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17th Annual International Congress on Hematologic Malignancies®:
Focus on Leukemias, Lymphomas, and Myeloma
Meeting in a Box
MULTIPLE MYELOMA
What Can We Learn From Multiple Myeloma Genomic Analysis?
Nikhil Munshi, MD
Genomic Analysis Takeaways
• Methods of genomic analysis
– Established techniques: cytogenetics, FISH
– Emerging techniques: RNA- and DNA-based arrays, transcript-processing arrays, genomic sequencing, and proteomics
• Current goals of genomic analysis in myeloma
– Understand the biology of myeloma
– Identify risk categories to improve prognostication
– Identify and validate novel targets
– Develop biologic agents that target the myeloma cell
– Ultimately, develop personalized therapy
• Currently, gene expression profiling has prognostic value, predicting survival of patients with different genomic signatures, but it cannot yet predict response to therapy.
High-Risk Smoldering Myeloma – Should We Intervene Early?
Ola Landgren, MD, PhD
Smoldering Myeloma
1Kyle RA, et al. Leukemia. 2010;24:1121-7.2Kyle RA, et al. N Engl J Med. 2007;356:2582-90.
3Dispenzieri A, et al. Blood. 2008;111:785-9.4Perez-Persona E, et al. Blood. 2007;110:2586-92.
• Definition of smoldering myeloma1
– Serum monoclonal IgG or IgA ≥ 3 g/dL and/or clonal bone marrow plasma cells ≥ 10% AND
– Absence of end-organ damage (ie, hypercalcemia, renal insufficiency, anemia, or bone lesions attributed to plasma cell proliferative disorder)
• Overall risk of progression2
– 10% per year in years 0-5
– 3% per year in years 6-10
– 1% per year in years 11-20
• Risk stratification
– Mayo Clinic analysis3 stratifies patients according to their 5-yr risk of progression into 3 groups: 25% risk, 51% risk, and 76% risk
– PETHEMA Study Group analysis4 stratifies patients according to their 5-yr risk of progression into 3 groups: 4% risk, 46% risk, and 72% risk
e
First Randomized Phase III Trial for Smoldering Myeloma
Median time to symptomatic progressionLen/dex: not yet reachedObservation: 21 months
4-year overall survivalLen/dex: 94%Observation: 85%
Mateos MV, et al. ASH 2011. Abstract 991.
HR = 5.67; P < .0001
HR = 3.5; P < .01
Lenalidomide 10 mg/day, D1-21 every 2 months
Therapeutic abstention
Primary endpoint: time to progression to symptomatic MM
Secondary endpoints: ORR, DOR, PFS, OS, and safety and tolerability
Lenalidomide 25 mg/day, D1-21 Dexamethasone20 mg D1-D4 and D12-D15
Therapeutic abstention
Randomization of high-risk smoldering MM patients:
Induction:Nine 28-day cycles
Maintenance:Until progression
Smoldering Myeloma Takeaways
• Current clinical recommendation for smoldering myeloma: no treatment unless part of a clinical trial1
• Better understanding of pathogenesis from MGUS to myeloma needed:
– To develop better biological markers
– To predict a patient’s risk of progression
– To develop early intervention strategies
1Kyle R, et al. Int’l Myeloma Working Group. Leukemia 2010.
Current Trends: Treatment Strategies for Newly Diagnosed Elderly Patients With
MyelomaJames Berenson, MD
Dexamethasone ± LenalidomideSWOG S0232
Zonder JA, et al. Blood. 2010;116:5838-41.
Objective: to determine the efficacy and safety of Len + Dex as induction therapy in NDMM patients
Primary endpoint: PFS
Len + Dex (n = 97)
Len: 25 mg/day, D1-28
Dex: 40 mg/day, D1-4, 9-12, 17-20
Three 35-day cycles
Len + Dex
Len: 25 mg/day, D1-21
Dex: 40 mg/day, D1-4 and 15-18
28-day cycles until progression
Dexamethasone (n = 95)
Placebo: 25 mg/day, D1-28
Dex: 40 mg/day, D1-4, 9-12, 17-20
Three 35-day cycles
Dexamethasone
Placebo: 25 mg/day, D1-21
Dex: 40 mg/day, D1-21
28-day cycles until progression
Unblinded Treatment
Len: 25 mg/day, D1-28
Dex: 40 mg/day, D1-4, 9-12, 17-20
Three 35-day cycles
Unblinded Len + Dex
Len: 25 mg/day, D1-21
Dex: 40 mg/day, D1-4 and 15-18
Responding/stable disease
Disease progression
Dexamethasone ± LenalidomideSWOG S0232
• 1-yr PFS was significantly improved with the addition of lenalidomide (78% vs 53%; P = .002)
Zonder JA, et al. Blood. 2010;116:5838-41.
Len + dex Placebo + dex0
10
20
30
40
50
60
70
80
90
26
4
37
12
15
32
PR
VGPR
CR
Pa
tie
nts
(%
)ORR = 78%
ORR = 48%
ORR, P < .0001VGPR, P < .001
Lenalidomide + High-Dose Dex vs Lenalidomide + Low-Dose Dex: ECOG
E4A03
Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.
Arm 1-yr OS 2-yr OS
RD (high-dose) 87% 75%
Rd (low-dose) 96% 87%
Survival significantly improved with Rd (low-dose) regimen (P = .0002 at 1 year)
Four 28-day cycles
Transplant-eligible patients can
proceed to SCT
Continue therapy until disease progression
Objective: to assess if a reduced dose of dex decreases toxicity while maintaining efficacy
Primary endpoint: ORR after first 4 cycles
Lenalidomide + High-Dose Dexamethasone (RD)a
Len: 25 mg/day, days 1-21
Dex: 40 mg/day, days 1-4, 9-12, 17-20 (n = 223)
Lenalidomide + Low-Dose Dexamethasone (Rd)
Len: 25 mg/day, days 1-21
Dex: 40 mg/day, days 1, 8, 15, 22 (n = 222)
aBased on the superiority of the Rd regimen, the study was stopped at a median follow-up of 12.5 months and patients in the RD arm crossed over to Rd therapy.
MP ± Bortezomib: VISTA
• 3-yr OS: 72% in VMP arm vs 69.5% in MP arm
San Miguel J, et al. N Engl J Med. 2008;359:906-17.Mateos MV, et al. J Clin Oncol. 2010;28:2259-66.
Previously untreated patients; not candidates for transplant
Efficacy Parameter Lenalidomide Placebo HR P Value
Median TTP, months 24.0 16.6 0.483 < .000001
Median OS, months NR NR 0.61 .008
► Endpoints: Primary: TTP; Secondary: CR, ORR, TTR, DOR, PFS, TNT, OS, QoL
ARM B (MP)MP: Nine 6-week cycles: Cycles 1-9Melphalan 9mg/m2 and prednisone 60mg/m2 days 1-4
ARM A (VMP)VMP: Four 6-week cycles: Cycles 1-4Bortezomib 1.3mg/m2 days 1, 4, 8, 11, 22, 25, 29, 32; Melphalan 9mg/m2 and prednisone 60mg/m2 days 1-4
Followed by five 6-week cycles: Cycles 5-9 Bortezomib 1.3mg/m2 days 1, 8, 22, 29; Melphalan 9mg/m2 and prednisone 60mg/m2 once daily on days 1–4
Max of 9 cycles (total 54 weeks) in both arms
RANDOMIZE
► Study Schema:
– 682 patients randomized 151 centers 22 countries worldwide
– IDMC recommended study stop in September 2007 based on protocol-specified interim analysis
– VMP was significantly superior for all efficacy endpoints
Phase II Studies for Newly Diagnosed Multiple Myeloma
1Reeder CB, et al. ASCO 2008. Abstract 8517.2Berenson JR, et al. Br J Haematol. 2011;155:580-7.
3Richardson PG, et al. Blood. 2009;114:501-2.4Berenson JR, et al. Eur J Haematol. 2009;82:433-9.
5Niesvizky R, et al. Blood. 2008;111:1101-9. 6Rossi A, et al. ASCO 2011. Abstract 8008.
7Jakubowiak AJ, et al. Blood. 2012;120:1801-9.8Mikhael J, et al. ASCO 2012. Abstract 8010.
9Kolb B, et al. ASCO 2012. Abstract 8009.
Regimen Drugs ORR CR
Cybor-D1 cyclophosphamide + bortezomib + dex 93% 39%
DVD2 bortezomib + pegylated liposomal doxorubicin + dex 86% 20%
VRD3 bortezomib + lenalidomide + dex 100% 37%
BAM4 bortezomib + ascorbic acid + melphalan → maintenance bortezomib 74% 13%
BiRD5,6 clarithromycin + lenalidomide + high-dose dex 90% 39%
CRd7 carfilzomib 27 mg/m2 + lenalidomide + dex 100% 85%
CYCLONE8 carfilzomib + cyclophosphamide + thalidomide + dex 96% 29%
CMP9 carfilzomib + melphalan + prednisone 89% 3%
Novel Combinations and New Drugs for Elderly Patients With Myeloma
• Approved drugs‒ Novel combinations
‒ Modifications of dose and schedule Improve efficacy
Better tolerability
• Drugs in development‒ Similar targets
Proteasome inhibitors - carfilzomib (FDA-approved!), ixazomib
IMiDs - pomalidomide (FDA-approved!)
‒ New classes of agents Monoclonal antibodies - anti-CS-1 (elotuzumab), anti-CD40
(dacetuzumab), anti-CD38
mTOR inhibitors - temsirolimus
PI3K inhibitors - perifosine
HDAC inhibitors - vorinostat, romidepsin, panobinostat
Maintenance Therapy – Is It for Everyone?
Nikhil Munshi, MD
Maintenance Therapy for Multiple Myeloma
• Maintenance therapy:
– Purpose is to prolong remission duration and life expectancy
– Requires periodic follow-up to monitor toxicity and response
• Patient must have:
– Disease that is in remission (undetectable or at a low level)
– Recovered from all previous toxicities
• Maintenance agent must have:
– Minimal toxicity or at least not overlapping with the toxicity of the induction regimen
– Convenient dosing
– Convenient route of administration
Lenalidomide Maintenance After Transplant: CALGB 100104
McCarthy PL, et al. N Engl J Med. 2012;366:1770-81.
Efficacy Parameter Lenalidomide Placebo HR P Value
Median TTP, months 46 27 -- < .0001
3-yr OS 88% 80% 0.62 .027
RestagingDays 90–100
Registration Randomization
D-S Stage 1-3, < 70 years> 2 cycles of induction Attained SD or better 1 yr from start of therapy> 2 x 106 CD34 cells/kg
Mel 200
ASCT
CRPRSD Lenalidomide
10 mg/d with ↑↓ (5–15 mg)
Placebo
Lenalidomide Maintenance Following Lenalidomide Consolidation: IFM
2005-02
• PFS significantly prolonged with lenalidomide maintenance compared with placebo (41 vs 24 months; P < 10-9)
• OS not significantly different between groups (P = .79)Attal M, et al. Proc International Myeloma Workshop 2011.
McCarthy P, et al. Proc International Myeloma Workshop 2011.
Primary endpoint: PFSSecondary endpoints: CR rate, TTP, OS, feasibility of long-term lenalidomide…
Phase III randomized, placebo-controlled trialN= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008
Patients age < 65 years, with nonprogressive disease, ≤ 6 months after ASCT in first line
Randomization: stratified according to Beta-2m, del13, VGPR
Consolidation:Lenalidomide alone 25 mg/day po
days 1-21 of every 28 days for 2 months
Arm A = Placebo(N=307)
until relapse
Arm B = Lenalidomide(N=307)
10-15 mg/d until relapse
Lenalidomide Maintenance in Patients Ineligible for Transplant: MM-015
Palumbo A, et al. N Engl J Med. 2012;366:1759-69.
• PFS significantly prolonged with the addition of lenalidomide maintenance following MPR induction therapy (HR = 0.349; P < .001)
• PFS benefit maintained across patient subgroups
MPM: 0.18 mg/kg, days 1-4P: 2 mg/kg, days 1-4PBO: days 1-21
MPRM: 0.18 mg/kg, days 1-4P: 2 mg/kg, days 1-4R: 10 mg/day po , days 1-21
Placebo
Placebo
MPR-RM:0.18 mg/kg, days 1-4P:2 mg/kg, days 1-4R:10 mg/day po , days 1-21
RA
ND
OM
IZA
TIO
N
Double- Blind Treatment Phase
DiseaseProgression
Maintenance
Lenalidomide
(25 mg/day) +/-
Dexamethasone
Open- Label Extension Phase
Lenalidomide10 mg/daydays 1-21
Cycles (28day) 1-9 Cycles 10+
Maintenance Lenalidomide and Second Primary Malignancies
• Both CALGB 100104 and IFM 2005-002 showed increased risk of second primary malignancies compared with placebo (23 vs 6 and 18 vs 4, respectively)1,2
• MM-015 also showed increase in frequency of second primary malignancies with lenalidomide use (n=12, MPR-R; n=10, MPR; n=4, MP)
1Attal M, et al. Proc International Myeloma Workshop 2011.2McCarthy P, et al. Proc International Myeloma Workshop 2011.
3Palumbo A, et al. N Engl J Med. 2012;366:1759-69.
PAD + Bortezomib Maintenance vs VAD + Thalidomide Maintenance:
HOVON Trial
Sonneveld P, et al. ASH 2010. Abstract 40.
Efficacy Parameter PAD → bortezomib VAD → thalidomide P Value
3-yr PFS 48% 42% .005
3-yr OS 78% 71% .02
MM Stage II or III, Age 18–65
CAD + GCSF
3 x VAD
CAD + GCSF
3 x PAD
MEL 200 + PBSCT
In GMMG 2nd
MEL 200 + PBSCT
MEL 200 + PBSCT
In GMMG 2nd
MEL 200 + PBSCT
Thalidomide maintenance 50 mg/day for 2 yrs
Allogeneic Tx
Bortezomib maintenance1.3 mg/m2/2 weeks for 2 yrs
Bortezomib 1.3 mg/m2 IV
Doxorubicin 9 mg/m2
Dexameth 40 mg
Randomization
Bortezomib + Thalidomide vs Bortezomib + Prednisone as
Maintenance: GEM2005MAS65
Arm ORR CR Median PFS
VT maintenance 95% 46% 39 months
VP maintenance 97% 39% 32 months
Mateos MV, et al. Lancet Oncol. 2010;10:934-41.
No significant differences between VMP and VTP in ORR (80% and 81%) and CR rate (20% and 27%)
MaintenanceBort/Thal
(VT)Bort/Pred
(VP)Bort/Thal
(VT)Bort/Pred
(VP)
Induction(6 cycles)
Bort/Mel/Pred(VMP)
Bort/Thal/Pred(VTP)
vs
Series of 260 elderly untreated MM patients included in the GEM2005 Spanish trial
Conclusions About Maintenance Therapy
for Multiple Myeloma• Maintenance therapy prolongs PFS.
• Low-dose oral agents preferable for maintenance therapy.
• Both bortezomib and lenalidomide are useful maintenance agents and may need to be combined for patients with high-risk disease.
• Slight increase in incidence of secondary malignancy after lenalidomide maintenance.
• Overall, everyone who meets prerequisites for maintenance therapy should be considered candidates for treatment.
How to Best Use New Proteasome Inhibitors and IMiDs in Myeloma
Sundar Jagannath, MD
Pivotal Trial of Immunomodulatory Agent Pomalidomide: MM-002
Aspirin (80–100 mg) or equivalent mandated for all patients.aPatients aged > 75 yrs had starting DEX dose of 20 mg/week.
Rand
omiz
ation
Progressive disease
Progressive disease
Progressive disease
• Primary endpoint: PFS• Secondary endpoints: ORR, DOR, OS, and safety
POM (4 mg days 1–21 of 28-day cycles)
Option to add LoDEXa
(40 mg/week)
POM (4 mg days 1–21 of 28-day cycles) +
LoDEXa (40 mg/week)
Discontinue and follow-
up for survival and subsequent treatment
• Median number of cycles received = 5 (range, 1-28)
• Disease control rate = 81% overall
Jagannath S, et al. ASH 2012. Abstract 450.
MM-002: Response Rates
ResponsePOM + LoDEX
(n=113)POM
(n=108)
ORR (%) 34 15
CR (%) 3 1
PR (%) 31 14
MR (%) 12 16
SD (%) 37 48
PD (%) 6 10
Median time to ORR, months 1.9 3.7
Median duration of response, months 8.3 8.8
MM-002: PFS, OS, and Safety
Age ≤ 65 years Age > 65 years
Grade 3/4 AEs ≥ 20%POM + LoDEX
(n=61)POM
(n=68)POM + LoDEX
(n=51)POM
(n=39)
Hematologic Neutropenia Anemia Thrombocytopenia
462618
402424
351820
592621
Nonhematologic Pneumonia Dyspnea
167
107
2920
218
• Other AEs of clinical relevance in POM +/- LoDEX:– Febrile neutropenia: 3%– Peripheral neuropathy (grade1/2): 13% (none > grade 2)– DVT: 2%
Efficacy Parameter POM + LoDEX POM HR P Value
Median PFS, months 4.6 2.6 0.67 .002
Median OS, months 16.5 13.6 0.92 .609
Jagannath S, et al. ASH 2012. Abstract 450.
Pomalidomide + Low-Dose DEX vs High-Dose DEX: MM-003
(n = 302)
POM: 4 mg/day D1-21 +
LoDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs) D1, 8, 15, 22
RAN
DO
MIZ
ATIO
N 2
:1
Follow-up for OS and SPM until
5 years post enrollment
(n = 153)
HiDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs)
D1-4, 9-12, 17-20
28-day cycles
PD* orintolerable AE
PD* Companion trialMM-003C
POM 21/28 days
Stratification• Age (≤ 75 vs > 75 yrs)• Number of prior Tx ( 2 vs > 2)• Disease population
Thromboprophylaxis indicated for those receiving POM or with DVT history
*Progression of disease independently adjudicated in real-time
Dimopoulos MA, et al. ASH 2012. Abstract LBA-6.
MM-003: PFS and OS
Arm POM + LoDEXn = 302
HiDEX n=153 HR P Value
Median PFS, months ITT population Refractory to bortezomib Refractory to lenalidomide Refractory to both
3.63.63.73.2
1.81.81.81.7
0.450.470.380.48
< .001< .001< .001< .001
Median OS, months ITT population Refractory to bortezomib Refractory to lenalidomide Refractory to both
NRNRNRNR
7.88.18.67.4
0.530.560.390.56
< .001.037.003.003
Pivotal Trial of Proteasome Inhibitor Carfilzomib: 003-A1
Carfilzomib20 mg/m2 days 1, 2, 8, 9, 15, 16
every 28 daysN = 46
MM: Progressive disease> 2 prior therapy lines
including bortezomib, thalidomide or lenalidomide,
an alkylating agent, and anthracycline alone or in
combination
CarfilzomibDose escalation to 27 mg/m2
after cycle 1 up to 12 cyclesN = 266
003-A0 003-A1
Primary Endpoint: ORR
Secondary Endpoints: clinical benefit rate (≥ minimal response), DOR, PFS, OS, and safety
Siegel DS, et al. Blood. 2012;120:2817-25.
Single-Agent Carfilzomib Pivotal Trial: Efficacy
ResponseCarfilzomib
(N=257)
ORR 24%
Clinical benefit rate 34%
Duration of response 8.3 months
Median PFS 3.7 months
Median OS 15.6 months
Single-Agent Carfilzomib Pivotal Trial: Safety
Adverse EventGrade 3/4 AEs
N =266
Hematologic Anemia Thrombocytopenia Lymphopenia Neutropenia
24%29%20%11%
Nonhematologic Fatigue Dyspnea Upper respiratory tract infection Headache
7.5%3.4%4.5%1.9%
Other Febrile neutropenia Peripheral neuropathy
0.8%1.1%
Siegel DS, et al. Blood. 2012;120:2817-25.
• Other AEs (any grade) of clinical relevance:– Dyspnea in 34%; 17% due to carfilzomib– CHF in 3.8%; myocardial infarction or cardiac arrest in 2.3%
Multiple Myeloma Takeaways• Genomic analysis is an important area of research that is expanding
rapidly, but to date it has had limited use in the myeloma clinic, restricted to its ability to predict survival on the basis of gene expression profiling.
• Active monitoring remains optimal approach for smoldering myeloma, although this may change in the future with further examination of lenalidomide/dexamethasone treatment.
• Elderly patients with newly diagnosed multiple myeloma can be treated with a number of distinct regimens, depending on their comorbidities and performance status. These include lenalidomide/low-dose dexamethasone and VMP (bortezomib, melphalan, and prednisone).
• Maintenance therapy with a convenient, low-toxicity regimen is suggested for all myeloma patients meeting the following criteria: achievement of remission and no ongoing toxicity.
• Proteasome inhibitor carfilzomib and IMiD pomalidomide recently granted accelerated approval by FDA for treatment of relapsed/refractory myeloma, on the basis of promising response rates, and PFS and OS results in this heavily pretreated population.
LYMPHOMA
Initial Management of Peripheral T-Cell Lymphoma: If CHOP Is No Good,
What Is?
Steven M. Horwitz, MD
Peripheral T-Cell Lymphoma Summary• With PTCL, first-line CHOP produces ORR of 60-80+%, CR of 30-60+%,
and durable remissions <20-30%. For most patients, CHOP is inadequate.
• Adding therapy to a CHOP backbone is feasible but: (1) benefit not equivalent in all subtypes,1 and (2) toxicity soon outweighs benefit because regimen operating near MTD.2,3
• ASCT has shown promise in some upfront trials with PTCL.4,5
• Potential approaches to explore:
‒ CHOP + etoposide
‒ CHOP + novel agent (ie, brentuximab data very encouraging)
‒ CHOP → maintenance therapy
‒ ASCT
‒ Entirely new regimen
• Current standard of care should be clinical trial, whenever possible.1Kim SJ. Eur J Cancer. 2012;48:3223-31.
2Kim JG, et al. Cancer Chemother Pharmacol. 2007;60:129-34.3Gallamini A, et al. Blood. 2007;110:2316-23.
4Reimer P, et al. J Clin Oncol. 2009;27:106-13.5d’Amore F, et al. J Clin Oncol. 2012;30:3093-9.
Management of Cutaneous T-Cell Lymphoma
Lauren Pinter-Brown, MD, FACP
Treatment and Supportive Care of Cutaneous T-Cell Lymphoma
• Treatment of mycosis fungoides and Sezary’s syndrome generally involves skin-directed therapy for early-stage (IA-IIA) and systemic therapy for later stages (≥IIB) or when skin-directed therapy fails.
‒ Skin-directed therapies: topical agents (corticosteroids, imiquimod, chemotherapy, retinoids), phototherapy, radiation therapy
‒ Systemic therapies: extracorporeal photochemotherapy, retinoids, interferon-alpha or gamma, alemtuzumab, denileukin diftitox (not currently available), HDAC inhibitors, chemotherapy
• Treatment considerations: stage, route (oral vs topical vs systemic), rapidity of response, availability (geographically or due to cost), and comorbidities
• Supportive care:
‒ Pruritus: distinguish generalized from localized; treat with moisturizers, emollients, and barrier protection, as well as topical steroids, camphor/menthol, others
‒ Infection: crucial to avoid central lines and maintain skin barrier. Consider bleach baths.
Treatment of CD30+ Lymphoproliferative Disorders
• Lymphomatoid papulosis:
‒ Treatment options: watch and wait (most cases), methotrexate, phototherapy, interferon
‒ Rapid relapse off treatment, so maintenance therapy necessary
‒ 10%-20% of these cases associated with Hodgkin lymphoma, mycosis fungoides, or ALCL, so follow-up required
• Primary cutaneous ALCL:
‒ Treatment options: skin-directed therapy, surgical resection, XRT, chemotherapy only with extracutaneous involvement (CHOP not recommended), retinoids, interferon, thalidomide, steroids, excimer laser.
‒ 90% 5-year overall survival
‒ Spontaneous remission possible
How I Manage Early-Stage Diffuse Large B-Cell Lymphoma
Daniel O. Persky, MD
Current Treatment Paradigm for Early-Stage DLBCL
• Early-stage DLBCL is curable malignancy, with >50% cure rate and a 70%-90% 5-year OS.1
‒ Differences in outcomes arise from variations in radiation therapy quality and patient selection
‒ Early-stage disease has pattern of late relapses
• Addition of rituximab to chemotherapy modestly improved PFS outcomes in early-stage disease, but has not improved OS.2,3
• Another option for early-stage DLBCL is R-CHOP x 3-4 (short course) → IFRT, which showed favorable results in a retrospective comparison to standard R-CHOP.4
1Miller TP. J Clin Oncol. 2004;22:2982-4.2Ketterer N, et al. Ann Oncol. 2013;24:1032-7.
3Pfreundschuh M, et al. Lancet Oncol. 2011;12:1013-22. 4Terada Y, et al. ASH 2012. Abstract 1628.
Regimen 3-yr PFS 3-yr OS
R-CHOP x 3-4 → IFRT 90% 96%
R-CHOP x 6-8 74% 86%
Novel Approaches for Early-Stage DLBCL• Radioimmunotherapy consolidation:
‒ SWOG 0313:1 CHOP x 3 + IFRT → ibritumomab: 4-yr est. PFS = 84%
‒ E3402:2 R-CHOP → ibritumomab → IFRT (if PET+): 4-yr PFS = 88%, OS = 98%
• PET risk-adapted therapy – mid-treatment PET prognostically significant in DLBCL3,4
‒ BCCA experience:5 R-CHOP x 3 → PET. If PET+, go on to IFRT. If PET‒, receive R-CHOP x 1
‒ Ongoing phase II trial, S1001, will test this PET risk-adapted approach in early-stage DLBCL, with PET+ population receiving R-CHOP x 3 → IFRT → ibritumomab 1Miller TP, et al. ASH 2008. Abstract 3598.
2Witzig T, et al. ASH 2012. Abstract 2687.3Haioun C, et al. Blood. 2005;106:1376-81.
4Spaepen K, et al. Ann Oncol. 2002;13:1356-63.5Sehn et al, Lugano 2008. Abstract 052; Sehn LH, et al. Lugano 2011. Abstract 028.
ResultPET –n=103
PET +n=30 P Value
3-yr TTP 92% 60% .09
3-yr OS 96% 83% .1
Biology of Early-Stage DLBCL
• DLBCL molecularly heterogeneous with different 5-year survivals:1
‒ Primary mediastinal: 64%
‒ Germinal center B-cell-like (GCB): 59%
‒ Activated B-cell-like (ABC): 30%
• GCB appears more prevalent in early-stage disease2 and with superior survival3 after R-CHOP compared with ABC
• Bottom line: Biology of early-stage DLBCL needs further exploration.
1Rosenwald A, et al. J Exp Med. 2003;198:851-62.2Lenz G, et al. N Engl J Med. 2008;359:2313-23.3Lenz G, et al. N Engl J Med. 2010;362:1417-29.
Advanced-Stage DLBCL
Craig Moskowitz, MD
R-CHOP Regimens for Advanced-Stage DLBCL
• R-CHOP21 vs R-CHOP14 phase III studies
‒ GELA:1 3-yr EFS similar (60% vs 56%; HR = 1.04; P = .76)
‒ UK:2 2-yr OS similar (81% vs 83%; HR = 0.95; P = .70)
• Current strategy: R-CHOP21 x 6-8 cycles → 2nd-line treatment if < CR3
‒ MSKCC:4 R-CHOP → ibritumomab
For those receiving RIT, 2-yr PFS = 79%, 2-yr OS = 84%
‒ Led to current US phase III trial:
R-CHOP → ibritumomab consolidation in elderly DLBCL
1Delarue R, et al. Lancet Oncol. 2013;14:525-33.2Cunningham D, et al. ASCO 2011. Abstract 8000.
3NCCN NHL guidelines. 2013.4Hamlin PA, et al. ASH 2010. Abstract 1793.
Risk-Adapted Therapy for Advanced-Stage DLBCL
• MSKCC 01-142:
• MSKCC 08-026:
1Moskowitz et al. Lancet Oncol. 2010;28:1896-903.
Results showed no difference in PFS among:1 • PET-negative• PET-positive/biopsy-negative• PET-positive/biopsy-positive
ICE x 2
RICE x 1
HDT/ASCT
ICE x 3
followed by
observation
Bx +
Bx -
PET -
Repeat Bx
+
R-C1000HOuncappedP-14 x 4
Augmented
RICE x 2
followed by
HDT/ASCT
ICE x 3
followed by
observation
Bx +
Bx -
PET -
Repeat Bx
+
R-R-C1000HOuncappedP-14 x 3
C1000HOuncappedP-21 x 1
Augmented
RICE x 2
followed by
observation
≥80% Ki-67 <80%
Results showed 4-yr OS > 80% and 4-yr PFS > 70%
Dose-Adjusted EPOCH-R for Advanced-Stage DLBCL
• CALGB phase II study1
‒ Excellent 5-yr results in overall population OS = 84% PFS = 81% EFS = 75%
‒ However, high-risk disease associated with worse outcomes than other subgroups IPI high-risk group, OS = 43% ABC OS inferior to GCB (P = .04) Ki67 < 60% OS inferior to ≥ 60% (P = .05)
• Ongoing phase III CALGB 50303: dose-adjusted EPOCH-R vs R-CHOP21
1Wilson WH, et al. Haematologica. 2012;97:758-65.
Relapsed DLBCL in the Rituximab Era
Anas Younes, MD
Salvage Phase III Trials in Relapsed DLBCL:
R-ICE + BEAM/ASCT Remains Standard• CORAL:1 Randomized patients who relapsed after CHOP ±R to R-ICE or R-
DHAP. Those achieving CR or PR then received BEAM ASCT.
‒ No difference between salvage therapies in OS (P = .49) or PFS (P = .44).
‒ Among those who relapsed within 12 months after diagnosis, prior rituximab associated with poor EFS (P = .001).
‒ Among those who relapsed more than 12 months after diagnosis, prior rituximab status had no impact on EFS (P = .11).
• Bio-CORAL:2 subset of patients from CORAL trial with histologic material available. Tumors classified as GCB or ABC.
‒ Among those receiving R-ICE, histologic type did not impact PFS (P = .82) or OS (P = .96).
‒ Among those receiving R-DHAP, patients with GCB tumors had significantly better PFS (P = .005) and potentially better OS (P = .06) compared with patients with ABC tumors.
1Gisselbrecht, et al. J Clin Oncol. 2010;28:4184-90.2Thieblemont et al. J Clin Oncol. 2011;29:4079-87.
Relapsed DLBCL Summary• As frontline therapy is changing based on tumor oncogenic properties, the
same should be done for salvage therapy and conditioning regimens.
‒ To achieve higher ORRs with salvage therapy and better ASCT outcome, patients should be pre-selected based on predictive biomarkers.
‒ Randomized biomarker-driven salvage dynamic combination regimens will need to be examined using innovative trial designs, such as shown below.
Lymphoma
PI3K/AKT/mTOR JAK/STAT BCR Biomarker -
P-PRAS40 + pSTAT3 + P-CD19 +
RCHOPRCHOP +
Drug ARCHOP
RCHOP +Drug C
RCHOPRCHOP +
Drug DRCHOP
New Directions in Follicular Lymphoma
Bruce D. Cheson, MD
Antibodies in Follicular Lymphoma• GA101: Anti-CD20 antibody
• Antibody-drug conjugates‒ DCDT2980S: anti-CD22 linked to MMAE. Showed CR in 2 of 3 patients with
DLBCL and 1 PR in patient with FL in phase I testing3
‒ DCDT4501A: anti-CD79b linked to MMAE. Showed responses in 5 of 8 patients at first assessment in phase I testing4
‒ Ongoing randomized crossover trial:
Trial Treatment n (FL) ORR
GAUGIN1 (BO20999)
GA101 low-dose 14 36%
GA101 high-dose 20 60%
GAUSS2GA101 74 43%
rituximab 75 39%
1Salles GA, et al. ASH 2011. Abstract 268.2Sehn LH, et al. ASH 2011. Abstract 269.
3Advani R, et al. ASH 2012. Abstract 59.4Palanca-Wessels MC, et al. ASH 2012. Abstract 56.
Arm A: R (d1) +DCDT2980S (d2)
Q 21 days
Arm B: R (d1) +DCDT4501A (d2)
Q 21 days
Response
Response
PD
Small-Molecule Inhibitorsin Follicular Lymphoma
• Ibrutinib (PCI-32765): BTK inhibitor produced 54% ORR in overall B-cell malignancy population and 38% in FL.1
‒ Duration of response impressive, particularly in FL, where multiple patients continue to receive ibrutinib after ≥2 years
• Idelalisib (GS-1101): PI3K delta inhibitor
• IPI-145: PI3K delta and gamma inhibitor‒ In phase I testing, IPI-145 showed early signs of clinical activity across multiple
heme malignancies.3
Phase I Treatment2
Decreased Adenopathy ORR 1-yr PFS
Idelalisib + rituximab 97% 77% 82%
Idelalisib + bendamustine 97% 85% 90%
Idelalisib + bendamustine/rituximab 100% 77% 78%
1Advani RH, et al. J Clin Oncol. 2013;31:88-94.2Fowler NH, et al. ASH 2012. Abstract 3645.
3Kahl B, et al. Lugano 2013. Abstract 066.
Apoptosis-Inducing Agents and IMiDs in Follicular Lymphoma
• ABT-199:1 apoptosis-inducing agent
• Lenalidomide:2 IMiD tested in combination with rituximab for untreated indolent lymphoma in phase II study:
• Results led to ongoing RELEVANCE phase III trial:
R2 = rituximab + lenalidomide
Population N ORR SDGr 3/4 Treatment-Related
AEs in >2 Patients
Overall (R/R NHL) 23 48% 30% 10% anemia
FL 8 12% 88% NR
1Davids MS, et al. ASH 2012. Abstract 304.2Fowler NH, et al. ASH 2012. Abstract 901.
Population N ORR SD 2-yr PFS
Overall (untreated indolent NHL) 103 90% 8% 83%
FL 46 98% 2% 89%
1st lineFL
N=1000
R2
R + chemo
R2 maintenance
Rituximab maintenance
R
Management of Hodgkin Lymphoma in the Elderly
Paul A. Hamlin, MD
Hodgkin Lymphoma: Differences in the Elderly Subset
• Approximately 20% of all HL patients are > 60 years old, but few are enrolled in clinical trials.
• HL biological factors in the older patient:
‒ Advanced stage1
‒ More aggressive histology1
‒ B symptoms1
‒ EBV positivity associated with worse disease-specific survival and OS2
• Bleomycin produces high incidence of toxicity in elderly.3
• Elderly outcomes:
‒ Elderly patients have worse outcomes in clinical trials than younger patients.4
‒ A study in Scotland of 674 patients with HL who were ≥ 60 years old reported a 5-year survival of only 35%.5
1Word, et al. ASH 2011. Abstract 3648.2Jarrett, et al. Blood. 2005;106:2444-51.
3Evens AM. ASCO Post. 2012;3.4Proctor SJ, et. al. Crit Rev Oncol Hematol. 2009;71:222-32.
5Proctor SJ, et al. Eur J Haematol. 2005;(suppl 66):63-7.
Reduced-Intensity Therapy for Hodgkin Lymphoma
• Reduced-intensity regimens:
‒ CVP/CEB
‒ VBM
‒ VEPEMB
‒ ChIVPP
• Less-toxic regimens produce more relapses.
‒ CVP/CEB produces 73% remission rate and is well tolerated (4% toxic death), but relapses are high (5-yr RFS 47%)1
• Phase II SHIELD study used VEPEMB2
1Levis A, et al. Haematologica 1996;81:450-6.2Proctor SJ, et al. Blood. 2012;119:6005-15.
Population Receiving VEPEMB N CR 3-yr OS 3-yr PFS
Patients with early-stage disease 31 74% 81% 74%
Patients with advanced-stage disease 72 61% 66% 58%
Anthracycline-Containing Therapy in Hodgkin Lymphoma
• Anthracycline-containing therapy:
‒ ChIVPP/ABV
‒ COPP/ABVD
‒ ABVD
‒ Stanford V
‒ BEACOPP
• GHSD10 and 11: ABVD1
‒ In patients age ≥ 60, ABVD associated with 14% dose reductions and delays, 68% grade 3/4 toxicity, and 5% treatment-related mortality.
• NLSG: ChIVPP vs ChIVPP/ABV2
‒ Retrospective analysis
‒ In patients age ≥ 60, those receiving ChIVPP/ABV had better 5-yr OS than those receiving ChIVPP (67% vs 30%; P = .0086).
‒ Both OS (39% vs 87%) and EFS (31% vs 75%) worse in patients age ≥ 60 compared with patients age < 60.
1Boll B, et al. J Clin Oncol. 2013;31:1522-9.2Weekes CD, et al. J Clin Oncol. 2002;20:1087-93.
1Evens AM, et al. Br J Haematol. 2013;161:76-86.
2Ballova V, et al. Ann Oncol. 2005;16:124-31.
Anthracycline-Containing Therapy in Hodgkin Lymphoma
• ABVD vs Stanford V1
‒ Analysis of patients age ≥ 60 treated on randomized E2496 trial (n=44)
‒ Among older patients, no survival difference between ABVD and Stanford V
‒ Compared with younger patients, older patients had worse treatment-related mortality (9% vs 0.3%), 5-yr OS (58% vs 90%), and 5-yr FFS (48% vs 74%).
• GHSD HD9elderly: COPP/ABVD vs BEACOPP2
‒ Analysis of patients age 66-75 years from randomized HD9 clinical trial
‒ BEACOPP associated with lower relapse rate (12% vs 23%), but at cost of increased toxicity
Treatment N CR 5-yr OS 5-yr FFTF Death due to acute toxicity
COPP-ABVD 26 77% 50% 46% 8%
BEACOPP 42 76% 50% 46% 21%
Relapsed and Refractory HL: Will We Be Able to Avoid Transplant?
Craig Moskowitz, MD
Transplantation for Relapsed/Refractory Hodgkin
Lymphoma• Current status of transplantation for relapsed/refractory HL:
‒ Toxicity and cost markedly decreased, but relapse rate remains relatively constant
‒ Standard conditioning regimens remain the same (CBV or BEAM)
‒ PFS = 30%-50%
‒ Adding more chemotherapy agents or escalating the dose has had minimal value
‒ Adverse prognostic factors in patients with relapsed/refractory disease (MSKCC model):1
B symptoms (night sweats, weight loss, fever without infection)
Extranodal disease
Complete remission duration < 1 year
1Moskowitz CH, et al. Blood. 2001;97:616-23.
FDG-PET to Identify Patients Needing Additional Salvage Therapy
• Normalization of PET prior to transplant is predictive of survival1 and identifies patients with excellent outcomes
• MSKCC Protocol 04-047 for relapsed/refractory HL:
1Moskowitz AJ, et al. Blood. 2010;116:4394-7.2Moskowitz CH et al. Blood. 2012;119:1665-70.
Results showed patients transplanted after standard or GVD salvage chemotherapy had EFS > 80%, compared with 29% EFS for patients with PET positivity.2
Restaging: FDG-PET, CT CAP
PET negative
Arm A = 0 or 1 risk factorsStandard ICE x 1
Augmented ICE x 1PBPC collection
Repeat biopsy, determine risk factorsStaging evaluation: FDG PET, diagnostic CT CAP, BM Bx
Induction:Nine 28-day cycles
Arm B = 2 risk factorsAugmented ICE x 2
PBPC collection
PET positive
Radiotherapy, if applicableHDT/ASCT
POD on ICE
GVD x 4
Restaging
CR, PR, MRPOD
off study
FDG-PET to De-escalate Salvage Therapy
in Hodgkin Lymphoma• Pre-transplant FDG-PET highly predictive of post-transplant outcome, so
perhaps PET can be used to identify patients appropriate for de-escalated salvage therapy.
• Brentuximab vedotin (SGN-35):
‒ Antibody directed against CD30 (antigen highly expressed on HL surface) conjugated to MMAE, an anti-tubulin agent.
‒ Well tolerated and highly active in HL following transplant failure
ORR = 75% and CR = 34% in phase II study of q3w dosing in relapsed/refractory HL1
Also being studied with qw dosing (3 wk on, 1wk off)
1Chen RW, et al. ASCO 2011. Abstract 8031.
Current/Proposed Brentuximab Clinical Trials in Relapsed/Refractory HL
MSKCC 11-142 ongoing trialFirst treatment following upfront therapy
Proposed international trial adding RTNodal-only relapse, RT-naïve patients
Further treatment
according to
treating physician
HDT/ASCTPET -
PET -
Augmented ICE x 2
+
Weekly SGN-35 x 2
+
Further treatment
according to
treating physician
HDT/ASCTPET -
PET -
Platinum-based salvage x 2
+
Weekly SGN-35 x 2
+
RT alone
randomize
New Directions in Hematologic Malignancies
Jonathan W. Freidberg, MD (Aurora kinase inhibition)Jennifer R. Brown, MD, PhD (Kinase inhibitors in lymphoma)
Anas Younes, MD (JAK inhibition in lymphoma)Andre Goy, MD (IMiDs in lymphoma)
Aurora Kinase Inhibition With Alisertib• Aurora kinase
‒ Key to the cell cycle, regulating mitotic entry/progression, centrosome maturation/separation, G2/M transition, chromosome alignment, and cytokinesis
‒ Present in aggressive T and B cell NHL
• Alisertib is an Aurora A kinase small-molecule inhibitor.
• Alisertib clinical development in T-cell lymphoma:
‒ Showed 57% ORR (4/7) in T-cell lymphomas in phase II NHL testing1
‒ Ongoing SWOG 1108, a phase II study in relapsed/refractory PTCL
‒ Ongoing phase III study in PTCL: alisertib vs investigator’s choice
• Alisertib clinical development in B-cell lymphoma:
‒ Because of preclinical synergy with vincristine, a phase I/II study is ongoing, testing alisertib, vincristine, and rituximab in patients with relapsed/refractory aggressive B-cell lymphomas.
1Friedberg J, et al. ASH 2011. Abstract 95.
Kinase Inhibitors in Lymphoma• Ibrutinib
‒ Bruton’s tyrosine kinase (BTK) small-molecule irreversible inhibitor
‒ Efficacy in FL: 55% ORR and 12.3 months DOR1
‒ Efficacy in ABC DLBCL: 41% ORR (compared with 5% ORR for GCB)2
‒ Efficacy in phase II relapsed or refractory MCL: 66.1% ORR3
• Idelalisib (GS-1101, CAL-101)
‒ PI3Kδ small-molecule inhibitor
‒ Efficacy in MCL and indolent lymphoma: 62% ORR for each4
‒ Efficacy in MCL in combination with everolimus, bortezomib, or bendamustine/rituximab: 46% ORR5
1Fowler NH, et al. ASH 2012. Abstract 156.2Wilson WH, et al. ASH 2012. Abstract 686.
3Wang M, et al. ASH 2012. Abstract 904.4Kahl B, et al. ASH 2010. Abstract 1777.
5Wagner-Johnston N, et al. ASCO 2013. Abstract 8501.
JAK and STAT Inhibitors• JAK/STAT signaling
‒ Janus kinase 2 (JAK2) and Signal Transducers and Activators of Transcription (STAT) pathways important to pathogenesis of hematologic malignancies
‒ JAK2, STAT3, and STAT6 frequently overexpressed in HL and NHL
‒ JAK2 inhibition in vitro associated with reduced proliferation in numerous lymphoma cell lines
• SB1518 is a JAK2 small-molecule inhibitor.
‒ Phase I study of daily SB1518 in 35 patients with relapsed lymphoma provided proof of principle of therapeutic value of inhibiting the JAK/STAT pathway in lymphoma.1
• Ongoing phase II study of ruxolitinib (JAK inhibitor already approved for the treatment of myelofibrosis) will provide additional information on potential value of targeting these pathways in DLBCL and PTCL.
1Younes A, et al. Lugano 2011. Abstract 157.
IMiDs in Lymphoma• Lenalidomide is an immunomodulatory agent with pleiotropic effects not
completely understood. Effects include increases in T-cell activation, NK-mediated killing, immune synapse formation, and APC function in B cells.
• Currently approved for use in multiple myeloma, MDS, and MCL and has activity across broad range of lymphomas
‒ Received approval in June 2013 for MCL based on MCL-001, a phase II study showing a 28% ORR and a median DOR of 16.6 months in heavily pretreated patients
‒ In 46 FL patients, lenalidomide + rituximab produced a 98% ORR1
‒ RELEVANCE: ongoing phase III trial of 1000 patients with untreated FL R-chemo → maint R (2 yrs) vs R + Len → maint R (2 yrs) + Len (1 yr)
‒ Len monotherapy activity in DLBCL appears to be concentrated within non-GCB population of relapsed/refractory patients (ORR, 53% vs 9%)2
‒ R2-CHOP (RCHOP + R and Len maint) produced a 100% ORR and 77% CR in DLBCL3
‒ Len-RICE shows promise (8/13 CR) as salvage therapy in DLBCL4
1Fowler NH, et al. ASH 2012. Abstract 901.2Hernandez-Ilizaliturri, et al. Cancer. 2011;117(22):5058-66.
3Reddy NM, et al. ASH 2012. Abstract 3668.4Feldman et al. ASH 2012. Abstract 3710.
Lymphoma Takeaways• Strategies being tested to replace CHOP for PTCL, including ASCT and
CHOP + novel agents. Treatment of CTCL continues to involve skin-directed therapy for early-stage disease and systemic therapy for later stages.
• Novel approaches for early-stage DLBCL include radioimmunotherapy consolidation and PET risk-adapted therapy. PET risk-adapted therapy also being studied for advanced-stage DLBCL, as is dose-adjusted EPOCH-R. Randomized biomarker-driven combination regimens need to be examined for relapsed DLBCL using innovative trial designs.
• New agents under investigation for follicular lymphoma include GA101, IPI-145, Ibrutinib, idelalisib, ABT-199, and ADCs DCDT2980S and DCDT4501A.
• Reduced-intensity therapies being examined in the elderly HL population. Strategies to improve ASCT in relapsed/refractory HL include pre-transplant PET imaging and inclusion of brentuximab vedotin into salvage therapy.
• Many promising agents under investigation for treatment of hematologic malignancies, including radioimmunoconjugates, antibody-drug conjugates, aurora kinase inhibitors, BTK inhibitors, PI3K inhibitors, JAK inhibitors, and IMiDs.
LEUKEMIA & MYELOPROLIFERATIVE NEOPLASMS
Debate: What Is the Optimal First-Line Treatment for CML in Chronic Phase?
Imatinib
Harry P. Erba, MD, PhD
Optimal First-Line CML Therapy:Cure Rate and OS Improvement
• When choosing an optimal therapy for CML, there are several considerations:
Can it provide a cure?
• Nearly 40% of patients from STIM trial who discontinued imatinib after sustained complete molecular response (CMR) of ≥ 2 years maintained CMR,1 but trial had short median follow-up of only 30 months, so premature to call those patients cured.
Can it improve overall survival (OS)?
• Randomized TKI trials likely never be able to show survival advantage because of crossover, inherent to all of these trials.
‒ IRIS trial: no OS improvement of imatinib vs IFN/Ara-C2 because of the frequency of crossover from IFN/Ara-C to imatinib
‒ ENESTnd: no difference in OS of imatinib vs nilotinib (300 mg) after 3 years (94% vs 95%; P = .44)3
‒ DASISION: no difference in OS of imatinib vs dasatinib (95% vs 95%; data still immature)4 1Mahon FX, et al. ASH 2011. Abstract 603.
2Druker BJ, et al. N Engl J Med. 2006;355:2408-17.3Kantarjian HM, et al. ASH 2012. Abstract 1676.
4Kantarjian HM, et al. Blood. 2012;119:1123-9.
Can it improve remission rate?
‒ Although major molecular response (MMR) at 24 months is inferior with imatinib, MMR offers no advantage over CCyR in defining long-term outcomes.3
‒ Shown above, no/modest differences in complete cytogenetic response (CCyR) present at 24 months between imatinib and 2nd-generation TKIs
Can it improve tolerability?‒ No clear tolerability advantage of 2nd-generation TKIs over imatinib. Safety
profiles different but overall AE incidences similar1,2
‒ Imatinib has no known late complications, unlike dasatinib and nilotinib
Optimal First-Line CML Therapy:Achievement of Remission and Tolerability
1Kantarjian HM, et al. Blood. 2012;119:1123-9. 2Saglio G, et al. ASH 2011. Abstract 452.
3Jabbour E, et al. J Clin Oncol. 2011;29:4260-5.4Kantarjian HM, et al. Lancet Oncol. 2011;12:841-51.
TrialExperimental
TKIMMR at 12 Months
vs ImatinibMMR at 24 Months
vs ImatinibP Value at 24 Months
DASISION1 dasatinib 46% vs 28% 64% vs 46% < .0001
ENESTnd2 nilotinib 300 mg 55% vs 27% 73% vs 53% < .0001
TrialExperimental
TKICCyR at 12 Months
vs ImatinibCCyR at 24 Months
vs ImatinibP Value at 24 Months
DASISION1 dasatinib 85% vs 73% 85% vs 82% NS
ENESTnd4 nilotinib 300 mg 80% vs 65% 87% vs 77% .0018
Can it prevent progression?
‒ Imatinib may permit more progressions to accelerated-phase/blast-phase (AP/BP) than dasatinib or nilotinib.
Does it have an acceptable cost?
‒ Imatinib will be generic in 2015.
‒ Guidelines suggest that if BCR-ABL/ABL ratio > 10% at 3 months, then switch therapy to 2nd-generation agent,3 showing that patients who have suboptimal response to imatinib can then switch to a 2nd-generation TKI.
Optimal First-Line CML Therapy:Prevention of Progression and Cost of
Therapy
1Kantarjian HM, et al. Blood. 2012;119:1123-9. 2Saglio G, et al. ASH 2011. Abstract 452.3NCCN CML guidelines. Version 4. 2013.
TrialExperimental
TKIProgression to AP/BP
vs Imatinib P Value
DASISION1 dasatinib 3.5% vs 5.8% NR
ENESTnd2 nilotinib 300 mg 3.2% vs 6.7% .0496
Imatinib as First-Line CML Therapy:Summary
• Cytogenetic and molecular response rates higher with 2nd-generation TKIs compared with imatinib for first-line treatment of adults with CML in chronic phase (CML-CP) at early time points, but advantage may disappear at later time points.
• Imatinib remains standard of care for the initial therapy of adults with CML-CP based on long-term follow-up data, OS, PFS, and tolerability.
Debate: What Is the Optimal First-Line Treatment for CML in Chronic Phase?
Second-Generation TKIs
Michael J. Mauro, MD
Prediction of Outcome Based on Early Response to Therapy
• Initially discovered that early reduction in BCR-ABL/ABL transcript levels correlates with later achievement of MMR:1
• More recently discovered that early reduction in BCR-ABL/ABL transcript levels correlates with survival:2
• NCCN guidelines now recommend switching TKIs if BCR-ABL transcript levels > 10% at 3 months.3
1Branford S, et al. Leukemia. 2003;17:2401-9.2Marin D, et al. J Clin Oncol. 2012;30:232-8.
3NCCN CML guidelines. Version 4. 2013.
Time Point Early Response MMR % P Value
3 months > 2-log reduction 100% < .001
0- to 2-log reduction 54%
6 months > 2-log reduction 86% < .001
0- to 2-log reduction 0%
Time Point Early BCR-ABL/ ABL Level 8-yr OS P Value
3 months < 9.84% 93% < .001
> 9.84% 57%
Is Early Response to Therapy Really Important?
• YES! Patients who don’t achieve CCyR after 12 months of treatment have greater risk of an event (loss of response, disease progression, or death) than those who don’t achieve CCyR after 3 months.1
• YES! Patients who don’t achieve MMR after 12 months of treatment have greater risk of progression to AP/BP than those who do achieve MMR.2
Months on Treatment Patients Not in CCyR (n)
Event (%)
3 109 23
6 47 34
12 26 38
1Quintas-Cardama A, et al. Blood. 2009;113:6315-21.2Hughes T, et al. Blood. 2010;116:3758-65.
MMR After 12 Months AP/BP (%) P Value
Yes 1.0004
No 10
Why Dasatinib and Nilotinib for First-Line Therapy?
• Both dasatinib and nilotinib produce more favorable early responses than imatinib.1-4
• Both dasatinib and nilotinib associated with less transformation to AP/BP than imatinib.5,6
• Currently no prognostic tool validated to determine who needs additional therapy.
Efficacy Measure at 12 Months Nilotinib Imatinib P Value Dasatinib Imatinib P Value
CCyR 80% 65% < .001 85% 73% .0002
MMR 55% 27% < .001 46% 28% < .0001
CMR 11% 1% < .001 ~5% ~5% NS
Trial Experimental TKITransformation to AP/BP (%)
vs Imatinib P Value
DASISION dasatinib 2.3% vs 5% NS
ENESTnd nilotinib 300 mg 0.7% vs 6.0% .0003
1Saglio G, et al. N Engl J Med. 2010;362:2251-9.2Kantarjian HM, et al. Blood. 2012;119:1123-9.
3Kantarjian HM, et al. Lancet Oncol. 2011;12:841-51.4Hochhaus A, et al. EHA 2011. Abstract 484.
5Kantarjian HM, et al. ASCO 2011. Abstract 6510.6Larson RA, et al. ASCO 2011. Abstract 6511.
Dasatinib and Nilotinib for First-Line Therapy:
Remaining Questions and Summary• Safety of long-term use of dasatinib and nilotinib needs further study.
‒ Imatinib has no known late effects of chronic use.1,2
‒ Dasatinib and nilotinib safety data less mature, but dasatinib associated with pulmonary arterial hypertension3 and nilotinib associated with peripheral arterial disease.4
• TKI discontinuation holds promise. Of 25 patients who discontinued dasatinib or nilotinib, 73% maintained MMR after 6 months.5
• Final thoughts:
‒ Perhaps rather than managing treatment failures, may be preferable to focus on prevention of treatment failure.
1Gambacorti-Passerini C, et al. JNCI. 2011;103:553-61.2Gambacorti-Passerini C, et al. ASH 2011. Abstract 3766.
3Montani D, et al. Circulation. 2012;125:2128-37.4Le Coutre P, et al. JNCI. 2011;103:1347-8.
5Rea D, et al. ASH 2011. Abstract 604.
Treatment for Elderly Chronic Lymphocytic Leukemia:
Is There a Standard?
Alessandra Ferrajoli, MD
Considerations in the Treatment of Elderly Patients With CLL
• Nearly 80% of patients with CLL are ≥ 65 years old at diagnosis.1
• Survival for patients aged 65-74 years with CLL is poorer than with age-matched controls.2
• Number of comorbidities increases with age in patients with CLL.3
• CIRS (Cumulative Illness Rating Scale), a measure of chronic illness burden, can be used to divide elderly patients into 3 categories:
– No go: use supportive therapy only
– Slow go: use reduced-intensity therapy
– Go go: use standard therapy
• Physically fit patients with no significant comorbidities and excellent renal function can receive standard FCR therapy, as shown by the CLL8 study in which addition of rituximab to FC produced a doubling of the CR rate (44% vs 22%; P < .0001).4
1SEER cancer statistics 1975-2007. 2Shanafelt T, et al. Cancer. 2010;116:4777-87.
3Cramer P, et al. ASH 2006. Abstract 2840.4Hallek M, et al. Lancet. 2010;376:1164-74.
First-Line Treatment of Elderly Patients
With Comorbidities• CLL208: R-chlorambucil– Phase II trial of 100 patients showed 80% ORR and 12% CR.1
– Median PFS 23.9 months; median OS not reached.1
• Rituximab + GM-CSF– Trial of patients ≥ age 70 years showed 68% ORR and 6% CR.2
– R + GM-CSF well tolerated, with 2% grade 3/4 neutropenia the only grade 3/4 AE.2
• CLL11: chlorambucil vs R-chlorambucil vs GA101-chlorambucil3
• Lenalidomide– Phase II study of 60 patients age ≥ 65 years produced 65% ORR and
15% CR. CR rate increased over time to 38%.4
– Median PFS = 52 months; median OS not reached.4
1Hillmen P, et al. ASH 2010. Abstract 697. 2Ferrajoli A, et al. Paper submitted.
3Goede V, et al. ASCO 2013. Abstract 7004.4Badoux XC, et al. Blood. 2011;118:3489-98.
Efficacy MeasureGA101 +
Chlor vs Chlor P ValueR + Chlor vs Chlor P Value
ORR, % 75.5 vs 30.2 NR 65.9 vs 30.0 NR
Median PFS, months 23.0 vs 10.9 < .0001 15.7 vs 10.9 < .0001
Targeted Therapy for CLL: Focusing on the B Cell Receptor Pathway
Jennifer R. Brown, MD, PhD
Therapies Targeting BCR Pathway: Idelalisib
• PI3Kδ inhibitor; BID dosing.
• Unique response pattern: causes simultaneous decline in lymphadenopathy (sustained over treatment) and increase in lymphocytosis (transient).
• Single-agent idelalisib produced 56% ORR, 81% nodal response, and median PFS of 17 months in relapsed/refractory CLL.1
• Phase Ib study of idelalisib in combination with rituximab and/or bendamustine in relapsed/refractory CLL:
– Patients from each group achieved nodal responses and ORR ≥ 78%.2
– Approximately 35% of patients relapsed in irst 12 months, after which a plateau through 28 months.2
• Ongoing phase III idelalisib trial in CLL:
– Idelalisib + BR vs placebo + BR in previously treated CLL
1Brown JR, et al. ASCO 2013. Abstract 7003. 2Barrientos JC, et al. ASCO 2013. Abstract 7017.
Therapies Targeting BCR Pathway: Ibrutinib• BTK inhibitor; QD dosing.
• Phase II monotherapy study (N=116) of 3 groups of patients: treatment-naïve ≥ age 65 years, relapsed/refractory, and high-risk relapsed/refractory1
– Most grade 3/4 AEs ≤ 5% incidence; neutropenia ~20% and infection ~40% in RR group. One death due to pneumonia in R/R group.
– Sustained improvements observed in hemoglobin and platelets for most relapsed patients with cytopenias.
– 68% ORR in treatment-naïve patients and 71% in R/R patients. Even patients with bulky disease or del17p had good responses.
– Lymphocytosis occurred in most patients but normalized by 12 months.
• Ongoing phase III ibrutinib trials in CLL:– BR ± ibrutinib in R/R CLL and ibrutinib vs chlorambucil in elderly CLL.
1Byrd JC, et al. ASH 2012. Abstract 189.
Efficacy at 26 Months TN
R/R
Overall del17p del11q No del IgVH Mut IGVH Unmut
Est. PFS 96% 75% 57% 73% 93% 83% 72%
Est. OS 96% 83% 70% 85% 93% 83% 82%
IMiDs and Combinations: How to Integrate Into Standard CLL
Therapy
Alessandra Ferrajoli, MD
Lenalidomide Monotherapy in CLL
• Properties of lenalidomide treatment
– Normalization of peripheral blood lymphocytes and T cells1,2
– Improvement in serum Igs2
• Single-agent lenalidomide as salvage therapy:
• Lenalidomide monotherapy as frontline therapy for CLL (n = 25):5
– PR = 56%
– Tumor flare = 88%
– Grade 3/4 neutropenia = 72%1Ferrajoli A, et al. Blood. 2008;111:5291-7.
2Badoux XC, et al. Blood. 2011;118:3489-98. 3Chanan-Khan AA, et al. J Clin Oncol. 2006;24:5343-9.
4Wendtner CM, et al. Leuk Lymphoma. 2012;53:417-23.5Chen CI, et al. J Clin Oncol. 2011;29:1175-81.
ResponseRPCI3
n = 45MDACC1
n = 44CLL-014
n = 52
ORR 47% 32% 12%
CR 9% 7% 0%
SD 18% 25% 58%
Lenalidomide Combination Therapy in CLL• Lenalidomide + fludarabine + rituximab in untreated CLL
– Phase !/II study: ORR = 56%, but combination too toxic, with myelosuppression and idiosyncratic drug reaction as DLTs.1
– REVLIRIT: Combination followed by lenalidomide and rituximab maintenance therapy. Dosages more tolerable; ORR = 87%, CR = 49%, MRDneg = 29%.2
• Lenalidomide + rituximab in frontline CLL3
– Phase II study of 69 patients, divided by age (65 years) into 2 groups:
• Ongoing phase III lenalidomide trials in CLL:
– Lenalidomide vs chlorambucil as frontline therapy.– Lenalidomide as maintenance (1 after 1st-line and 1 after 2nd-line).
1Brown JR, et al. Leukemia. 2010;24:1972-5. 2Egle A, et al. ASH 2011. Abstract 292.
3James DF, et al. ASH 2011. Abstract 291.
Group N ORR CR
Age < 65 years
40 95% 20%
Age ≥ 65 years 29 78% 7%
Overall 69 88% 15%
Lenalidomide Combination Therapy in CLL• Lenalidomide + rituximab in relapsed CLL1
– Phase II study of 59 patients who received prior purine analog therapy
– Median 2 prior regimens; 93% prior FCR, PCR, CFAR, or OFAR
– No grade 3/4 tumor flare; combination well tolerated
Deletion status did not impact PFS outcomes. Fludarabine-refractory patients had inferior PFS compared with patients
not refractory to fludarabine (P = .019).
• Lenalidomide + ofatumumab in relapsed CLL2
– Phase II trial of 34 patients who received prior purine analog therapy (100% received FCR).
1Badoux XC, et al. J Clin Oncol. 2013;31:584-91.2Ferrajoli A, et al. ASH 2012. Abstract 720.
Treatment ORR CR Median PFS 2-yr OS
Lenalidomide + ofatumumab 68% 24% 16 months 73%
Treatment ORR CR Median TTF 3-yr OS
Lenalidomide + rituximab 66% 12% 17.4 months 71%
Management of Patients With MDS Refractory to Hypomethylating Agents
David Steensma, MD
Hypomethylating Agents for MDS: Response to Treatment
• Treatment with hypomethylating agents (HMAs; azacitidine and decitabine):
– Improves survival by 9 months in high-risk patients1
– Delays progression to AML by 4-6 months2
– Improves quality of life3
– Has low early treatment-related mortality4
• However, it also:
– Produces low CR rate5,6
– Produces hematologic responses in only 30%-60% of patients7,8
– Has variable duration of response9
– Is associated with poor survival – < 6 months – after HMA failure10
1Fenaux P, et al. Lancet Oncol. 2009;10:223-32. 2Kantarjian H, et al. Cancer. 2006;106:1794-803.
3Kornblith AB, et al. J Clin Oncol. 2002;20:2441-52.4Santos FP, et al. Expert Rev Anticancer Ther. 2010;10:9-22.
5Itzykson R, et al. Blood. 2011;117:403-11.6Lubbert M, et al. J Clin Oncol. 2011;29:1987-96.
7Lee JH, et al. Haematologica. 2011;96:1441-7.8Lyons RM, et al. J Clin Oncol. 2009;27:1850-6.
9Steensma DP, et al. J Clin Oncol. 2009;27:3842-8.10Prebet T, et al. J Clin Oncol. 2013;29:3322-7.
Hypomethylating Agents for MDS: Outcomes After HMA Failure
• Common reasons for azacitidine failure:1
– Primary failure (progression or stable disease): 55%
– Secondary failure (initial response, then progression or stable disease): 36%
– Intolerance: 9%
• Outcomes after HMA failure:
1Prebet T, et al. J Clin Oncol. 2013;29:3322-7.2Mishra A, et al. ASH 2012. Abstract 2815.
3Jabbour E, et al. Cancer. 2010;116:3830-4.
HMA Median OS 1-yr OS
Azacitidine High risk1
Intermediate-1 risk2
Low risk2
5.6 months15 months46 months
29%NRNR
Decitabine Intermediate-1 to high risk3 4.3 months 28%
Hypomethylating Agents for MDS: Treatment Options After HMA Failure
• Rigosertib is a multikinase inhibitor that inhibits PI3K/Akt/ERK pathway that is in phase III testing for MDS patients who have progressed after or did not respond to an HMA.
1Prebet T, et al. J Clin Oncol. 2011;29:3322-7.
Treatment Option After HMA Failure Median OS, months1
Allogeneic transplant 19.5
Clinical trial with investigational agent 13.2
Intensive cytotoxic chemotherapy 8.9
Low-dose chemotherapy 7.3
Supportive care 4.1
Randomize 2:1
Rigosertib 1800 mg/24h as 72h continuous infusion days 1, 2, and 3 of a 2-week cycle
Best supportive care or low-dose cytarabine
Primary endpoint: OSSecondary endpoints: IWG 2006 response, AEs
BiTE Antibodies for Treatment of ALL
Daniel J. DeAngelo, MD, PhD
Bispecific T-Cell Engager (BiTE) Antibodies
• BiTE antibodies are bispecific antibodies that harness patient’s immune system by engaging T cells with tumor cells via variable region from a T-cell-specific antibody linked to variable region from a tumor-specific antibody.
• Blinatumomab is a BiTE antibody with variable regions of anti-CD3 antibody and anti-CD19 antibody linked together.
Blinatumomab for Treatment of ALL in Hematologic CR
• Blinatumomab phase II study of 21 patients with ALL in hematologic complete remission with either molecular failure or relapse after ≥ 3 cycles of chemotherapy.1
– Patients received single-agent blinatumomab 15 µg/m2/d continuous infusions 4 wk on/2 wk off.
– Responses were rapid, occurring within first cycle of treatment.– Median DFS not yet reached.
• E1910: phase III study of blinatumomab in patients with newly diagnosed BCR-ABL-negative ALL. Will be followed by consolidation and maintenance chemotherapy for both groups.
TreatmentMolecular
CRDFS After
Median 15 Months FU
Blinatumomab 80% 60%
1Topp MS, et al. J Clin Oncol. 2011;29:2493-8.
Blinatumomab for Treatment of Relapsed/Refractory ALL
• MT103-206 study design:
• Most common AEs were pyrexia, fatigue, headache, tremor, and leukopenia. Medically important AEs were cytokine release syndrome (n=3), reversible CNS AEs (n=6), and infection (n=1 death due to fungal encephalitis).
Scr
eeni
ng &
enr
ollm
ent
Saf
ety
eval
uatio
n
Cohort 2b5-15-30 µg/m2/d
Cohort 3extension phase
5-15 µg/m2/d
Dose-finding run-in phase
Primary endpoint: CR and CRh* rate within 2 cycles
Treatment CRMolecular Remission in Pts with CR/CRh* Median RFS Median OS
Blinatumomab 69% 88% 7.6 months 9.8 months
N=36
Cohort 2a5-15 µg/m2/d
Cohort 115 µg/m2/d
Cohort 2 was selected as dosage for extension phase because it had lowest incidence of treatment-emergent AEs.
*CRh = CR with only partial hematologic recovery
A Critical Evaluation of the Role of JAK2 Inhibitors for Myeloproliferative
Neoplasms
Ruben Mesa, MD
JAK2 Inhibitors and Myelofibrosis• Ruxolitinib – approved by FDA in 2011 for myelofibrosis
– COMFORT I and II – phase III trials of ruxolitinib vs placebo showed ruxolitinib produced dramatic reduction in splenomegaly (both P < .001), reduced overall and individual symptoms (P < .001), and improved OS (HR = 0.50 and 0.58; P ≤ .04).1,2
• SAR302503 – in phase III testing (JAKARTA)– Phase II data from 31 patients showed mean spleen volume reduction of
42% in patients receiving the highest dose (500 mg daily). Also evidence of symptom improvement in majority of patients.3
• Pacritinib – in phase III testing– In a phase II study of 34 patients, pacritinib reduced splenomegaly by
≥ 25% in one-third of patients.4
• CYT387 – in phase II testing– Phase II study of 166 patients demonstrated rapid and sustained
reductions in splenomegaly, marked improvement to complete resolution of constitutional symptoms by majority of patients, and increased transfusion independence.5
1Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 2Harrison C, et al. N Engl J Med. 2012;366:787-98.
3Talpaz M, et al. ASH 2012. Abstract 2837.4Komrokji RS, et al. ASH 2011. Abstract 282.5Pardanani A, et al. ASH 2012. Abstract 178.
Ruxolitinib for Polycythemia Vera and Essential Thrombocythemia
• Polycythemia vera (PV)– Hydroxyurea and IFN are frontline therapies. Ongoing trial will determine
standard of care for PV.
– Ruxolitinib examined in open-label phase II study of patients with PV refractory or intolerant to hydroxyurea.
• Nearly three-quarters of patients remained on-study and phlebotomy-free for ≥ 144 weeks.1
• Clinically meaningful improvements in pruritus, night sweats, and bone pain sustained through week 1441
• In phase III testing (RESPONSE and RELIEF)
• Essential thrombocythemia– Of 39 patients, 79% achieved ≥ 50% reduction in platelets during ruxolitinib
use.2
– Ruxolitinib in phase III testing (RELIEF)
1Verstovsek S, et al. ASH 2012. Abstract 804. 2Verstovsek S, et al. ASH 2010. Abstract 313.
Leukemia and MPN Takeaways• Ongoing debate regarding best TKI for frontline treatment of CML-CP: imatinib
or 2nd-generation agents dasatinib and nilotinib. Imatinib has excellent long-term safety, but 2nd-generation TKIs produce more early cytogenetic and molecular responses.
• A number of novel regimens being tested in elderly patients with CLL, including rituximab + GM-CSF, GA101 + chlorambucil, and lenalidomide.
• Ibrutinib and idelalisib have shown promising efficacy and safety in CLL and are currently in late-stage development for treatment of this disease. Lenalidomide, alone or in combination with other agents (primarily anti-CD20 antibodies), is currently under investigation for several CLL indications.
• Treatment options limited for MDS after failure of hypomethylating agents. Rigosertib is a targeted agent in phase III testing for this indication.
• Blinatumomab is a BiTE antibody that has demonstrated encouraging efficacy and safety for treatment of ALL and is undergoing phase III evaluation.
• JAK2 inhibitor ruxolitinib approved for treatment of myelofibrosis and under investigation in polycythemia vera and essential thrombocythemia. Several other JAK2 inhibitors in development for myelofibrosis.
