Non-Hodgkin’s Lymphomas HIV and other Non-Hodgkin’s Lymphomas Matthew Cheung Sunnybrook Health Sciences Centre Feb 27 2009

Outline Review of HIV Lymphomas Overview of miscellaneous lymphomas Epidemiology/Pathophysiology/Treatment Overview of miscellaneous lymphomas Burkitt lymphoma T-cell lymphomas Mantle cell lymphoma

Current classification - how does it differ from previous…. Based on previou 1994 REAL classification, which used all available info including clinical, morphology, IHC, genetic features to define “real” disease entities……..some disease used some of these features more than others, and there is no one gold standard……

Key Points Current classification system - WHO Composite lymphomas (13%) Small lymphocytic (6%) Follicular (22%) Mantle cell (6%) Peripheral T cell (6%) Marginal zone B cell, MALT (5%) Other subtypes with a frequency < 2% (9%) Diffuse large B cell (31%) Marginal zone B cell, nodal (1%) Lymphoplasmacytic (1%)

1982 Morbidity Mortality Reports Weekly 1982;31:277-279 From a historical standpoaint….if we first go back about 25 years…….The link between lymphoma and the HIV virus actually predates the definition of A.I.D.S itself created .by the CDC in 1982……. -so amonst this first year of reports of the constellation Ois…was this initial finidng of 4 cass of NHL amongst thie same high risk population…… Quite early on was the recognition that these were similar cancers or lymphomas that occurred in the non-HIV population…..but in this potpulation seen at a much higher frequency than expected… AIDS case definition - 1981 to 1985 - Main point - what is lymphoma (B-cell lymphoid malignancy - in the context of advanced immnosuppresion) Morbidity Mortality Reports Weekly 1982;31:277-279

Epidemiology of ARL So has the epidemiology of ARL changed in the modern era…

Relative Risk of AIDS-Defining Illness in (early) HAART Era Swiss HIV Cohort Study This is a Swiss HIV Cohort published early in the HAART era comparing the risk of opportunistic illnesses in the post-HAART era compared to the incidences before HAART was available. Clearly, there has been a profound decrease in all opportunistic infections and KS, but a stable incidence of NHL following HAART therapy. And the real question now iin the HAART era is whether ARL still exists or whether it has essentially disappeared like many other AIDS-related complications….. Lederberger et al., BMJ 1999

AIDS-Defining Illnesses in 1994 (pre-HAART) vs. 1998 (post-HAART) EuroSIDA Study of 7300 HIV Outpatients AIDS-defining Illness (n=1667) % of all ADIs (1994) % of all ADIs (1998) p-value Esophageal candidiasis 15% 17% NS PCP pneumonia 10% 11% CMV retinitis 9% 2% 0.0058 MAC 8% 3% 0.0022 AIDS dementia 7% 4% Non-Hodgkin’s Lymphoma 16% 0.001 As a result.…during the early HAART time frame, NHL was become one of the most common initial AIDS-defining illnesses. So prior to 1994, prior to HAART therapy, NHL was about the 8th most common ADI representing about 4% of ADIs. After HAART, the initial ADI is NHL in about 16%, one of the most common AIDS-defining diagnoses. Mocroft et al. (EuroSIDA Study), Lancet 2000 – adapted from A. Levine

French Database Study of 80,000 HIV patients Pre-HAART CD4 – 63/цL Post-HAART CD4 – 191/цL Lymphoma incidence per 10,000 patient-years CD4 count Pre-HAART (1993/1994) Post-HAART (1997/1998) p-value > 350 15.6 15.9 NS 200 - 349 34.8 33.6 100 - 199 76.8 73.3 50-99 103.8 164.7 0.053 < 50 253.8 223.2 TOTAL INCIDENCE 86.0 42.9 <10-30 -does this actually mean that the incidence of ARL is increasing? Probably not…..more recent larger studies are beginning to show a clear reduction in incidence of ARL. In this large FHD study, the pre-HAART era patients had a median CD4 value of ……. -as the CD4 count went up, the incidence of lymphoma went way down….. -what’s interesting is that if you look at the individual CD4 strata, you find that the risk of lymphoma at a given CD4 count did not change between the pre-HAART period and the post-HAART period. So, it appears that most of the decrease in ARL is related to the fact that fewer patients have a very very low CD4 count in the current HAART era….…… Besson et al., Blood 2001 – adapted from A. Levine

Southern Alberta CD4 counts AIDS-related cancers related to improvements in CD4 counts…. In this study from a large group of individuals with HIV in Southern Alberta….you can see that over time, CD4 counts have improved from low 300s to high 300s, and more importantly for development of ARL, these blue vertical bars represent the numbers of individuals with very low CD4 counts …less than the 50 range…and with less people with that degree of immunosuppression, there has been a dramatic reduction in all types of AR cancers….not just KS but also CC and ARL. …confirmed with recent CDN data… Comparing pre- to post-HAART eras….increase in median CD4 count from low 300s to high 300s, and more importantly for development of ARL, a virtual elim of cohort with extremly low CD4 counts. Coincident with this has been a significant reduction in all types of AR cancers, not just KS but also CC and ARL. AIDS-related cancers Gill et al., HIV medicine 2006

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) Is this the same for all malignancies in HIV…interestingly, may not be the case for HD in the HIV setting… This is a recent study in the US to describe the incidence of HL since the HAART era. Unlike NHL, they found an increasing incidence in the era of HAART. What was even more surprising was that incidence of HL rose significantly on the vertical axis here as the CD4 count on the x-axis increased, with the most marked increases in the higher cD4 counts for the Nod Sclerosis subtypes…as seen in these black bars. Hodgkin’s and HIV Why increase - RS gerenate cytokines/chemokines which result in influx of CD4 and other inflammatory cells - these cells provide signals needed for prolife/survival of RS…..perhaps CD4 needed to generate the inflamm milieu In persons with HIV/AIDS (PWHAs), Hodgkin lymphoma (HL) risk is increased. However, HL incidence in PWHAs has unexpectedly increased since highly active antiretroviral therapy (HAART) was introduced. We linked nationwide HIV/AIDS and cancer registry data from 1980 through 2002. Immunity was assessed by CD4 T-lymphocyte counts at AIDS onset. Annual HL incidence rates were calculated for 4 through 27 months after AIDS onset. During 477 368 person years (py's) of follow-up in 317 428 persons with AIDS (PWAs), 173 HL cases occurred (36.2 per 10(5) py's). Incidence was significantly higher in 1996 to 2002 than earlier. Incidence in PWAs with 150 to 199 CD4 cells/muL was 53.7 per 10(5) py's, whereas in PWAs with fewer than 50 CD4 cells/muL, it was 20.7 per 10(5) py's (P(trend) = .002). For each HL subtype, incidence decreased with declining CD4 counts, but nodular sclerosing decreased more precipitously than mixed cellularity, thereby increasing the proportion of mixed cellularity HL seen in PWAs. We conclude that HL incidence is lower with severe immunosuppression than with moderate immunosuppression, and HAART-related improvements in CD4 counts likely explain the increasing HL incidence in PWHAS observed since 1996. With more severe immunosuppression, nodular sclerosing HL becomes infrequent, explaining the higher proportion of mixed cellularity HL found in PWAs. Pathogenesis implications are discussed. Biggar et al. Blood 2006

Levine, A. M. Blood 2006;108:3630 Levine slide Why woul dthe inceidne increase with improved immunity…one hypothesis is that the generation of HL requires an constant interaction between the maignnat RS cells..that prodcues this profound cytokine milieu…. and surrounding inflam cells that include CD4 cells……..in advanced HIV..pts just don’t have enough of these CD4 cells to support the progression of HIV-Hodgkin’s….so it only developments when the immune system is reconstituted enough because of HAART to generate this microenvironment…… All of this is suggestive than, that we have not seen the end fo the AIDS-realted cancers….especially with patients living longer than ever before…… We can speculate about why these relationships are observed. An essential feature of HL is the nonneoplastic milieu of reactive cells in the tumor mass. The neoplastic Hodgkin-Reed Sternberg (H-RS) cells usually constitute only 0.1% to 1% of the cells present in the tumor. The H-RS cells are likely of B-lymphocyte lineage and therefore are unlikely to be directly impacted by HIV, which infects CD4􏰁 T-lymphocytes. However, H-RS cells produce many cytokines and chemokines, resulting in an influx of activated CD4 cells (CD40􏰁, CD26􏰂), histiocytes, and other cells. Moreover, H-RS cells can respond to the inflammatory cells surrounding them. Thus, recruited inflammatory cells may provide essential feedback signals that stimulate proliferation or inhibit apoptosis of H-RS cells. HL incidence may decline in severely immunosuppressed PWAs because the malignant H-RS cells are not able to recruit lymphocytes and histiocytes required for their survival. Alternatively, with advanced immunosuppres- sion, perhaps HL remains occult until the immune system is sufficiently reconstituted to respond to the H-RS cells, or lym- phomagenesis could shift toward NHL phenotypes, which are independent of an inflammatory milieu. 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 To summarize this section on epidemiology….. So early evidence in the HAART era suggested that the incidence of ARL was not decreasing to the extent of other ADIS….and I wonder if it was just that we needed more time to see the population of pts with very low CD4 counts shrink….with that, more mature data now have demonstrated that if ……… Howevefr, this may not be the end of AR-malignancies…infact..the incidence of HL as one example…., paradoxically…… better HIV control……fewer competing mortaliies such as OIs and prolonged survival with subtle impriaments in immunity – it is clear that the ARL and HL are here to stay…

Pathogenesis Only going to highlight a new aspect of pathogenesis….

Pathogenesis - HIV Factors ……no one has ever been able to find HIV viral sequences within the tumour clone, suggesting that HIV may not play a direct role in lymphomagenesis…HIV is thought to result in lymphoma however, through three classic mechanisms….that is reduced immune surveillance, cytokine dysregulation, and along with co-infections like hepatitis, EBV, or HHV8, ….chronic B-cell hyperstimulation….that later leads to a defining translocation and lymphogenesis. Pathophysiology of HIV lymphoma -likely multifact resulting in variability in presentations -classic is chronic antigenic stimulation from HIV or co-infections, such as EBV or HHV-8 leading to hyperstimulation of B-cells and eventual transformation -infectious agents are also the likely cause of a dysreg cytokine profile that includes potent growth factors and anti-apoptotic b-cell factors -markers of activation - 27,30,44 -markers of isotype switching 23, -marker of B-cell stimulation - IL-10 -all elevated in lymphoma patients - may also predict lymphoma in that they were higher for 6 mos prior to NHL diagnosis The Multi-Center AIDS Cohort Study (MACS) evaluated the cytokine profile in serum of homosexual/bisexual men who went on to develop lymphoma within the next 6-month period.12 Markers of activation, including soluble CD27, CD30, and CD44 were elevated when compared with HIV-positive controls who did not develop lymphoma. In addition, markers of isotype switching, including soluble CD23 and IgE, were elevated, as was serum interleukin (IL)-10, a marker of B-cell stimulation. Serum levels of immunoglobulin (Ig) M and IgG were decreased when compared with controls. In multivariate analysis, serum CD23, CD27, IgM, IgG, IgE, and IL10 were independently associated with lymphoma. While it is highly likely that lymphoma had already developed in these patients, who were formally diagnosed within 1 to 6 months after serum collection, it is of interest that a particular pattern of markers, related to B-cell activation, stimulation and isotype switching were consistently expressed. These markers may provide the ability to predict which HIV-infected patients are at increased risk for development of B-cell lymphoma. -stromal derived factor-1 mutation- chemokine that naturall binds CXCR4 - increases risk of infection -however, complete block fo the CCR5 receptor may have effects on the immune system - maraviroc story. Carbone et al. Eur J Cancer 2001

Treatment Ideal chemotherapy combinations Role of HAART Role of rituximab (Supportive care) Shift gears……talk about the major treatment controversies….which I see as ….what is the ideal

Chemotherapy in ARL Study Treatment N CR OS HAART 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) 50 47% 55% (2 years) HAART era – Infusional / Novel therapies ECOG (2004) CDE 55 45% 45% (2 years) NCI (2003) EPOCH 39 74% 60% (5 years) Levine et al. (2004) Liposomal doxo + CVP 24 75% ~50% (2 years) -this is a selection of some of the regimens that have been studied in ARL…. Prior to the advent of HAART, patients with AIDS-related NHL were managed with lower-dose regimens. Trials comparing standard to reduced combination chemotherapy showed no benefit in terms of OS or DFS in patients receiving standard therapy but much higher toxicity and longer hospitalizations. Survival at 2 years for both low- or standard-regimens was approximately 10%. -in the HAART era…..standard-dose regimens, including CHOP have been tried, demonstrating moderate response rates and acceptable tolerability….and are now considered the standard of care…. -more recently, there has been increased interest in standard-dose infusional anthracycline-based regimens…..designed to further reduce toxicity and address the hypothesis that ARL are prone to excessive drug resistance through the p-gp mechanism

Early trials – Pre-HAART ACTG RCT of reduced vs. standard dose mBACOD Overall Survival Disease-Free Survival Prior to the advent of HAART, patients with AIDS-related NHL were managed with lower-dose palliative regimens. Trials comparing standard to reduced palliative dose chemotherapy showed no benefit in terms of OS or DFS in patients receiving standard therapy but much higher toxicity and longer hospitalizations in patients receiving standard dose chemotherapy. Survival at 2 years for both low- or standard-regimens was approximately 10%. Kaplan et al. (NCI-AMC Study), NEJM 1997

Chemotherapy in ARL Study Treatment CR OS N HAART 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) 50 47% 55% (2 years) HAART era – Infusional / Novel therapies ECOG (2004) CDE 55 45% 45% (2 years) NCI (2003) EPOCH 39 74% 60% (5 years) Levine et al. (2004) Liposomal doxo + CVP 24 75% ~50% (2 years) -in the HAART era…..standard-dose regimens, including CHOP have been tried, demonstrating moderate response rates and acceptable tolerability….and are now considered the standard of care…. -more recently, there has been increased interest in standard-dose infusional anthracycline-based regimens…..designed to further reduce toxicity and address the hypothesis that ARL are prone to excessive drug resistance through the p-gp mechanism

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 GCSF day +6 until ANC > 10,000 cells/µL This research culminated in this recent phase II study of an infusional regimen, consisting of a infusional chemothearpy drugs and dose-adjustments according to initial CD4 count tto minimize toxicity. HAART was not given due to concerns of drug-interactions with chemotherapy and inconsistent compliance with antiretrovirals resulting in increased resistance. 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% 39 patients (to give you an idea of the type of evidence we have to guide lymphoma therapy) were enrolled and HAART therapy was not administered until after the final cycle of chemotherapy. 2/3 of patients were in an advanced stage. Median CD4 count was 198/mm3 Results of this trial was amazing. A complete remission rate of 74% was achieved which is comparable to results we would expect in a non-HIV population. Response was better in patients with a higher baseline CD4 count >100 compared to CD4 <100. It should be kept in mind that this is a small phase II single centre trial, but all the same, these are the highest response rates seen in HIV lymphoma to date…. Little et al. (NCI), Blood 2003

OS at 53 months Little et al. (NCI), Blood 2003 Spectacular results in this trial….. -PFS 73% and OS 60% at median follow-up of 53 months. -Patients with initial CD4 count <100/mm3 had worse survival compared to patients with CD4 count >100/mm3 (CR 87% vs. 16%). CHEMOTHERAPY MESSAGE – ANTHRACYCLINE BASED REGIMENS ARE TOLERABLE AND NOW STANDARD OF CARE…INFUSIONAL REGIMSESN HAVE BIOLOGIC RATIONALE. Little et al. (NCI), Blood 2003

HIV Parameters During Chemotherapy without HAART HIV RNA levels – increased 0.83 log What happens if we omit HAART completely… During treatment, the median CD4 count fell 189 cells/mm3, but returned to baseline by 6-12 months after completion of EPOCH. VL increased by almost 1 log during treatment, but decreased after chemotherapy was stopped and HAART was initiated. No opportunistic infections occurred during treatment, although 3 patients developed OIs within 2 months of completion of EPOCH...which emphasizes that if HAART is not used during chemotherapy, than treatment should be started immediately after chemotherapy is complete. Little et al. (NCI), Blood 2003

HIV Parameters During Chemotherapy without HAART CD4 count – decreased by 187 cells/mm3 What happens if we omit HAART completely… During treatment, the median CD4 count fell 189 cells/mm3, but returned to baseline by 6-12 months after completion of EPOCH. VL increased by almost 1 log during treatment, but decreased after chemotherapy was stopped and HAART was initiated. No opportunistic infections occurred during treatment, although 3 patients developed OIs within 2 months of completion of EPOCH...which emphasizes that if HAART is not used during chemotherapy, than treatment should be started immediately after chemotherapy is complete. Little et al. (NCI), Blood 2003

Should HAART be given at the same time as chemotherapy?

Survival is improving in the HAART era \And there’s certainly no debate that HAART has made a tremondous difference in the sruvival of pts once they develop ARL…..but that doesn’t establish whether you need to treat with HAART at the same time as chemohtearpy or if you can get away with starting it just after the completion of chemohterapy……. Or whether there is actually an anti-cancer or anti-lymphoma effec of the HAART itself…. Is it necessary to obtain a resopnse to lymphoma – that question still neeeds to be answered…. It may be possible that the better outocmes are not because of better lmphoma control but becaue of better supportive care options, the change in pathogenesis that we’ve talked about, the even overally better HIV outcomes…in which case there may not be an urgency to start HAART… -JCO prognosis - improved mortality -HAART and immune reconstitution (better HIV outcomes) -HAART and improved response/OS (better NHL responses) -supportive care improved - infection -change in pathology (from immunoblastic to centroblastic) PROS Associated with OS – no debate in this…but doesn’t answer the question of the timing of HAART Associated with improved RR – but this is controversial – more data suggests no association Ability to control HIV replication (VL) – Ratner study -without it what happens – Wilson study Lim, S.-T. et al. J Clin Oncol; 23:8477-8482 2005

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 What evidence is there of a direct benefit of using HAART then at the same time as chemo… …..surprisingly few studies have addressed this……. Early studies in the HAART era studied the PK of giving chemotherapy with HAART. The AMC performed a non-randomized, sequential study of standard-dose and reduced dose CHOP with GCSF support in combination with an early HAART regimen (d4T, 3TC, and indinivir). 65 patients were enrolled. Cyclophosphamide clearance was reduced 1.5-fold compared to historical controls, without clinical significance. So there is at least a theoretical benefit to providing immune reconstition and contorlling viral replication during chemotherapy… Improved CD4 and VL – that alone may justify using HAART during chemothearpy 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 P450 CYP3A4 - decr. clearance of etop and vincas CYP2B6 - decr. activity of cyclophos Nevirapine Induces P450 CYP3A4 - incr. clearance of etop and vincas CYP2B6 - incr. activity of cyclophos Efavirenz Inhibits / Induces CYP3A4 Variable effects on etoposide, vincas, etc. One major concern is the unknown PK consequence of mixing ARVs and chemohterapies……. The likelihood of drug interactions with combined therapy is high, since protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are inhibitors or inducers of the cytochrome P450 (CYP) system. Also many chemotherapies..including….EVC….are substrates of the CYP system…. One ex. Is the finding that most Pis…but ritonavir in particular can inhibit isoenzymes such as cyp3a4…resulting in decreased clearance and detoxification of the vinca alkaloids…. The ARVS..particularly the Pis..have effects on the cyto P450 systems… So what you see here is the ARVs and the effects on the P450 systems……and the resultant impact on the chemotherapy drugs… Julie’s email about PI and vinca alkaloid use Substrates/inducers/inhibitors (CYP P450) NNRTI/Pis Cyclo Doxo Etoposide Vinca alkaloids Pglycoprotein pathway - modulated by some Pis and NNRTIs Concerns re: CYP P450 The likelihood of drug interactions with combined therapy is high, since protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are substrates and potent inhibitors or inducers of the cytochrome P450 (CYP) system. Since many antineoplastic drugs are also metabolised by the CYP system, coadministration with HAART could result in either drug accumulation and possible toxicity, or decreased efficacy of one or both classes of drugs. Although formal, prospective pharmacokinetic interaction studies are not available in most instances, it is possible to infer the nature of drug interactions based on the metabolic fates of these agents. Paclitaxel and docetaxel are both metabolised by the CYP system, although differences exist in the nature of the isoenzymes involved. Case reports describing adverse consequences of concomitant taxane-antiretroviral therapy exist. Although other confounding factors may have been present, these cases serve as reminders of the vigilant monitoring necessary when taxanes and HAART are coadministered. Similarly, vinca alkaloids are substrates of CYP3A4 and are, thus, vulnerable to PI- or NNRTI-mediated changes in their pharmacokinetics. Interactions with the alkylating agents cyclophosphamide and ifosfamide are complicated as a result of the involvement of the CYP3A4 and CYP2B6 isoenzymes in both the metabolic activation of these drugs and the generation of potentially neurotoxic metabolites. Existing data regarding the metabolic fate of the anthracyclines doxorubicin and daunorubicin suggest that clinically detrimental interactions would not be expected with coadministered HAART. Commonly used endocrine therapies are largely substrates of the CYP system and may, therefore, be amenable to modulation by concomitant HAART. In addition, tamoxifen itself has been associated with reduced concentrations of both anastrozole and letrozole, raising the concern that similar inducing properties may adversely affect the outcome of PI- or NNRTI-based therapy. Similarly, dexamethasone is both a substrate and concentration-dependent inducer of CYP3A4; enhanced corticosteroid pharmacodynamics may result with CYP3A4 inhibitors, while the efficacy of concomitant HAART may be compromised with prolonged dexamethasone coadministration. Since PIs and NNRTIs may also induce or inhibit the expression of P-glycoprotein, the potential for additional interactions to arise via modulation of this transporter also exists. Further research delineating the combined safety and pharmacokinetics of antiretrovirals and antineoplastic therapy is necessary.

Kaletra-based HAART (lopinavir/ritonavir) 45M with HIV-Hodgkin’s Kaletra-based HAART (lopinavir/ritonavir) Vinblastine (ABVD) = + We actually faced this first hand with a pt on lopinavir/ritonavirbased ARVs and receiving ABVD for Hodgkins……the likely inhibition of 3a4resulted in excessive neuropathy and you can see these massively distended bowel loops…and eventually perforation… And in fact at SMH…after discussion around these cases, they’ve already automatically moved on to 25% dose reduction of the vincas with PI combinations… …we have submitted an abstract to this year’s ASH about our experience with HIV-Hodgkin’s across Toronto and Vancouver…and we’ve found that significant grade 3-4 NT occurs in ½ of the population receiving concurrent HAART and ABVD with the most prominent predictor for NT being exposure to ritonavir or ritonavir-boosted regimens…… On the other hand, more recent evidence suggests that CYP3A4 is involved in the detoxification of vinblastine and vincristine, since less vinca mediated cytotoxicity was observed in cells expressing CYP3A4.70 Thus, inhibition of metabolism would be expected to increase the risk and severity of common dose related toxicities of the vinca alkaloids, particularly neurotoxicity and myelosuppression. Currently available evidence supports the latter possibility, as several published cases exist describing severe neurotoxic symptoms when vincristine was given concomitantly with the 3A4 inhibiting azole itraconazole

(2) Overlapping Drug Toxicities Anotehr concern is the worsening of other chemotherapy toxicities with the addition of certain antiretrovirals….most commonly in the past, the use of AZT was associated with much more severe mhelosuppression..and now we would geenrally suggest switching people off of AZT-containting combinations… PIs may be associated with higher rates of neutropenia – but not clinically relevant…. Neuropathy is a concern with the vincas and can be greatly exacerbated with the addition of DDI or stavudine…….these combinations snould also be used with caution.. A third concern is the worsening of other chemotherapy toxicities with the addition of certain antiretrovirals….most commonly in the past, the use of AZT was associated with much more severe mhelosuppression..and now we would geenrally suggest switching people off of AZT-containting combinations…

(3) Adherence Finally…..one other major concern is the ability of pts to adhere to ARVs at the same time that they’re starting anywhere from 10-1t5 othert drugs and experiencing new side effects like n/v……

What is the role of rituximab?

AMC RCT of CHOP-R vs. CHOP (+HAART) p-value Regimen CHOP+R + R q month x 3 n 99 51 CR 58% 47% NS OS 139 weeks 110 weeks Death due to lymphoma 14% 29% 0.02 This led to the AMC initiating a study of the role of rituximab therapy in patients with HIV-related lymphoma. HAART was recommended but it was unclear how many pts actually adhered to the regimens. R was given in an unusual dosing regimen with a brief maintenance phase following induction chemotherapy. CR rate with R-CHOP was similar to CHOP alone (57% vs. 49%; p=NS), as was median event-free survival (approximately 1 year). There appeared to be a decrease in mortality from lymphoma in the R-CHOP group (10% vs. 20%; p=NS). Kaplan et al. reported a phase III 2:1 randomized trial of CHOP versus CHOP and rituximab (375mg/m2). Kaplan et al. (AMC Study), Blood 2005

Rituximab and Infection CHOP + R CHOP p-value Infectious deaths 14% 2% 0.035 *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 However, treatment with rituximab was associated with a statistically significant increased risk of death from infection (14% vs. 2%; p=0.027). Of the 14 deaths in the R-CHOP group, 7 were from culture-positive bacterial sepsis, 4 from sepsis of undetermined cause, 2 from pneumonia of undertermined cause, and 1 from a fungal pneumonia (Sparano 2003). In the deaths with CD4 counts documented, 60% were in patients with CD4 <50/mm3 and 40% occurred during the maintenance phase of rituximab. Validity concerns Short follow-up (<3 yrs) - obscures potential late differences (benefit) -also..because lymphoma deaths and lymphoma progressions were reduced ….would have probalby detected a difference in PFS…but only EFS (which incorporates toxicity) was presensted…. *no differneces in bcl-2 positive or negative survival Kaplan et al. (AMC Study), ASH 2003

The effect of CHOP and rituximab therapy on B cells and immunoglobulins -why might this be happening……. -this is a patient from the AMC trial who received CHOP+R treatment who promptly developed severe B-cell depletion and panhypogammaglobulin for the following 2 years….until the treating physicians decided to administer IVIG to prophylax against infection…. -the concern is that neutropenia alone may not be the culprit, and that the humoral immune response is also severely impaired if we give these patients rituximab in addition to chemotherapy….. -Until further clarified, it may be reasonable to withhold rituximab therapy. 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 Ceratinly…we know that improving CD4 counts with the use HAART can prevent non-Hodgkin’s lymphoma…..does this mean HAART should be stareted earlier…..will there be more information about the use of the CCR5 inhibitors and preventing this disease…….

Clinical Case 29F Noted unusually heavy menstrual bleeding Presented to gynecologist – performed endometrial biopsy

Chest CT – no LAD Pelvic – Multiple mesenteric, several subcentimeter retroperitoneal LN Splenomegaly – moderate Large bilateral solid masses within ovaries – left ovarian mass – 6.8 x 4.9 cm Right mass – 6.1 x 4.2 cm Several low attenuation masses in uterine canal – 3.4 x 2.8 cm Enlarged right obturator LN – 1.2 x 1.2 cm Multiple inguinal LN Omental caking in lower abdomen

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 Lesions involving one or both sides of face and upper or lower jaws…and kidneys. Children ages 4 – 7 yrs - EBV in 100% M:F 2:1 Bones of jaw and face, kidneys, GI tract, ovaries, breast, and other extranodal sites. Tropical Africa, greater rainfall areas (associated with endemic malaria). EBV associated. 80% long term survival. HIV – younger, higher CD4 count (>200) and usually no prior HIV dx. AIDS defining criteria HIV associated – similar to endemic in pathogenetic aspect. EBV related 25-40%

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%

Medium-sized cells with abundant, basophilic cytoplasm, often containing lipid vacuoles; round nuclei with clumped chromatin and multiple nucleoli; and a diffuse, monotonous pattern of infiltration are characteristic of classic BL.7,13 A "starry sky" appearance has been described in this type of NHL because of its abundant proliferative rate, frequent apoptoses, and numerous macrophages containing ingested apoptotic tumor cells Figure 1 = tonsil of child – diffuse infiltrate of atypical lymphoid cells with numerous mitoses, prominent starry sky pattern d/t multiple tingible body macrophages, HPF – medium sized, round, uniform, nuclei similar in size to or slightly smaller than nuclei of tingible body macrophages. 80% have myc translocation to Ig heavy chain - 8;14 Less commonly at lamda 22 or kapp 2 10% hae no myc translocation by FISH but either are typical for BL in every other way or myc translocation detected by other methods Blum K A, Lozanski G, Byrd J C. Blood 2004;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)

Genetics The expression of c-myc gene is placed under control of the trancription-controlling enhancer sequences of an immunoglobulin heavy chain (IgH) gene. Figure 4.13a The Biology of Cancer (© Garland Science 2007)

All of these subtypes possess chromosomal rearrangements of the c-myc oncogene, the genetic hallmark of Burkitt lymphoma that contributes to lymphomagenesis through alterations in cell cycle regulation, cellular differentiation, apoptosis, cellular adhesion, and metabolism. 80% of BL – t(8;14)  juxtaposition of c-myc gene on chromo 8 with IgH enhancer elements on chromo 14  drives c-Myc mRNA and protein production. 20% - translocations between chromo 2 and 8, t(2;8)(p12;q24) T(8;22)(q24;q11) - c-myc adjacent to kappa or lambda light chain loci and enhancer elements C-myc – helix-loop-helix leucine zipper transcription factor Blum K A, Lozanski G, Byrd J C. Blood 2004;104:3009-3020

Treatment Short duration, high-intensity regimens CNS prophylaxis Tumor lysis prevention Complete responses - 75-90% Overall survival - 50-70% High-intensity CHOP-like regimens,

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 – 83% EFS – 60%

OS 81.5% OS 69.9%

Hyper-CVAD + Rituximab 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 No(%) induction deaths 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 53 70 19 <0.01 % 3y EFS 80 76 52 68 % 3y DFS 88 60 30 0.03 % 3y CRD 91 100 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 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 Most common aggressive histology T-cell NHL - 1/3 relapsed/heavily pretraetd pts respond…but with significant toxicity…. Pralatrexate Upfront - controversial - phase II results are mixed..(mainly Spanish)

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 NPM-ALK - PI3K-AKT pathway

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 100 Survival ALK+ (n=132) 75 p<0.001 50 ALK - (n=22) 25 60 120 180 240 Months

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

Mantle Cell Lymphoma 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 NHL, non-Hodgkin’s lymphoma; OS, overall survival; PFS, progression-free survival. Mantle cell lymphoma is a B-cell cancer composing about 6% of all adult non-Hodgkin’s lymphoma diagnoses. Although this is a fairly rare subtype, it results in a large proportion of lymphoma-related deaths and was formally recognized in 1992. MCL is associated with an aggressive clinical course and a poor prognosis, with a median progression-free survival of less than 2 years and an overall survival of about 3 years. Few if any patients with mantle cell lymphoma are cured. Fisher RI, et al. Lymphoma Annual Update. 2005;29-41. Gascoyne R. Lymphoma Annual Update. 2005;5-20.

Mantle Cell Lymphoma: Diagnostics 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 CLL, chronic lymphocytic lymphoma. Mantle cell lymphoma is diagnosed based on cellular morphology. It is characterized by a CD20+, CD5+, and CD23- immunophenotype. By contrast, CLL carries the CD23+ immunophenotype. Mantle cell lymphoma also features the classic chromosomal translocation t(11;14), which activates the BCL-1 gene, causing overexpression of the protein cyclin D1, which leads to rapid proliferation and resistance to standard chemotherapy. Fisher RI, et al. Lymphoma Annual Update. 2005;29-41. Yarbro CH, et al, eds. Cancer Nursing 5th ed. 2000;1340.

Genetics 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 PRAD 1 CCND1 11q13 Cu Enhancer 14q32 bcl-1 120 Kb Cyclin D1 G1 S + Reciprocal translocation initially identified in 25-50% of patients by breakpoint DNA probe, by PCR likely 60-90% Rarely seen in other types of NHL, lymphocytic leukemia and MM T(11;14) cloned in 1984: chromosome 11 breakpoint near bcl-1 (B-cell leukemia/lymphoma-1) juxtapositioning of bcl-1 oncogene to the enhancer of Ig heavy chain locus on chromosome 14 PRAD 1 is 110kb from bcl-1 and codes for cyclin D1 Cyclin D1 overexpression is noted in nearly all MCLs Overexpression of cyclin D1 results in a shortened G1 phase cdks affect various stages of the cycle by forming complexes with their respective cyclins. The cell cycle begins in G1 during which there is increased synthesis of D-type cyclins that associate with cdks 4 and 6. When the complex is formed, the cdks are activated and then phosphorylate the retinoblastoma (Rb) protein (tumor suppressor) preventing from binding transcription factor E2F which inhibits cell cylce progression. As the cycle goes through G1, Cyclin E is synthesized and associates with cdk2, which permits the cycle to proceed to S. After cyclin A is synthesized during the G1/S transition phase, it is associated with cdk2 in early S phase and cdk1 in late S phase and early G2. Cyclin B is synthesized late in G2 and M phase and associates with cdk1. The increased cyclins A and B, complexed with cdk1 at the end of M phase, are necessary to move the cell into the next G1 phase. The action of cyclins/cdks is regulated on multiple levels. For example, along with cyclin synthesis is the process of cyclin degradation. Cyclin/cdk activity is controlled by two families of inhibitors. The first group includes the cyclin and kinase inhibitory proteins (Cip/Kip) p21waf1/cip1, p27kip2 and p57kip2. These appear to function at several points during the cycle inhibiting cdks 4, 6, and 2. p53 helps regulate the cell cycle through transcription of p21, which retains the cell in G1 permitting DNA repair. The other group includes p15ink4a, p15ink4b, p18ink4c and p19ink4d, which specifically inhibit cyclin D-associated cdk4 and cdk6. Mutants of p53 that cause inactivation are associated with worse prognosis CCND1 is not oncogenic alone in transgenic mouse models (myc is required) G1S1 irreversibly commits the cell to complete the cycle Chiarle, R., Budel, L., et al., Blood 2000;95(2):619 Rosenwald, A., Wright, G., et al., Cancer Cell 2003;3:185 Weisenburger Blood 1996;87(11):4483

Mantle Cell Lymphoma: Frontline Therapy Current approaches R-HyperCVAD R-CHOP R-CVP Consider first-line ASCT for those who attained CR and <65/functionally fit Allo, allogeneic; ASCT, autologous stem cell transplant; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; EPOCH, etoposide, vincristine, doxorubicin, cyclophosphamide; HyperCVAD, fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; R, rituximab. There is no standard front-line treatment for mantle cell lymphoma. The addition of rituximab to induction therapy is currently in vogue. However, there is little evidence that it increases progression-free survival. HyperCVAD, CHOP, and EPOCH are the suggested front-line combination chemotherapies, and first-line consolidation therapy followed by ASCT may prolong progression-free survival. NCCN v.I 2006 Clinical Practice Guidelines in Oncology.

Progression-free survival European MCL Network First prospective RCT All patients responding to CHOP induction RCT of high-dose therapy/ASCT vs. IFNa maintenance Progression-free survival 43% of patients had a low-risk, 41% a low-intermediate, 11% a high-intermediate, and 6% a high-risk IPI profile Estimated 3 yr OS as median survival not yet reached GLSG R-CHOP v CHOP  AutoHSCT trial showed a 2yr PFS 25% and OS 77%

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 adolescents SFOP 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 52 at 5yr McMaster et al7 Vanderbilt 20 44.5 (21-69) 85 Longo et al8 ProMACE-MOPP ProMACE-Cytabom 17 8 36 (19-90) 64.7 100 61 at 15yr 86 at 15yr 35 at 15yr 88 at 15yr Divine et al9 ACVBP 52 34 47 at 5y 53 at 5yr Soussain et al10 LMB 81,84,86,89 65 26 (17-65) 89 71 at 3y 74 at 3yr Divine et al11 51 33 83 61 at 2y 66 at 2yr Hoelzer et al12 BNHL83 24 33 (15-38) 63 50 at 8 yr 49 at 8yr BNHL86 35 36 (18-65) 74 71 at 4 yr 51 at 4yr Todeschini et al13 Modified POG 8617 35 (19-64) 75 at 28 mo Adde et al14 CODOX-M/IVAC 26 25 (18-59) 92.3 84 at 1y LaCasce et al15 14 47 86 72 at 21mo Mead et al16 35(15-60) 75 64.6 at 2y 72.8 at 2yr Thomas et al17 Hyper-CVAD 58 (17-79) 81 61 at 3 yr 49 at 3yr Cabanillis et al18 R-Hyper-CVAD 52 (27-77) 86 at 1 yr Lee et al19 CALGB 9251 54 44 (18-71) 50 at 4yr 52 at 4yr Thomas et al20 R-HyperCVAD 31 46 (17-77) 88% at 3yr 80% at 3y 89% at 3yr Blum K A, Lozanski G, Byrd J C. Adult Burkitt Leukemia and lymphoma. Blood 2004;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 D1 D 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 Cyclophosphamide 800mg/m2 D1 D 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” HIV-1 CD4 Now…what’s new in the current era…….well theres actually a lof of excitement about whether host factors have a role in determining whether someone with HIV develops ARL……and this is the co-receptor story So this is the hiv virus…iti wants to enter our t-cells….and remember it does so by biding of proteins like GP120 to host proteins like CD4…but it also requires binding to co-receptors…the most common being CCR5….. So if we have a normal CCR5 co-receptor…HIV can bind and infect T-cells…some people have genetic mutations in the CCCR5 co-receptro….and that’s actually a good thing….because in some circumstances…it can prevetn binding of HIV and infection itself…. …..recall that entry of the HIV virus into host cells requires interaction of viral proteins like gp120 and host proteins such as CD4 (the primary receptor) but also co-receptors….the two most commonly used co-receptors required by HIV-1 strains are CCR5 and CXCR4… The importance of CCR5 in HIV-1 infection became apparent in the mid-1990s….when Now…what’s new in the current era…….well there may be a role of host or genetic factors in determining whether someone with HIV develops ARL……Recall that entry of the HIV virus into host cells requires interaction of viral proteins like gp120 and host proteins such as CD4 (the primary receptor) but also co-receptors….the two most commonly used co-receptors required by HIV-1 strains are CCR5 and CXCR4… CCR5 T-Cell Surface

HIV-1 T-Cell Surface CD4 CCR5 So if we have a normal CCR5 co-receptor…HIV can bind and infect T-cells…some people have genetic mutations in the CCCR5 co-receptro….and that’s actually a good thing….because in some circumstances…it can prevetn binding of HIV and infection itself…. CCR5 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 When a common genetic variant of the co-receptor …..a 32bp deletion within the gene known as delta-32 mutation was discovered… -the mutation was associated with a non-functional co-receptor and so a block in the ability of HIV to enter cells…. -it was found that delta 32 homozygotes …which is common in the caucasian population….were highly resistant to HIV and no known deleterious effects -delta 32 heterozygotes could be infected with HIV-1 but had a slow progression to full-blown AIDS…whereas, -normal wt variant - susceptible to HIV and rapid progression… CCR5 co-receptor antagonists - blocks HIV virus from binding CD4/co-receptor - no infection of cell and no replication 32bp deletion in CCR5 termed CCR5-delta-32 is found in 20% of caucasians and prevents expression of the coreceptor on cell surfaces…..in homozygous indivuiduals, it confers a highlevel protection against HIV-1 infection whereas heterozygotes can be infected but have a delayed progression to AIDS.

CCR5-∆32 and ARL OR for lymphoma - 0.32 (0.13-0.79) Now what emerged in the late 90s was that the frequency of the d32 allele was farily consistnet across different AIDS outcomes…being about 17-20% whether pts had KS or no, OI or not, PCP or not….but in large cohort studies ….there was a significantly lower number of individs with the delta 32 allele with lymphoma than without lymphoma..suggesting that having the allele might be somewhat protective against lymphoma…. In fact …in a matched case-control study…the presence of the d32 allele was associated with an OR of 0.32 for an approx 3x reduced risk of lymphoma development… THE PROBLEM - WE DON”T KNOW WHY CCR5 dysfunction PROTECTS AGAINST LYMPHOMA IN THIS POPULATION What’s exciting is that the newest full class of ARV therapy is the entry inhibitors…that is the new group of CCR5 CRA that have recently been FDA approved…..you would think that this class might even further reduce the risk of lymphoma development…. 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 ..and it’s not only the classic HIV factors that cause lymphoma but we’re starting to understand the role of host factors..some of which may become MODIFIABLE IN THE FUTURE with the newer classes of HIV drugs….. Like the non-HIV setting…GC…and part of why indidviduals are doing better may actually be a shift in pathogenesis in the era of HAART….

BC Provincial Database (Retrospective) No difference in toxic deaths (p = NS) What’s the point… -retrospective data - no difference in toxic deaths although higher rates of viral reactivation…therefore they gived acyclovir and are now using rituximab in all patients Boue Ezza et al., HIV Clin Trials 2007

Lymphoma MD Preferences BC (n=22) vs. ON (n=92) physicians % of physicians * So that’s why…if you look across the country…you’ll see this huge variability in the way that pts with HIV lymphoma are being managed….we completed a survey study of MDs who treat lymphoma….supported by CANFAR…..and found that most physicians in BC and ON would use HAART in combination with CHOP chemotherapy for treatment of ARL…..whereas a majority of physicians in BC would use rituxiamb….a minority in ON would choose thise tratment…and aside from diff in how we interpret the evidence…there may also be funding and guideline differences between the provicnes to explain this variability….. -Canada - some variability -cART..most physicians but not a vast majroity as you would expect. -chemotherapy - most physicains are now comfy giving full standard dose and not palliative doses of chemotherapy. -interestingly, a lot of regional variation in treatment using rituximab….with the vast majority choosing R in BC while few chose R in ON. Rituximab - differences in formulary availability/differences in guidelines/differences in local experience Supportive care ARL treatment options Cheung M et al, Ann Hematology 2007