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Advances in clinical management of chronic lymphatic leukemia CLL

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Title: Advances in clinical management of chronic lymphatic leukemia CLL


1
Advances in clinical management of chronic
lymphatic leukemia (CLL)
  • Maria Cristina Pasquini
  • UO-Ematologia CTMO Fondazione Policlinico,
    Mangiagalli Regina Elena,
  • Università degli Studi Milano

2
The past
  • CLL is the most frequent leukemia in adults
    (25),
  • 3/100.000 per years in western hemisfere.
  • 50/100.000 per years gt 70 years old
  • incurable disease of elderly
  • the typical patient was expected to die with
    CLL than for CLL.
  • the goal of chemoterapy was purely palliative in
    intent
  • alkylators were the only therapy

3
The present
  • the incidence is increasing
  • one-third of B-CLL patients are younger than 55
    years old.
  • the majority CLL-patients dies for CLL-related
    complications.
  • considerable progress has been made in
  • defining the molecular basis for the pathogenesis
    of CLL
  • finding new therapeutic options

4
Advances in molecular basis of CLL
  • Two types of CLL pregerminal and post germinal
    origin with unmutated or mutated status of
    variable heavy chain genes(IgVH)
  • This differential mutational status of IgVH genes
    has a significant impact on patients survival (
    MUTATED good prognosis, UNMUTATED poor prognosis)
  • FISH have been demonstrated several typical
    abnormalities with clinical impact
  • 13q- low risk
  • 12 intermediate risk
  • 11q- , 17p- high risk

5
  • Specific genetic features such as del(17),
    del(11), p53 mutation, and unmutated Ig VH can
    now identify patients with clinically aggressive
    disease and suboptimal responses to current
    treatments.

6
Advances in therapy
  • Historically, chlorambucil has been the most
    frequently used chemotherapeutic agent in the
    treatment of CLL.
  • Chlorambucil remains an aviable treatment choice
    for elderly patients and whenever pallation is
    needed.
  • The introduction of purine analogs in 1980s
    invigored clinical research in CLL and
    dramatically changed the treatment disease.

7
Purine analogs (fludarabine)
  • The introduction of purine analogs has increased
    CR, OR, PFS compared to single-agent alkylator
  • Fludabine in frontline setting
  • higher remission rate
  • longer remission duration
  • 80 OR rate but low CR (20-30)
  • Randomized trials Rai NEJM 2000, Johnson Lancet
    1996, Leporrier Blood 2001

8
Combinations purine analogs alkylators
  • The most widely studied combination is
    fludarabine and cyclophosphamide (FC)
  • FC is better than fluda alone as first line
    therapy
  • better ORR
  • better response duration
  • (randomized trials Catovsky Blood 2005,
    Eichhorst Blood 2006)

9
Monoclonal antibodies
  • Monoclonal antibodies have led a profound shift
    in the therapeutic landscape of CLL.
  • selective targeting of tumor-relevant and more or
    less specific markers
  • distinct mechanism of action involving elements
    of human effector functions
  • such as ADCC

10
Rituximab
  • Rituximab is a chimeric anti-CD20 monoclonal
    antibody.
  • Response rates in relapsed CLL to standard-dose
    (375 mg/m2) were disappointingly low
  • Improved efficacy was demonstrated using higher
    dose(500 to 2250 mg/m2 x dose) or more intensive
    schedule.
  • Higher responses has also been achieved in
    previously untreated patients.
  • In addition, in vitro studies demonstrated
    sensitization of CLL cells by rituximab to the
    cytotoxic effects of a number of chemotherapy
    drugs ( including fludarabine and CTX) and vice
    versa.

11
Chemoimmunotherapy combination (FCR) (first line
therapy)
  • Chemoimmunotherapy combination achieved
    significantly
  • higher CR rates 70 versus 35 (plt0.05)
  • longer TTF
  • longer TTP .
  • no statistically significant differences in the
    number and grade of infections.

Comparative, retrospective analyses Keating JCO
2005, Byrd Blood 2005
12
Chemoimmunotherapy in relapsed and refractory CLL
ORR 72 OS improved
Wierda, Cancer 2006
In pts gt70 yrs in advanced stage disease have
been reported lower response rate and higher
myelosuppression
13
Alemtuzumab
  • Alemtuzumab (Campath 1H) binds specifically to
    the CD52 antigen.
  • CD52 is highly expressed on the surface of
  • normal and abonrmal B and T lymphocytes
  • monocytes,
  • macrofages
  • small percentage of granulocyte,
  • CD52 is not expressed on the surface of
    erithrocytes, platelets or bone marrow stem
    cells.
  • Data on the activity of alemtuzumab in patients
    with CLL is rapidly accumulating.
  • better efficacy in CLL as single therapy instead
    of Rituximab

14
Pivotal study
ALEMTUZUMAB 30 mg x3/wk x 12 weeks i.v
15
Alemtuzumab therapy
  • First line therapy
  • CAM 307( open label, international phase III
    study)
  • 297 patients were enrolled and randomized to
    received
  • Alemtuzumab 30 mgX3/w iv x 12weeks
  • Chlorambucil 40 mg/m2 orally once every 28 days
    X 12 cycles.
  • Alemtuzumab is clearly superior to CHL as front
    line therapy
  • OR 83 compared to 56, and CR 24 vs 2
  • Subcutaneous administration
  • 41 previously untreated patients with CLL
    (Lundin, Blood 2002)
  • Alemtuzumab 30 mg subcutaneously x3/w x18 weeks
  • ORR 87 ( CR 19, PR 68)
  • The subcutaneous route reduces the number and
    the severity of first-dose site effects ( such as
    rigor) with a preserved clinical efficacy

16
Alemtuzumab therapy
  • Consolidation treatment of CLL
  • (Montillo Haematologica 2002 , OBrien Cancer
    2003, Moreton JCO 2006)
  • Patients who achieved an MRD-negative complete
    response have a significantly longer
    treatment-free survival and overall survival
    compaired with MRD-positive responders.
  • Combination therapy ( FLUCAM, FR)
  • Several studies are ongoing.
  • The most successful strategy has not been
    defined yet, but will likely involve a
    combination of cytotoxic chemotherapy and
    immunotherapy
  • Alemtuzumb activity is largely p-53 indipendent
    enabling this MoAb to be effective also in very
    poor-risk 17p-patients

17
SCT approach
  • Autologous transplants may prolong survival in
    selected patients
  • The experience by Montillo successully
    demonstrated that low doses of alemtuzumab can
    safely applied as consolidation to CLL patients
    candidates to HSC autograft, with the aim of
    improving quality of response and realizing an in
    vivo purging with this MoAb.

18
SCT approach
  • Allogeneic stem-cell transplant rapresents the
    only curative therapy for CLL
  • GvL
  • High morbidity and TRM
  • GVHD
  • Age lt55 y (just 10 of patients diagnosed with
    this disease)
  • Examination of outcome with this approach in
    several series demonstrates similar PFS and
    plateau is reached at 3-5 years f.u.
  • RIC ( non myeloablative transplant)
  • Lower toxic deaths
  • GvL
  • GVHD
  • Age lt70 y
  • To test the efficacy of non-myeloablative stem
    cell transplant in CLL, it will be necessary to
    apply this therapy earlier in the course of the
    disease.

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Gene therapy in CLL
  • CD40 is expressed on normal B cells
  • CD40 Ligand (CD40 or CD154) is expressed on
    activated CD4T cells.
  • The CD40/40L interaction stimulates the B cell.
  • The first clinical trial was conducted by Kibbs
    with CLL transfected cells with an adenovirus
    vector wich expresses CD40L as transgene.
  • Clinically reduction in leukemia cells count and
    lymph-node sizes was demonstred.
  • The activation of CLL cells makes them sensitive
    to agents that activate the extrinsic pathway of
    apoptosis
  • Ongoing work aims to optimize this strategy to
    identify the appropiate and optimal patient
    subset in wich apply vaccine therapy.

31
Conclusions
  • The last two decades have seen a major paradigm
    shift in the therapy of CLL
  • The treatment goal moves from symptom palliation
    to the attainment of maximal disease control
    using the most effective frontline regimens
    avaible, thus prolonging survival and possibly
    leading to cure
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