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

EFS – 60%

EFS – 83%

OS 69.9%

OS 81.5%

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