Chronic lymphocytic leukemia is eradication feasible and worthwhile? - - PowerPoint PPT Presentation

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Chronic lymphocytic leukemia is eradication feasible and worthwhile? - - PowerPoint PPT Presentation

Feb 02, 2024 325 likes •618 views

Chronic lymphocytic leukemia is eradication feasible and worthwhile? Gianluca Gaidano, MD, PhD Division of Hematology Department of Clinical and Experimental Medicine Amedeo Avogardo University of Eastern Piedmont Novara, Italy Minimal

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Chronic lymphocytic leukemia is eradication feasible and worthwhile?

Gianluca Gaidano, MD, PhD Division of Hematology Department of Clinical and Experimental Medicine Amedeo Avogardo University of Eastern Piedmont Novara, Italy

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Minimal residual disease (MRD) negativity in CLL

MRD

negativity

Is MRD homogeneously defined in the literature? Is MRD eradication a realistic goal in most CLL? Is MRD eradication a surrogate marker of biologically favourable CLL? What is the clinical cost of MRD eradication? Is there any advantage in treating CLL until MRD eradication?

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Minimal residual disease (MRD) negativity in CLL

MRD

negativity

Is MRD homogeneously defined in the literature? Is MRD eradication a realistic goal in most CLL? Is MRD eradication a surrogate marker of biologically favourable CLL? What is the clinical cost of MRD eradication? Is there any advantage in treating CLL until MRD eradication?

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Technical approaches for MRD detection in CLL are heterogeneous

Dual color flow cytometry Consensus- primer IgH PCR Multiparametric flow cytometry RQ-ASO IgH PCR Applicability CD5+/CD19+ cells Amplifiable IgH gene R Typical phenotype Amplifiable IgH gene R Limit of detection 1% - 0.1% 1% - 0.1% 0.01% 0.001% Advantage Low cost Low cost Fast Sensitive Disadvantage Usually uninformative Least informative assay Fresh material necessary Cost and time

(needs patient specific primers)

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Sensitivity of technical approaches for MRD detection in CLL

Consensus- primer IgH PCR Multiparametric flow cytometry RQ-ASO IgH PCR Dual color flow cytometry DIAGNOSIS

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Technical approaches for MRD detection in CLL: caveat heterogeneity among centers and among trials! Heterogeneity for MRD evaluation in CLL:

  • in methods utilized
  • in sensitivity threshold
  • among clinical trials
  • in the clinical practice
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Technical approaches for MRD detection in CLL: caveat heterogeneity among centers and among trials! Heterogeneity for MRD evaluation in CLL:

  • in methods utilized
  • in sensitivity threshold
  • among clinical trials
  • in the clinical practice

Despite current limitations, it should be acknowledged that CLL MRD investigators are making efforts toward MRD standardization

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IWCLL – NCI guidelines 2008 Threshold for defining MRD eradication according to IWCLL-NCI guidelines

Consensus- primer IgH PCR Multiparametric flow cytometry RQ-ASO IgH PCR Dual color flow cytometry DIAGNOSIS

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The deeper is the response, the longer is time to progression, independent of the treatment strategy

Bottcher S, ASH 2008 (CLL 8 trial) 0 12 24 36 48

Time (months)

100% 80% 60% 40% 20% 0%

PFS < 0.01% ≥ 1%

FC FCR

≥ 0.01% – < 1%

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MRD standardization: CLL vs CML Despite efforts from the IWCLL-NCI guidelines for standardizing sensitivity, MRD in CLL is far from reaching the standardization of MRD in CML:

  • lack of standardized technique
  • lack of standardized timing
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Minimal residual disease (MRD) negativity in CLL

MRD

negativity

Is MRD homogeneously defined in the literature? Is MRD eradication a realistic goal in most CLL? Is MRD eradication a surrogate marker of biologically favourable CLL? What is the clinical cost of MRD eradication? Is there any advantage in treating CLL until MRD eradication?

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Algorithm for the management of CLL patients Group 1

  • Completely

indipendent in ADL

  • No comorbidity
  • Normal age-

mached life expectancy

Group 2

  • Somewhat impaired

Group 3

  • Severely

handicapped

  • High comorbidity
  • Reduced life

expectancy

“Go go”

Intensive therapy: FC, FCR, R-FCM  Long-lasting remission

“Slow go”

Mild therapy: CLB, alemtuzumab F-mono  Control of symptoms

“No go”

Palliative Care

Elderly patients Young patients Young patients group

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MRD-negative CR can be currently obtained only with intensive treatments

Keating, JCO 2005 Hillmen, JCO 2007 Bosch, CCR 2008 Bosch, JCO 2009

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Minimal residual disease (MRD) negativity in CLL

MRD

negativity

Is MRD homogeneously defined in the literature? Is MRD eradication a realistic goal in most CLL? Is MRD eradication a surrogate marker of biologically favourable CLL? What is the clinical cost of MRD eradication? Is there any advantage in treating CLL until MRD eradication?

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Minimal residual disease (MRD) negativity in CLL Two different settings:

  • induction therapy
  • consolidation / maintenance therapy
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Infections in different CLL chemotherapeutic regimens (induction therapy)

Keating, JCO 2005 Hillmen, JCO 2007 Bosch, CCR 2008 Bosch, JCO 2009

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Strategies for tailoring MRD eradication: consolidation with monoclonal antibodies

Fludarabine 25mg/m

2

Alemtuzumab 30mg

median time interval 67days Range 45-90

1 5 9 13 17 21

Weeks

From day 1 to day 5 of each cycle

1 2 3 4 5 6 7 8 9 10 11 12

Weeks

Three times per week (first week dose escalation from 3mg to 30mg)

Wendtner et al. Leukemia, 2004

Trial closed for unacceptable toxicity

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ALEMTUZUMAB: CONSOLIDATION / MRD ERADICATION

(Montillo et al., J Clin Oncol 24: 2337, 2006) CR 12 (35%) 12

  • PRn

7 (21%) 6 1

  • PR

15 (44%) 9 3 3 Total 27 (79.4%) 4 (11.8%) 3 (8.8%) Poly IgH 0% 19 (56%) After Fluda CR PRn PR Response to Alemtuzumab

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Fludarabine based + alemtuzumab or rituximab consolidation in CLL

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Minimal residual disease (MRD) negativity

MRD

negativity

Is MRD homogeneously defined in the literature? Is MRD eradication a realistic goal in most CLL? Is MRD eradication a surrogate marker of biologically favourable CLL? What is the clinical cost of MRD eradication? Is there any advantage in treating CLL until MRD eradication?

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GOLDEN AGE

  • f NEW CLL

PROGNOSTICATORS

TP53 exon 8 C13397T > Arg213STOP

Telomere length TP53 mutation

23130 9240 6560 4360 2320 2020

2830 bp bp Case

CD49d expression IGH translocation Host SNPs

VDJ CDR3 aa sequence V4-39 D6-13 J5 IYGYSSSWYGGSNWFDP V4-39 D6-19 J5 SR-------E------- V4-39 D6-13 J5 NS------FR-YS---- V4-39 D6-13 J5 HL--------AA-----

Stereotypic HCDR3

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A single study (FCR) tested the relationship between MRD and biological predictors

Lin et al. Blood, 2009

The proportion of patients archieving MRD-negative CR were: 57% in IGHV unmutated 67% in IGHV mutated

p =.21

Caveat definition of MRD- negativity: <1% CLL cells detected by dual color flow cytometry

Landmark analysis of MRD neg pts

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Minimal residual disease (MRD) negativity

MRD

negativity

Is MRD homogeneously defined in the literature? Is MRD eradication a realistic goal in most CLL? Is MRD eradication a surrogate marker of biologically favourable CLL? What is the clinical cost of MRD eradication? Is there any advantage in treating CLL until MRD eradication?

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Few clinical trials in CLL include MRD evaluation PubMed research criteria:

  • Keyword : “chronic lymphocytic leukemia”
  • Limits:  date: from 2001/01/01 to 2010/08/01

 journals: NEJM, Lancet, JCO, Blood  type of article: clinical trial

Total no. of clinical trails: 112 Clinical trials including MRD assesment: 11 Clinical trials including MRD eradication as a primary end-point: 0

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Methods to monitor clinical response and to detect MRD in CLL clinical trials

Consensus- primer IgH PCR Multiparametric flow cytometry RQ-ASO IgH PCR Dual color flow cytometry DIAGNOSIS

  • No. 0 trials
  • No. 3 trials
  • No. 3 trials
  • No. 5 trials
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MRD-negativity archievement can be considered curative in CLL only in allo-transplanted patients

0 10 20 30 40

50

Time (months)

100% 80% 60% 40% 20% 0%

PFS Time (months) PFS

100% 80% 60% 40% 20% 0%

0 12 24 36 48 60 72 96

Allogenic stem cells transplantation FCR regimen MRD-negativity MRD-positivity

MRD-negativity curve reaches a plateau only in patients undergoing allogeneic stem cells transplantation

Bottcher S, ASH 2008 (CLL 8 trial) Dreger, Blood 2010

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Minimal residual disease (MRD) negativity in CLL: A provocative question

MRD

negativity

Is MRD homogeneously defined in the literature? Is MRD eradication a realistic goal in most CLL? Is MRD eradication a surrogate marker of biologically favourable CLL? What is the clinical cost of MRD eradication? Is there any advantage in treating CLL until MRD eradication? Are current MRD targets (BM, PB) the best possible targets?

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The proliferation centers of CLL reside predominantly in lymph nodes BM and PB may not fully reflect the events taking place in proliferation centers