Emerging Therapies for Fludarabine Refractory CLL

1
Emerging Therapies for Fludarabine Refractory CLL

• Todd A Fehniger
• Hematology/Oncology Grand Rounds
• 03-23-07

2
Case

• 58yo gentleman with relapsed CLL
• Dx 9/04 Rai stage IV CLL
• WBC 531,000 (93 lymphs), Hb 8.6, Plt 103
• Smear mature appearing small lymphs
• BM Bx gt90 small mature lymphocytes
• Flow CD20dimCD5CD23CD10- K-restricted
• Cytogenetics 12
• ZAP-70 gt80, CD38 92
• B2M 7.83, LDH 362
• CT extensive LAD, Mild Splenomegaly

3
Case

• Fludarabine x 4 cycles (10/04-1/05)
• WBC decreased 185,000
• CT Stable Disease (no change in LAD)
• Fludarabine, Cytoxan, Rituximab (FCR) x 4 cycles
  (1/05-4/05)
• WBC 2.5, Hb 13.9, Plts 153
• CT CR, no enlarged LAD
• CRu
• PD in 3 months
• WBC 20 (7/05)-gt56.9 (9/05)-gt107 (11/05)
• Hb 10.4, Plts 94

4
Case

• Referred for 2nd additional opinion 12/05
• WBC 137,000 (no large cells or pro-lymphocytes),
  Hb 10.4, plts 114
• CT PD (increased LAD, marked SM)
• BM Bx gt80 small lymphocytes
• Fatigued, no B sx, ECOG PS 1

What is the next best therapy?
5
What is FludarabineRefractory CLL?

• PD during or 6 months after flu-regimen
• Two Single Institution Experiences
  (Retrospective)
• MDACC n147
• WRAMC n47
• Median age 60-67 years
• Median Prior Regimens 3
• Responses to conventional or research treatment
• 10-11
• 40-80 develop life threatening infections with
  therapy
• Median survival 9-13 months
• 40-50 w/ p53 mutations or poor-px cytogenetics
  (11q-, 17p-)

Keating MJ et al. Leuk Lymphoma 431755,
2002 Perkins JG et al. Cancer 942033, 2002 Byrd
JC et al. Sem Oncol 33310, 2006
6
Relapsed/Refractory CLL
Fludarabine in past 6 months?
No
Yes
Flu Refractory CLL
Relapsed CLL
Campath (anti-CD52) Repeat purine-analog
regimen (FCR, PCR) NHL salvage regimen High Dose
Steroids Allo SCT Clinical Trial w/ Novel Agent
Repeat Flu-containing regimen (40 RR, adding
Rituxan and/or Cytoxan) Clinical Trial
7
Standard FDA-Approved Treatment of Fludarabine
Refractory CLL

• Campath (anti-CD52 mAb) IV
• N91 flu-refractory B-CLL pts
• RR 33, median duration 9.5 mo, OS 16 months
• Poor responses w/ LAD gt5cm, PS gt2
• Keating et al. Blood 993554, 2002
• N131 flu-refractory B-CLL pts
• RR 40 (7 CR), median PFS 7 months, OS 13
  months
• Rai KR Blood 98365a, 2002
• SQ Campath Regimens
• Confirmed similar efficacy, no infusion toxicity
• Responses in p53 mutated patients
• PCP, VZV, CMV, infections, myelosuppression
  remain a significant issue

8
Are there promising novel therapeutic agents
in flu-ref CLL?
9
Emerging Therapy for CLL
Lenalidomide (Revlimid)
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Lenalidomide
Activity
?Mechanism(s)
Alter cytokine profiles
Multiple Myeloma
Lenalidomide (Revlimid)
Block Angiogenesis
MDS (w/ 5q-)
Direct Effects on tumor
NHL
Costimulate T cells
CTCL
Augment NK cells
MF
?CLL
11

• Single Institution (RPCI) Phase II trial
• N45 relapsed CLL pts (9/04-5/06)
• 51 fludarabine-refractory
• Len 25 mg PO / day d1-21/28 day cycle
• Due to TLS in 2 pts, protocol ammended to ramp up
  Len 5 mg every 1-2 wks to 25mg dose (n16 final
  pts)
• If PD on Len, add Rituxan LR
• Cycle 1 of LR 375 mg/m2 on d1, 8, 15
• Cycles 2-6 of LR 375 mg/m2 on d1, 15

Chanan-Khan JCO 245343,2006
12

• Eligibility
• Indication for treatment per CLL NCI96 guidelines
• Failed at least one prior therapy
• Objectives
• ORR
• Cytostatic Response CRPRSD
• Duration of response, PFS

Chanan-Khan JCO 245343,2006
13

• Toxicity Management / Dose Reductions
• Neutropenia
• Grade 4 or Grade 3 w/ Fever dose held
• G-CSF support allowed
• Dose resumed when lt grade 2
• Thrombocytopenia
• Grade 4, dose held and then restarted lt grade 2
• If multiple grade 4 episodes, dose reduced 5mg
• Tumor Flare Reaction
• Sudden onset tender/red LNs with fever/rash
• Ibuprofen 400 mg q6h until resolved
• Prophylaxis w/ Prednisone (n16) 20mg qD x 7days,
  10 mg qD x 7 days

Chanan-Khan JCO 245343,2006
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Chanan-Khan JCO 245343,2006
15
Within 24h 14 day duration
no bleeding
N6 FN
Chanan-Khan JCO 245343,2006
16

• Intent-to-treat
• Responses seen in
• 47 11q
• 40 bulky dz
• 3 pts w/ PD, all had PR w/ Rituxan
• PFS at 1 year 81
• 12 not assessable
• 5 consent withdrawn
• 7 did not get 2 cycles

Chanan-Khan JCO 245343,2006
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Significant ALC (CLL lymphs) Drop within 7 days
Chanan-Khan JCO 245343,2006
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Lenalidomide in rel CLL - MDACC

• ASH Abstract 305 at 2006 Annual Meeting
• Phase II, N35 (22 evaluable)
• Lenalidomide 10mg w/ 5mg increments q28d to max
  dose 25 mg
• Evaluated at 3 months of therapy
• 8/22 (36) fludarabine-refractory
• 32 ORR (5 CR, 28 PR)
• 41 SD yielding 73 Cytostatic Response
• PFS or duration of response not reported
• Toxicity similar to published Phase II trial

Ferrajoli A et al ASH 2006 305
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Lenalidomide and CLL future

• Larger, Multi-Center, trials of len in relapsed
  CLL
• Combinations of Len with traditional CLL
  chemotherapy agents
• Combinations with mAbs (campath, rituxan)
• ? Mechanism action

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Emerging Therapies in CLL
Flavopiridol
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Flavopiridol

• Synthetic flavone initially developed as a
  tyrosine kinase inhibitor by NCI (derived from
  flavone in Dysoxylum binectiferum), same family
  as UCN-01
• Found to be a broad CDK inhibitor, inhibiting
  CDK1, CDK2, CDK4, CDK7, and CDK9
• RNA polymerase II inhibitor through inhibition of
  CDK9 (and potentially CDK7/8) global reduction
  in transcription

Byrd JC ASH 2006 Oral Session
22
In vitro studies of Flavopiridol in CLL Clinical
Rationale

• Induces apoptosis in CLL lines and human CLL
  cells
• p53 independent apoptosis (key for pt population)
• Caspase-dependent apoptosis
• Decreases expression of Mcl-1 and XIAP proteins
  in vitro

Byrd JC ASH 2006 Oral Session Byrd JC and Grever
MR Blood 923804, 1998 Kitada S and Reed JC Blood
96 393, 2000
23
Flavopiridol Clinical Trials in CLL
A Failure?
Byrd JC ASH 2006 Oral Session
24
Whats the deal?In Vitro Study Re-Examination

• Virtually all pre-clinical in vitro studies in
  cell lines utilize fetal calf serum
• Increased drug binding in human serum (95-98)
  versus FCS (virtually 0 above 0.1 uM)
• Review of 72 hr CIVI, 24 hr CIVI and 1 hr IVB
  demonstrates inadequate levels obtained relative
  to that required to induce apoptosis in human
  serum
• Extensive PK modeling demonstrates 30 minute
  bolus followed by 4 hour infusion will attain
  human plasma level needed to kill CLL cells

Byrd JC ASH 2006 Oral Session
25
Flavopiridol LC50 by Culture Condition
Byrd JC ASH 2006 Oral Session
26

• Single institution open label Phase I/II trial
  sponsored by NCI (Ohio State)
• PK target changed due to updated in vitro data
• Dose escalation Phase I design
• 4 cohorts published in paper (1,2,1a,3)
• 4th cohort presented at ASH, updated

Byrd JC Blood 109399, 2007
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Byrd JC Blood 109399, 2007
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Phase I / Cohort 1

• 30 mg/m2 load/ 30 mg/m2 4-hr infusion
• N6 pts
• 1 DLT (neutropenic fever)
• 2 PR in flu-refractory pts
• 1 with del(17p13.1)
• 1 with del(11q22.3)

Byrd JC ASH 2006 Oral Session
29
Phase I / Cohort 2

• 40 mg/m2 load/ 40 mg/m2 4-hr infusion
• Early DLT Hyper-acute tumor lysis syndrome in
  two patients requiring hospitalization and
  leading to death to one patient 8 hours into
  therapy
• Late DLT Hyperacute tumor lysis syndrome leading
  to temporary CVHD (reversible)
• Trial Suspended

Byrd JC ASH 2006 Oral Session
30
Phase I / Cohort 1a (dose descalated) w/ TLS
Prophylaxis/Monitoring

• Patients are admitted for first 5 doses
• Aggressive anti-TLS care
• Hydration overnight
• Rasburicase 0.15 mg/kg before first dose
• Hourly monitoring of serum K during therapy
• Aggressive intervention for hyperkalemia
• Hemodialysis if life-threatening hyperkalemia
• Therapy moves to outpatient if no TLS
• 1 of 14 pts required dialysis for TLS 2 x d,
  recovered

Byrd JC ASH 2006 Oral Session
31
Phase I / Cohort 3 / Design and Results

• 30 mg/m2 bolus, ? in 4-hr dose (50 mg/m2) in pts
  without PR after 4th weekly dose (new PK data)
• N19 pts
• 4 pts required HD for TLS
• 14/19 patients dose escalated
• Increased biochemical TLS with 5th Rx as compared
  to 1st Rx in these pts
• 10 of 19 pts have attained at least a PR (52)

Byrd JC ASH 2006 Oral Session
32
Grade III or IV Toxicity (n42 pts)
Byrd JC ASH 2006 Oral Session
33
Response Features Cohorts 1-3

• 19 of the 42 (45) PR by NCI96 criteria
• PFS for responding patients was a median of 13
  months (95 CI of 7.7-18.8 mo)
• 16/31 (51) w/ bulky (gt5cm) responded
• Responses in high risk pts
• 5 of 12 (42) pts with del(17p13.1) responded
• 13 of 18 (72) pts with del(11q22.3) responded

Byrd JC ASH 2006 Oral Session
34
Cohort 4 Design and Patients

• Enrollment includes relapsed CLL/SLL without any
  count parameter or requirement to be off therapy
  for 4-weeks
• Patients with WBC gt 200 x 109/L excluded (high
  risk)
• Treatment is given as follows
• Week 1 as inpatient patients receive 30 mg/m2
  over 30 minutes followed by 30 mg/m2 over
  4-hours
• Week 2 as inpatient patients receive 30 mg/m2
  over 30 minutes followed by 50 mg/m2 over
  4-hours
• Week 3 and thereafter as outpatient pts receive
  30 mg/m2 over 30 minutes followed by 50 mg/m2
  over 4-hours
• PK and PD studies done weeks 1 and 2
• 16 pts with fludarabine-refractory CLL enrolled

Byrd JC ASH 2006 Oral Session
35
Cohort 4 Results

• Week 1 to 2 transition tolerated well with dose
  increase in 14 pts
• Toxicity acceptable
• Responses in 6 of 16 (38) of pts with 2 more pts
  meeting organomegaly PR criteria but with
  hematologic improvement

Byrd JC ASH 2006 Oral Session
36
Overall Results by Cytogenetic Risk Criteria
Byrd JC ASH 2006 Oral Session
37
Ongoing Clinical Trials with Flavopiridol in CLL

• Phase II study of flavo (4th cohort regimen)
  ongoing in CLL Research Consortium in previously
  treated CLL patients with 20 pts enrolled
• Fludarabine Rituximab Flavopiridol in NHL and
  CLL, preliminary -very active in NHL and CLL
• Phase I/II study of flavopiridol following
  cytoreductive therapy to eliminate minimal
  residual disease
• Phase I study of flavopiridol in combination with
  alemtuzumab
• Phase I/II study of novel CLL schedule in mantle
  cell lymphoma, multiple myeloma, follicular
  lymphoma, large cell lymphoma, Hodgkins disease,
  and solid tumors (responses seen)

Byrd JC ASH 2006 Oral Session
38
Followup Pt.

• R-ESHAP salvage therapy x 2 cycles
• PR
• Fludarabine/Busulfan/ATG non-myeloablative URD
  (10/10) PBSCT 4/4/06
• Day 100 visit
• WBC 7.9, Hb 13, Plts 60,000
• Doing well, back to work full-time, PS 0, no GVHD
• Complete donor chimerism
• Day 180
• Limited skin chronic GVHD
• ?PD based on LN on CT
• Day 312
• CT no change in residual LAD
• STR 90 donor on Prednisone 10mg
• Resolution of skin GVHD
• WBC 7.6, Hb 13.6, Plts 59,000
• Doing well