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

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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” 8024 63

Fludarabine 20132 85

Flu + Cyclo 11037 88

Flu/Cyclo/Rit 30072 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%)


Current phases of clinical trials in cll

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


Why not treat all patients with fcr

Why not treat all patients with FCR?


Response to fcr front line by age stage 2 m

Response to FCR (Front-Line) by Age, Stage, 2M

CharacteristicValue Pts. %CR p-value

Age (years)<55 112 76

55-69 147 69.002

>70 41 46

Rai Stage0-II 199 73*.002

III-IV 101 59

2Microglobulin <3 91 86

3-4 78 76<.001

>4 122 53


Current phases of clinical trials in cll

Survival FCR by Rai Stage

Proportion Alive


Current phases of clinical trials in cll

Survival FCR by b2-Microglobulin

Proportion Alive

p<.001


Current phases of clinical trials in cll

Survival FCR by Age and b2M

Proportion Alive

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p<.01

}

p=.03

}

}


Current phases of clinical trials in cll

Time to Fail FCR by Age and b2M

Proportion

}

p<.001

}

p= ns

}

}


Survival by treatment fc fm vs fcr fcr3 age 70

Survival by TreatmentFC/FM vs. FCR/FCR3 Age > 70

Proportion


Current phases of clinical trials in cll

Present Front Line Priorities for Advanced/Progressive CLL


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%)

PR18 (56%)

Fail10 (32%)


Survival vs time to fail rituxan gm csf untreated cll age 70

Survival vs. Time to Fail Rituxan + GM-CSF Untreated CLL Age > 70

Proportion


Time to fail patients age 70 by treatment fcr vs ritux gmcsf

Time to Fail Patients Age > 70 by Treatment FCR vs Ritux+GMCSF

Proportion


Survival patients age 70 by treatment fcr vs ritux gmcsf

Survival Patients Age > 70 by Treatment: FCR vs Ritux+GMCSF

Proportion

p = .ns


Time to treatment failure by b 2 m fcr age 70 years

Time to Treatment Failure by b2-MFCR Age > 70 years

Proportion


Current phases of clinical trials in cll

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

CharacteristicValue 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 CLL12

Richter’s 3

Prior Rx: Median(Range) 3 ( 0 – 9 )

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

FISH17p 6


Ofar in relapsed refractory cll and richter s syndrome 20 evaluable patients

OFAR in Relapsed/Refractory CLL and Richter’s Syndrome20 evaluable patients


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