Transcript Aggressive NHL Slides
Recurrent 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
Disclosures
Consulting advice: Gilead, Onyx, Teva, Celgene, Medimmune, Genentech, Hospira, Biotest, Pharmacyclics, Dr. Reddy’s Laboratory.
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.
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.
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
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
Chemotherapy data for recurrent indolent NHL (until recently)
Regimen
Rituximab monotherapy FCM Rituximab + FCM CHOP R-CHOP
N
166 30 35 231 234
RR
48% 70% 94% 72% 85%
TTF/PFS, Mo
13 21 Not reached (median follow-up: 3 years) 20 33 FCM=fludarabine, cyclophosphamide, mitoxantrone. McLaughlin.
J Clin Oncol
. 1998;16:2825; Forstpointner.
Blood
. 2004;104:3064; Van Oers.
Blood
. 2006;108:3295; Vose.
J Clin Oncol
. 2000;18:1316; Witzig.
J Clin Oncol
. 2002;20:2453; Witzig.
J Clin Oncol
. 2002;20:3262; Horning.
J Clin Oncol
. 2005;23:712.
Bendamustine in rituximab-refractory indolent NHL
• 100 pts, rituximab-refractory indolent NHL (no response to R or response < 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
Key novel agents for recurrent FL
Novel anti-CD20s Anti-apoptotic agents Antibody-drug conjugates Radioimmunotherapy Lenalidomide PI3K inhibitors BTK inhibitors
Current RIT for Recurrent Disease
Regimen
131 I-tositumomab Rituximab 90 Y-ibritumomab 90 Y-ibritumomab* 131 I-tositumomab*
N
45 70 73 54 40
RR
57% 56% 80% 74% 65%
TTF/PFS, Mo
9.9 (DOR) 10 11 6.8
10.4
*Rituximab-refractory patients defined as no response to last course of rituximab or response lasting ≤6 months.
McLaughlin.
J Clin Oncol
. 1998;16:2825; Forstpointner.
Blood
. 2004;104:3064; Van Oers.
Blood
. 2006;108:3295; Vose.
J Clin Oncol
. 2000;18:1316; Witzig.
J Clin Oncol
. 2002;20:2453; Witzig.
J Clin Oncol
. 2002;20:3262; Horning.
J Clin Oncol
. 2005;23:712.
RIT can induce durable remissions
I-131 tositumomab in relapsed indolent or transformed NHL Time to progression (all patients) (N=250) 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 0 2 4 6 Time from treatment, years 8 10
Fisher, et al, J Clin Oncol 2005 23(30):7565-73
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
CALGB 50401 Amended schema
Relapsed Follicular NHL after ≥ 1 rituximab based regimens R A N D O M I Z E Rituximab (n=90) Rituximab + Lenalidomide (n=45) Lenalidomide (n=45) L days 1-21d, q 28d x 12 months, R weekly x 4 Modified September 2007, completed accrual April 2011
Key subject characteristics
Median age FLIPI Low Intermed High L (N=45) 63 (34-85) 31.4 % 42.9 25.7
TTP since last R dose 1.6 yrs Stage I/II III/IV LDH > NL 20.0 % 80.0 16.3 % L + R (N=44) 62 (36-89) 48.5 % 30.3
21.2 1.3 yrs 30.2 % 69.8 2.4 %
N=89 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)
Response and event-free survival
Overall (ORR) L (N=45) 51.1% 95% CI (35.8-66.3) L + R (N=44) 72.7% 95% CI (52.2-85.0) Complete (CR) Partial (PR) 13.3% 37.8% 36.4% 36.4% Median EFS 2 year EFS 1.2 yrs 27% 2.0 yrs 44%
Median F/U 1.7 years (0.1 – 4.1) Unadjusted EFS HR of L vs L+R is 2.1 (p=0.010) Adjusted (for FLIPI) EFS HR of L vs L+R is 1.9 (p=0.061)
Event-free survival
L + R median 2 yrs L median 1.2 yrs
Median F/U 1.7 years (0.1 – 4.1)
B-cell receptor signaling and inhibition in B cell malignancies .
Ibrutinib Idelalisib Fostamatinib
Modified from Stevenson F K et al. Blood 2011;118:4313-4320
Class I PI3K Isoform
Idelalisib (CAL-101, GS-1101)
a b g d
Expression EC 50 (nM) Ubiquitous >20,000 Ubiquitous 1,900 Leukocytes 3,000 Leukocytes 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
19
Idelalisib combinations in recurrent indolent NHL Best Overall Response +50 +25
Rituximab + Idelalisib (N=32)
0 -25 -50 a -75
Bendamustine + Idelalisib (N=33)
-100
Inevaluable (patients without a follow-up tumor assessment) a Criterion for response [Cheson 2007] Bendamustine Rituximab + Idelalisib (N=14)
20
Idelalisib combinations in indolent NHL Best Overall Response 100
Rituximab Idelalisib (N=23/32) Benda Idelalisib (N=28/33) BR Idelalisib (N=10/14) All combinations + Idelalisib (N=61/79)
100 80
85%
60
72% 71%
40
43% CR
20 0
19% CR 27% CR a Criterion for response [Cheson 2007] 78% 26% CR
80 60 40 20 0
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)
Ibrutinib in Rel/Ref Follicular Lymphoma Efficacy Efficacy (n=16)
ORR CR/CRu PR Median DOR, mo Median time to first response, mo (range) Median time to first PR, mo (range) Median time to first CR, mo (range) Median PFS, mo Median OS, mo
n (%)
7 (44) 3 (19) 4 (25) 12.3
4.7 (2-12) 4.6 (2-11) 11.5 (5-12) 13.4
No deaths
1.25 mg/kg/d (n=4 FL)
25% 0 25% NE − − − NE − Median time on treatment = 7 mo (range, 0-29)
≥ 2.5 mg/kg/d (n=11 FL)
55% 27% 27% 10.3
≥ 5.0 mg/kg/d (n=9 FL)
56% 33% 22% 12.3
− − − − 13.4
− − − 19.6
− Dose of 5 mg/kg/day or higher recommended for phase II studies Fowler et al. ASH 2012, Abstract 156.
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
Key novel agents for FL Key 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?
CUP trial in of AuSCT in relapsed FL
Schouten, et al,
JCO
2003, 21(21): 3918-3927
CUP trial - PFS
Schouten, et al,
JCO
2003, 21(21): 3918-3927
CUP trial - OS
Schouten, et al,
JCO
2003, 21(21): 3918-3927
Remission Duration of Patients Receiving AuSCT for FL in Second or Later Remission St. Barts and DFCI Rohatiner et al. J Clin Oncol. 2007;25:2554-9.
Rituximab purging and/or maintenance in R-naive patients with chemosensitive relapsed FL.
280 enrolled and randomized (purged/non-purged) Approximately 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 2013;31:1624-1630
Progression-free survival by treatment arm
Pettengell R et al. JCO 2013;31:1624-1630
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
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 102:2003;3521-3529
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, 2006;12(12): 1326-34.
One approach to treat a patient with recurrent FL (post chemoimmunotherapy) needing treatment?
• Late relapse (> 2 yrs or so) Many options, decision based on tolerability/efficacy balance • Early relapse (< 2 yrs or so) Chemotherapy RIT SCT Novel/investigational agents