Flashcards in Hodgkin's Lymphoma Deck (69):
Tell me about the staging of Hodgkin's Disease
- Involvement of a single lymph node region (I) or
- Localized involvement of a single extra lymphatic organ/site (Ie)
- Involvement of 2 or more LN regions on the same side of the diaphragm (II) or
- Localized involvement of a single associated extralymphatic organ/site and its regional LN(s), with/without involvement of other LN regions on the same side of the diaphragm (IIe)
- Involvement of LN regions on both sides of the diaphragm (III) which may be accompanied by localized involvement of an associated extralymphatic organ or site (IIIe), by involvement of the spleen (IIIs) or by both (IIIe+s)
- Disseminated (Multifocal) involvement of one or more extralymphatic organs, with or without associated LN involvement, or isolated extralymphatic organ involvement with distant (Non-regional) nodal involvement
What are the B symptoms?
Unexplained fevers >38 degrees
Drenching night sweats
LOW >10% of Body weight (within 6 months prior to diagnosis)
What qualifies as a large mediastinal mass?
If tumor is 1/3 or more of the maximum thoracic diameter
What are the risk factors according to the GHSG?
Mediastinal Mass (M)
Extra nodal sites (E)
- >50 if no B symptoms
- >30 if B symptoms
Nodal sites must be 3 or more (N)
Tell me about the IPS score
1) Gender (Male)
2) Age 45 years and above
3) Stage IV
4) Hb 15x10^9/L
Prognostic score by Hasenclever in NEJM
-n =5000 with advanced HL
-75% had Doxorubicin Tx and 20% had MOPP or similar
-33% with full/selected IFRT, 2% with mantle or inverted Y-field RT, 5% with STNI
Each risk factor confers an ~7% reduction in cure rate at 5 years
Found that the higher the score, the lower the freedom from progression of disease percentage.
Correlated with 5y OS as well
IPS 0 = 5y FFP 84%, 5yr OS 90%
IPS 1 = 5y FFP 77%, 5yr OS 90%
IPS 2 = 5y FFP 70%, 5yr OS 80%
IPS 3 = 5y FFP 60%, 5yr OS 80%
IPS 4 = 5y FFP 50%, 5yr OS 60%
IPS 5 or more = 5y FFP 40%, 5yr OS 56%
What is MOPP?
What is the Canellos trial about?
B/g: MOPP was the standard Tx for HD for ~20 years then.
Aim was to compare if newer tx regimens can be as efficacious
Stage III/IV newly Dx HD
Pts in 1st relapse after RT was eligible
1) MOPP for 6-8#
2) MOPP alternating with ABVD for 12 cycles
3) ABVD for 6-8#
- ORR: 70% vs 80% vs 80%
- 5y FFS rates: 50% vs 65% vs 60%
- 5y OS: 66% vs 75% vs 73%
- OPP had more severe toxic effects on the BM and was a/w greater reductions in the prescribed doses.
Conclusion = ABVD for 6-8months was as effective as 12 months of MOPP alternating with ABVD. And both were superior to MOPP alone
What is ABVD
What was the evidence that led to the need to consider ABVD in the treatment of advanced HD?a
Duggan JCO 2003
- CR 76% vs 80%
- 5y FFS 63% vs 66%
- 5y OS 82% vs 81%
- no diff in cardiac toxicity
- significant acute pul/hematologic rates more common with MOPP/ABV
- 9 deaths with ABVD, 15 with MOPP/ABV
- 18 secondary malignancies with ABVD, 28 with MOPP/ABV
- 13 developed MDS/Acute leukemia (11 with MOPP/ABV)
ABVD should be considered the standard regimen for Tx of advanced HD
Tell me about the Standford V regimen
Sandra Horning JCO 2002 with updated results at 5 years
N=142, Phase II
Stage III/IV or; Stage I/II with locally extensive mediastinal disease
Standford V chemo (12 weeks) --> 36 Gy RT to initial sites of bulky (5cm or more) disease or macroscopic splenic disease
- 5 yr FFP 90%, OS 96%
- no secondary leukemia
- 42 pregnancies
- among 16 who relapsed, FF2R was 70% at 5 years
Tell me about Standford V
- maintain/improve cure rates
- minimizing acute/long-term toxicities
- abbreviated course of treatment
- maintenance/increase in dose-intensity of individual drugs
- reduction in cumulative doses of bleomycin and doxorubicin
- marked reduction of nitrogen mustard with omission of Procarbazine
- Consolidative RT was restricted to bulky disease / macroscopic splenic disease
Vinblastine 6 mg/m2 + Doxorubicin 25mg/m2
- Weeks 1,3,5,7,9,11
Vincristine 1.4mg/m2 (max 2mg) + Bleomycin 5 units/m2
- Weeks 2,4,6,8,10,12
- Weeks 1,5,9
Etoposide 60mg/m2 BD on week 3, 7, 11
Prednisone 40mg/m2 daily Week 1 to 10, tapered during 11 and 12
What are the 3 risk groups in Hodgkin's lymphoma?
- Stage I/II with NO risk factors
- Stage I/II with Risk Factors
- Stage III/IV
- Stage IIB with large mediastinal mass or Extranodal disease
What are the risk factors in Hodgkin's Lymphoma?
ESR > 50 with no B symptoms; >30 with B symptoms
3 or more nodal sites
What is the IPS score for Hodgkin's Disease?
Age (45 or older)
What does IPS correlate with?
Correlates with freedom from progression of disease & OS at 5 years
What was the evidence that made ABVD the Standard of care in the treatment of Hodgkin's?
1) George Canellos NEJM 1992
MOPP was standard of care then.
- ABVD 6-8#
- MOPP 6-8#
- Alternating MOPP/ABVD for 12 weeks
- CR rates 70% with MOPP, 80% with ABVD and 80% with MOPP/ABVD
- 5y FFS 50% vs 60% vs 60%
- Life-threatening events to fatal neutropenia: 20% vs 3% vs 30%
2) David Duggan JCO 2003
- 2 arms:
>> ABVD vs MOPP/ABV
>> CR rates 70-80%~
>> 5y FFS 60-70%~
>> 5y OS 80%~
>> More 2nd malignancies a/w MOPP/ABG
Tell me about the evidence for Standford V and RT?
Sandra Horning JCO 2002
Aim was to provide more data re: efficacy and complications using Standford V and RT
Stage III/IV/Locally extensive mediastinal stage I/II
S/p Standford V chemox12 weeks --> 36 Gy RT to initial sites of bulky (5cm or more) or macroscopic splenic disease
5y FFP 90%
No secondary leukemia
What is the evidence that Standford V is not better than ABVD?
1) Gordon et al Blood 2010
-5y FFS comparable
2) Hoskin JCO 2009 UK NCRI Lymphoma study group
Aim: Comparing ABVD vs Standford V
Stage IIB/III/IV or I-IIA with bulky disease or other adverse features
Results: ORR 90%~
5yr PFS 75%~
5y OS 90%~
3) Gobbi et al Intergruppo Italiano Linfomi JCO 2005
Aim: to compare Stanford V vs MOPPEBVCAD vs ABVD to select which regimen would best support a reduced RT program
N=350 Stage IIB/III/IV
- CR rates 90% (ABVD); 80%(Stanford V) and 90% (MOPPEBVCAD)
- 5y FFS 80% vs 50% vs 80%
- 5y PFS 85% vs 70% vs 90%
- 5y OS 90% vs 80% vs 90%
- myelotoxic for MOPPEBVCAD
What is HD9 about?
First published by Volker Diehl in NEJM, updated in JCO by Engert 2009
Aim: to investigate 3 combinations of chemo to find out the best regimen for advanced Hodgkin's disease
Treatment-naive, unfavorable Stage IIB/IIIA/IIIB/IV
3 groups, each followed by RT-prn:
5y FFTF 70% vs 80% (BEACOPP) s 90% (eBEACOPP)
5y OS 80% vs 90% vs 90%
Rates of early progression were significantly lower with eBEACOPP
10y FFTF 60% vs 70% s 80%
10y OS 75% vs 80% vs 90%
Risk of 2nd malignancies 5% vs 8% vs 5%
Overall mortality 20% vs 20% vs 10%
Death due to HL 11% vs 8% vs 3%
What is HD12 about?
Peter Borchmann JCO 2011
Aim: To evaluate:
1) Reduce chemo to reduce toxicities
2) Omit RT in pts responding to chemo to reduce toxicities
1) 8# eBEACOPP +RT
2) 8# eBEACOPP - RT
3) 4# eBEACOPP + 4#baseBEACOPP + RT
4) 3# eBEACOPP +4#baseBEACOPP -RT
RT was given to:
- sites of initial bulk >5cm
- residual disease 1.5cm or more
- inadequate response to chemo
5y FFTF 86% (eBEACOPP) vs 85%(4+4)
5y OS 92% vs 90%
FFTF was inferior without RT. 90% vs 87%
Rates of early PD 1% vs 3% (4+4)
- 4+4 did not substantially reduce severe toxicity, but may decrease efficacy
- No evidence to omit consolidation RT for residual disease I
How did HD15 come about?
Newly Dx advanced stage HD, 18-60yo
persistent mass 2.5cm or larger + PET+ --> Additional RT 30Gy
Aim is to find out:
1) 4+4 not > to 8#eBEACOPP
Hence wanted to reduce the toxicities of 8#eBEACOPP, but maintain efficacy
2) Can we use a PET-directed approach to decide who needs RT
5y FFTF 84% (8#eBEACOPP) vs 90% (6#eBEAOPP) vs 85% (8#BEACOPP14)
5y PFS 86% vs 90% vs 86%
5y OS 92% vs 95% vs 94.5%
Secondary AML/MDL 3% vs 0.3% vs 1%
Death due to Tx-related toxic effects 2% vs 1% vs 2%
If post-to PET-, no need RT.
How about between ABVD and BEACOPP.
Which is better?
Federico JCO 2009
Stage IIB/III/IV HL
A) 6# ABVD
B) 4#eBEACOPP + 2#baseBEACOPP
C) 6# CEC (cyclo, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, Procarbazine, vinblastine, bleomycin)
5y PFS 70% (ABVD) vs 80% (BEACOPP) vs 80% (CEC)
5y OS 80% vs 90% vs 90%
Is there any study that directly compares ABVD with BEACOPP?
Viviani NEJM 2011
Stage IIB/III/IV or IPS of 3 or more
A) 6-8# ABVD
Residual/PD to proceed with salvage.
7y FFFP 85% (4+4) vs 70%
7y EFS 80% vs 70%
7y Rate of freedom from 2nd progression 90% vs 80%
7y OS rate 90% vs 80% (trend)
Which is better? BEAM-HSCT vs HDCT
BEAM-HSCT > HDCT in terms of FFTF, but OS did to differ significantly
Lancet 2002 study
Relapsed HD 16-60yo
A) 2# Dexa-BEAM --> CR/PR --> 2#Dexa-BEAM
B) 2# Dexa-BEAM --> CR/PR --> HSCT
3y FFTF 55% vs 34%
No diff in OS
Is more HDCT then better?
JCO 2010 Andreas Josting
ASCT had become standard of treatment then for relapsed HD.
Investigated because the intensity of treatment needed is unclear. Hence, wanted to evaluate the impact of sequential HDCT before myelo-ablative therapy.
A) 2#DHAP --> no PD --> BEAM+ASCT
B) 2# DHAP --> no PD --> sequential HD Cyclo/MTX/Etoposide --> BEAM+ASCT
3y OS 90% vs 80% (Seq HDCT)
3y PFS 72% vs 67%
3y FFTF 71% vs 65%
Significant toxicities with Seq HDCT
Is allogenic or autologous SCT better in relapsed HD?
Milpied JCO 1996
AlloBMT vs AutoBMT in relapsed HD
4y OS 25% vs 40% (auto)
4y PFS 15% vs 25% (auto)
4y Relapse 60% vs 60%
4y non-relapse mortality 50% vs 30% (Auto)
Is upfront ASCT better?
No. Federico JCO 2003
Aim: determine if upfront ASCT should be done.
4#ABVD/Doxo-containing regimens --> CR or PR --> Randomized:
- HDT + ASCT
- 4# conventional chemo
CR 92% (HDT+ASCT) vs 89%
5y FFS 75% vs 80%
5y OS 90% vs 90%
5y RFS 88% vs 94%
CONCLUSION: no benefit with HDT and ASCT
What is Brentuximab?
Antibody-drug conjugate, aka SGN-35
Chemo = Monomethyl auristatin E (MMAE)
Binds to CD30 receptor
Gets internalized by endocytosis, lysosomes fuse with the vesicle.
MMAE is then released by cathepsin B and other lysosomal cysteine proteases.
MMAE is then released in the tumor micro environment , causing cell cycle arrest and then apoptosis
What are the 2 common lymphomas expressing CD 30?
What are the common side-effects of Brentuximab?
What is the evidence for Brentuximab
Phase I and II conducted by Anas Younes
Phase II published JCO 2012
Relapsed/refractory HD after auto-SCT
Historically documented CD30+ HL
N=100, IV Brentuximab at 1.8mg/kg q3weekly, up to 16#
ORR 75%, CR in 34%. Disease control rate of 96%
Med time to objective response 5-6 weeks, med time to CR 12 weeks
med PFS 5.6m
Med duration of response for those in CR 20.5m, others 6.7m
Any role for Brentuximab as consolidation therapy after ASCT?
Yes. AETHERA trial
Moskowitz Lancet 2015
Unfavorable-risk relapsed/primary refractory Classic HL
Then randomized into 2 arms:
- Brentuximab (16# 1.8mg/kg)
Med PFS 43m vs 24m
Any evidence for Immunotherapy in HD?
Yes. PD-1 blockade with Nivolumab
Phase I study Ansell et al.
S/p Brentuximab 80%
S/p ASCT 80%
Received Nivolumab 3mg/kg Q2w until CR/PD or excessive toxic effects.
ORR 90% CR 20%
Rate of PFS at 24weeks was 90%
Pembrolizumab in HD
Phase 1 study
All failed Brentuximab
70% failed ASCT
ORR 50%, CR 20%
What are the risk factor for Bleomycin Toxicity?
>400 Units of cumulative dose
Use with other chemo agents (CDDP, cyclophosphamide, Gemcitabine)
Tell me about the GHSG HD7 trial
Andreas Engert, JCO 2007
Aim: Invx if Combined modality treatment > EF-RT
Combined modality = 2#ABVD-->EF-RT
Stage IA to IIB with no risk factors
A) 30Gy EF-RT + 10Gy IF-RT
B) 2#ABVD --> 30Gy EF-RT+10Gy IF-RT
- no difference in terms of C (95%), OS ( 90%)
- FFTF significantly different 70% and 90%
Conclusion --> CMT with 2# ABVD + EF-RT
What are the 3 main conclusions from the EORTC-Lymphoma Group H7 trial?
1) Clinical staging is sufficient for stratifying early stages of the disease
2) Chemotherapy followed by IF-RT should be standard treatment
3) Duration of chemotherapy should be adapted to severity of disease
Tell me about the EORTC-GELA H8 trial
Ferme et al NEJM 2007
Aim: to evaluate the standard treatment for HD
Treatment-naive, Stage I/II with favorable Prognostic and unfavorable prognostic features.
2 arms to this trial
1) H8-Favorable. Split into 2 groups:
- STNI alone
- 3#MOPP/ABV + IF-RT
2) H8-Unfavorable. Split into 3 groups:
- 6#MOPP-ABV + IF-RT
- 4#MOPP-ABV + IF-RT
- 4#MOPP-ABV + STNI
Prognostic factors were based on the same ones used in H7 trial.
RESULTS: (Med f/u 7.5 years)
- 5y EFS 98% vs 74% (no chemo)
- 10y OS 97% vs 92%
- 5y EFS 84% (6#) vs 88% (4+IF-RT) vs 87% (4+STNI)
- 10y OS 88% vs 85% vs 84%
- Early Favorable: Chemo + IF-RT should be standard of care
What is the relapse rate with RT alone in early HD?
Tell me about the HD10 trial
Aim: Determine if FEWER cycles of chemo and LOWER doses of RT could be delivered while maintaining high rates of disease in control in early HD with favorable prognosis
Stage I/II with no Risk factors, n=1400
A) 4# ABVD + 30Gy IF-RT
B) 4# ABVD + 20Gy IF-RT
C) 2# ABVD + 30Gy IF-RT
D) 2# ABVD + 20Gy IF-RT
RESULTS (8y f/u):
5y FFTF 93% (4#) vs 91% (2#)
Also no differences when comparing 20Gy and 30Gy
CR rates across the board 96%
OS 97%~, maintained at 8yrs
- No difference in efficacy btwn 2# ABVD and 4#ABVD when combined with IF-RT
- In early-stage HD with favorable prognosis, 2#ABD+20Gy IF-RT is as effective and less toxic than 4# ABVD + 30Gy IF-RT
Tell me about GHSG HD13 study
Karolin Behringer Lancet 2015
Done to Invx whether omission of Bleomycin +/- Dacarbazine from ABVD reduced the efficacy in the treatment of early-stage favorable HD
Newly Dx, classic or Nodular LPHL
A) 2# ABVD
B) 2# ABV (Reduced intensity)
C) 2# AVD
D) 2# AV
30Gy IF-RT were given after 2# chemo in each group
5y FFTF 93% (ABVD) vs 81% (ABV) vs 89% (AVD) vs 77% (AV)
Dacarbazine cannot be omitted from ABVD without substantial loss of efficacy
Bleomycin also cannot be safely omitted.
- Because of high-event rates, assignment to AV and ABV groups stopped early
- Despite differences in tumor control, no survival differences, 5y OS ~94-98%
>> likely secondary to good response to 2nd line treatment.
Tell me about HD11
Hans Eich et al JCO 2010
Aim: Invx if treatment results can be improved with more chemo and to evaluate which RT dose
16-75, newly Dx early unfavorable HL
2x2 factorial design:
A) 4#ABVD + 30Gy IF-RT
B) 4#ABVD + 20Gy IF-RT
C) 4# baseBEACOPP + 30Gy IF-RT
D) 4# baseBEACOPP + 20Gy IF-RT
5y FFTF 85%, OS 95%, PFS 86%
BaselineBEACOPP + 20Gy RT > ABVD + 20Gy RT
BaselineBEACOPP +30Gy RT = ABVD + 30Gy RT
ABVD + 30Gy RT uncertain if = ABVD + 20Gy RT
Tell me about HD14
Tresckow et al JCO 2012
Aim: 4#ABVD+30Gy IF-RT gives long-term tumor control of 80%. To try and improve that with more intensive chemo
Newly Dx early unfavorable HL
A) 4# ABVD --> 30Gy IF-RT
B) 2# eBEACOPP + 2# ABVD --> 30Gy IF-RT
5y FFTF HR 0.4, difference of 7%. 88% vs 95%
5y PFS difference 6%, 89% vs 95%
5y OS 97%~
No overall differences in treatment-related mortality or secondary malignancies
Tell me about the NCIC-ECOG study for early HD
Meyer NEJM 2012
Aim: to evaluate if chemo alone will suffice, as chemo+RT is a/w late treatment-related deaths
Previously Untx IA/IIA
A) ABVD 4-6#
- Favorable: STNI alone
C) 4-6#ABVD + STNI if unfavorable
OS 94% (ABVD alone) s 87% (those receiving STNI)
FFDP 87% vs 92%
EFS 85% vs 80%
ABVD alone compared with treatment that included STNI was a/w higher rate of OS
- due to lower rate of death from other causes I
What is the PET 5-point scale?
1 - No uptake above background
2 - Uptake equal or less than that of the mediastinum
3 - Uptake > mediastinum but equal or less than that of liver
4 - Uptake moderately > liver
5 - Uptake markedly higher than liver +/- new lesions
X - New areas of uptake, unlikely to be related to lymphoma
What is the typical immunophenotype expected for classical HL?
PAX5 weak +
What is the immunophenotype for Nodular lymphocyte-predominant HL?
What are they subtypes of classical HL?
Mixed cellular laity
Lymphocyte depleted HL
Lymphocyte rich HL
How would you follow-up and monitor after 5 years for a HL patient?
1) Look out for complications of treatment
- 2nd malignancies: Breast screening, low-dose C
- Thyroid function if previous RT
- CVS risk assessment including stress test/echo at 10-yr interval
- Carotid US if neck is radiated
2) Maintain current health levels
3) General Precautions
- Smoking cessation
- Lifestyle management
- Vaccinations - Haemophilus Pneumococcal, meningococcal, annual influenza vaccine
- General cancer screening
4) Referral to survivorship clinic
What are some of the Advanced RT technologies that you know of?
In Nodular Lymphocyte Predominant HL, when is it enough to to treat with RT alone?
Stage IA - IIA
1) Schlembach et al:
- 5y RFS 95% and 5y OS 100% for Stage A disease treated with IFRT and regional RT alone.
2) Retrospective analysis by GHSG of 3 options in Stage IA disease:
-Comined modality treatment
CR 98% in EFRT, 95% after combined modality and 100% after IFRT. FFTF similar.
What is the value of Rituximab in NLPHL?
1) Prospective Phase II by Stanford Group
- Stage I-IV s/p 4 weekly doses of Rituximab at 375mg/m2
- ORR 100%, 45% CR+uCR
- median FFP 10m
2) GHSG phase II
Investigated Rituximab I newly Dx stage IA NLPHL
CR 86%, PR 14% --> ORR 100%
3.5y OS 100%
3y PFS 80%
Conclusion: Rituximab alone or in combination with chemo has activity in the Mx of newly Dx and relapsed NLPHL
What are the options for Stage IA NLPHL?
1) ISRT 30-36Gy
- Stage IA, IIA (Non-bulky)
2) Observation for Stage IA disease with a completely excised solitary LN
3) Brief course of chemo + ISRT +/- Rituximab if Stage IA (bulky)
What is recommended for Stage III/IV NLPHL?
Chemotherapy +/- Rituximab +/- ISRT
What are the two types of LPHL?
- Atypical Lymphocytic and Histiocytic (L&H) or popcorn cells
- cells embedded in a Nodular background composed of small B lymphocytes and other reactive cells
- L&H cells are set against a diffuse background consisting mainly of reactive T cells
?if able to discriminate reliable.
In addition, purely diffuse subtype would be classified as DLBCL or T-cell-rich B cell lymphoma.
What is the immunophenotype of NLPHL?
What are HRS cells?
Hodgkin Reed-Sternberg cells are germinal center B cells that cannot synthesize immunoglobulin molecules
What constitutes refractory HL?
Patients who fail to obtain CR with initial therapy
Those who relapse within 3 months from the end of initial therapy
What constitutes relapsed HL?
Reappearance of HL greater than 3 months after the attainment of CR
What are the predictors of poor outcome in patients who relapse in HL?
Relapse 3-12 months from end of treatment
Poor response to 2nd line therapy
How can EBV infection be detected?
1) by IHC for latent membrane protein-1
2) ISH for EBV small nuclear RNA transcripts (EBERs)
How common is EBV infection in cHL?
Infrequent in NS subtype
40% of Lymphocyte-rich HL
70% of Mixed-cellularity HL
Close to 100% of lymphocyte-depleted HL
What are the differential diagnosis for cHL?
- T-cell rich B Cell Lymphoma
4) EBV-positive mucocutaneous ulcer
What does extended-field RT (EFRT) encompass?
Radiation field includes:
- clinically involved LN
- adjacent, clinically uninvolved sites
What does IFRT (involved-field) RT encompass?
Radiation field is limited to:
- clinically involved regions
What does ISRT involve ? (Involved-site RT)
RT field includes:
- pre and post-chemo nodal volumes
- margin of healthy tissue to accommodate uncertainties in determining the pre-chemo tumor volume
What does involved-nodal RT involve? (INRT)
RT field includes:
- pre- and post-chemo nodal volumes
- very limited margin of healthy tissue (0.5-1cm)
INRT requires optimal pre-chemo PET/CT imaging acquired with the patient in the treatment position that can be fused with post-chemo imaging
What is the evidence for ABVD as a standard?
Santoro JCO 1987
Combined modality in the past used MOPP
In attempt to reduce some of the delayed complications, ABVD was compared to MOPP in Stage IIB/IIIA/IIIB patients
1) ABVD --> Extensive RT
2) MOPP --> Extensive RT
- CR rate was 80% in MOPP and 90% in ABVD
- 7y FFP 80% in ABVD and 60% in MOPP
- 7y RFS 85% with ABVD and 75% with MOPP
- 7y S 75% with ABVD and 65% with MOPP
Subsequently, George Canellos published in NEJM 1992
- ABVD x 6 months = 12 months of MOPP-ABVD > MOPP