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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: [email protected]
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
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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)