R-CHOP%20%20Recurrent%20follicular%20lymphoma:%20Stem%20cell%20transplantation%20vs.%20novel%20agents

1
R-CHOPRecurrent follicular lymphoma Stem
cell transplantation vs. novel agents

• John P. Leonard, M.D.
• Richard T. Silver Distinguished Professor of
  Hematology and Medical Oncology
• Associate Dean for Clinical Research
• Vice Chairman, Department of Medicine

2
Disclosures

• Consulting advice
• Gilead, Onyx, Teva, Celgene, Medimmune,
  Genentech, Hospira, Biotest, Pharmacyclics, Dr.
  Reddys Laboratory.

3
Case A

• A 63-year-old male presented with follicular,
  grade 2 NHL with symptomatic diffuse LAN in the
  5-cm range. He is treated with R-CHOP x 6 cycles
  and then observed.
• 5 years later, he presents with progressive
  pelvic LAN in the 3-cm range on routine imaging.
  
• Blood counts, chemistries, and LDH are in the
  normal range. Bone marrow biopsy is negative for
  evidence of lymphomatous involvement.

4
Case B

• A 50-year-old male presented with follicular,
  grade 2 NHL with symptomatic diffuse LAN in the
  5-cm range. He is treated with R-CHOP x 6 cycles
  and then observed.
• 1.5 years later, he presents with progressive
  pelvic LAN in the 3-cm range on routine imaging.
  He is treated with R-Bendamustine and has a CR.
• 1 year later he has recurrent, progressive pelvic
  LAN in the 3 cm range on routine imaging.
• Blood counts, chemistries, and LDH are in the
  normal range. Bone marrow biopsy is negative for
  evidence of lymphomatous involvement.

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Issues to consider in selection of therapy for FL

• Indications for therapy
• Bulk of disease
• Comorbidities
• Toxicity concerns
• Interest in and availability of clinical trials
• R/O transformation

6
Caveats from data in this population

• Heterogeneous prior therapies
• Heterogeneous prior use of rituximab
• Heterogeneous prior use of R-CHOP and
  R-bendamustine
• How much these data apply an individual patient
  today unclear
• Expect that with better upfront therapy a
  resistant patient will be worse with respect
  to prognosis, relapsed unknown

7
Chemotherapy data for recurrent indolent NHL
(until recently)
Regimen N RR TTF/PFS, Mo
Rituximab monotherapy 166 48 13
FCM 30 70 21
Rituximab FCM 35 94 Not reached (median follow-up 3 years)
CHOP 231 72 20
R-CHOP 234 85 33
FCMfludarabine, cyclophosphamide, mitoxantrone.
McLaughlin. J Clin Oncol. 1998162825
Forstpointner. Blood. 20041043064 Van Oers.
Blood. 20061083295 Vose. J Clin Oncol.
2000181316 Witzig. J Clin Oncol. 2002202453
Witzig. J Clin Oncol. 2002203262 Horning. J
Clin Oncol. 200523712.
8
Bendamustine in rituximab-refractory indolent NHL

• 100 pts, rituximab-refractory
• indolent NHL (no response to R
• or response lt 6 months)
• Median 3 prior regimens
• (range 1-10), 47 chemoresistant
• Bendamustine 120 mg/m2
• ORR 84 (29 CR),
• median PFS 9.7 months

Kahl, B, et al, Cancer 2010
9
Key novel agents for recurrent FL

• Novel anti-CD20s
• Anti-apoptotic agents
• Antibody-drug conjugates
• Radioimmunotherapy
• Lenalidomide
• PI3K inhibitors
• BTK inhibitors

10
Current RIT for Recurrent Disease
Regimen N RR TTF/PFS, Mo
131I-tositumomab 45 57 9.9 (DOR)
Rituximab 70 56 10
90Y-ibritumomab 73 80 11
90Y-ibritumomab 54 74 6.8
131I-tositumomab 40 65 10.4
Rituximab-refractory patients defined as no
response to last course of rituximab or response
lasting 6 months.
McLaughlin. J Clin Oncol. 1998162825
Forstpointner. Blood. 20041043064 Van Oers.
Blood. 20061083295 Vose. J Clin Oncol.
2000181316 Witzig. J Clin Oncol. 2002202453
Witzig. J Clin Oncol. 2002203262 Horning. J
Clin Oncol. 200523712.
11
RIT can induce durable remissionsI-131
tositumomab in relapsed indolent or transformed
NHL Time to progression (all patients) (N250)

Study RIT-I-000 L/T, n 42
Study RIT-II-001, n 47
Study RIT-II-002 Arm A/Crossover, n 61
Study RIT-II-004, n 60
Study CP-97-012, n 40
Fisher, et al, J Clin Oncol 2005 23(30)7565-73
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Timing of RIT

• Clearly a useful option for many situations
• Elderly can particularly benefit
• Benefits vs other options (e.g. chemo/rituximab)
  remain debatable in early treatment
• Offers advantages in relatively resistant pts
• Long-term effects as well as acceptance in
  practice are an issue
• Keep period of cytopenias in mind

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CALGB 50401Amended schema
Rituximab (n90)
R ANDOMIZE
Relapsed Follicular NHL after 1 rituximab based
regimens
Rituximab Lenalidomide (n45)
Lenalidomide (n45)
L days 1-21d, q 28d x 12 months, R weekly x
4 Modified September 2007, completed accrual
April 2011
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Key subject characteristics
L (N45) L R (N44)
Median age 63 (34-85) 62 (36-89)
FLIPI Low Intermed High 31.4 42.9 25.7 48.5 30.3 21.2
TTP since last R dose 1.6 yrs 1.3 yrs
Stage I/II III/IV 20.0 80.0 30.2 69.8
LDH gt NL 16.3 2.4
N89 total (data not reported for 3 pts R alone
arm, 3 never treated, 2 insufficient) Pending
data on FLIPI (31 pt), prior R (3 pt), stage (1
pt) and LDH (4 pt)
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Response and event-free survival
L (N45) L R (N44)
Overall (ORR) 51.1 95 CI (35.8-66.3) 72.7 95 CI (52.2-85.0)

Complete (CR) 13.3 36.4
Partial (PR) 37.8 36.4

Median EFS 1.2 yrs 2.0 yrs
2 year EFS 27 44
Median F/U 1.7 years (0.1 4.1) Unadjusted EFS
HR of L vs LR is 2.1 (p0.010) Adjusted (for
FLIPI) EFS HR of L vs LR is 1.9 (p0.061)
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Event-free survival
L R median 2 yrs L median 1.2 yrs
Median F/U 1.7 years (0.1 4.1)
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B-cell receptor signaling and inhibition in B
cell malignancies.
Ibrutinib Idelalisib
Fostamatinib
Modified from Stevenson F K et al. Blood
20111184313-4320
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Idelalisib (CAL-101, GS-1101)
Class I PI3K Isoform
g
a
d
b
Expression Ubiquitous Ubiquitous Leukocytes Leukocytes
EC50 (nM) gt20,000 1,900 3,000 8

• Targeted, selective, oral inhibitor of PI3K delta
• Inhibits proliferation and homing, induces
  apoptosis in B-cell malignancies
• Active in CLL, FL, MCL
• iNHL ORR 48, DOR 18 mo, CLL ORR 46, PFS 17 mo
• MCL ORR 40, PFS 3.7 mo
• Principal toxicities GI, liver enzymes, fatigue,
  rash

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Idelalisib combinations in recurrent indolent
NHLBest Overall Response
Rituximab Idelalisib (N32)
Bendamustine Rituximab Idelalisib (N14)
Bendamustine Idelalisib (N33)
Inevaluable (patients without a follow-up tumor
assessment)
a Criterion for response Cheson 2007
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Idelalisib combinations in indolent NHLBest
Overall Response
Benda Idelalisib (N28/33)
Rituximab Idelalisib (N23/32)
BR Idelalisib (N10/14)
All combinations Idelalisib (N61/79)
78
85
72
71
43 CR
26 CR
27 CR
19 CR
a Criterion for response Cheson 2007
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Selected idelalisib studies ongoing

• B-R /- idelalisib Ph 3 CLL, Ph 3 iNHL
• Rituximab /- idelalisib Ph 3 CLL, Ph 3 iNHL
• Ofatumomab /- idelalisib Ph 3 CLL
• Triplets (Alliance)

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Ibrutinib in Rel/Ref Follicular Lymphoma Efficacy
Efficacy (n16) n () 1.25 mg/kg/d (n4 FL) 2.5 mg/kg/d (n11 FL) 5.0 mg/kg/d (n9 FL)
ORR 7 (44) 25 55 56
CR/CRu 3 (19) 0 27 33
PR 4 (25) 25 27 22
Median DOR, mo 12.3 NE 10.3 12.3
Median time to first response, mo (range) 4.7 (2-12) - - -
Median time to first PR, mo (range) 4.6 (2-11) - - -
Median time to first CR, mo (range) 11.5 (5-12) - - -
Median PFS, mo 13.4 NE 13.4 19.6
Median OS, mo No deaths - - -

• Median time on treatment 7 mo (range, 0-29)
• Dose of 5 mg/kg/day or higher recommended for
  phase II studies

Fowler et al. ASH 2012, Abstract 156.
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Kinase inhibition as a component of
chemotherapy-free approaches in FL and MCL

• Alliance A051202 (Leonard PI)
• Phase I trial of PI3K inhibitor Idelalisib
  (CAL-101,GS-1101) lenalidomide and rituximab in
  recurrent FL
• Establish dosing, safety and preliminary activity
• Alliance A051103 (Ujjani PI)
• Phase I/II trial of Btk inhibitor Ibrutinib
  lenalidomide and rituximab in previously
  untreated FL
• Establish dosing, safety and preliminary activity
• Alliance A051201 (Smith PI)
• Phase I/randomized II trial of PI3K inhibitor
  Idelalisib lenalidomide and rituximab in
  recurrent MCL
• Establish dosing, safety and preliminary activity

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Key novel agents for FLKey questions vs. SCT

• What fraction of patients, if any, can have
  durable remissions with these agents?
• If comparable, how does QOL (short-term vs.
  chronic) compare?

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CUP trial in of AuSCT in relapsed FL
Schouten, et al, JCO 2003, 21(21) 3918-3927
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CUP trial - PFS
Schouten, et al, JCO 2003, 21(21) 3918-3927
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CUP trial - OS
Schouten, et al, JCO 2003, 21(21) 3918-3927
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Remission Duration of Patients Receiving AuSCT
for FL in Second or Later Remission St. Barts and
DFCI
Rohatiner et al. J Clin Oncol. 2007252554-9.
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Rituximab purging and/or maintenance in R-naive
patients with chemosensitive relapsed FL.
280 enrolled and randomized (purged/non-purged) Ap
proximately 200 transplanted (100 purged/100 non
purged) Approximately 50 maintenance R in each
arm Rituximab naïve, 80 2 prior regimens, 30
CR, 70 VGPR
Pettengell R et al. JCO 2013311624-1630
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Progression-free survival by treatment arm
Pettengell R et al. JCO 2013311624-1630
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AuSCT at first relapse after R-CHVP-IFN
PFS and OS After ASCT vs no ASCT

• 175 relapsers after FL2000 study
• (R-CHVP-I vs CHVP-I)
• 70 relapsers after R-CHVP-I
• Various second line rx (65
• included R)
• 13 with ASCT
• ASCT associated with improved
• PFS and OS

Le Gouill S, et al, Haematologica 2011
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Allo vs. Auto SCT

• IBMTR Registry data
• N 904 patients with FL
• Transplants between 1990-1999
• Probability of improved long-term OS not improved
  by allo ASCT
• Significant heterogeneity in subjects

OS
DFS
van Besien K, et al, Blood 10220033521-3529
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Allo vs. non-myeloablative SCT in FL

• Retrospective, 88 pts (48 allo, 40 miniallo)
• Characteristics
• Miniallo pts were older and more often had prior
  autoSCT
• Outcomes
• Relapse rate 13 (allo) vs 28 (miniallo)
• 1 year TRM 33 (allo) vs 28 (miniallo)
• 2 year OS and PFS (allo) 52 and 46
• 2 year OS and PFS (miniallo) 53 and 40
• Chemosensitive disease and no prior AutoSCT
  correlated with outcome

Rodriguez R, et al, Biol Blood Marrow Transplant,
200612(12) 1326-34.
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One approach to treat a patient with recurrent FL
(post chemoimmunotherapy) needing treatment?

• Late relapse (gt 2 yrs or so)
• Many options, decision based on
  tolerability/efficacy balance
• Early relapse (lt 2 yrs or so)
• Chemotherapy
• RIT
• SCT
• Novel/investigational agents