273–1283.&
Age&at&CLL&diagnosis&(years)&&
Pa>ents1&(%)&
Mean&&comorbidi>es2&(all&cancer&types,&
n)&
≤&54& 11& n/a&55–64& 19& 2.9&65–74& 27& 3.6&75+& 43& 4.2&
Mean&no.&of&co[morbidi>es&
2.9&
3.6&
4.2&
n/a&
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The Rai classification allows risk stratification
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The Rai classification allows risk stratification
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The Binet classification allows risk stratification
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The Binet classification allows risk stratification
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4"
Prognos'c)Score)based)on)GCLLSG)studies)(Bahlo'et'al.,'ASH'2011)'
))
Variable" Adverse"factor" Hazard"ra4o"for"death"
Factor"7"grading"
Chromosomal"aberra4on" del(17p)))
6.0) 6"
s7TK" >)10.0)U/L))
2.8) 2"
s7β2m" >)3.5)mg/L))
2.3) 2"
IgHV"muta4onal"status" unmutated))
1.9) 1"
s7β2m" >)1.7)mg/L)G)≤)3.5)mg/L))
1.7) 1"
ECOG""
>)0) 1.7) 1"
Chromosomal"aberra4on""
del(11q)) 1.4) 1"
Gender""
Male) 1.3) 1"
Age""
>)60)years) 1.3) 1"
*)Based)on)1223)pa'ents)exhibi'ng)all)7)factors)with)a)significant)influence)on)OS)in)univariate)analyses)
A novel, molecularly-guided risk score allows more detailed risk stratification
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5"
p"<"0.0001"
Overall'Survival'and'Risk'Groups'Using'a'Weighted'Score'of'Clinical,'Biological'and'Gene=c'Variables'(n=1223)'
(Bahlo'et'al.,'ASH'2011)'
Low"Risk,"002"points"(N=300)"Survival"a?er"5"years:"95.2%""
Intermediate"risk,""305"points"(N=460)"Survival"a?er"5"years:"86.9"
High"risk,"6010"points"(N=410)"Survival"a?er"5"years:"67.7"
Very"high"risk,">"6"points"(N=53)"Survival"a?er"5"years:"18.7"
A novel, molecularly-guided risk score allows more detailed risk stratification
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Summary I
- CLL is the most common leukemia in the Western World
- CLL is characterized by the accumulation of mature lymphocytes
- Multiple risk scores exist and allow patient stratification
- CLL cells are addicted to micro-environmental stimuli
- Transformation can occur before or after somatic hypermutation
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The genetics of high risk CLL
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Nature Reviews | Immunology
ImmatureB cell
MatureB cell
Marginalzone B cell
GerminalcentreB cell
MemoryB cell
B-ALLr BCR–ABL1 translocationr Mutations in RUNX1, PBX1,
MLL, PTPN11 and/or RASFollicular lymphomar Mutations in BCL2DLBCLr Mutations in BCL6Burkitt’s lymphomar Mutations in MYC
B-CLLMCLr Mutations
in CCND1
SMZLr Mutations in NOTCH2MALT lymphomar Mutations in MALT1 or BCL10
Multiple myelomar Mutations in CCND1,
MAF, FGFR3 or IRF4
Mutated B-CLL
Large pre-B cell
Smallpre-B cell
VpreB
Pre-BCR
Bone marrow
Follicle
Marginal zone
Germinal centre(secondary follicle)
Spleen or lymph node
Vλ5
BCR
Plasmacell
B cell-derived acute lymphocytic leukaemia(B-ALL). A leukaemia subtype that accounts for the majority of ALL cases and that is derived from the proliferative pro-B cell or pre-B cell compartment in the bone marrow. The genetic basis of B-ALL is usually attributed to the breakpoint cluster region (BCR)–ABL1 translocation or to mutations affecting one or more of the runt-related transcription factor 1 (RUNX1), pre-B cell leukaemia homeobox 1 (PBX1), mixed-lineage leukaemia (MLL), protein tyrosine phosphatase non-receptor type 11 (PTPN11) and RAS genes.
Small pre-B cell stageA resting stage in which the pre-B cell receptor is down- regulated and recombination activating gene (RAG)- mediated rearrangement of immunoglobulin light-chain genes occurs.
Marginal zone B cellsA mature B cell subset that localizes to the splenic marginal zone and to the area proximal to the marginal sinus.
alter BCR specificity and affinity. Notably, the majority of B cell non-Hodgkin’s lymphomas (B-NHLs) (including follicular lymphoma, Burkitt’s lymphoma and diffuse large B cell lymphoma (DLBCL)) are derived from germinal centre B cells (FIG. 1), and the presence of mutations in the V gene segments of immunoglobulin heavy-chain genes is an important molecular indication of malig-nancies that are derived from germinal centre B cells or from post-germinal centre B cells (including malig-nancies derived from memory B cells, such as mutated B cell chronic lymphocytic leukaemia (B-CLL))6. The expression of AID can be detrimental and has been linked to mutational events affecting the expression of numerous potential oncogenes7, including the translo-cation of MYC into the immunoglobulin heavy-chain (Igh) locus8,9, which results in the constitutive expres-sion of MYC in B cells. Recent studies have shown that MYC expression is normally restricted to small sub-sets of germinal centre B cells that are actively engaging
antigens and that interact with cognate T cells10,11; how-ever, the aberrant expression of MYC, together with other oncogenic events, promotes the development of B cell lymphomas.
Marginal zone B cells are located at the interface between the circulation and the lymphoid tissue and they rapidly respond to microorganism-associated Toll-like receptor (TLR) ligands, as well as to antigens, by dif-ferentiating into antibody-producing plasma cells in a T cell-dependent or T cell-independent manner. Notably, marginal zone B cells are thought to be the cells of origin for several indolent types of lymphoma that progress in the spleen (for example, the subtype of marginal zone lym-phoma (MZL), splenic MZL (SMZL)), in the lymph nodes (nodal marginal zone lymphoma (NMZL)) or at extran-odal sites such as the mucosa-associated lymphoid tissue (MALT lymphoma) (FIG. 1). A signalling-competent BCR is thought to be required for the continued propagation of marginal zone B cell-derived lymphomas12.
(KIWTG���̂ �$|EGNN�PGQRNCUOU�CTKUG�CV�FKHHGTGPV�UVCIGU�QH�$|EGNN�FKHHGTGPVKCVKQP�� $|EGNN�OCNKIPCPEKGU�JCXG�DGGP�CUUQEKCVGF�YKVJ�FKUVKPEV�UVCIGU�QH�$|EGNN�FGXGNQROGPV��%JTQOQUQOCN�VTCPUNQECVKQPU�CPF�IGPG�OWVCVKQPU�CTG�HTGSWGPVN[�KPXQNXGF�KP�VJGUG�$|EGNN�PGQRNCUOU��CPF�CFFKVKQPCN�IGPGVKE�CDGTTCVKQPU�UWEJ�CU�J[RGTRNQKF[�CPF�CPGWRNQKF[�CTG�CNUQ�KORQTVCPV�EQPVTKDWVQTU�VQ�VJG�FKUGCUG�PQV�UJQYP���$�EGNN�CEWVG�N[ORJQE[VKE�NGWMCGOKCU�$�#..U��CTKUG�HTQO�RTG�$|EGNNU�CPF�WUWCNN[�KPXQNXG�C�DTGCMRQKPV�ENWUVGT�TGIKQP�BCR�sABL1�VTCPUNQECVKQP�QT�OWVCVKQPU�CHHGEVKPI�QPG�QT�OQTG�QH�VJG�TWPV�TGNCVGF�VTCPUETKRVKQP�HCEVQT���RUNX1���RTG�$�EGNN�NGWMCGOKC�JQOGQDQZ���PBX1���OKZGF�NKPGCIG�NGWMCGOKC�MLL���RTQVGKP�V[TQUKPG�RJQURJCVCUG�PQP�TGEGRVQT�V[RG����PTPN11��CPF�RAS IGPGU��6JGUG�VTCPUHQTOKPI�GXGPVU�CHHGEV�VJG�TCRKFN[�RTQNKHGTCVKPI�NCTIG�RTG�$|EGNNU�DWV�PQV�VJG�TGUVKPI�UOCNN�RTG�$|EGNNU��YJKEJ�WPFGTIQ�NKIJV�EJCKP�IGPG�TGCTTCPIGOGPV��$�EGNN�EJTQPKE�N[ORJQE[VKE�NGWMCGOKC�$�%..��KU�CP�KPFQNGPV�OCNKIPCPE[�CPF�CP�WPOWVCVGF�V[RG�QH�$�%..�FGTKXGU�HTQO�OCVWTG�%&��RQUKVKXG�$|EGNNU�����/CPVNG�EGNN�N[ORJQOC�/%.��CNUQ�CTKUGU�HTQO�EKTEWNCVKPI�OCVWTG�$�EGNNU��5GXGTCN�V[RGU�QH�N[ORJQOC�CTKUG�HTQO�FKHHGTGPVKCVGF�UWDUGVU�QH�OCVWTG�$|EGNNU�KP�VJG�UGEQPFCT[�N[ORJQKF�QTICPU��5RNGPKE�OCTIKPCN�\QPG�N[ORJQOC�5/<.��CPF�OWEQUC�CUUQEKCVGF�N[ORJQKF�VKUUWG�/#.6��N[ORJQOC�CTG�KPFQNGPV�OCNKIPCPEKGU�FGTKXGF�HTQO�OCTIKPCN�\QPG�$|EGNNU��(QNNKEWNCT�N[ORJQOC��FKHHWUG�NCTIG�$|EGNN�N[ORJQOC�&.$%.��CPF�$WTMKVVoU�N[ORJQOC�CTG�CNN�FGTKXGF�HTQO�IGTOKPCN�EGPVTG�)%��$|EGNNU��6JG�FKXGTUKV[�QH�)%�FGTKXGF�N[ORJQOCU�RCTCNNGNU�VJG�FKXGTUKV[�QH�VJKU�F[PCOKE�EQORCTVOGPV��KP�YJKEJ�KPVGPUG�$|EGNN�UGNGEVKQP�QEEWTU�� +P�UQOG�V[RGU�QH�$|EGNN�PQP�*QFIMKPoU�N[ORJQOC��OQUV�PQVCDN[�&.$%.��VJGTG�KU�GXKFGPEG�VJCV�EQPVKPWCN�$�EGNN�TGEGRVQT�$%4��UKIPCNNKPI�KU�TGSWKTGF�HQT�N[ORJQOC�UWTXKXCN�CPF�RTQITGUUKQP��#�OWVCVGF�V[RG�QH�$�%..�VJCV�UJQYU�GXKFGPEG�QH�J[RGTOWVCVKQP�QH�VJG�KOOWPQINQDWNKP�JGCX[�EJCKP�XCTKCDNG�IGPG�UGIOGPV�OKIJV�CTKUG�HTQO�)%�FGTKXGF�OGOQT[�$|EGNNU��/QTGQXGT��OWNVKRNG�O[GNQOC�KU�C�)%�FGTKXGF�RNCUOC�EGNN�OCNKIPCPE[�VJCV�RGTUKUVU�KP�VJG�DQPG�OCTTQY�CPF�VJCV�KU�FGRGPFGPV�QP�UVTQOCN�EGNN�EQPVCEV�CPF�E[VQMKPGU�UWEJ�CU�KPVGTNGWMKP����&QYPTGIWNCVKQP�QH�VJG�$%4�KP�OWNVKRNG�O[GNQOC�RTGENWFGU�C� TQNG�HQT�$%4�UKIPCNNKPI�KP�VJG�RTQRCICVKQP�QH�VJG�FKUGCUG��BCL��$�EGNN�N[ORJQOC��CCND1��E[ENKP�&���FGFR3��HKDTQDNCUV�ITQYVJ�HCEVQT�TGEGRVQT����IRF4��KPVGTHGTQP�TGIWNCVQT[�HCEVQT����MALT1��/#.6�N[ORJQOC�VTCPUNQECVKQP�IGPG���
REVIEWS
NATURE REVIEWS | IMMUNOLOGY VOLUME 13 | AUGUST 2013 | 579
© 2013 Macmillan Publishers Limited. All rights reserved
CLL clones can emerge before and after Ig hypermutation
IgVH-unmutated CLL clones are associated with poor prognosis
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13q deletion
Pat
ien
ts s
urv
ivin
g (
%)
100
80
60
40
20
0 0 24 48 72 96 120 144 168
Months
17p deletion
11q deletion 12q trisomy
Normal
Döhner'et'al'NEJM'2000'343:1910'
Two distinct cytogenetic aberrations are associated with poor survival
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The ATM/p53 axis is a key determinant of the chemotherapy response�
ATM
Chk2
p53
Noxa Puma
DSB
apoptosis Döhner et al.; NEJM, 2000
Disabling mutations in apoptosis-mediating pathways represent high-risk aberrations in CLL
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CLL is a dynamic disease and clonal evolution represents a clinical challenge
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the therapy is often directed at a particular genetic context whichmay not be shared by all subclones. This relationship betweentherapy and genetic adaptation is likely to result in convergentevolution, in which a mutation that confers resistance will becomehighly prevalent in relapsed disease. Indeed, this process has beenreported in relapsed T-cell ALL after treatment with nucleoside-analog chemotherapy drugs.86
An alternative process contributing to the emergence ofcontinuously more aggressive clones may be entirely independentof differential sensitivity to therapy (Figure 2c). We recentlyobserved a higher number of large subclones (410% of cancercells) in 149 CLL cases that were exposed to treatment beforesampling compared with patients who received therapy after thesample was obtained. This finding of increased clonal diversitywith treatment held true even after accounting for potentialconfounders, such as longer follow-up time.40 We interpret thisobservation to result, at least in part, from the outgrowth of many
diverse pre-existing minor but fit subclones.76,87 This latterinterpretation is further supported by our observation of anincreased frequency of subclonal-driver events (presumably fitter)in treated relative to untreated patients. Overall, our data supportthe idea that CLL therapy, by markedly reducing disease bulk, mayact as a classic evolutionary restriction point and reset interclonaldynamics.88
Within this conceptual framework, when subclones with highfitness already exist within a tumor population, treatment couldfavor the development of more aggressive clones, potentiallyreducing post-relapse survival.40 In this context, cytotoxic therapywould effectively remove the incumbent clone89—acting like a‘mass extinction’ event89—and thereby shift the evolutionarylandscape90,91 in favor of one or more aggressive subclones.92
Thus, highly fit subclones probably benefit from treatment andexhibit rapid outgrowth.78 These data provide mechanisticsupport to the observation that the ‘watch and wait’ strategy for
Figure 2. Three models of how cancer therapy may accelerate clonal evolution. First, cancer therapy, particularly containing genotoxic agents,can induce novel mutagenesis (a). Second, therapy can accelerate clonal evolution by selecting a clone (here illustrated in red) containing amutation that confers resistance to the therapeutic agent used (b). The resistance of the selected clone is reflected in the depiction of the cellpopulation after cytoreduction, composed almost entirely of the resistant clone (in red). A third model postulates similar sensitivity totreatment of the different subpopulations, reflected in similar proportions before and after cytoreduction (c). The clearing niche alters thedynamic evolutionary landscape allowing a faster rise of a fitter clone.
Clonal evolution and therapeutic strategiesDA Landau et al
38
Leukemia (2014) 34 – 43 & 2014 Macmillan Publishers Limited
Therapeutic interventions shift the selective pressure
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Therapeutic interventions shift the selective pressure
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Multiple competing clones might exist in the same patient
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CLL clones can acquire additional genetic aberrations
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Summary II
- CLL is the most common leukemia in the Western World
- CLL cells are dependent on their microenvironment
- CLL is a genetic disease
- CLL cells frequently harbor cytogenetic aberrations
- Loss of p53 and ATM are associated with chemo-resistance
- Therapeutic intervention applies selective pressure that facilitates clonal evolution in CLL
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So, how do we actually treat CLL?
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Chemotherapy still remains the backbone of CLL therapy
Purine analogue fludarabine
Alkylating agent cyclophosphamide
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Antibodies constitute an important pillar of CLL therapy
Rituximab-opsonized B cells are subject to attack and killing by at least three pathways.
1) Complement-mediated membrane attack 2) Phagocytosis by macrophages 3) Antibody-dependent cell-mediated cytotoxicity
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When should we initiate treatment?
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Can we optimize the components of our
current regimens?
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Obinutuzumab displays enhanced response rates compared to rituximab, when combined with Clb
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Obinutuzumab displays enhanced response rates compared to rituximab, when combined with Clb
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G-Clb enhances OS in CLL patients with comorbidities compared with Clb
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Can we be smarter?
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Through activating PI3K generates PIP3 to activate AKT signaling
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PTEN is a phosphatase the counteracts PI3K-mediated AKT activation
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PI3K inhibitors have recently been developed
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PI3K inhibition proves effective in CLL
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BTK inhibitors have recently been developed
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BTK inhibition proves effective in CLL
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BCL2 stabilizes the mitochondrial membrane and antagonizes apoptosis
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BCL2 inhibitors have recently been developed
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The BCL2 inhibitor ABT-199 displays remarkable activity against CLL
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Summary III
- FC-R chemoimmunotherapy is the standard for fit patients
- G-Clb is the standard for patients with comorbidities
- High-risk patients benefit from early therapeutic intervention
- New compounds, such as TKI and BCL antagonists might replace chemotherapy
- The search for actionable driver lesions is ongoing
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