HODGKIN LYMPHOMA Lalita Norasetthada, MD. Overview Limited-stage disease Advanced-stage disease ...
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Transcript of HODGKIN LYMPHOMA Lalita Norasetthada, MD. Overview Limited-stage disease Advanced-stage disease ...
HODGKIN LYMPHOMA
Lalita Norasetthada, MD
Overview
Limited-stage disease Advanced-stage disease Challenging problems
Pregnancy HIV infection Elderly
Limited-Stage HL
Objectives in limited-stage HL To maximize the number of cures and
minimize late toxicity, particularly cardiovascular disease and 2nd cancers by optimizing the mix of available intervention
Unfavorable risk factors for Stage I-II HL
Risk GHSG EORTC NCIC
Age > 50 > 40
Histology MC or LD
ESR and B-Symptoms
> 50 if A; > 30 if B
> 50 if A; > 30 if B
> 50 orAny B-symptoms
Mediastinal mass
MMR > .33 MTR > .35 MMR > .33 or > 10 cm
Nodal sites > 2 > 3 > 3
Extranodal lesion
Any
GHSG HD7 trialEFRT vs 2 x ABVD + EFRT
7 year FFTF : 67% vs 88%
7 year OS : 92% vs 94%
Engert A, et al. J Clin Oncol. 2007; 25: 3495
GHSG HD8 trials :COPP/ABVD & EFRT vs COPP/ABVD & IFRT in limited-stage unfavorable HL
5-year OS : 90.8% vs 92.4%
5-year FFTF : 85.8% vs 84.2%
Engert A, et al. J Clin Oncol. 2003; 21: 3601
N = 532 N = 532
EORTC H8-F trialLimited-stage favorable HL
Early stage with favorable features randomly assigned to 3 MOPP-ABV plus
IFRT (n = 270) STNI (n = 272)
10-year EFS : 98% vs 74%
10-year OS : 97% vs 92%
Ferme C, et al. N Engl J Med. 2007; 357: 1916
EORTC H8-U trialLimited-stage unfavorable HL
Limited-stage with unfavorable features randomly assigned to 6 cycles MOPP-ABV
plus IFRT (n = 336) 4 cycles MOPP-ABV
plus IFRT (n = 333) 4 cycles MOPP-ABV
plus STNI (n = 327)
Ferme C, et al. N Engl J Med. 2007; 357: 1916
10-year EFS : 84% vs 88% vs 87%
10-year OS : 88% vs 85% vs 84%
GHSG HD10 trial : 2 vs 4 x ABVD plus 30 Gy vs 20 Gy IFRT in St I-II favorable HL randomized between
4 x ABVD & 30 Gy IF-RT (arm A) 4 x ABVD & 20 Gy IF-RT (arm B) 2 x ABVD & 30 Gy IF-RT (arm C) 2 x ABVD & 20 Gy IF-RT (arm D)
CR rate : 98.4% 2-year FFTF : 96.6% 2-year OS : 98.5%
Eich H, et al. Int J Radiat oncol Biol Phys. 2005; 63(suppl): S1
no statistical difference between arms
A meta-analysis: the influence of radiotherapy and chemotherapy on long term outcome of limited-stage HL 1974 patients treated in 8 randomized trials
comparing more vs less RT Reduction in RT field sized to IFRT has little if any
impact on survival
1,688 patients treated in 13 randomized trials comparing RT plus CT vs RT alone Addition of CT to RT produced large effect on
disease control but a small non-significant effect on overall survival
Specht L, et al. J Clin Oncol. 1998; 16: 830
GHSG HD14 : BEACOPP escalated in limited unfavorable HL
BEACOPP escalated x 2 + ABVD x 2 + IFRT
ABVD x 4 + IFRT
3-year FFTF 96% 90%
Disease progression
1.8% 5.9%
This more aggressive treatment strategy will become the new standard for early unfavorable HL patients within the GHSG
Whether the improved FFTF translates into an improved overall survival must be awaited
Borchmann P, et al. ASH 2008: abstract
ABVDx6 & RT vs ABVD alone in St I-IIIA non-bulky disease
5-year FFP : 86% vs 84%5-year OS : 97% vs 90%, p= .08
Straus D, et al. Blood. 2004; 104: 3483
Response adapted therapy using FDG-PET : UK NCRN Rapid trials in St I-IIA Initial treatment : ABVD x 3 Re-assessment
if NR/PD, off study If CR/PR, PET scan performed
PET +ve PET -ve
4th cycle of ABVD then IFRT
IFRT
No further treatment
Randomization
(79%)(21%)
Radford J, et al. ASH 2008: Abstract
Treatment modality for limited stage HL
Combined chemotherapy with IFRT is the standard treatment of care Favorable disease : ABVD 2-4 cycles Unfavorable disease : ABVD 4-6 cycles
Chemotherapy alone can be the option in selected subgroup of patients with favorable non-bulky disease, if the long-term toxic risks of radiation are to be avoided, especially for patients younger than 40 years.
Advanced-stage HL
The landmark randomized trial by CALGB for advanced HL
MOPP (n =123)
MOPP/ABVD (n=123)
ABVD(n= 115)
P-value
CR rate 67 82 83 .006
5-year FFS
50 61 65
5-year OS
66 73 75 .28-ABVD for 6-8 months was as effective as 12 months of MOPP/ABVD, and both were superior to MOPP alone in the treatment of advanced Hodgkin's disease
- ABVD was less myelotoxic than MOPP or ABVD alternating with MOPP.
Canellos GP, et al. N Engl J Med. 1992; 327: 1478
Intergroup trial : ABVD vs MOPP/ABVD for advanced HL
MOPP/ABVD(n = 433)
ABVD(n =419)
P-value
CR rate (%) 80 76 .16
5-year FFS (%) 66 63 .42
5-year OS (%) 81 82 .82
Pulmonary toxicity (> gr 2) (%)
30.6 24.5 .06
Hematologic toxicity ( > gr 3) (%)
74.6 63.6 <.001
Second malignancy (no.)
28 18 .13
MDS/leukemia 11 2 .011Duggan DB, et al. J Clin Oncol. 2003; 21: 607
UK NCRI Lymphoma Group Study, ISRCTN 64141244 : ABVD 6-8 + RT vs Standford V
ABVD (n- 261) Standford V (n= 259)
Gr III-IV Pulmonary toxicity (no.)
27 10
Gr III-IV non-pulmonary toxicity (%)
8 19
Overall response rate (%) 89 90
5-yr PFS 76 74
5-y OS 90 92
Involved field irradiation to sites of initial bulk disease (>5cm) or splenic deposits, and to residual
masses
Johnson P, et al. ASH 2008: abstract
GHSG HD9 : COPP/ABVD vs escalated- dose BEACOPP vs standard-dose BEACOPP in St IIB-IV
Diehl V, et al. N Engl J Med. 2003; 348; 2386Diehl V, et al J Clin Oncol 2007; 25(suppl 18): LBA8015
10-year FFTF : 64% vs 70% vs 82%10-year OS : 75% vs 80% vs 86%
GHSG HD12 final analysis : RCT comparing escalated BEACOPP x 8 vs escalated BEACOPP x 4 followed by standard-dose BEACOPP
Entire cohort
Escalated BEACOPP x 8 +/- RT
Escalated BEACOPP x 4 Standard BEACOPP x 4 +/- RT
Gr 3-4 anemia 65% 51%
Gr 3-4 thrombocytopenia
65% 51%
5-yr OS 91% NS NS
5-yr FFTF 85.5% NS NS
5-yr PFS 86.2% NS NS
Diehl V, et al. Blood. ASH 2008 : abstract
Risk-adapted BEACOPP regimen
Relapse or progression occurred in 27% of patients with interim positive PET/CT versus 2.3% of negative scans (P < .02)
5-year EFS and OS for patients with early unfavorable and standard risk vs patients with high risk : 84%, 90% vs 85%, 91%
Limited stage, unfavorable/Advanced stage, IPS <2
Advanced stage, IPS > 3
Standard BEACOPP x 2
Escalated BEACOPP x 2
Restaging with PET or Ga67
Negative : Standard BEACOPP x 4
Positive : Escalated BEACOPP x 4
Dan E, et al. Blood. 2007;109:905
Chemotherapy for advanced HL ABVD x 6-8 cycles is generally recommended Escalated-dose BEACOPP x 4 should be considered
for high-risk patients with an IPS score > 4 If CR : Standard-dose BEACOPP x 4 If PR : Escalated-dose BEACOPP x 4
The ongoing EORTC 20012 trial is comparing escalated BEACOPP and ABVD in advanced HL
The recently completed E2496 intergroup trial compared the Stanford V regimen with ABVD + RT for advanced HL, results are awaited
NCCN. Practice Guidelines in Oncology-v.2 2009
EORTC 20884 trial : Role if IFRT in advanced HL
MOPP/ABVD x 6-8 cycles
CR PR
No further therapy IFRT
Aleman BMP, et al. N Engl J Med. 2003;109:2396
RandomizationIFRT
CR; no further Rx
CR; IFRT PR; IFRT
5-year EFS (%) 84 79 79
5-year OS (%) 91 85 87• IFRT did not improve outcome in patients achieving CR after chemotherapy • Consolidative IFRT is beneficial for patients experiencing PR after chemotherapy
GHSG HD15 : Response adapted therapy using FDG-PET; preliminary result
1-year PFS : 96% vs 86%
Multicenter RCT in advanced HL treated with standard-dose BEACOPP x 8 or escalated-dose BEACOPP x 6 or time-condensed BEACOPP-14 x 8
IFRT was restricted to patients with PET-positive after chemotherapy Negative predictive value of PET after chemotherapy : 94% (95% CI:
91-97)
Kobe C, et al. Blood. 2008; 112 : 3989
Role of IFRT after chemotherapy in advanced HL
Additional IFRT is beneficial for patients with residual disease after chemotherapy
IFRT is routinely recommended for patients with bulky disease
Consolidative IFRT can be omitted in PET negative patients after chemotherapy
HIV related HL
HIV related HL
HIV infection also increases the risk of classical Hodgkin lymphoma, with a relative risk of 8–10-fold compared to the general population
A greater proportion of the subtypes (mixed cellularity, lymphocyte depleted) with less favorable prognosis compared to the general population
The greater proportion of MC and LD subtypes is related to severe immunocompromise, while those with modest immunocompromise are more at risk for the NS subtype
Histology of HIV related cHL
MC LMP1
CD30 CD15
Grogg, et al. J Clin Path. 2007; 60 : 1365
HIV related HL
There is coincident EBV infection, with nearly all cases showing EBER and LMP-1 expression in the HRS cells
The composition of the reactive inflammatory infiltrate in HIV-related HL is often characterized by a predominance of CD8-positive T lymphocytes over CD4-positive lymphocytes, by contrast with the background in HL without HIV infection
Epidermiology of HIV-related HL and the effect of HARRT
Biggar et al. Blood. 2006; 108: 3786
HAART-related improvement in CD4 counts likely explain the increasing HIV related HL incidence since 1996
Characteristic of HIV related HL
Connors J. ASH Educational session. 2008
HIV related HL in HAART era
Patients treated in the pre-HAART era (1984–1996) were compared with those belonging to the HAART era (1997-2004)
By multivariate analysis patients without HAART had a 5.6-fold higher risk for 3-year mortality; HR 5.6, (95% CI 2.20–14.26)
Biggar, et al. Blood. 2006; 108: 3786
2-year OS 74% vs 34%, p <.0001
Response of HAART and survival outcomes
HR P-value
Response to HAART
.19 .0045
Age < 45 .23 .003
CR .30 .007
Kaplan Meier cumulative survival plot Multivariate analysis
2-year OS 89% vs 44%, p <.0001
Hoffman C, et al. Br J Haematol. 2004; 125: 445
Chemotherapy regimens for HIV-related HL
Standford V1
BEACOPP2 VEBEP3 ABVD4
No. 56 12 28 62
Stage III-IV (%)
71 92 71 100
CD4 (/uL) 238 205 257 129
HARRT Yes Yes Yes (25%) Yes
G-CSF Yes Yes NS 20%
CR (%) 81 100 75 87
Survival, % (year)
51 (3) NA 86 (2) 76 (5)
Spina, et al. Blood. 2002; 100: 19871; Hartman P, et al. Ann Oncol. 2003. 14: 15622
Spina M, et al. Blood. 2005; 106: 100a3; Xicoy B, et al. Haematologica. 2007; 92: 191 4
Additional therapy in HIV related HL
HAART Opportunistic infection prevention Hematopoietic growth factor Psychological support
HL during Pregnancy
HL during pregnancy
Two patients need to be managed Mother : optimally controlling lymphoma Fetus : avoiding toxicity and allowing the
normal term delivery
Information about the best approach to management of coincident HL and pregnancy is limited
HL and birth outcomes : a Danish nation wide cohort study
Langagergaard V, et al. Br J Cancer. 2008; 98: 183
Dx within 2 yr prior to pregnancy
Dx during Preg
Staging in HL during pregnancy Avoiding the use of imaging that requires
radiation CXR with proper shielding and abdominal
ultrasonography MRI Abdominal and pelvic CT should be avoided FDG-PET can cross the placenta and reach
the fetus, it may involve higher radiation exposure than regular CT and its use cannot be recommended during pregnancy
HL during pregnancy
As a general rule any treatment, radiation or chemotherapy should be avoided during the first trimester unless severely threatening symptoms are present
More than 50% of patients can continue the pregnancy to term without any treatment for the lymphoma
Management HL during pregnancy
If treatment are required Radiation Single agent chemotherapy Combined chemotherapy
RT during pregnancy
From 2 case series : 11 patients with limited-stage received supradiaphargmatic RT with special shielding 10 patients achieved CR without evident fetal injury
When conventional doses of radiotherapy are administered, a distance of over 30 cm from the field edges will limit the total exposure of the fetus to only 4-20 cGy
Therefore, radiotherapy may be considered in specific circumstances such as lymphoma confined to the neck or axillary lymph nodes
Exposure to 10-20 cGy of radiation is considered as the threshold dose for severe congenital malformation when given during organogenesis
Gelb AB, et al. Cancer1996; 78: 304; Nisce LZ, et al. J Clin Oncol. 1986; 9: 146;
Kal HB, et al. Lancet Oncol 2005; 6: 328
Radiation exposure during the second and third trimesters is associated with a carcinogenic effect that may include an increased risk for the development of leukemia and solid tumors within the first decade of life
Another concern is the increased risk of neurodevelopmental impairment, including a decrease in the IQ and even severe mental retardation
RT during pregnancy
Kal HB, et al. Lancet Oncol 2005; 6: 328
Chemotherapy during pregnancy
Chemotherapy during the first trimester may increase the risk of spontaneous abortions, fetal death and major malformations
The fetus is extremely vulnerable from the 2nd -8th week of gestation, during which organogenesis occurs
Between the 14th to 16th weeks of gestation the risk of severe malformations or mental retardation is reduced significantly
Cardonick E, et al. Lancet Oncol 2004; 5: 283; Leslie KK, et al. Obstet Gynecol Clin North Am 2005; 32: 627
Second and third trimester exposure is not associated with malformations but increases the risk of Fetal or neonatal death IUGR Pre-term delivery Low birth weight
These complications may be associated with adverse long-term effects such as neurodevelopmental impairment, increased rate of cardiovascular risk factors
Cardonick E, et al. Lancet Oncol 2004; 5: 283; Leslie KK, et al. Obstet Gynecol Clin North Am 2005; 32: 627
Chemotherapy during pregnancy
Case series: HL during pregnancy
24 cases of HL during pregnancy 12 cases received MOPP, MOP or cyclophosphamide during
1st trimester Spontaneous abortion : 2 Fetal malformation : 5
10 cases receiving combined chemotherapy after 1st trimester delivered normal infants
Based on this observation and the known carcinogenicity of alkylating agent such as mechlorethamine, cyclophosphamide, procarbazine and chlorambucil should be avoided
Ebert U, et al. Pharmacol Ther. 1997; 74: 207
ABVD regimen in pregnancy 2 case series involving 13 cases
No fetal adverse outcomes after receiving ABVD during first, second and third trimesters
Anselmo AP, aet al. Fetal Diagn Ther. 1999; 14: 102; Cardonick E, et al. Lancet Oncol. 2004; 5: 283
Single agent : Vinblastine > 75% response rate in treatment naïve HL patients
and modest toxicity
Reported to be teratogenicity in mice No similar effect reported in human at doses
therapeutic for lymphoma
The combination of high level of effectiveness, minimal acute toxicity and low likelihood of negative effect on the fetus make vinblastine a useful agent to suppress HL during pregnancy
Armstrong JG, et al. Science. 1964; 143: 703 Lacher MJ, et al. Ann Intern Med. 1964; 61: 113
Rosenzweig AI, et al. Ann Intern Med. 1964; 61: 108 Connors J, et al. ASH Educational session. 2008
Management after delivery Patients who have been able to complete the
pregnancy without treatment Repeat full staging Consider appropriate therapy according to stage
of lymphoma
Patients who have been treated with vinblastine Multi-agent chemotherapy 6-8 cycles as accurate
staging cannot be performed
Connors J, et al. ASH Educational session. 2008
Suggesting algorithm for the treatment of HL during pregnancy
Perek D, et al. Hematologica. 2007; 92: 1230
HL in elderly
GHSG: HL in elderly
Age < 60, n = 3879 Age > 60, n = 372
Median Age (years) 31 65
Stage III-IV (%) 40 48
B-symptom (%) 43 50
Bulky disease (%) 60 49
PS < 70 (%) 3 11
IPS > 4 (%) 11 13
Histology (%) NS MC
6619
4135
Engert, et al. J Clin Oncol. 2005; 23: 5052
Engert, et al. J Clin Oncol. 2005; 23: 5052
GHSG: HL in elderly
Dose intensity and the outcomes in elderly patients
Langren O, et al. Haematologica. 2007; 88: 438
Factors contributing to poorer outcomes in elderly
Less favorable histologic subtypes Co-morbidity Delayed diagnosis Inadequate adherence to treatment
protocols Failure to maintain dose intensity
Chemotherapy regimen for HL in elderly
Engert A, et al. J Clin Oncol. 2005; 23: 50521; Feltl D, et al. Leuk Lymphoma. 2006: 47: 15182
Kolstad A, et al. Leuk Lymphoma ; 2007; 48: 5703; Ballova V, et al. Ann Oncol. 2005 4 Levis A, et al. Ann Oncol. 2004; 16:1245; Mcpherson N, et al. LeuK Lymphoma. 2002: 43: 13956
1
23
4 5 6
ABVD compared with other chemotherapy regimens in elderly
Connors J. ASH Educational session. 2008
Management for HL in elderly Chemotherapy regimens
No special regimen superior ABVD remains the goal standard
Anticipate increase toxicity Hematologic Pulmonary Cardiac Neurologic
Hemopoietic growth factors
Can bleomicin be omitted in patients with compromised pulmonary function?
Canellos G, et al. J Clin Oncol. 2004; 22: 1533
Overall treatment plan for HL in elderly
Favorable non-bulky limited stage ABVD x 2 + IFRT
Unfavorable limited stage or advanced stage HL ABVD until 2 cycles past CR (minimum 6)
Patients with quite advanced age and too frail to receive chemotherapy Radiation
Connors J. ASH Educational session. 2008
THE END