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2. Another study found that a combination of BV and bendamustine had a high overall response rate of 96% for relapsed/refractory HL, with a complete response rate of 83%. This compared favorably to historical data for these agents as single therapies.
3. A trial evaluated the use of positron emission tomography (PET)-driven therapy for early stage HL and found that patients who were PET-
Describes the emerging resistance of epithelial cancer of the ovary to current therapies and the role of PARP inhibitors in the management in view of the recent drug approvals.
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Describes the emerging resistance of epithelial cancer of the ovary to current therapies and the role of PARP inhibitors in the management in view of the recent drug approvals.
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Volker Diehl, M.D., Professor, University of Cologne, Germany Customization: The Treatment of Hodgkin's Disease
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This presentation covers the guidelines for follow up of patients with Hodgkin's lymphoma after they achieve complete remission and complete their therapy.
What is Lymphoma?
Malignant lymphoma is a term given to tumors of the lymphoid system and specifically of lymphocytes and their precursor cells
i.e.
Cancer of the lymphatic system.
Many lymphomas are known to be due to specific genetic mutations.
Presentación realizada por la Dra. Dolores Isla del
Servicio de Oncología Médica del Hospital Clínico Universitario Lozano Blesa de Zaragoza, en el marco de la I Jornada de actualización e innovación en Oncología que tuvo lugar en el CIBA en enero de 2015.
ASCO 2015 Melanoma Immunotherapy
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Large patient cohort prospective study with more than 500 patients and more than 5
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HIV Alert:Emerging Updates on Dual Therapy.2018hivlifeinfo
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Format: Microsoft PowerPoint (.ppt)
File size: 375 KB
Date posted: 1/5/2018
Model Attribute Check Company Auto PropertyCeline George
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The French Revolution, which began in 1789, was a period of radical social and political upheaval in France. It marked the decline of absolute monarchies, the rise of secular and democratic republics, and the eventual rise of Napoleon Bonaparte. This revolutionary period is crucial in understanding the transition from feudalism to modernity in Europe.
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The Roman Empire, a vast and enduring power, stands as one of history's most remarkable civilizations, leaving an indelible imprint on the world. It emerged from the Roman Republic, transitioning into an imperial powerhouse under the leadership of Augustus Caesar in 27 BCE. This transformation marked the beginning of an era defined by unprecedented territorial expansion, architectural marvels, and profound cultural influence.
The empire's roots lie in the city of Rome, founded, according to legend, by Romulus in 753 BCE. Over centuries, Rome evolved from a small settlement to a formidable republic, characterized by a complex political system with elected officials and checks on power. However, internal strife, class conflicts, and military ambitions paved the way for the end of the Republic. Julius Caesar’s dictatorship and subsequent assassination in 44 BCE created a power vacuum, leading to a civil war. Octavian, later Augustus, emerged victorious, heralding the Roman Empire’s birth.
Under Augustus, the empire experienced the Pax Romana, a 200-year period of relative peace and stability. Augustus reformed the military, established efficient administrative systems, and initiated grand construction projects. The empire's borders expanded, encompassing territories from Britain to Egypt and from Spain to the Euphrates. Roman legions, renowned for their discipline and engineering prowess, secured and maintained these vast territories, building roads, fortifications, and cities that facilitated control and integration.
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Culturally, the Romans were eclectic, absorbing and adapting elements from the civilizations they encountered, particularly the Greeks. Roman art, literature, and philosophy reflected this synthesis, creating a rich cultural tapestry. Latin, the Roman language, became the lingua franca of the Western world, influencing numerous modern languages.
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http://sandymillin.wordpress.com/iateflwebinar2024
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Knowledge and skills frameworks, generally called competency frameworks, for ELT teachers, trainers and managers have existed for a few years now. However, until I created one for my MA dissertation, there wasn’t one drawing together what we need to know and do to be able to effectively produce language learning materials.
This webinar will introduce you to my framework, highlighting the key competencies I identified from my research. It will also show how anybody involved in language teaching (any language, not just English!), teacher training, managing schools or developing language learning materials can benefit from using the framework.
"Protectable subject matters, Protection in biotechnology, Protection of othe...
Hodgkin's Lymphoma: Treatment Update
1. Management of Hodgkin Lymphoma:
An ASCO/ICML Update
F B Hagemeister, MD
Professor of Medicine
Department of Lymphoma and Myeloma
M D Anderson Cancer Center
Bangkok 28 August 2015
2. Update on Therapy for Hodgkin
Lymphoma: ASCO/ICML
1. Brentuximab Trials
• Single Agent Therapy
• Combination Programs
1. PET-Driven Therapy
• Stage I-II Disease
• Stage III-IV Disease
1. Novel Agents
• Anti-PD-1 for Relapse
• Gem/Bu/Mel for SCT
3. BV Consolidation After Auto SCT for
Primary Refractory HL
• 2 yr PFS and 3 Yr OS rates for this group are 40% and
50%, respectively, post autoAST.
• AETHERA: BV vs placebo for Rel/Ref HL after ASCT
Initial
Therapy
Relapse
Assess
RFs
Primary
Refractory
< 12 Mo
remission
Relapse > 12
Mo with EN DZ
Salvage
Therapy
PD
Off
Study
ASCT
BV
Placebo
Moskowitz et al. ICML-13, 2015, #120.
CR
PR
SD
Treatment Schema
Crossover to
BV at PD
4. BV after ASCT for Primary Refractory HL
Subgroup Feature No. Pts (%) HR Range
EN DZ Yes 53 (27) 0.37 0.18-0.78
No 143 (73) 0.61 0.37-0.98
B Symptoms Yes 56 (28) 0.36 0.19-0.72
No 140 (72) 0.63 0.38-1.04
# Prior TXs > 2 97 (49) 0.39 0.22-0.71
2 99 (51) 0.79 0.44-1.4
# of RFs > 1 196 (100) 0.55 0.37-0.83
> 2 175 (90) 0.47 0.31-0.72
> 3 110 (57) 0.4 0.24-0.66
Moskowitz et al. ICML-13, 2015, #120.
• Study of 196 Patients with Primary Refractory HL.
• PFS results favor BV in all groups.
• The lower the HR, the more significant the difference
5. Update on Therapy for Hodgkin
Lymphoma: ASCO/ICML
1. Brentuximab Trials
• Single Agent Therapy
• Combination Programs
1. PET-Driven Therapy
• Stage I-II Disease
• Stage III-IV Disease
1. Novel Agents
• Anti-PD-1 for Relapse
• Gem/Bu/Mel for SCT
6. Phase II BV Plus AVD for
34 Non-Bulky Stage I-II HL
• Treatment Schema
Abramson et al. ASCO 2014, Abst 8505.
BV x 2
1.2mg/k
g q 2 wk
PET CR,
PR, SD
Enroll
PD off
study
A-AVD
X 2
PET CR
PET PR
or SD
PD off
study
A-AVD X 2
A-AVD X 4
• Patients: Favorable in 68%, unfavorable in 32%.
• CR rates: After BV, 18 pt (53%). After 2 A-AVD, 33 pt (97%).
At end of therapy, CR=88%, and 6/8 Pos PETs were
false positive (? due to BV).
• Gr 3-4 AEs: FN in 29%, PN in 24%
• At med f/u of 14 mo, PFS=90% and OS= 97%.
• Randomized study needed to prove benefit of BV
7. Phase I/II Brentuximab Plus Bendamustine
for Relapsed/Refractory HL
• CR rates for Rel/Ref HL with standard agents range 19-60%
– Brentuximab vedotin alone: CR 34%
– Bendamustine alone: CR 33%
• Treatment Plan: 1.8 mg/m2 BV day 1, Benda 90 mg/m2 days 1,2.
– Cycles repeated q 3 wks
– Benda de-escalated if DLT (delay of > 2 wk) in > 3/10 pts.
• Tolerability: No DLT reached
• Infusion Reactions before adding Steroids and Antihistamines
LaCasce et al. ASH 2014 # 293; Kuruvilla et al. ICML-13, 2015, # 80.
Tming # Pts SAEs Gr 3 Stop Tx
Prior to giving S and A 36 6 8 6
After adding S and A 20 0 2 1
8. Phase I/II Brentuximab Plus Bendamustine
for Relapsed/Refractory HL
• For a total of 54 patients, 48 are evaluable
• Features:
• Comparisons of Therapy
• 20 pts went to SCT with good collections,1 relapsed
Disease Status Dur Prior Resp Patients (%)
Primary Refractory Not applicable 27 (50)
Relapsed < 1 Yr 10 (19)
Relapsed > 1 Yr 17 (31)
Studies ORR (%) CR (%) MED PFS
BV Alone 75 34 12 mo for CRs
BV + Benda 96 83 NR for ORRs
LaCasce et al. ASH 2014 # 293; Kuruvilla et al. ICML-13, 2015, # 80.
9. Update on Therapy for Hodgkin
Lymphoma: ASCO/ICML
1. Brentuximab Trials
• Single Agent Therapy
• Combination Programs
1. PET-Driven Therapy
• Stage I-II Disease
• Stage III-IV Disease
1. Novel Agents
• Anti-PD-1 for Relapse
• Gem/Bu/Mel for SCT
10. FDG-PET positive
16 Patients, prog=11
2-year PFS 0%
1.0
.08
.06
.04
.02
0.0
PercentProgression-Free
PET neg
61 Pts, 3 prog
2 yr PFS 96%
3210
PET after 2 cycles
P < .001
Years
1.0
.08
.06
.04
.02
0.0PercentProgression-Free
CR, PR
2 Pts, 0 prog
2 yr PFS 100%
3210
CT after 2 cycles
< PR
62 Pts, 11 prog
2 yr PFS 82%
P < .554
Years
PET vs CT for Stage I-IV HL: PFS by
Radiographs after 2 CT Cycles
Hutchings et al. Blood 107:52-59, 2006
PET ps
14 Pts, 11 prog
2 yr PFS 0%
11. Reasons for the “False Positive” PET
Intrinsic – hardware
– Improved detection
Criteria for positive
– Visual or SUV
– Reader variation
Benign variants
– Sarcoidosis
– Thyroiditis
Inflammation
– Infection
– Trauma
Iatrogenic causes
– Injections
– Post RT
– Post Surgery
Type/Location of lymphoma
– Marginal Zone/SLL/T-Cell
– Bowel, Marrow Disease
– Hyperplasia?
Other tumors
– Benign
• Warthin’s
• Thyroid adenomas
• Bowel adenomas
– Malignant (Any)
Therapy
– Use of Rituximab
– G-CSF
Timing of scan
– How many days after last
chemotherapy
12. Routine Imaging Strategies (RIS) for
Classical HL in First Remission
• Three centers: Retrospective comparison of Clinical (CS)
and RIS
• RIS by NCCN: Imaging Q 6 mo for 2-3 years
Chemotherapy: ABVD - 79%, Stanford V - 15%
Pingali et al, ASCO 2013 # 8505.
Group Mean #
scans
%
Deaths
%
Relapses
Scans per
Relapse
CS, n=77 1.14 4.6 6.6 17.6
RIS, n=164 4.25 5.3 4.6 122.3
• RIS conferred no OS advantage (p=0.47)
• CR rates with relapse therapies were also similar for
CS and RIS Suggests that routine imaging after
therapy is completely unnecessary.
13. IFRT vs None for After 3 ABVD for PET Neg
Stage I-IIA HL: The UK NCRI RAPID Trial
602 cases with newly diagnosed, stage IA/IIA HL
without bulky med mass after 3 cycles of ABVD
Therapy Choice according to the PET Result, n=571
PET Negative (75%) PET Positive
IF RT
(n=209)
No Further
Therapy (n=211)
4th ABVD cycle +
IF RT (n=145)
Radford et al. NEJM 372: 1598-1607, 2015.
14. IFRT vs None for PET Negative HL
After 3 ABVD: The RAPID Trial
Result IF RT
(n=209)
No RT
(n=211)
4xABVD + IF
RT (n=145)
Progressive DZ 8 20 12
3 YR PFS 94.5% 90.8% 86%
3 YR OS 97.1% 99.5% 94%
Radford et al. NEJM 372: 1598-1607, 2015
From randomization From registration
Median FU:
48.6 months
There is a 4% improvement by giving RT to those with
negative PET, considered “acceptable” for no RT.
16. PET Scan Results From the RAPID Trial:
Prognostic Value of the Positive PET
Radford et al. ICML-13, 2015, #82
• Positive PET after 3 ABVD defined as Deauville
score of 3-5
• 145 received a 4th
ABVD and IFRT
• 88% and 85% had risk criteria to define EORTC
and GHSG favorable HL (66% and 68%,
respectively).
• P values by MVA: PET 3-5: 0.001, EORTC: 0.48,
GHSG: 0.62
• By Hazard Ratios: PET 5 vs 4- 6.7, vs 3- 9.3, vs 2-
3.2, vs 1- 5.1.
17. 2 ABVD
2 ABVD
2 BEACOPPesc + RT 30
H10H10
FavFav P
E
T
2 ABVD
1 ABVD + RT 30PET
+
-
+
2 ABVD
4 ABVD
2 BEACOPPesc + RT 30
H10H10
UnfavUnfav P
E
T
2 ABVD
2 ABVD + RT 30PET
+
-
+
RR
RR
EORTC/GELA/IIL HD10 Study of ABVD for
Early-Staged HL
Using PET
Raemakers et al. JCO 32: 1-
8, 2014
18. Intergroup H10 Trial of PET Driven Therapy
for Stage I/II HL: An Interim Analysis
Favorable: Supradiaphragmatic disease, CS1-2 with 1-3 nodal
areas, MTR < .35, Age <50, ESR < 50 with B SX or < 30 with B SX
Unfavorable: Any of the above features
Raemakers et al. JCO 32: 1-8, 2014
Feature Therapy No. Pt Relapse 1 Yr PFS % P
Favorable 3 ABVD/RT 188 1 100
4 ABVD 193 9 94.9 0.017
Unfavorable 4 ABVD/RT 251 7 97.3
6 ABVD 268 16 94.7 0.026
Despite these good results, because of the inferior results
with only chemotherapy, the chemotherapy-only arms
were closed to patient entry.
19. The HD10 Trial: BEACOPP for PET
Positive HL After Two ABVD
• EORTC-defined Stage I-II HL
• PET positive considered Deauville Score 3-5
N=1950 Randomized
Unfavorable
N=1196
Favorable
N=754
ABVD
N=54,14%
BEACOPP
N=43,11%
ABVD
N=138,23%
BEACOPP
N=126, 21%
PET Positive
Raemakers et al. ICML 2015
5 Yr Result ABVD + RT (%) BEACOPP + RT (%) P value
PFS 77 91 0.002
OS 89 96 0.062
20. Update on Therapy for Hodgkin
Lymphoma: ASCO/ICML
1. Brentuximab Trials
• Single Agent Therapy
• Combination Programs
1. PET-Driven Therapy
• Stage I-II Disease
• Stage III-IV Disease
1. Novel Agents
• Anti-PD-1 for Relapse
• Gem/Bu/Mel for SCT
21. ABVD vs BEACOPP vs CEC for Advanced
HL: The Fondazione Italiana HD 2000 Trial
ABVD x 6 (N=103)
BEACOPPesc x 4,
BEACOPPstd x 2
(N=100)
CEC x 6
(alternating
COPP/EBV/CAD)
(N=102)
R
Merli et al. ASH 2014 # 499
RT
in
130
305 Pts
cHL
Stages
IIB, III, IV
22. 10 Yr Results ABVD BEACOPP CEC P
PFS (%) 69 74 74 0.64
OS 84 84 86 0.88
# MDS/AML 0 1 1 -
# NHL 0 1 1 -
# Solid
Tumors
1 4 2 -
2nd
Ca Risk 0.9 6.7 4.4 ** P = 0.027 for BEACOPP vs ABVD
• Early data had better PFS with BEACOPP than ABVD
• With longer follow-up, PFS advantage of BEACOPP is
diminished by deaths due to second cancers
ABVD vs BEACOPP vs CEC for Advanced
HL: The HD 2000 Trial
Merli et al. ASH 2014 # 499
23. GITIL HD0607 Study of BEACOPP + R After 2
ABVD for PET Positive Stage II-IV 497 HL
PET
IIB-IVB, IIA
with >3 nodal
sites, ESR >
50, or bulky dz
PET positive, n=41, 15% PET negative, n=222, 84%
Gallamini et al, ASCO 2010 # 8006
Gallamini et al, ASH 2012 #.550
CR n=212/222CR n=30/41 REF n=6REF n=8
Primary
endpoint:
3 Yr FFS
ABVD x2
ABVD x4 ± RT
PR n=1
4 escBEACOPP vs
4 escBEACOPP
+ R
PR n=2
If PET Neg after
4 ABVD, RT randomized
24. BEACOPP + R for PET Pos Stage II-IV HL
After 2 ABVD: The GITIL/FIL HD0607 Study
Gallamini et al, ASCO 2010 # 8006
Gallamini et al, ASH 2012 # 550
PET Neg
PET Pos
All Patients
(Comparison Data)
Failure Free Survival Results
Updated 1 YR PFS
Results:
97.3, 94.7, 80.5%
25. BEACOPP + R for PET Positive PET After
Two ABVD: ICMLTreatment Outcomes
Response PET2 Neg % PET2 Pos % Total
CR 520 96 89 75 605
PR 4 0.7 3 2.6 7
SD 4 0.7 1 0.9 5
PD 6 1.1 13 11 19
Relapse 4 0.7 7 6 11
Gallamini et al. ICML-13, 2015
2 Yr FFS
PET Neg
ABVD + RT (%) ABVD No RT (%) P value
88 94 0.063
2 Yr FFS
PET Pos
R-BEACOPP (%) BEACOPP (%)
62 72 0.27
2 Yr OS by PET Pos, 91% Neg, 99% <0.001
26. Phase II ASCT for PET Positive HL
After Two ABVD: A FIL HD0801 Trial
1. 512 patients with Untreated Stage IIB-IV HL
2. Therapy: 2 ABVD then a PET
• Negative PET (Deauville 1-2) receives 4 ABVD
1) If Pos at end, off study
2) If Neg at end, randomize RT
• Positive PET (Deauville 3-5) receives 4 IGEV
1) If Pos at end, and no donor, receives M/BEAM
and ASCT
2) If Pos at end, with donor, receives M and AlloSCT
3) If Neg at end, receives BEAM and SCT
Zinzani et al. ICML-13, 2015.
Result All (%) Pos (%) Neg (%) P value
2 Yr PFS from PET2 79 76 81 NS
2 Yr OS from Start 96 - - -
27. Update on Therapy for Hodgkin
Lymphoma: ASCO/ICML
1. Brentuximab Trials
• Single Agent Therapy
• Combination Programs
1. PET-Driven Therapy
• Stage I-II Disease
• Stage III-IV Disease
1. Novel Agents
• Anti-PD-1 for Relapse
• Gem/Bu/Mel for SCT
28. PD-1 is Inactivated by PD-L1 and PD-L2
on Tumor Cells
• PD-1 is a protein on T-Cells that dampens the normal
immune response
•Tumor cells can evade normal T-cell attack
• Inactivate T-cell function by activation of PD-1 via PD-L1 and
PD-L2
• T-Cells are “exhausted”
• Cannot attack tumor cells
• Inactivation is reversible
29. PD-L1 is Upregulated in Tumor cells
• Chromosome 9p24.1 amplification upregulates
PD-L1, as can EBV infection
• Multiple tumor types utilize the PD-L1 and PD-L2
interaction with PD-1 to escape immune
surveillance
– Breast, NSCLC, Kidney, Colon, Melanoma,
Hematologic Malignancies overexpress PD Ligands
– Pembrolizumab FDA-approved for Metastatic
Melanoma
– Nivolumab recently approved for Metastatic
Melanoma
– Ongoing studies in many other tumors
30. Phase I Nivolumab in Rel/Ref HL: Preliminary
Safety, Efficacy and Biomarker Results
• 23 Hodgkin lymphoma patients from larger study in
hematologic malignancies
– Dosing: 1-3 mg/kg with no MTD reached in Phase I
– Expansion cohort 3 mg/kg chosen, week 1, 4 and q 2
wk for maximum 2 years
• Drug-related adverse events (> 10%, all reversible)
Armand et al. ASH 2014 # 289; Timmerman et al. ICML-13, 2015, # 10.
Event Any Gr, # (%) Gr 3, # (%)
Any 18 (78) 5 (22)
Rash 5 (22) 0
Platelets 4 (17) 0
Fatigue, fever, diarrhea,
nausea, pruritis
3 each (13) 0
31. Armand et al. ASH 2014 # 289; Timmerman et al. ICML-13, 2015, #10.
Phase I Nivolumab in Rel/Ref HL: Preliminary
Safety, Efficacy and Biomarker Results
Response Pts,
N =24
(%)
SCT Fail,
BV Fail
N=15, %
SCT Naïve,
BV Fail
N=3, %
BV
Naïve
N=5,%
Overall 20 (87) 87 100 80
Best Resp CR 4 (17) 7 0 60
PR 16 (70) 80 100 20
SD 3 (13) 13 0 20
6 MO PFS % 86 85 n/c 80
1st
evaluation at 8 weeks of therapy
Median follow-up – 40 weeks
32. Phase Ib Pembrolizumab (MK-3475) for HL after
Brentuximab Failure: KEYNOTE-013
• 31 with Rel/Ref HL: Path NS or MC
– All relapsed from or failed BV therapy
– 3 or more prior therapies in 28 (97%)
– Prior ASCT = 20 (69%)
• Pembrolizumab given 10mg/kg every 2 weeks
– Evaluation based on response at 12 weeks (6 doses)
• Tolerability: 16 (55%) of pts experienced one or more
treatment-related Aes, but no Gr 4-5 events.
• Results at med follow-up at 38 weeks
– 29 Cases evaluable
– ORR 66%, CR 21%, PR 45%, SD 21%
Moskowitz, ASH 2014 # 290
34. Update on Therapy for Hodgkin
Lymphoma: ASCO/ICML
1. Brentuximab Trials
• Single Agent Therapy
• Combination Programs
1. PET-Driven Therapy
• Stage I-II Disease
• Stage III-IV Disease
1. Novel Agents
• Anti-PD-1 for Relapse
• Gem/Bu/Mel for SCT
35. Gem/Bu/Mel SCT for Refractory or High-Risk
HL: Comparison with Other Regimens
Nieto et al. Biol Blood Marrow Transplant 19: 410-417, 2013.
EFS Results
P=0.01
OS Results P=0.04
36. Management of Hodgkin Lymphoma:
An ASCO/ICML Update
F B Hagemeister, MD
Professor of Medicine
Department of Lymphoma and Myeloma
M D Anderson Cancer Center
Bangkok 28 August 2015