Refractory CLL: Treatment Approaches

1
Refractory CLL Treatment Approaches

• George Ansstas, MD
• 10/02/09

2
Introduction

• Resistance to purine analogs is a challenging
  issue in the therapeutic management of patients
  with CLL
• Treatment of CLL is usually deferred until
  indications for therapeutic intervention are
  present

3
Refractory CLL

• Lack of response, or disease progression within
• 6 months of a PR or CR to purine analog
  therapy
• Disease progression or relapse within 12 months
• of SCT
• Very poor prognosis, with median survival
• measured in months
• It should be distinguished from
  progressive disease
• More common in patients with deletions at 17p13.1
  (p53),11q22.3 (ATM), and high Bcl-2/Bax ratio

Montserrat E, et al. Blood. 20061071276-1283.
4
Survival

• The median survival from the time of diagnosis in
  the series of patients studied by Rai et al were
  
• Stage 0 150 months
• Stage I 101 months
• Stage II 71 months
• Stages III and IV 19 months

5
Survival Based on Five Genetic Categories
N325
Döhner H, et al. N Engl J Med. 20003431910-1916.
6
Overall Survival
Months From Diagnosis
Del Principe MI, et al. Blood. 2006108853-861.
7
Time from Diagnosis to Initial TherapyN 705
Rassenti LZ, et al. N Engl J Med.2004351893-901.
8
Prognosis of Advanced, Relapsed CLL
Thomas D, et al. In Cheson BD ed. Chronic
lymphoid leukemias. M. Dekker 2001275-335.
9
Salvage Therapy in Refractory CLL Need for
Active, New Agents

• Poor prognosis for fludarabine-refractory CLL (1)
• - Median OS 10 mo
• No standard treatment option if also refractory
  to alemtuzumab, or with bulky lymph nodes (2)
• -Response with salvage regimens
• ORR 20-26 median TTF 2-3 mo
• -Median OS 8 mo and 14 mo,
  respectively

• Keating et al. Leuk Lymphoma 2002 43 17552.
• Tam et al. Leuk Lymphoma 2007 48 1931

10
Survival of Fludarbine-Refractory CLL After 1ST
Salvage Rx
a 22 response (CR plus PR)

Keating et al.
Leuk Lymphoma 2002 43 17552.
11
The Natural History of Fludarabine-Refractory CLL
Who Fail Alemtuzumab or Have Bulky Lymphadenopathy
Tam et al. Leuk Lymphoma
2007 48 1931
12
The Natural History of Fludarabine-Refractory CLL
Who Fail Alemtuzumab or Have Bulky Lymphadenopathy
Tam et al. Leuk Lymphoma 2007 48 1931
13
Genomic profile of F-refractory CLL stratified
by TP53 mutation
Zenz, T. et al. Blood 20091142589-2597
14
Salvage Therapy
15
Therapeutic role of alemtuzumab in patients who
have failed fludarabine
Median survival was 32 months
Median survival was 16 months
Keating MJ, et al. Blood. 2002993554-3561.
16
Subcutaneous Alemtuzumab in Fludarabine-Refractor
y CLL Clinical Results and Prognostic Marker
Analyses From the CLL2H Study of the German CLL
Study Group
Overall survival (OS) of the full patient set (N
103) is 19.1 mo
Time to treatment failure of the full patient set
(N 103) is 5.6 mo
OS after next therapy, grouped by type of
subsequent treatment. Blue curve allogeneic SCT,
n 8, median not reached gold curve other
salvage therapies, n 66, median 9.2 months.
(17p deletion, 11q deletion, unmutated VH,
mutated TP53) were not associated with
significant differences in response rates or
survival end points (ie, OS, PFS, and TTTF),
Stilgenbauer, S. et al. J Clin Oncol
273994-4001 2009
17
Subcutaneous Alemtuzumab
Phase II study of SQ alemtuzumab 30 mg TIW in
fludarabinerefractory CLL with 103 pts enrolled
Demographics include median age 63, Rai 3/4
disease 74, median of 3 prior Rx, 29
del(17p13.1), 68 IgVH un-mutated Median of 8
wks of Rx given Toxicity includes grade 3/4
neutropenia (56) thrombocytopenia (57), anemia
(56), non-CMV infection (29) noted
CMV reactivation (16 total, grade 3/4 occurred
in 8 pts)
S Stilgenbauer et al Blood 112329 (abst), 2008
18
Subcutaneous Alemtuzumab
At median f/u of 38 months 75 (73) pts had
died, 56 due to PD,31 infection, and 13
non-CLL related ORR 34 (CR 4, PR 30), with
median PFS 7.7 mo and OS 19.1 months in MVA for
OS only age (age gt 65 y (12.2 vs 29.0 mo, plt.001)
but not genomic features predictive Next Rx
choice influenced survival with 2-year OS rate
for allogeneic SCT 86 as compared to other
subsequent treatments 27 (p0.009) Importance
of this trial is emphasis that in relapsed pts
with high risk disease (genomic or clinical) it
is essential to target nonablative allogeneic
stem cell transplant early
S Stilgenbauer et al Blood 112329 (abst), 2008
19
Bendamustine Rituximab in CLL

• Old Eastern German drug with uncertain novel
  mechanism of action approved for marketing in US
  as primary therapy in CLL based upon superiority
  to chlorambucil little relapsed CLL data
• Phase II study of B (70 mg/m2) day 1, 2 and R
  (375 mg/m2, c1 and 500 mg/m2 c2) Q28 days x 6
  cycles in pts with 1-3 prior Rx
• Mean 4.5 courses administered with grade 3/4
  anemia (6) neutropenia (12), thrombocytopenia
  (9) , and infections (4.9) most common Rx
  mortality in 4 of pts
• A ORR 77 with CR in 14 and PR in 63 of pts
  with 2 MRD pts
• no CR and lower ORR (44) in del(17p13.1) pts

20
Bendamustine Rituximab in CLL Salvage

• 62 pts enrolled
• Median number of therapies 2 (1-3)
• Median age 67 yrs Binet C 53
• Bendamustine70 mg/m2d12 Rituximab 375 mg/m2d1q 4
  wks for x 6 cycles
• Bendamustine Rituximab an active therapy in
  early-relapsed CLL, must monitor counts closely

Fischer K et al. Blood 2008 112 abs 330
21
Bendamustine Rituximab in CLL Salvage
22
Bendamustine Rituximab in CLL Salvage
Selected Grade 3 Adverse Events (N75)
Grade 3-5 1 fatal urosepsis and 2 fatal
pneumonias
23
Probability of OS for Standard conditioning group
and RIC group
Months

M Michallet, et al Blood 112330
(abstr), 2008
24
Outcome after allogeneic hematopoietic stem-cell
transplantation (HCT) in patients with
17p-chronic lymphocytic leukemia (CLL)
Schetelig, J. et al. J Clin Oncol 265094-5100
2008
25
The REACH TrialR-FC vs FC in Relapsed/ Relapsed
CLL
26
The REACH TrialR-FC vs FC in Relapsed CLL
27
The REACH TrialR-FC vs FC in Relapsed CLL
PFS benefit observed for R-FC vs. FC in patients
with adverse prognostic factors, including Binet
C, del(11q), unmutated IgVH, ZAP70disease.
28
Ofatumumab
Rituximab binding site
Ofatumumab binding site

• Human CD20 mAb
• Binds a small-loop epitope of CD20
• Potent lysis of B cells
• More effective in vitro CDC versus rituximab
• Effective CDC of cells with low CD20 expression,
  including CLL cells
• Promising activity in pilot CLL study ORR 50 in
  high-dose group (n27)

29
Ofatumumab
30
Ofatumumab
Kipps et al. J Clin Oncol 2009 27(suppl)366s
(abstract 7043). Wierda et al. J Clin Oncol 2009
27(suppl)366s (abstract 7044).
31
Ofatumumab
Percent of patients with improvement from
baseline to Week 24 Number of patients with
abnormal baseline clinical parameters FA-ref
fludarabine-and alemtuzumab-refractory BF-ref
bulky fludarabine-refractory
32
Ofatumumab
a Refractory to fludarabine-and
alemtuzumab-containing regimens b Refractory to
fludarabine-containing regimens inappropriate
for alemtuzumab due to bulky nodes
33
Ofatumumab
Average tumor burden over time in patients with
lymphadenopathy
34
Lumiliximab in CLL

• Primatized antibody initially developed for
  asthma treatment
• Induces caspase dependent apoptosis but no ADCC
  or CDC in CD23 transformed B-cell lines and CLL
  cells
• Lumiliximab induces down-regulation of
  antiapoptotic proteins Bcl-2, Mcl-1, and XIAP in
  CLL cells
• Single agent in vivo activity and synergistic
  survival enhancement of Fludarabine or Rituximab
  in CD23 lymphoblastic cell lymphoma in xenograft
  mice model
• Phase I study of monotherapy in CLL performed
  with no PR or CR at any dose

Pathan et al, Blood 111524, 2008
35
Phase 1/2 Study LumiliximabFCR

• Multicenter, dose -escalation with objectives to
  characterize the safety profile, phase 2 dose of
  lumiliximab FCR, and efficacy to decide if
  future clinical development warranted
• Lumiliximab combined with FCR using MDA regimen
  in 31 relapsed CLL patients
• 65 of pts with grade III/IV toxicity but all
  expected and at the same frequency as observed in
  previous phase II study with FCR
• Using response criteria of NCI-96, responses
  occurred in 65 of pts including 52 with CR
• Phase III study (LUCID) registration study
  launched upon these results

36
Phase II Trial of the Galectin-3 Antagonist
GCS-100 in Elderly Patients With Relapsed CLL
GCS-100 was administered at 160 mg/m2/day I.V.
for 5 days every 3 weeks Response (n
24)Partial response in 6 patients (25) Stable
disease in 12 patients (50) SafetyMinimal
hematologic toxicity Discontinuation in 9
patientsProgressive disease in 6 patients Grade
3 toxicities rash, indigestion and epigastric
pain
Cotter et al. J Clin Oncol 2009 27(suppl)357s
(abstract 7006)
37
Background GCS-100 is a polysaccharide
antagonist of galectin-3, a protein whose
overexpression on certain tumor cells is
associated with poor prognosis in cancer
patients. GCS-100 has been shown to induce
apoptosis of patient CLL cells ex vivo. In
addition, GCS-100 potentiates the in vitro
activity of other agents commonly used to treat
CLL, including rituximab. This phase II clinical
trial evaluated the potential of GCS-100 as a
novel single-agent therapeutic for relapsed CLL.
Methods Patients with Rai Stage II or higher CLL
who had relapsed after one or two prior therapies
were eligible. Prior therapies included a range
of chemotherapy combinations including FCR,
cyclophosphamide/vincristine/rituximab, and
chlorambucil/prednisone. Patients received
GCS-100 i.v. at 160 mg/m2 for 5 days every 21
days until disease progression. Peripheral blood
was collected on study days 1, 4, and 8 of each
cycle to assess peripheral leukocyte counts and
apoptosis. CD38 and Zap70 expression were
assessed where possible. Results 24 pts were
enrolled16 men and 8 women (median age 67 years,
range 4086 years, 15/24 pts were over 65 years).
GCS-100 was well-tolerated. There were no cases
of drug-related grade 3 or 4 hematological
toxicity or other serious AE. Two patients
discontinued treatment due to rash, which
resolved with cessation of treatment and which
has been shown to be responsive to steroids. Six
(25) patients experienced PR, including 4
patients with gt50 shrinkage of lymph node
lesions. Currently 6 patients remain on study
with a median duration of 5 months (range 4.59
months). In addition, apoptosis of peripheral
leukocytes was confirmed by caspase activation
and by DNA fragmentation. Conclusions GCS-100
has significant single-agent activity in relapsed
CLL. Its lack of myelosuppression and potential
synergy with other agents makes GCS-100 a strong
candidate for further development in CLL,
particularly for elderly patients for whom there
is a major need for less toxic agents.
38
Apoptosis Dysregulation in CLL
Kang and Reynolds Clin Cancer Res(2009)
39
Bcl-2 Antagonists ABT-263

• Second generation, orally bioavailable BH3
  inhibitor
• Exerts mechanism-based cytotoxicity through
  dose-dependent disruption of Bcl-2 family
  protein-protein interactions
• Induces rapid but reversible thrombocytopenia
  Likely mediated by Bcl-XL-induced platelet
  apoptosis
• Reported DLT in ABT-263-treated CLL patients
• Platelet nadir can recover during continued
  exposure

40
Bcl-2 Antagonists ABT-263

• 2 phase I studies have explored single-agent
  activity in CLL/SLL patients
• - 14/21d and 21/21d schedules
• Responses seen in both cohorts
• - 14/21d among 27 CLL/SLL patients, 3
  radiographic PR, 2 unconfirmed PR, 6 maintained
  50 decrease ALC x gt2mo., 11 SD
• - 21/21d among 16 patients, 1 unconfirmed PR,
  3 50 decreasedALC x gt2mo.
• Thrombocytopenia mitigated by 7-day lead-in and
  continuous dosing (21/21d schedule)
• - Minimizes platelet nadir and cycle variability

Wilson, W. et al. ASCO Annual Meeting 2008
(Abstr 8574) Roberts, AW et al. ASCO Annual
Meeting 2009 (Abstr 3505)
41
ABT-263 in Relapsed Lymphoid Malignancies,
Including CLL and SLL Efficacy and Safety
Phase I Studies of ABT-263 Safety
Phase I Studies of ABT-263 Efficacy
a Not related to treatment
Wilson et al. J Clin Oncol 2009 27(suppl)452s
(abstract 8574).
42
Interactions in the microenvironment potential
targets in CLL

• Lenalidomide activity likely dependent on
  microenvironmental factors
• Cell-cell interactions with stromal cells can
  rescue CLL cells from apoptosis
• -CXCR4-CXCL12 interaction can be exploited
  therapeutically

43
CLL Microenvironment
44
Linalidomide

• Thalidomide derivatives with novel properties
  including innate and cellular immune activation,
  stromal cell interaction, apoptosis in subset of
  cell types clinical trials in CLL promising
• Mechanism of action in uncertain in B cells but
  has been shown to
• Down regulate TNF a production by monocytes
  when stimulated by LPS
• Alter tumor microenvironment by decreasing
  stromal cell production of IL-6, other cytokines
• Enhance ADCC
• Enhance T-cell activation as co-activator with
  CD3 ligation
• Up-regulate expression of select tumor suppressor
  genes such as SPARC

45
Linalidomide
A Chanan-Khan et al (J Clin Oncol 2006) 45
pt relapsed phase II study of lenalidomide 25
mg/day x 21 days with 7 days off Among 23
patients with fludarabine-refractory CLL, 7 (30)
patients responded to lenalidomide (CR in 1
patient and PR in 6 patients) Cytopenias,
fatigue, and tumor flare observed. Tumor flare
treated with motrin A Ferrajoli et al (Blood
2008) phase II study of lenalidomide 10 mg day
with dose escalation to 25 mg as tolerated
(median dose 10 mg) 12 patients with
fludarabine-refractory CLL were treated, and 3
(25) patients responded to lenalidomide,
compared with a response rate of 38 in 32
patients with fludarabine-sensitive disease
cytopenias and tumor flare observed. Tumor flare
treated with corticosteroids Lenalidomide has
activity in fludarabine refractory CLL and
perhaps del(17p) CLL
46
Correlation Between Lenalidomide-Associated
Tumor Flare and Response in Relapsed/Refractory
CLL Phase II Results
a Increased to 25 mg/day
Of the 8 patients achieving a CR, 7 developed
TF. Of the 15 patients without TF, only 1
achieved a CR.
Sher et al. Haematologica2009 94(suppl 2)373
(abstract 0928).
47
Cyclin-dependent kinase inhibitors demonstrate
marked activity in CLL
Flavopiridol targets CDK1, CDK2, CDK4, CDK6,
CDK7, CD9
Lapenna and
Giordano Nature Rev Drug Disc (2009)
48
Flavopiridol
CDK inhibitor with significant activity in
relapsed CLL using pharmacologic derived
schedule 116 pts with relapsed CLL (n107) or
small lymphocytic lymphoma (n10) treated on
successive phase 1-2 studies at OSU
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Conclusion
Better understanding of CLL-cell biology has
facilitated the rapid development of newer
therapies Effective treatment options for
several sub-groups (fludarabine-refractory,
high-risk genetics) remain limited Clinical
trial participation should be encouraged -
Earlier in disease course - All patients with
high-risk features (unmutated IgVH, del17p/del11q)