current phases of clinical trials in cll
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Current Phases of Clinical Trials in CLL. Induction phase Eradication of minimal residual disease Salvage therapy Allogeneic Cellular Immunotherapy. ?How do we decide therapy at each phase?. Comparison of Response Rates by Regimen. Regimen Pts. %CR %OR

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current phases of clinical trials in cll
Current Phases of Clinical Trials in CLL
  • Induction phase
  • Eradication of minimal residual disease
  • Salvage therapy
  • Allogeneic Cellular Immunotherapy

?How do we decide therapy at each phase?

comparison of response rates by regimen
Comparison of Response Rates by Regimen

Regimen Pts. %CR %OR

“CHOP-like” 80 24 63

Fludarabine 201 32 85

Flu + Cyclo 110 37 88

Flu/Cyclo/Rit 300 72 95

(FCR)

survival cll by front linetreatment

Survival CLL by Front-lineTreatment

}

p<.01

}

p= ns

}

p<.001

Proportion Alive

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}

chemosensitization by rituximab and vice versa
Chemosensitization By Rituximab And Vice Versa

Rituximab

  • Increases cytotoxicity of Fludarabine and Cyclophosphamide
  • Down regulates Bcl-2 protein

Fludarabine

  • Prevents DNA repair of alkylating agent cross links
  • Down Regulates CD46, CD55, CD59 (Complement Defense Proteins)
fc rituximab schedule in cll
FC + Rituximab Schedule In CLL

(Allopurinol 300mg/day)

response to fc rituximab nci wg 300 patients
Response to FC + Rituximab(NCI-WG: 300 Patients)

Response # Pts. ( % )

CR 217 (72%)

Nodular PR 31 (10%) 95%

PR 37 (12%)

No Response 13 ( 4%)

Early Death2 ( 1%)

slide7

Survival FCR by Response

Proportion Alive

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p=ns

}

p<.001

}

p<.002

conclusions from randomized clinical trials
Conclusions from Randomized Clinical Trials

Each Confirmed the superiority of the new therapy 5-7 years after MDACC single institution studies

response to fcr front line by age stage 2 m
Response to FCR (Front-Line) by Age, Stage, 2M

Characteristic Value Pts. %CR p-value

Age (years) <55 112 76

55-69 147 69 .002

>70 41 46

Rai Stage 0-II 199 73* .002

III-IV 101 59

2Microglobulin <3 91 86

3-4 78 76 <.001

>4 122 53

slide12

Survival FCR by b2-Microglobulin

Proportion Alive

p<.001

slide13

Survival FCR by Age and b2M

Proportion Alive

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p<.01

}

p=.03

}

}

slide14

Time to Fail FCR by Age and b2M

Proportion

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p<.001

}

p= ns

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}

response rituxan gm csf untreated cll age 70

Response Rituxan + GM-CSF Untreated CLL Age > 70

Total patients: 32

CR 2 ( 6%)

nPR 2 ( 6%)

PR 18 (56%)

Fail 10 (32%)

slide22

Clinical and Flow Cytometry Response

(<70 years & b2m <4mg/l)

Time to Treatment Failure identical

clinical and flow cytometry response 70 years b 2m 4mg l
CFAR (N=26) FCR (N=119)

Response %Pts %Pts

CR 69 60

nPR -- 17

PR cytopenia 19 6

PR disease 8 11

Overall 96 93

Flow negative84 59

Clinical and Flow Cytometry Response(<70 years & b2m >4mg/l)
newer prognostic markers in cll
Newer Prognostic Markers in CLL

Characteristic Value Unfavorable

IgVh Mutation Status <2% Mutated

ZAP 70 (Tyrosine Kinase) >20% of cells

CD 38 (Activation Marker) >30%, or 20%, or 7%

FISH (Cytogenetics) 11q-, 17p-

background ofar in rs rcll
Background OFAR in RS & rCLL

Platinum compounds:

  • Activate excision DNA repair mechanisms
  • Synergistic with ara-C and fludarabine

Fludarabine & ara-C: inhibit the resynthesis step of excision repair

Fludarabine: ↑ ara-CTPaccumulation in leukemic cells

Oxaliplatin:

  • Synergistic with fludarabine in vitro
  • Minimal renal/auditory toxicity
ofar treatment design

Course 1

OFAR Treatment Design

Oxaliplatin 17.5/20/25 mg/m2

Fludarabine 30 mg/m2

Cytarabine 1000 mg/m2

Rituximab 375 mg/m2

1

2

3

4

8

15

22

29

Day

Courses 2-6

1

2

3

4

8

15

22

29

Day

ofar in relapsed refractory cll and richter s syndrome phase 2 20 evaluable patients

OFAR in Relapsed/Refractory CLL and Richter’s SyndromePhase 2 (20 evaluable patients)

Characteristics:

Relapsed CLL 5

Refractory CLL 12

Richter’s 3

Prior Rx: Median(Range) 3 ( 0 – 9 )

b2 Micro: Median(Range) 4.3 mg/L (2.4-14.4)

FISH 17p 6

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