Download - HIV and other Non-Hodgkin’s Lymphomas Matthew Cheung Sunnybrook Health Sciences Centre Feb 27 2009
HIV and otherNon-Hodgkin’s Lymphomas
Matthew CheungSunnybrook Health Sciences CentreFeb 27 2009
Outline
• Review of HIV Lymphomas– Epidemiology/Pathophysiology/Treatment
• Overview of miscellaneous lymphomas– Burkitt lymphoma– T-cell lymphomas– Mantle cell lymphoma
Key Points
• Current classification system - WHO
Follicular (22%)Follicular (22%)
Diffuse large B cell (31%)Diffuse large B cell (31%)
Small lymphocytic (6%)Small lymphocytic (6%)
Mantle cell (6%)Mantle cell (6%)
Peripheral T cell (6%)Peripheral T cell (6%)
Marginal zone B cell, Marginal zone B cell, MALT (5%)MALT (5%)
Other subtypes with a Other subtypes with a frequency < 2% (9%)frequency < 2% (9%)
Marginal zone B cell, nodal (1%)Marginal zone B cell, nodal (1%)Lymphoplasmacytic (1%)Lymphoplasmacytic (1%)
Composite lymphomas (13%)Composite lymphomas (13%)
1982
Morbidity Mortality Reports Weekly 1982;31:277-279
Epidemiology of ARL
Relative Risk of AIDS-Defining Illness in (early) HAART Era
Swiss HIV Cohort Study
Lederberger et al., BMJ 1999
AIDS-Defining Illnesses in 1994 (pre-HAART) vs. 1998 (post-HAART)
AIDS-defining Illness (n=1667)
% of all ADIs (1994)
% of all ADIs (1998)
p-value
Esophageal candidiasis
15% 17% NS
PCP pneumonia
10% 11% NS
CMV retinitis 9% 2% 0.0058
MAC 8% 3% 0.0022
AIDS dementia 7% 4% NS
Non-Hodgkin’s Lymphoma
4% 16% 0.001
Mocroft et al. (EuroSIDA Study), Lancet 2000 – adapted from A. Levine
EuroSIDA Study of 7300 HIV Outpatients
French Database Studyof 80,000 HIV patients
Besson et al., Blood 2001 – adapted from A. Levine
CD4 countPre-HAART (1993/1994)
Post-HAART (1997/1998)
p-value
> 350 15.6 15.9 NS
200 - 349 34.8 33.6 NS
100 - 199 76.8 73.3 NS
50-99 103.8 164.7 0.053
< 50 253.8 223.2 NS
TOTAL INCIDENCE
86.0 42.9 <10-30
Pre-HAART CD4 – 63/цL Post-HAART CD4 – 191/цL
Lymphoma incidence per 10,000 patient-years
Gill et al., HIV medicine 2006
AIDS-related cancers
CD4 counts
Southern Alberta
Hodgkin’s Lymphoma and HIV
Incidence (per 105 py) Adjusted RR (95% CI) SIR (95% CI)
1980-1989 30.9 1.00 7.0 (4.5-10.4)
1990-1995 30.4 0.96 (0.57-1.61) 8.1 (6.4-10.1)
1996-2002 49.4 1.60 (0.91-2.82) 13.2 (10.3-16.7)
Biggar et al. Blood 2006
Levine, A. M. Blood 2006;108:3630
Epidemiology of ARL
• If HAART is effective (in reducing the proportion of individuals with very low CD4 counts), the incidence of NHL should decrease
• PI- and NNRTI-based HAART appear equally protective
• However, the incidence of HL (and potentially other malignancies) may be increasing with better HIV control
Pathogenesis
Pathogenesis - HIV Factors
Carbone et al. Eur J Cancer 2001
Treatment
1. Ideal chemotherapy combinations
2. Role of HAART
3. Role of rituximab
4. (Supportive care)
Chemotherapy in ARLStudy Treatment N HAART CR OS
Pre-HAART era
ACTG (1997)
mBACOD vs. ½mBACOD
198 No ~40-50%~10% (2 years)
HAART era
AMC (2001) CHOP 25 Yes 48% NR
AMC (2005) CHOP 50 Yes 47% 55% (2 years)
HAART era – Infusional / Novel therapies
ECOG (2004)
CDE 55 Yes 45% 45% (2 years)
NCI (2003) EPOCH 39 No 74% 60% (5 years)
Levine et al. (2004)
Liposomal doxo + CVP
24 Yes 75%~50% (2 years)
Early trials – Pre-HAART
Kaplan et al. (NCI-AMC Study), NEJM 1997
Disease-Free SurvivalOverall Survival
ACTG RCT of reduced vs. standard dose mBACOD
Chemotherapy in ARLStudy Treatment N HAART CR OS
Pre-HAART era
ACTG (1997)
mBACOD vs. ½mBACOD
198 No ~40-50%~10% (2 years)
HAART era
AMC (2001) CHOP 25 Yes 48% NR
AMC (2005) CHOP 50 Yes 47% 55% (2 years)
HAART era – Infusional / Novel therapies
ECOG (2004)
CDE 55 Yes 45% 45% (2 years)
NCI (2003) EPOCH 39 No 74% 60% (5 years)
Levine et al. (2004)
Liposomal doxo + CVP
24 Yes 75%~50% (2 years)
Infusional DA-EPOCH
• NCI trial of infusional EPOCH • HAART suspension
Infused agents
Etoposide 50 mg/m2/24 hrs x 96 hrs C.I.
Doxorubicin 10 mg/m2/24 hrs x 96 hrs C.I.
Vincristine 0.4 mg/m2/24 hrs x 96 hrs C.I.
Bolus agents
Cyclophosphamide (cycle 1)
CD4+ cells >100/mm3 375 mg/m2/day IV on day 5
CD4+ cells <100/mm3 187 mg/m2/day IV on day 5
Prednisone 60 mg/m2/day po x 5 days
GCSFday +6 until ANC > 10,000
cells/µL
Little et al. (NCI), Blood 2003
DA-EPOCH in ARL
Total CD4<100 CD4>100
N 39 16 23
Median Age 40 yrs
Stage III / IV 67%
Median CD4 198/mm3
Complete Remission
74% 56% 87%
Little et al. (NCI), Blood 2003
OS at 53 months
Little et al. (NCI), Blood 2003
HIV Parameters During Chemotherapy without HAART
HIV RNA levels – increased 0.83 log
Little et al. (NCI), Blood 2003
HIV Parameters During Chemotherapy without HAART
CD4 count – decreased by 187 cells/mm3
Little et al. (NCI), Blood 2003
Should HAART be given at the same time as chemotherapy?
Lim, S.-T. et al. J Clin Oncol; 23:8477-8482 2005
Survival is improving in the HAART era
Can HAART be given with Chemotherapy?
AMC trial of CHOP + HAART (Indinavir-based)
• n=65 • CR 48%
– Pharmacokinetics – cyclophosphamide clearance reduced x 1.5
– Median VL decreased from 29,000 to 500 copies/mL
– Median CD4 increased from ~130 to 216 cells/mm3
Ratner et al. (AMC Study), JCO 2001
What are the CONS to using HAART?
(1) Drug – Drug Interactions
Antiretroviral ARV effect Chemotherapy Impact
All PIs Inhibit P450CYP3A4 - decr. clearance of etop and vincas
CYP2B6 - decr. activity of cyclophos
Nevirapine Induces P450CYP3A4 - incr. clearance of etop and vincas
CYP2B6 - incr. activity of cyclophos
EfavirenzInhibits / Induces CYP3A4
Variable effects on etoposide, vincas, etc.
45M with HIV-Hodgkin’s
Kaletra-based HAART (lopinavir/ritonavir)
Vinblastine (ABVD)
+ =
(2) Overlapping Drug Toxicities
(3) Adherence
What is the role of rituximab?
AMC RCT of CHOP-R vs. CHOP (+HAART)
Kaplan et al. (AMC Study), Blood 2005
CHOP + R CHOP p-value
RegimenCHOP+R
+ R q month x 3CHOP
n 99 51
CR 58% 47% NS
OS 139 weeks 110 weeks NS
Death due to lymphoma
14% 29% 0.02
Rituximab and Infection
• *more CHOP-R pts died of infection than lymphoma• n=14 patients dying of infection
– 7 culture-positive sepsis– 4 culture-negative sepsis– 2 pneumonia– 1 fungal
• 60% deaths in patients with CD4 <50• 33% deaths during the maintenance phase of R
Kaplan et al. (AMC Study), ASH 2003
CHOP + R
CHOP p-value
Infectious deaths
14% 2% 0.035
The effect of CHOP and rituximab therapy on
B cells and immunoglobulins
Copyright © American Society of Clinical Oncology
Miles et al. J Clin Oncol 2005
Future Trends and Outlook
• Chemotherapy: CHOP is the standard…infusional
chemotherapy showing early promise
• Rituximab: may improve lymphoma outcomes but at the cost of
increased toxicity
• HAART: outcomes in the current era are better
– ?due to improved lymphoma outcomes vs. HIV outcomes
• Combining HAART and chemotherapy
– need to understand more about PK/adherence
Clinical Case
• 29F– Noted unusually heavy menstrual bleeding– Presented to gynecologist – performed
endometrial biopsy
Bone Marrow Biopsy
• Sheets of large, pleomorphic atypical cells infiltrating bone marrow
• CD45+ hematopoeitic malignancy• CD20, CD79a – diffuse positivity B-cell lineage• IHC – TdT, Pancytokeratin, CK7, CK20, TTF-1 –
negative• Cellularity >90%, sparse maturing myeloid cells. • Ki67 – 100%
Endometrial biopsy
• Round blue cell infiltrate composed of moderately sized, round lymphoid cells with fine chromatin, multiple distinct nucleoli.
• CD79a, CD10• Ki67- near 100% proliferation in neoplastic B-cells. • In situ hybridization for EBV RNA – negative. • FISH – consistent with c-myc containing
chromosomal rearrangement.
Diagnosis
Stage IV Burkitt’s Lymphoma
WHO Classification 2008
• Endemic
• Sporadic
• Immunodeficiency – associated• HIV/AIDS – 30% of NHL in HIV+• Congenital immunodeficiency
Sporadic BL
• Worldwide• 1 – 2% of lymphoma in adults• Abdomen, especially ileocecal area
– Abdo pain, nausea, vomiting, bowel obstruction, GI bleeding, syndromes mimicking acute appendicitis, intussusception.
• +Extranodal sites– Ovaries, kidneys, omentum, Waldeyer’s ring– Breast involvement in association with onset of puberty or
with lactation– CNS involvement in adults – ~15-20%
• EBV + in 15-30%
Blum K A, Lozanski G, Byrd J C. Blum K A, Lozanski G, Byrd J C. Blood Blood 2004;104:3009-30202004;104:3009-3020
Intermediate BL/DLBCL (B-cell lymphoma, unclassifiable, with features intermediate
between DLBCL and BL)
• Similar to BL - but with greater variation in nuclear morphology
• Ki67 100%, CD10 +, bcl-2 -
• Cytogenetics or molecular genetics desirable for diagnosis - should have a c-myc translocation
• Key Points– GEP can distinguish BL from DLBCL– BL profiles include high expression of c-
myc and c-myc activated genes– May be more accurate diagnostically than
current methods (but not routinely available)
Figure 4.13a The Biology of Cancer (© Garland Science 2007)
GeneticsThe expression of
c-myc gene is placed under control of the trancription-controlling enhancer
sequences of an immunoglobulin
heavy chain (IgH) gene.
Blum K A, Lozanski G, Byrd J C. Blum K A, Lozanski G, Byrd J C. Blood Blood 2004;104:3009-30202004;104:3009-3020
Treatment
• Short duration, high-intensity regimens
• CNS prophylaxis
• Tumor lysis prevention
• Complete responses - 75-90%
• Overall survival - 50-70%
Magrath Regimen
• A. CODOX-M and B. IVAC (alternating)– HR patients
• A. CODOX-M for 3 cycles for low risk disease– LR patients - LDH/Performance status/No
bulk
P
Parameter Hyper-CVAD + Rituximab
(n=31)
Hyper-CVAD Alone
(n=48)
Overall Age >60
No (%) CR 24/28 (86) 41 (85) 1.0 --
Median F/U, mos (range
22 (9-65) 74 (11-154) -- --
Age, yrs All <60 >60 All <60 >60 -- --
No(%) induction deaths
0 0 0 6(13) 1(3) 5(10) 0.04 --
% relapse 2/28(7) 2/19(11) 0/9(0) 14/41(34) 9/31(29) 5/10(50) 0.008 0.02
% 3yr survival
89 90 89 53 70 19 <0.01 <0.01
% 3y EFS 80 76 89 52 68 19 0.02 <0.01
% 3y DFS 88 88 88 60 70 30 0.03 0.03
% 3y CRD 91 88 100 66 73 44 0.024 0.016
Thomas, et al. Cancer 2006;106:1569-80
Survival with hyper-CVAD plus rituximab compared with hyper-CVAD
(A) Overall
(B) Age < 60
(C) Age > 60
Thomas, et al. Cancer 2006;106:1569-80
Prognosis
• Most patients attain CR within 4-6 weeks of initiating therapy.
• Relapse - within 1st year
Briefly….T-cell NHLs• PTCL-u
• Nodal T-cell lymphoma• Most common in Western countries (60-70%)• Advanced/unfavourable features• Treatment - CHOP is the standard
– ~30% long-term disease-free survival– Campath– Pralatrexate - 54% response rate in relapsed disease– ASCT - in relapse - inferior outcomes compared to
relapsed DLBCL
• ALCL (primary systemic)• ALK+ if expression of ALK TK - t(2;5) - 50-60%
– Results in fusion protein NPM-ALK– Young men, advanced-stage/extranodal disease– 5-yr OS 80%
• ALK-– Older– 5-yr OS 33%
• CHOP is standard
t(2;5)
• Fusion of nucleophosmin (NPM) on chromosome 5 to the catalytic domain of anaplastic lymphoma kinase (ALK) on chromosome 2– ALK: tyrosine kinase receptor with homology to the insulin
receptor kinase subfamily– Transforming capability of fusion protein demonstrated– Unclear mechanism
Survival of with systemic ALCL
Su
rviv
al
Months
ALK+ (n=132)
ALK - (n=22)
0
75
120 180 240
25
50
100
60
p<0.001
Cutaneous ALCL
• Unique subtype of ALCL• AKL-negative• Typically isolated cutaneous red
nodules/tumours• PFS 55% (propensity to relapse)• 10-year disease specific survival ~95%• Typically responsive to radiotherapy
• Role of chemotherapy unclear
Extranodal NK/T-cell lymphoma, nasal type
• Generally extranodal• Upper aerodigestive most commonly• Extensive midfacial destruction common• Extranasal presentations (esp skin/GI) also possible
• Prevalent in Asian/Native Central/South American populations
• EBV associated• Angiocentric/destructive infiltrate of NK/T cells
• Typically CD2+, CD56+, cytoplasmic CD3+, EBV+ (EBER)
• Prognosis - poor (long-term survival ~30%)
Treatment
• Chemotherapy resistance common -• p-glycoprotein mediated
• Primary radiotherapy may be priority• Retrospective review of 105 Chinese patients• RT alone - 83% CR• CT alone - 20% CR (increased to 81% with RT)• No diff OS/PFS with RT vs. CMT
Li et al. JCO 2006
Enteropathy-type intestinal T-cell lymphoma (EITCL)
• Associated with antecedent celiac disease (or concurrent celiac serologies)
• T-cell lymphoma involving SB (especially jejunal ulcers)
• Poor prognosis • OS 20%• DFS 3%
• Treatment• CHOP +/- ASCT• Parenteral/enteral nutrition• Gluten-free diet
MCL
Fisher RI, et al. Lymphoma Annual Update. 2005;29-41. Gascoyne R. Lymphoma Annual Update. 2005;5-20.
• B-cell non-Hodgkin’s lymphoma• 6% of all adult NHL • Clinical features
• Most patients have LN/HSM/BM involvement • PB involvement is common• Unique entity to MCL - lymphomatous polyposis
• Poor prognosis • Incurable with standard therapy
• Median PFS: ~ 2 years after initial treatment• Median OS: ~ 3-5 years
Mantle Cell Lymphoma
Mantle Cell Lymphoma: Diagnostics
Fisher RI, et al. Lymphoma Annual Update. 2005;29-41. Yarbro CH, et al, eds. Cancer Nursing 5th ed. 2000;1340.
• Cellular morphology• Immunophenotype
– CD5+, like CLL – CD20+– CD23-, unlike CLL (CD23+)
• Chromosomal translocation t(11;14)• 70% of MCL• Resultant overexpression of cyclinD1 in majority
Genetics
Chiarle, R., Budel, L., et al., Blood 2000;95(2):619Rosenwald, A., Wright, G., et al., Cancer Cell 2003;3:185Weisenburger Blood 1996;87(11):4483
PRAD 1CCND111q13
C Enhancer PRAD 1CCND1
14q32 11q13
bcl-1120 Kb
Cyclin D1
G1 S+
• t(11;14)(q13;q32) – overexpression of cyclin D1 (under regulation of Ig heavy chain enhancer)
in almost all cases– Results in cell cycle progression
Mantle Cell Lymphoma: Frontline Therapy
NCCN v.I 2006 Clinical Practice Guidelines in Oncology.
• Current approaches– R-HyperCVAD– R-CHOP– R-CVP
• Consider first-line ASCT for those who attained CR and <65/functionally fit
European MCL Network
• First prospective RCT• All patients responding to
CHOP induction• RCT of high-dose
therapy/ASCT vs. IFN maintenance
Progression-free survival
What is BL
• HIV and non-HIV associated
• EBV associated
• Pathology picture
• C-myc oncoprotein expression
Results in children and adults of short intensive therapy for Burkitt and Burkitt-
like lymphoma n EFS
Children and adolescentsSFOP 420 92%BFM - 90 322 89%NCI - CODOX-M IVAC 21 86%
Adults NCI - CODOX-M/ IVAC 20 100%UKLG - CODOX-M - IVAC 52 65%SFOP - LMB 65 74%*
*OS @ 3 yrs
REFERENCES PROTOCOL # PTS
MEDIAN AGE
(Range)
CR,
%
DFS
%
EFS
%
OS
%
Bernstein et al5 Stanford 18 25 (15-75) 78 71.3 at 1yr N/A 66.8 at 2yr
Lopez et al6 MD Anderson
81-01 & 84-30
44 32 (17-72) 80 60 at 5yr N/A 52 at 5yr
McMaster et al7 Vanderbilt 20 44.5 (21-69) 85 60 at 5yr N/A N/A
Longo et al8 ProMACE-MOPP
ProMACE-Cytabom
17
8
36 (19-90) 64.7
100
61 at 15yr
86 at 15yr
N/A
N/A
35 at 15yr
88 at 15yr
Divine et al9 ACVBP 52 34 85 N/A 47 at 5y 53 at 5yr
Soussain et al10 LMB 81,84,86,89 65 26 (17-65) 89 N/A 71 at 3y 74 at 3yr
Divine et al11 LMB 81,84,86,89 51 33 83 N/A 61 at 2y 66 at 2yr
Hoelzer et al12 BNHL83 24 33 (15-38) 63 50 at 8 yr N/A 49 at 8yr
BNHL86 35 36 (18-65) 74 71 at 4 yr 51 at 4yr
Todeschini et al13 Modified POG 8617 8 35 (19-64) 100 N/A 75 at 28 mo
N/A
Adde et al14 CODOX-M/IVAC 26 25 (18-59) 92.3 N/A 84 at 1y N/A
LaCasce et al15 CODOX-M/IVAC 14 47 86 72 at 21mo N/A N/A
Mead et al16 CODOX-M/IVAC 52 35(15-60) 75 N/A 64.6 at 2y
72.8 at 2yr
Thomas et al17 Hyper-CVAD 26 58 (17-79) 81 61 at 3 yr N/A 49 at 3yr
Cabanillis et al18 R-Hyper-CVAD 20 52 (27-77) 89 86 at 1 yr N/A N/A
Lee et al19 CALGB 9251 54 44 (18-71) 80 50 at 4yr N/A 52 at 4yr
Thomas et al20 R-HyperCVAD 31 46 (17-77) 86 88% at 3yr 80% at 3y
89% at 3yr
Blum K A, Lozanski G, Byrd J C. Adult Burkitt Leukemia and lymphoma. Blum K A, Lozanski G, Byrd J C. Adult Burkitt Leukemia and lymphoma. Blood Blood 2004;104:3009-30202004;104:3009-3020
CODOX-M14,15,16
• Low risk – Stage I-IIE, tumor mass <10cm, normal serum LDH, WHO performance status 0-1
– Cyclophosphamide 800mg/m2 D1D 2-5 – 200g/m2
– Vincristine 1.5 mg/m2/day, D1 & D8– Methotrexate 1200 mg/m2 over 1 hr, and then
240 mg/m2 for 23hrs (with leucovorin) D10– IT cytarabine 70mg D1 & D3– IT MTX 12mg D15
IVAC14,15,16
• Ifosfamide 1500 mg/m2/d D1-5 (with mesna)
• Etoposide 60 mg/m2/d D1-5
• Cytarabine 2000 mg/m2 every 12 hrs for 4 doses, D1 & 2
• IT methotrexate 12 mg D5
“The Co-receptor Story”
CD4
CCR5 T-Cell Surface
HIV-1
CCR5
HIV-1
CD4
T-Cell Surface
CCR5 – ∆32 mutation• Associated with a co-receptor that limited
ability of HIV-1 virus to enter/infect host cell
– ∆32 homozygotes - high HIV resistance
– ∆32 hetero - slow HIV progression
– normal (wt) CCR5 - susceptible to HIV-1
CCR5-∆32 and ARL
• OR for lymphoma - 0.32 (0.13-0.79)– CCR5-∆32 mutation is associated with x3 reduced odds
of lymphoma
• Now…CCR5 co-recpt antagonists emerging
Dean et al. Cancer Research 1999
Pathogenesis/Biology
• Classic pathogenesis - virally-induced chronic B-cell stimulation
• Development of ARL is likely multifactorial - host genetic factors may play a role (CCR5 status)
• GC vs. non-GC cell of origin also impacts outcome and may be evolving in era of HAART
• BC Provincial Database (Retrospective)
• No difference in toxic deaths (p = NS)
Chemo + R Chemo
n Total pts in group 9 24 Infection
OI 3 2 Bacterial 5 2 Febrile neutropenia 4 5 Viral 8 Other
Unspecified 9
Toxic deaths, n (%) 2 (22) 13 (54)
Ezza et al., HIV Clin Trials 2007
Lymphoma MD PreferencesBC (n=22) vs. ON (n=92) physicians
0
10
20
30
40
50
60
70
80
90
100
HAART CHOP chemo Rituximab ProphylacticAbx
ON
BC
H
*
% of physicians
ARL treatment options
P<0.0001
Cheung M et al, Ann Hematology 2007