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Transcript of Morton Coleman, M.D. Director, Center for Lymphoma and Myeloma Weill Cornell Medical Center New York...
Morton Coleman, M.D.Director, Center for Lymphoma and
MyelomaWeill Cornell Medical Center
New York Presbyterian HospitalNew York, New York
Early Stage Hodgkin Lymphoma: Latest
Concepts & Controversies
THE MAIN INTENT: LESS TOXICITY
THE MAIN INTENT: LESS TOXICITY
At least 85% of Hodgkin patients can anticipate a cure. The charge: cure even more patients with the least impact on their well being
EARLY STAGE HODGKIN HISTORY
• 5-10 yr. relapse rate lower for chemotherapy + IF RT than EF RT alone (JCO 24: 3128-35, 2006; JC0 25: 3495-3502, 2007; NEJM 357: 1916-27, 2008)
• No difference in OS at 4-5-yrs. between ABVD alone and ABVD + RT for patients with limited stage non-bulky HL (Blood 104: 3483-89, 2004; JCO 23: 4634-42, 2005)
• RT is associated with late 2nd malignancies and cardiovascular events especially after 10 yrs. (JCO 21: 3431-9, 2003; NEJM 355: 1572-82, 2006; JCO 27 [Suppl.] abs. 8547, 2009
courtesy Straus,D
Kaplan–Meier Estimates of Overall Survival and Freedom from Disease Progression.
Meyer RM et al. N Engl J Med 2012;366:399-408
Kaplan–Meier Estimates of Overall Survival and Freedom from Disease Progression among Patients with an Unfavorable Risk Profile.
Meyer RM et al. N Engl J Med 2012;366:399-408
What role does PET Scans play in this effort?
What role does PET Scans play in this effort?
May interim PET/CAT scans be of value or should scans be used only at the end of
treatment?
In Vivo Treatment Sensitivity With Positron Emission /Computed
Tomography After One Cycle of Chemotherapy for Hodgkin
Lymphoma
In Vivo Treatment Sensitivity With Positron Emission /Computed
Tomography After One Cycle of Chemotherapy for Hodgkin
Lymphoma
Martin Hutchings, Lale Kostakoglu, Morton Coleman, et al.
JCO 32: 2705-2711, 2014
FDG-PET: After one (two treatments) versus two cycles
(four treatments) of therapy
FDG-PET: After one (two treatments) versus two cycles
(four treatments) of therapy
Early determination of treatment sensitivity in Hodgkin lymphoma:
FDG-PET/CT after one cycle of therapy has a higher negative
predictive value than after two cycles of therapy
Participating NationsParticipating Nations
Denmark
United States
Italy
Poland
(Nine Institutions)
Patient Population:126 Pts.Patient Population:126 Pts.
• Stage I 8%
• Stage 2 46%
• Stage 3 19%
• Stage4 27%
• B Sxs 56%
• Bulky 37%
Comparison of the prognostic value of PET 1 and PET 2: Progression Free Survival at 2 Years PET 1 PET2
Comparison of the prognostic value of PET 1 and PET 2: Progression Free Survival at 2 Years PET 1 PET2
• Negative predictive value 98% 91%
• Positive predictive value 63% 85%
• Sensitivity 94% 61%
• Specificity 86% 97%
• Concordance >90%
Involved Field Radiotherapy Versus No Further Treatment in Patients with Early- Stage Hodgkin Lymphoma and
Negative PET Scan After 3 ABVD Cycles: Resuts of the UK NCRI RAPID
Trial
Involved Field Radiotherapy Versus No Further Treatment in Patients with Early- Stage Hodgkin Lymphoma and
Negative PET Scan After 3 ABVD Cycles: Resuts of the UK NCRI RAPID
Trial
Proc ASH 120,2012; Abstract 547
Radford J, Barrington S, Counsell N, et al
Initial treatment: ABVD x 3
Reassessment: if NR/PD, patient goes off study571pts if CR/PR, FDG-PET scan performed
4th cycle ABVD then IFRT Randomization
IFRT (209 pts)
No further treatment (211pts)
PET-positive (145pts) PET negative (420 pts)
RAPID Trial Design
Radford J, et al. Blood. 2012;120: Abstract 547.
PET negative; randomized to
IFRT(n = 209)
PET negative; randomized to
NFT(n = 211)
PET positive; 4th cycle
ABVD/IFRT (n = 145)
Progressions 9 20 11
Deaths 8 1 8
PFS at 3 years 93.8% 90.7% 85.9%
OS at 3 years 97.0% 99.5% 93.9%
Outcomes After Median Follow-Up of 45.7 Months
Radford J, et al. Blood. 2012;120: Abstract 547.
SummarySummary
• 602 pts registered between 2003 and 2010
• 75% PET-negative at central review after ABVD x 3
• In the randomized PET-negative population, 3 yr PFS is 92.8% IFRT and 90% NFT
• Risk difference -3% is within the maximum allowable difference of -7%
Radford J, et al. Blood. 2012;120: Abstract 547.
CommentaryCommentary• These data are similar to those reported from
Argentina several years ago for all stages of disease when PETs were obtained after 3 cycles (Pavlosky, et al.)
• CAUTION: Were the deaths in the IFRT arm ‘flukes’ and not related to the IFRT? If so, would the data and conclusions be different.
Radford J, et al. Blood. 2012;120: Abstract 547.
An Individual Patient-Data Comparison of Combined Modality
Therapy and ABVD Alone for Patients with Limited Stage Hodgkin
LymphomaA study of the NCIC (HD 6) and the
German Hodgkin Study Group (HD 10 &11)
An Individual Patient-Data Comparison of Combined Modality
Therapy and ABVD Alone for Patients with Limited Stage Hodgkin
LymphomaA study of the NCIC (HD 6) and the
German Hodgkin Study Group (HD 10 &11)
Hay AE, Klimm B, Chen BE, et al
Annals of Oncology 24 (12) 3065-3069, 2013
Favorable: CS IA,IB, IIA, IIB without risk factors Unfavorable: CS IA, IB, with at least one ofthe risk factors a-d given below or CS IIB with risk factor c, d, or both given below:and IIA
Favorable: CS IA,IB, IIA, IIB without risk factors Unfavorable: CS IA, IB, with at least one ofthe risk factors a-d given below or CS IIB with risk factor c, d, or both given below:and IIA
a) Large mediastinal mass (≥1/3 of maximum transverse thorax diameter)b) Extranodal involvementc) High erythrocyte sedimentation rate (≥50 mm/h in patients without B-symptoms, ≥30 mm/h in patients with B-symptoms)
d) 3 or more involved lymph node areas
Eich HT, et al. J Clin Oncol. 2011;28:4199-4206.
GHSG Early-Stage HL Risk Factors
HD.6 Trial
Meyer RM, et al. N Engl J Med. 2012;366:399-408.
Study schema of a randomized trial comparing a strategy that includes radiation therapy with ABVD in patients with limited-stage Hodgkin lymphoma
Patients with Clinical Stage I-IIA Hodgkin Lymphoma
Exclude low-risk patients
Stage IA with single node of Hodgkin lymphoma and all of:
•Lymphocyte predominant or nodular sclerosis histology•Bulk <3cm•ESR <50 mm/hour•Disease involving high neck or epitrochlear region only
Exclude high-risk patients
Patients with either:•Bulk >10 cm or ≥1/3 chest wall diameter, or•Intra-abdominal disease
Favorable or unfavorable cohort
Unfavorable cohort patients have any of:
•Age ≥40 years•ESR ≥50 mm/hour•Mixed cellularity or lymphocyte deplete histology•≥4 sites of disease
Treatment that includes radiation therapy
•Favorable cohort: subtotal nodal radiation therapy•Unfavorable cohort: combined modality therapy with ABVD x 2 cycles plus subtotal nodal radiation therapy
ABVD as a single modality
•Both cohorts: ABVD x 2 cycles•IF CR or CRu, ABVD x 2 more cycles (total 4 cycles)•If <CR or CRu, ABVD x 4 more cycles (total 6 cycles)
Stratify
Randomly Assign
2 ABVD + 20 Gy IFRT
Comparison of NCIC CTG HD.6 and GHSG HD10 and HD11 Staging, Eligibility and
Preferred Arms
Comparison of NCIC CTG HD.6 and GHSG HD10 and HD11 Staging, Eligibility and
Preferred Arms
4 ABVD + 30 Gy IFRT
4 – 6 ABVD alone
Early, unfavorable
HD11
Early, favorable
HD10
AdvancedHD.6
FavorableUnfavorable
NCIC CTG
GHSG
Advanced
Not necessarily to scale
Hay AE, et al. Blood. 2012;120: Abstract 549.
Very good prognosis B or Bulk
Early, unfavorable
HD11
Early, favorable
HD10
AdvancedHD.6
FavorableUnfavorable
NCIC CTG
GHSG
Advanced
Not necessarily to scale
Hay AE, et al. Blood. 2012;120: Abstract 549.
Comparison of NCIC CTG HD.6 and GHSG HD10 and HD11 Staging, Eligibility and
Preferred Arms
Comparison of NCIC CTG HD.6 and GHSG HD10 and HD11 Staging, Eligibility and
Preferred Arms
Attribution of Death: All PatientsAttribution of Death: All Patients
Cause of DeathNumberMed. F/U
GHSG HD10/11406
7.6 Years
NCIG CTG HD.6182
11.2 Years
Hodgkin lymphoma Immediate toxicity
52
41
Second cancerCardiacOther
246*
320
Total 19 10
*Other deaths were: 1 suicide, 1 respiratory failure, 1 cerebral hemorrhage, 1 progression of NHL, 2 unknown
Hay AE, et al. Blood. 2012;120: Abstract 549.
Outcomes: All PatientsOutcomes: All Patients
Hay AE, et al. Blood. 2012;120: Abstract 549.
EndpointNumber Med. F/U
GHSG HD10/11
4067.6 Years
NCIG CTG HD.6182
11.2 Years
HR (95% CI)
GHSGPD/OS
NCIC CTGPD/OS
8-yr TTP 93% 87% 0.44 (0.24, 0.78) 25/0 23/0
8-yr PFS 89% 86% 0.71 (0.42, 1.18) 25/13 23/4
8-yr OS 95% 95% 1.09 (0.49, 2.40) 19 10
Overall CommentaryOverall Commentary
• Combined modality therapy (CMT) improves disease control by 4%-7%
• Could this difference in control have been obviated by the use of PET scans after one cycle of therapy since there was a 7% difference in PET negative results between cycles 1 and 2, much less cycle 3?
• The relatively long term outcomes associated with IFRT remain to be clarified
Omitting Radiotherapy in Early Positron Emission Tomography-
Negative Stage I/II Hodgkin Lymphoma Is Associated With an Increased Risk of Early Relapse:
Clinical Results of the Preplanned Interim Analysis of the Randomized
EORTC/LTSA/FIL H10 Trial
Omitting Radiotherapy in Early Positron Emission Tomography-
Negative Stage I/II Hodgkin Lymphoma Is Associated With an Increased Risk of Early Relapse:
Clinical Results of the Preplanned Interim Analysis of the Randomized
EORTC/LTSA/FIL H10 Trial
• Raemaekers, J.M.M., Andre, Marc P.E., Federico, M. JCO 32:1188-1194, 2014
Study design of European Organisation for Research and Treatment of Cancer, Lymphoma Study Association, and Fondazione Italiana Linfomi H10 20551 trial of patients age 15 to 70 years
with untreated supradiaphragmatic clinical stage I/II Hodgkin lymphoma
Raemaekers J M et al. JCO 2014;32:1188-1194
2014 by American Society of Clinical Oncology
Flowchart of patients included in interim analysis.
Raemaekers J M et al. JCO 2014;32:1188-1194
2014 by American Society of Clinical Oncology
Results: ProgressionResults: Progression
Favorable: no RT – 9 (5%) with RT-1 (0.5%)
Unfavorable: no RT-16 (5%) with RT-7 (2.6%)
Study is now closed.
Early-Stage Hodgkin's Disease: The Utilization of Radiation Therapy and Its Impact on
Overall Survival
Early-Stage Hodgkin's Disease: The Utilization of Radiation Therapy and Its Impact on
Overall SurvivalRahul R. Parikh, M.D.1, Joachim Yahalom, M.D.2, James A. Talcott, M.D.3, Michael L. Grossbard, M.D.3, & Louis B. Harrison, M.D.4
1 Mt. Sinai Beth Israel Medical Center & Mt. Sinai St. Luke’s-Roosevelt Hospitals, Mount Sinai Health System, Department of Radiation Oncology, New York, NY2 Memorial Sloan-Kettering Cancer Center, Department of Radiation Oncology, New York, NY3 Mt. Sinai Beth Israel Medical Center & Mt. Sinai St. Luke’s-Roosevelt Hospitals, Mount Sinai Health System, Department of Hematology-Oncology, New York, NY4 Department of Radiation Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL
Abstract No: CT-08
BackgroundBackgroundNational Cancer Database
(NCDB) Joint program of the Commission on Cancer and the
American Cancer Society Prospectively collected; Nationwide outcomes database
covering 75% of all newly diagnosed cancers (>1,500 U.S. hospitals);
Not population-based dataset Not geographically limited (care in all states included) Reflects contemporary treatment programs RT specifics available for analysis (modality, dose, fx,
volume/site)
Aims of the StudyAims of the StudyPrimary Endpoint:
Determine relationship between use of RT and overall survival in patients with early-stage Hodgkin’s Disease
Secondary Endpoints: Determine the trends of utilization rates of RT Determine other factors (socioeconomic
factors, timing of chemotherapy, co-morbid conditions) associated with overall survival
MethodsMethods
Did NOT receive Radiation Therapy
(N = 20,897, 51%)
Did NOT receive Radiation Therapy
(N = 20,897, 51%)
Received Radiation Therapy as part of CMT
(N = 20,523, 49%) Median RT dose = 30.6 Gy
Received Radiation Therapy as part of CMT
(N = 20,523, 49%) Median RT dose = 30.6 Gy
Hodgkin’s Disease, Stage I/II, diagnosed 1998-2011
(N = 41,420) Median f/u = 6.4 years; Median age = 37 years (range: 18-90)
Multi-agent chemotherapy given to 96% of the pts
Hodgkin’s Disease, Stage I/II, diagnosed 1998-2011
(N = 41,420) Median f/u = 6.4 years; Median age = 37 years (range: 18-90)
Multi-agent chemotherapy given to 96% of the pts
Evaluated clinical features & survival outcomes
The association between RT use, co-variables, and outcome was assessed in a multivariate Cox proportional hazards model.
Survival was estimated using the Kaplan-Meier method.
Prognostic Factor HR (95% CI) p-value RT No 1.00 (Ref.)
<0.0001*
Yes 0.51 (0.48-0.54)
Age (years) at Diagnosis ≤ 40 0.19 (0.18-
0.20)
<0.0001*
> 40 1.00 (Ref.) Gender Male 1.00 (Ref.)
<0.0001*
Female 0.81 (0.76-0.86)Stage 1 1.00 (Ref.)
<0.0001*
2 0.70 (0.66-0.74) Presence of “B” Symptoms No 1.00 (Ref.)
<0.0001*
Yes 1.65 (1.46-1.87) Charlson/Deyo co-morbidity score 0 1.00 (Ref.)
<0.0001*
1 3.14 (2.76-3.57) 2 5.19 (4.23-6.36)Transplant Proc. No 1.00 (Ref.) 0.012* Yes 1.64 (1.15-2.35)
Prognostic Factor HR (95% CI) p-value Timing of Chemotherapy ≤30 days from dx 0.67 (0.64-
0.72)
<0.0001*
>30 days from dx 1.00 (Ref)
Education (% not HS grad) ≥ 29% 1.00 (Ref.)
<0.0001*
20-28.9% 0.84 (0.76-0.92) 14-19.9% 0.75 (0.69-0.82) <14% 0.62 (0.56-0.67Household Income < $30,000 1.00 (Ref.) <0.0001* $30,000-34,999 0.92 (0.83-1.01) $35,000-45,999 0.79 (0.72-0.87) ≥ $46,000 0.62 (0.57-0.68)
Insured Status <0.0001* Insured (Medicare, Private / Managed Care)
1.00 (Ref.)
Not Insured / Medicaid 5.27 (4.97-5.59)
Facility Type Comm. Cancer Prog. 1.00 (Ref.)
<0.0001*
Comprehen Cancer Prog 0.84 (0.77-9.23) Academic/Res. Prog. 0.66 (0.60-0.73)
Other 0.96 (0.77-1.19)
Univariate Survival Analysis (OS)
HR LCL UCL
Utilization of RT (yes vs. no) 0.47 0.43 0.53
Age (≤40 vs. >40) 0.23 0.20 0.26
Race (black vs. white) 0.93 0.79 1.11
Race (other vs. white) 0.81 0.69 0.91
Insured status (Uninsured vs. Insured) 3.48 3.13 3.87
Stage (1 vs. 2) 0.89 0.77 1.02
B Symptoms (yes vs. no) 1.72 1.50 1.97
Transplant performed (yes vs. no) 2.66 1.59 4.45
Co-morbidity score (1 vs. 0) 1.94 1.69 2.23
Co-morbidity score (2 vs. 0) 2.93 2.34 3.65
Timing of chemo (≤30 days vs. >30days)
0.84 0.76 0.94
Factors Associated with Overall Survival (MVA)
Overall Survival by RT use84%
76%
RT Utilization
Reason for No Radiation Freq. %Radiation was not part of the planned initial treatment strategy 18,482 86.30Radiation was contraindicated 185 0.86Radiation recommended but not administered 1,041 4.86Radiation recommended but refused by the patient 279 1.30Radiation recommended, unknown whether delivered 872 4.07Unknown if recommended or administered 561 2.62Total 21,420 100.00
`
41% 2011
56%1998
Conclusions Largest contemporary dataset of patients with early- stage HD
(n=41,420)
The use of RT is associated with improved 10-yr OS (84% vs. 76%, HR=0.51, p<0.00001) BUT THIS MAY BE DUE
TO A POPULATION WITH AN INHERENT BETTER PROGNOSIS
Utilization of RT has decreased by 15% from 1998 to 2011 (5641%; not part of initial treatment strategy)
Specific factors (socioeconomic, insurance status, facility type) were associated with underutilization of RT which may be targeted to improve patient access to RT, IF RT IS INDEED INDICATED
Brentuximab Vedotin Mechanism of Action
Brentuximab Vedotin Mechanism of ActionBrentuximab vedotin (SGN-35) ADCmonomethyl auristatin E (MMAE), potent antitubulin agent
protease-cleavable linker
anti-CD30 monoclonal antibody
ADC binds to CD30
MMAE disruptsmicrotubule network
ADC-CD30 complex traffics to lysosome
MMAE is released
Apoptosis
G2/M cellcycle arrest
Frontline Therapy With Brentuximab Vedotin Combined
with ABVD or AVD in Patients with Newly Diagnosed Advanced-Stage
Hodgkin Lymphoma
Frontline Therapy With Brentuximab Vedotin Combined
with ABVD or AVD in Patients with Newly Diagnosed Advanced-Stage
Hodgkin Lymphoma
Abstract 798, ASH 2012
Ansell SM, Connors JM, Park SI, et al
Study DesignStudy Design• Phase I, multicenter, dose-escalation study
• Major eligibility criteria– Treatment-naïve HL patients– Age ≥18 to ≤60 years– Stage IIA bulky disease or Stage IIB-IV disease
• Treatment design– 28-day cycles (up to 6 cycles) with dosing on Days 1 and 15– Dose escalation cohorts – I-6, II-13, III-6, IV-6, expansion-20
A(B)VD
Brentuximab Vedotin
Cycle 1 Cycle 2 Cycle 3
6 Cycles +/- XRT
Weeks0 2 4 6 8 10 12
Ansell SM, et al. Blood. 2012;120: Abstract 798.
Response Results at End of Front-Line Therapy
Response per Investigatora
ABVD with brentuximab vedotin
N = 22
AVD with brentuximab vedotin
N = 25
Response at end of front-line therapy, n (%)
Complete remission 21 (95) 24 (96)
Progressive disease 0 1 (4)
Not evaluable due to AEs 1b (5) 0a Assessed using Cheson 2007b Patient had a Grade 5 event of pulmonary toxicity prior to the end of front-line therapy
• Response results at end of front-line therapy:
◦ ABVD cohorts: 21 of 22 CR (95%)
◦ AVD cohorts: 24 of 25 CR (96%)
• In addition, 1 patient withdrew consent and 3 patients were lost to follow-up prior to completion of front-line therapy and were not evaluable for response
Ansell SM, et al. Blood. 2012;120: Abstract 798.
CONCLUSIONS: EARLY STAGE HL PET SCANS HAVE ALLOWED THE REDUCTION OF
CHEMOTHERAPY CYCLES IN EARLY STAGE HL. COMBINED MODALITY THERAPY (CMT)PROVIDES ABOUT
ABOUT A 5% (+/- 3%)ADVANTAGE OVER CHEMOTHEAPY ALONE IN PFS ALTHOUGH OS ADVANTAGE REMAINS TO BE PROVEN.
THE LONG TERM TOXICITY OF LIMITED OR NODAL FIELD RT IS STILL UNKNOWN. ACUTE TOXICITY MAY PLAY A ROLE IN REDUCING OS?
PET SCANS AFTER 1 CYCLE MAY REDUCE THE PFS ADVANTAGE OF CMT.
PATIENT SELECTION IS CRITICAL IN DECIDING WHAT RX TO ADMINISTER.
WILL BRENTUXIMAB VEDOTIN REPLACE THE ‘NEED’ FOR RT?
Acknowledgment
Clinical Research (Cornell) Jia Ruan, M.D., Ph.D.Richard Furman, M.D.John P. Leonard, M.D.Peter Martin, M.D.Maureen Joyce, R.N.Patricia Glenn, R.N.Jamie KetasJessica HansenKaren WeilJennifer O’Loughlin
Biostatistician
Madhu Mazumdar, Ph.D. (Cornell)
Translational Core Maureen Lane, Ph.D. (Cornell)Maureen Ward
Laboratory Research Ari Milneck, M.D., Ph.D.(Cornell)Katherine Hajjar, M.D. (Cornell)Shahin Rafii, M.D. (Cornell)
Lymphoma Research Foundation
ASCO Foundation (YIA, CDA)
NIH / NHLBI
THANK YOU FOR YOUR ATTENTION