The evolution of HIV associated lymphoma over three decades

Ramya Ramaswami2 MBBS MRCP MPH, Germaine Chia1 BSc, Alessia Dalla Pria2, David Pinato2 MD MRes MRCP PhD, Kizzy Parker2 RCN, Mark Nelson3

MA FRCP, Mark Bower2 PhD FRCP FRCPath

1Imperial College School of MedicineLondon SW7 2AZ, United Kingdom

2Departments of Oncology & 3HIV medicineNational Centre for HIV malignanciesChelsea & Westminster HospitalLondon SW10 9NH, United Kingdom

*Address for correspondence:

Professor Mark Bower PhD FRCP FRCPathNational Centre for HIV malignanciesChelsea & Westminster Hospital369 Fulham RoadLondon SW10 9NHTel: +44-203-315-5054Fax: +44-208-746-8863E-mail: m.bower@imperial.ac.uk

There are no conflicts of interest to declare

Word Count: 2173Abstract word count: 204Running Title: Evolution of HIV-associated lymphoma

2

AbstractIntroduction: The emergence of combined antiretroviral therapy (cART) and improvements

in the management of opportunistic infections have altered the HIV epidemic over the last

30 years. We aimed to assess changes to the biology and outcomes of HIV-associated

lymphomas over this period at the national centre for HIV oncology in the United Kingdom.

Methods: Clinical characteristics at lymphoma diagnosis have been prospectively collected

since 1986, along with details of lymphoma treatment and outcomes. The clinical features

and outcomes were compared between 3 decades: pre-cART decade (1986-1995), early

cART decade (1996-2005) and late cART decade (2006-2015).

Results: A total of 615 patients with HIV-associated lymphoma were included in the study:

158 patients in the pre-cART era, 200 patients in the early cART era and 257 patients in the

late cART era. In more recent decades patients were older (p<0.0001) and had higher CD4

cell counts (p<0.0001)at lymphoma diagnosis. Over time there has also been a shift in

lymphoma histological subtypes, with an increase in lymphoma subtypes associated with

moderate immunosuppression. The overall survival for patients with HIV-associated

lymphoma has dramatically improved over the 3 decades (p<0.0001).

Conclusion: Over the last 30 years, the clinical demographic of HIV associated lymphomas

has evolved and the outcomes have improved.

3

IntroductionHuman Immunodeficiency Virus (HIV) infection increases the risk of cancer [1] and after

Kaposi’s sarcoma, lymphomas are the second most common malignancy among people

living with HIV (PLWH). The relative risk for non-Hodgkin lymphoma (NHL) is estimated as

60-200 fold and for Hodgkin lymphoma (HL) as 8-10 fold compared to the general population

[2-5]. Prior to routine use of combined antiretroviral therapy (cART), diffuse large B-cell

lymphoma (DLBCL) and primary central nervous system lymphoma (PCNSL) were the most

common AIDS defining non-Hodgkin’s lymphoma (NHL), with an incidence of 453 and 233

cases per 100 000 patient-years respectively [6-8]. The introduction of cART in 1996 in the

UK, along with better management of opportunistic infections led to a substantial

improvement in life expectancy for PLWH. This has resulted in changes in the demographics

of the UK population of PLWH who are now older and generally have higher CD4 cell counts

but HIV associated lymphoma remains a significant cause of morbidity and mortality [9].

Over the last 30 years since the emergence of the HIV epidemic, in addition to changes to

the treatment of HIV and opportunistic infections, treatment of lymphoma in PLWH has also

evolved. In the 1980s, curative chemotherapy for systemic NHL in PLWH was usually

restricted to patients with good prognostic factors and even then the marked toxicity and

high frequency of opportunistic infections lead to dose modifications of standard

chemotherapy regimens such as the modified mBACOD used by the AIDS clinical trial group

[10] and the weekly alternating chemotherapy schedule used at our centre [11]. With the

introduction of cART, infusional chemotherapy regimens designed to reduce

pharmacokinetic drug interactions with concurrent cART were widely used including

infusional cyclophosphamide, doxorubicin and etoposide (CDE) [12] used at our centre [13].

With outcomes approaching those seen in the general population and the availability of the

monoclonal antibody rituximab, many centres including ours, shifted to using standard doses

and intensive chemotherapy regimens, which are comparable to non-HIV patients [14] and

achieving equivalent outcomes in DLBCL [15] and HL [16]. These improved outcomes since

the introduction of cART have been demonstrated by many studies [9, 17].

As well as improvements in the survival of PLWH diagnosed with lymphomas, there has been

a change in the histological subtypes of lymphomas diagnosed. Following the introduction of

cART, the incidence of PCNSL fell significantly in both registry linkage and cohort studies [18-

20]. In contrast, the effects on systemic NHL were less clear although some cohort studies

4

suggested a modest non-significant decline in the incidence [21-23] including in the

haemophilia population [24]. An international meta-analysis of 20 cohort studies compared

the incidence of systemic NHL between 1992-6 and 1997-9. This meta-analysis confirmed an

overall reduction in the incidence of both primary cerebral lymphoma (rate ratio 0.42) and

systemic immunoblastic lymphoma (rate ratio 0.57) but not Burkitt’s lymphoma (rate ratio

1.18) [25]. More recent publications confirm the decline in PCNSL and DLBCL [17], suggest a

rise in BL [17], whilst the rates of HL are reported as stable in the Swiss cohort [26] but rising

in studies from the US [27, 28].

We aimed to study alterations in the clinical characteristics and the rates of survival of HIV-

associated lymphoma at the national HIV oncology centre in the United Kingdom over three

decades.

5

Methods

Patient selection and data collection

At the National Centre for HIV malignancies at the Chelsea and Westminster Hospital we

prospectively collect routine data on all individuals who attend. All HIV seropositive patients

diagnosed with lymphoma between the years 1986 and 2015 were included in the study.

Data on patient characteristics and prognostic factors, including patient gender, age at HIV

diagnosis and duration of HIV, age at lymphoma diagnosis, prior diagnosis of AIDS, CD4

counts and viral load, and treatment with cART at time of lymphoma diagnosis was extracted

from the database. The date from lymphoma diagnosis till the date of death, study censoring

or loss to follow-up was used to calculate overall survival.

Statistical analysis

Comparison of variables between the groups was by 2 test for for categorical data and the

Kruskal-Wallis test for non-parametric continuous variables; all p values are two-sided.

Survival was calculated from KS diagnosis until death (overall survival) or last follow-up.

Survival curves were plotted according to the method of Kaplan and Meier [29]. The log rank

method was used to test for the significance of differences in survival distributions [30].

Results

Patient characteristics

A total of 615 patients were included in the study. There were 158 patients diagnosed with

lymphoma in the pre-cART decade (1986-1995), 200 patients in the early cART era (1996-

2005) and 257 patients in the late cART era (2006-2015). Patient characteristics are

summarised in Table 1.

Mean age at HIV diagnosis has increased over the last 3 decades, from 34 years of age in

1986-1995 to 37 and 40 years of age in 1996-2005 and 2006-2015 respectively (p<0.0001).

This was accompanied by an increased in the mean age at lymphoma diagnosis, from 38

years of age in 1986-1995 to 42 and 45 years of age in 1996-2005 and 2006-2015

respectively (p<0.0001). The proportion of patients with an AIDS defining illness prior to the

lymphoma diagnosis has decreased significantly over the years, from 44% in 1986-1995 to

27% in 1996-2005 to 18% in 2006-2015 (p<0.0001). Similarly, the median CD4 cell count at

6

lymphoma diagnosis has increased from 36cells/mm3 to 132cells/mm3 and then

221cells/mm3 in 1986-1995, 1996-2005 and 2006-2015 respectively (p<0.0001).

Fifty-eight percent of patients were on cART at the time of their lymphoma diagnosis, and

this has remained the same between 1996-2005 and 2006-2015. Additionally, from the first

decade of cART (1996-2005) to the second decade of cART (2006-2015), the proportion of

patients with undetectable plasma HIV viral load has doubled from 38% to 76% (p<0.0003).

Incidence of HIV-associated lymphoma and changes in CD4 count over time

Systemic B cell lymphoma is the most common type of lymphoma in each of the three

decades and overall with 69% of cases (Figure 1). DLBCL is the most common subtype of

systemic B cell lymphoma overall with 51% of cases. In the 1986-1995 era, 63% of cases

were DLBCL, and over time this has reduced to 59% in 1996-2005 and 37% in 2006-2015. The

proportion of BL cases has increased over time, with the 3% of BL cases in 1986-1995 to 20%

in 2006-2015. Other subtypes of NHL such as Primary Effusion Lymphoma (PEL) and

Plasmablastic lymphoma (PBL) have increased the three decades, with no cases of PBL pre

cART to 6% in 2006-2015, although this entity was only included in the WHO classification in

2008 [31]. Two percent of cases in 1986-1995 were PEL and this has increased to 5% of cases

in 2006-2015.

The proportion of HL cases has increased over the three periods, from 4% in 1986-1995 to

11% in 1996-2005 and 26% in 2005-2015. Conversely, PCNSL cases have decreased from 25%

of cases in 1986-1995 to 13% in 1996-2005 and 1% of cases in 2005-2015. Other types of

lymphoma such as T-cell and low-grade subtypes are a small proportion of cases overall (T-

cell: 3%, Low grade: 1%), and have not changed over three decades.

The median CD4 cell count at the lymphoma diagnosis for HD is 245 cells/mm3 (range: 4-

1160), for BL is 199 cells/mm3 (range: 7-864), for DLBCL is 102 cells/mm3 (range: 0-2308), for

PCNSL is 22 cells/mm3 (range: 0-748). Over three decades, the CD4 cell count at lymphoma

diagnosis has increased for all lymphomas (p<0.0001) but when evaluated separately by

histological type, this was only significant for DLBCL (p<0.0001) not for HL (p=0.063), BL

(p=0.10) or PCL (p=0.19).

7

Survival

Overall survival increased significantly in patients who were diagnosed in 1996-2005

compared to 1986-1995, and again in patients who were diagnosed in 2006-2015 compared

to 1996-2005 (p<0.0001) (Figure 2). This trend was significant at 2 years (p<0.0001) and 5

years (p<0.0001) (Table 1). Stratifying patients by histological subtypes showed a significant

increase in survival across the 3 decades for DLBCL (p<0.0001), BL (p=0.009) and HL

(p<0.0001) but not PCNSL (p=0.09) (Figure 3).

Discussion This study of a single institution prospective cohort of 615 patients over three decades

including the pre-cART, early cART and current c-ART eras, demonstrates a change in the

baseline characteristics and outcomes of HIV associated lymphoma. The most dramatic

evolution has been the rising CD4 cell count at lymphoma diagnosis and the shift towards

histological subtypes that are associated with less severe immunosuppression. There has

been a steady decrease in proportion of patients with PCNSL and DLBCL which are

associated with a greater degree of immunosuppression. Conversely, the proportion of

patients with BL and HL has risen and these subtypes tend to occur at higher CD4 cell counts

and are associated with less profound immunosuppression. The increase in both PEL and PBL

can in part be attributed to increasing recognition of these subtypes as distinct entities and

improvements in immunohistochemical diagnostics that are required to make these

diagnoses. The other dramatic change over the last 30 years is the improvement in overall

survival following a diagnosis of lymphoma in PLWH. It is clear that this is not simply

attributable to changes in the histological subtypes as the improvement in prognosis is seen

for DLBCL, BL and HL separately.

Patients in the modern era are older, have already commenced cART and have higher CD4

counts at lymphoma diagnosis, and this has also been noted in previous studies [9, 32, 33].

The increasing age at lymphoma diagnosis is intriguing as there has been no change in the

age at HIV diagnosis in the UK over time [34] but the cohort of PLWH is ageing as a

consequence of improvements in survival as a consequence of cART. In general, increasing

age is a more important risk factor for non-AIDS defining epithelial cancers [35] although HL

has a bimodal age distribution and the risk of NHL does increase with age in the general

population. Interestingly, Robbins et al. have suggested that demographic factors such as

8

age, gender and duration of HIV infection do not correlate with the risk of HL and NHL in

PLWH [36].

The shift in histological subtypes over time may be due to a combination of factors related to

immunosuppression, and the interaction between immunity and the oncogenic

herpesviruses Epstein Barr Virus (EBV) and Kaposi’s sarcoma herpesvirus (KSHV) [37]. Our

data suggest a decline in the incidence of both PCNSL and DLBCL that are both associated

with latency 3 EBV infection and severe immunosuppression. Conversely, there is a rise in

the proportion of lymphomas that are BL and HL, which both occur at higher CD4 cell counts

and are associated with less permissive patterns of EBV latency. The introduction of cART is

the most likely factor to be responsible for the shift in histological subtypes by increasing

immune function and CD4 cell counts in PLWH. Indeed an increased risk of HL has been

described in the first three months after starting HIV treatment [38] which has been

attributed to immune reconstitution of CD4 T-cells creating a cellular microenvironment to

perpetuate tumour growth [39, 40].

The great improvement in overall survival in this study has been well described previously [6,

41, 42] and is attributable to a number of factors including: the use of cART, better focus on

opportunistic infection prophylaxis and improved chemotherapy. For example, results from

phase II studies and case-control series have reported higher response rates and improved

survival with the addition of cART to CHOP chemotherapy [43-47]. There have been several

significant advances in the clinical management of lymphoma over the three decades

including the introduction of rituximab, the use of autologous stem cell transplants and the

introduction of novel agents used mainly in salvage. One example is the use of the anti-CD20

chimeric monoclonal antibody rituximab which initially was not advocated in PLWH based on

results from an early trial [48]. However, a subsequent pooled meta-analysis of 1546

patients with HIV-associated NHL treated with rituximab and chemotherapy had improved

complete remission (Odds Ratio 2.89, p<0.001) and overall survival (Hazard Ratio 0.51,

p<0.0001) compared with chemotherapy [49]. Similarly, routine implementation of

prophylaxis for opportunistic infection and use of granulocyte colony-stimulating factor are

supportive measures that improve care of patients undergoing lymphoma treatment [14].

There are several limitations to this single centre observational study. There are confounders

that cannot accounted for in the survival analysis. The effects of the introduction of cART

9

and the development of better chemotherapy regimens over time could not be evaluated

independently. Similarly the changes in incidence of the lymphomas cannot be evaluated as

the denominator of PLWH has not remained stable or known as our centre is a major

national referral centre for a number of local as well as national HIV care centres, not just

our hospital. Finally, changes in histological subtypes are subject to changes in the

classification of lymphomas over the years. The WHO classification of lymphoma has evolved

over the last decades, partly as a consequence of improved molecular and

immunohistochemical techniques, and now includes histological subtypes that occur in

PLWH.

10

References

1. Grulich, A.E., van Leeuwen, M. T., Falster, M. O, et al., Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. . Lancet, 2007. 370: p. 59-67.

2. Carbone A, Vaccher E, Gloghini A, et al., Diagnosis and management of lymphomas and other cancers in HIV-infected patients. Nat Rev Clin Oncol, 2014. 11: p. 223-238.

3. Simard, E.P., Pfeiffer, R. M. & Engels, E. A. , Cumulative incidence of cancer among individuals with acquired immunodeficiency syndrome in the United States. . Cancer, 2011. 117: p. 1089-1096.

4. Shiels, M.S., et al. , The epidemic of non-Hodgkin lymphoma in the United States: disentangling the effect of HIV, 1992–2009. Cancer Epidemiol. Biomarkers Prev, 2013. 22: p. 1069-1078.

5. Polesel, J., et al. , Non-Hodgkin lymphoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy. AIDS, 2008. 22: p. 301-206.

6. Rubinstein PG, Aboulafia DM, Zloza A., Malignancies in HIV/AIDS: from epidemiology to therapeutic challenges. . AIDS, 2014. 28(4): p. 453-465.

7. Shiels MS, Pfeiffer RM, Hall HI, et al. , Proportions of Kaposi sarcoma, selected non-Hodgkin lymphomas, and cervical cancer in the United States occurring in persons with AIDS, 1980-2007. JAMA, 2011. 305: p. 1450-1459.

8. Cote TR, Biggar RJ, Rosenberg PS, et al., Non-Hodgkin's lymphoma among people with AIDS: incidence, presentation and public health burden. AIDS/Cancer Study Group. International journal of cancer, 1997. 73: p. 645-650.

9. Gopal, S., et al., Temporal trends in presentation and survival for HIV-associated lymphoma in the antiretroviral therapy era. J Natl Cancer Inst, 2013. 105(16): p. 1221-9.

10. Kaplan LD, et al., Low dose compared with standard dose m-BACOD chemotherapy for non-Hodgkin's lymphoma associated with human immunodeficiency virus infection. N Engl J Med, 1997. 336: p. 1641-1648.

11. Bower, M., et al., Weekly alternating combination chemotherapy for good prognosis AIDS- related lymphoma. Eur J Cancer, 2000. 36(3): p. 363-7.

12. Sparano, J.A., et al., Infusional cyclophosphamide, doxorubicin, and etoposide in human immunodeficiency virus- and human T-cell leukemia virus type I-related non-Hodgkin's lymphoma: a highly active regimen. Blood, 1993. 81(10): p. 2810-5.

13. Bower, M., et al., Protease inhibitors potentiate chemotherapy-induced neutropenia. Blood, 2004. 104(9): p. 2943-6.

14. Bower, M., et al., British HIV Association guidelines for HIV-associated malignancies 2014. HIV Med, 2014. 15 Suppl 2: p. 1-92.

11

15. Coutinho, R., et al., HIV status does not impair the outcome of patients diagnosed with diffuse large B-cell lymphoma treated with R-CHOP in the cART era. AIDS, 2013.

16. Montoto, S., et al., HIV status does not influence outcome in patients with classical Hodgkin lymphoma treated with chemotherapy using doxorubicin, bleomycin, vinblastine, and dacarbazine in the highly active antiretroviral therapy era. J Clin Oncol, 2012. 30(33): p. 4111-6.

17. Barta, S.K., et al., Changes in the influence of lymphoma- and HIV-specific factors on outcomes in AIDS-related non-Hodgkin lymphoma. Ann Oncol, 2015. 26(5): p. 958-66.

18. Ledergerber, B., et al., Risk of HIV related Kaposi's sarcoma and Non-Hodgkin's lymphoma with potent antiretroviral therapy: prospective cohort study. British Medical Journal, 1999. 319: p. 23-24.

19. Inungu, J., M.F. Melendez, and J.P. Montgomery, AIDS-related primary brain lymphoma in Michigan, January 1990 to December 2000. AIDS Patient Care STDS, 2002. 16(3): p. 107-12.

20. Kirk, O., et al., Non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy. Blood, 2001. 98(12): p. 3406-12.

21. Buchbinder SP, et al., Declines in AIDS incidence associated with highly active anti-retroviral therapy (HAART) are not reflected in KS and lymphoma incidence. Proc 2nd National AIDS malignancy Conference, Bethesda, Maryland., 1998: p. S7.

22. Jacobson, L.P., et al., Impact of potent antiretroviral therapy on the incidence of Kaposi's sarcoma and non-Hodgkin's lymphomas among HIV-1-infected individuals. Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr, 1999. 21(Suppl 1): p. 34-41.

23. Rabkin, C.S., et al., Kaposi's sarcoma and non-Hodgkin's lymphoma incidence trends in AIDS Clinical Trial Group study participants. J Acquir Immune Defic Syndr, 1999. 21 Suppl 1: p. 31-3.

24. Wilde, J.T., et al., The incidence of lymphoma in the UK haemophilia population between 1978 and 1999. Aids, 2002. 16(13): p. 1803-7.

25. International Collaboration on HIV and Cancer, Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst, 2000. 92: p. 1823-1830.

26. Clifford, G.M., et al., Hodgkin lymphoma in the Swiss HIV Cohort Study. Blood, 2009. 113(23): p. 5737-42.

27. Biggar, R.J., et al., Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood., 2006. 108(12): p. 3786-91. Epub 2006 Aug 17.

28. Engels, E.A., et al., Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer., 2008. 123(1): p. 187-94.

29. Kaplan, E. and P. Meier, Nonparametric estimation from incomplete observations. J Am Stat Assoc, 1958. 53: p. 457-481.

30. Peto, R., et al., Design and analysis of randomised clinical trials requiring prolonged observation of each patient II: analysis and examples. Br J Cancer, 1977. 35: p. 1-39.

31. Swerdlow, S.H., et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Fourth Edition.2008, Lyon: IARC Press.

12

32. Matthews, G.V., et al., Changes in acquired immunodeficiency syndrome-related lymphoma since the introduction of highly active antiretroviral therapy. Blood, 2000. 96(8): p. 2730-4.

33. Robbins, H.A., et al., Epidemiologic contributions to recent cancer trends among HIV-infected people in the United States. AIDS, 2014. 28(6): p. 881-90.

34. Desai, S., et al., An overview of the HIV epidemic among men who have sex with men in the United Kingdom, 1999-2013. Euro Surveill, 2015. 20(14).

35. Gopal S, Achenbach CJ, Yanik EL, et al., Moving Forward in HIV-Associated Cancer. JCO, 2014. 32(9): p. 876-880.

36. Robbins HA, Shiels MS, Pfeiffer RM, et al., Epidemiologic contributions to recent cancer trends among HIV-infected people in the United States. AIDS, 2014. 28(6): p. 881-890.

37. Pinzone, M.R., et al., Epstein-barr virus- and Kaposi sarcoma-associated herpesvirus-related malignancies in the setting of human immunodeficiency virus infection. Semin Oncol, 2015. 42(2): p. 258-71.

38. Lanoy, E., et al., HIV-associated Hodgkin lymphoma during the first months on combination antiretroviral therapy. Blood, 2011. 118(1): p. 44-9.

39. Hoffmann C, Hentrich M, Gillor D, et al., Hodgkin lymphoma is as common as non-Hodgkin lymphoma in HIV-positive patients with sustained viral suppression and limited immune deficiency: a prospective cohort study. HIV Medicine, 2015. 16(4): p. 261-264.

40. Kowalkowski MA, Mims MA, Day RS, , Longer duration of combination antiretroviral therapy reduces the risk of Hodgkin lymphoma: A cohort study of HIV-infected male veterans. Cancer Epidemiology, 2014. 38(4): p. 386-392.

41. Rios A., HIV-Related Hematological Malignancies: A Concise Review. Clinical Lymphoma Myeloma and Leukemia, 2014. 14(Supplement): p. S96-S103.

42. Lim, S.T., et al., AIDS-related Burkitt's lymphoma versus diffuse large-cell lymphoma in the pre-highly active antiretroviral therapy (HAART) and HAART eras: significant differences in survival with standard chemotherapy. J Clin Oncol, 2005. 23(19): p. 4430-8.

43. Antinori, A., et al., Better response to chemotherapy and prolonged survival in AIDS-related lymphomas responding to highly active antiretroviral therapy. AIDS, 2001. 15(12): p. 1483-91.

44. Navarro, J.T., et al., Influence of highly active anti-retroviral therapy on response to treatment and survival in patients with acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma treated with cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone. Br J Haematol, 2001. 112(4): p. 909-15.

45. Vaccher, E., et al., Concomitant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy plus highly active antiretroviral therapy in patients with human immunodeficiency virus-related, non-Hodgkin lymphoma. Cancer, 2001. 91(1): p. 155-63.

46. Hoffmann, C., et al., Response to highly active antiretroviral therapy strongly predicts outcome in patients with AIDS-related lymphoma. AIDS, 2003. 17(10): p. 1521-9.

47. Weiss, R., et al., Acquired immunodeficiency syndrome-related lymphoma: simultaneous treatment with combined cyclophosphamide, doxorubicin,

13

vincristine, and prednisone chemotherapy and highly active antiretroviral therapy is safe and improves survival--results of the German Multicenter Trial. Cancer, 2006. 106(7): p. 1560-8.

48. Kaplan, L.D., et al., Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010. Blood, 2005. 106(5): p. 1538-43.

49. Barta SK, et al., Treatment factors affecting outcomes in HIV-associated non-Hodgkin lymphomas: a pooled analysis of 1546 patients. . Blood, 2013. 122: p. 3251-3262.

Table 1 - Total of 615 (547 male) patients diagnosed with HIV associated lymphomas over 30 years between 1986 and 2015.

14

All 1986-1995 1996-2005 2006-2015 pMale (%) 547/615 (89%) 153/158 (97%) 178/200 (89%) 216/257 (84%) <0.0003

Mean age at HIV (range)

37 (0-73) years 34 (19-58) years 37 (13-73) years 40 (0-71) years <0.0001

Mean age at lymphoma (range)

42 (19-78) years 38 (22-59) years 42 (21-78) years 45 (19-75) years <0.0001

Mean duration HIV (range)

61 (0-362) months 46 (0-137) months

64 (0-249) months 68 (0-362) months

0.53

Prior AIDS (%) 196/615 (32%) 96/158 (44%) 54/200 (27%) 46/257 (18%) <0.0001

Median CD4 at lymphoma (range)

130 (0-2308) cells/mm3

36 (0-763) cells/mm3

132 (0-814) cells/mm3

221 (2-2308) cells/mm3

<0.0001

On cART at lymphoma (%)

264/615 (43%) 0/158 (0%) 116/200 (58%) 149/257 (58%) <0.0001

On cART with undetectable plasma HIV VL (%)

158/615 (26%) 0 45/116 (38%) 113/149 (76%) <0.0003

Lymphoma SubtypesPCNSL 69 (11%) 39 (25%) 27 (13%) 3 (1%)Systemic B cell 426 (69%) 106 (67%) 145 (72%) 175 (68%)

DLBCL 312 (51%) 99 (63%) 119 (59%) 94 (37%)BL 76 (12%) 4 (3%) 20 (10%) 52 (20%)PEL 18 (3%) 3 (2%) 2 (1%) 13 (5%)Plasmablastic 20 (3%) 0 (0%) 4 (2%) 16 (6%)Hodgkins 96 (16%) 7 (4%) 22 (11%) 67 (26%)

T-cell 18 (3%) 6 (4%) 4 (2%) 8 (3%)Low grade 6 (1%) 0 (0%) 2 (1%) 4 (2%)Survival2 year overall survival-all lymphomas (95%CI)

51.2% (47.2-55.2) 19.7% (13.1-26.3) 48.2% (42.0-54.4) 74.3% (68.7-79.9)

P<0.00015 year overall survival-all lymphomas (95%CI)

45.8% (41.6-50.0) 13.2% (7.4-19.0) 44.5% (37.3-51.7) 69.6% (63.4-75.8)

15

Figure 1: Lymphoma subtypes over three decades, 1986-1995 (pre-cART), 1996-2005 (early cART), 2006-2015 (late cART)

1986-1995 1996-2005 2006-20150%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Low gradeT-cellPELPlasmablasticBurkittHodgkinsDLBCLPCL

Axis Title

16

Figure 2: Cumulative survival over three decades among all patients diagnosed with HIV-associated lymphoma.

0

.2

.4

.6

.8

1

Cum

. Sur

viva

l

0 5 10 15 20 25 30

Years

2006-2015

1996-2005

1986-1995

17

Figure 3: Cumulative survival over three decades among patients diagnosed with Diffuse large B cell lymphoma (DLBCL), Burkitt lymphoma (BL), Primary CNS lymphoma (PCNSL) and Hodgkin lymphoma (HL)