Advances in clinical management of chronic lymphatic leukemia CLL

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Advances in clinical management of chronic
lymphatic leukemia (CLL)

• Maria Cristina Pasquini
• UO-Ematologia CTMO Fondazione Policlinico,
  Mangiagalli Regina Elena,
• Università degli Studi Milano

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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

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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

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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

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• 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.

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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.

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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

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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)

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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

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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.

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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
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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
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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

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Pivotal study
ALEMTUZUMAB 30 mg x3/wk x 12 weeks i.v
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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

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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

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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.

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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.

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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