– Christian Hoffmann –
A close association between systemic NHL and AIDS has been described for a long time – the first cases were published only about a year after the first description of AIDS and even before the discovery of HIV (Ziegler 1982). High-grade B-NHLs have been AIDS-defining since 1985.
More than 90% of HIV-associated NHLs are of B-cell origin. They are almost always of high-grade malignancy. Two main histological types dominate: according to the WHO classification these are Burkitt’s lymphomas, which comprise 30-40% of cases, and diffuse large-cell B cell lymphomas, comprising 40-60%. However, a relatively large proportion of HIV-associated lymphomas (up to 30%) cannot be classified even by reference laboratories. A small proportion of NHLs (1-3%) are primary effusion or body cavity-based lymphomas and are considered as a distinct entity (see below).
The prognosis of patients with NHL was poor in the pre-HAART era, being between 6 and 9 months (Levine 2000). Due to the introduction of combination antiretroviral therapy this has changed dramatically. However, in a recent analysis, which compared the variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy, NHL was the AIDS-defining event with the greatest mortality hazard ratio (ART-CC 2009). Whether the clinical and pathological spectrum of lymphoma subtypes is also changing, is still unclear. A French study showed no differences in lymphoma features in antiretrovirally treated patients compared to treatment naïve patients (Gérard 2009). However, it seems possible that, compared to HL or Burkitt’s lymphoma, the percentage of “opportunistic” NHL such as immunoblastic lymphoma will decrease.
Prevention, early detection
There is no data supporting specific therapies or diagnostic procedures (such as periodical ultrasound controls etc.) for prevention or for early detection of malignant lymphomas. Antiretroviral therapy seems to be the best protection against lymphoma. ART does not only improve the immune status but it also reduces the chronic B-cell stimulation, which is another risk factor for the development of lymphoma (Grulich 2008). HIV plasma viremia should be as low as possible as cumulative HIV viremia is an independent and strong predictor of AIDS-related lymphoma among patients receiving ART (Zoufaly 2009).
Besides ART, there have been numerous studies evaluating factors (so called “biomarkers”) which may precede the development of AIDS-associated lymphoma. For example, it has been shown that the levels of serum globulins (Grulich 2000), interleukin 6 (Breen 2003), soluble CD44 or CD30 (Breen 2005+2006, Pordue 2009), activity of activation induced cytidine deaminase (Epeldegui 2007) or circulating immunoglobulin-free light chains (Landgren 2009) may predict the risk of NHL. These activation markers were markedly elevated in those patients who developed AIDS-NHL, when compared to AIDS patients and HIV-negative controls. These findings may help us to understand the pathogenesis of lymphomas in HIV infected patients. However, they found so far no entrance into the routine diagnostics.
Signs and symptoms
The main symptom is lymph node enlargement. Lymphomas are firm, immobile or barely mobile and painless. A large proportion of patients have advanced-stage lymphoma at the time of diagnosis. Ann Arbor stages III-IV are almost always the rule, and B symptoms with fever, night sweats and/or weight loss are found in the majority of cases (60-80%). General asthenia, significant malaise and rapid physical deterioration are also frequently seen. Extranodal involvement is common, and may be to a grotesque extent. In our own cohort of 203 patients, 81% had at least one extranodal focus (Hoffmann 2003). Every conceivable region of the body can be affected—the orbital cavity, testes, heart, breasts, bladder, kidneys, muscles, or bones, etc. However, the gastrointestinal tract, liver, and bone marrow are affected particularly frequently. Secondary CNS involvement can also occur. With extra-nodal disease, additional symptoms arise depending on the localization. These include, for example, abdominal pain from hepatosplenomegaly, hemorrhage or ileus symptoms due to intestinal involvement, bone pain with skeletal infiltration, or headache caused by brain disease.
Rapid histological diagnosis is essential. If bone marrow biopsy cannot secure the diagnosis, then a lymph node (e.g. cervical, axillary or inguinal) should be extirpated. Mere puncture biopsy of a lymph node is often not sufficient to secure a representative specimen. It is imperative to send the material to a specialized pathology laboratory with extensive experience in lymph node morphology. Every case should be discussed with the pathologist and caution taken to avoid a misdiagnosis. A typical yet mostly wrong diagnosis is that of a high- or low-grade T cell lymphoma in an AIDS patient. T cell lymphoma are very rare in AIDS patients and in most cases, T cell infiltrates indicate several infectious diseases like malignant syphilis rather than lymphoma.
The basic pathological diagnosis should include information about the subtype of lymphoma (Burkitt?), the proliferation rate and the expression profile (definitely: CD20, and desirably: CD10, CD138, MUM-1) as these can influence the therapeutic consequences (see below).
All patients with suspected NHL should be staged according to the Ann-Arbor classification (Tables 2a, b).
Table 2a: Staging according to the updated Ann-Arbor classification
|I||Involvement of a single lymph node region (I) or involvement of a single extralymphatic organ or site (IE)|
|II||Involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site plus its regional lymph nodes, with or without involvement of other lymph node regions on the same side of the diaphragm (IIE)|
|III||Involvement of lymph nodes regions on both sides of the diaphragm (III), can be accompanied by localized extralymphatic organ involvement (IIIE) or spleen involvement (IIIS) or both (IIIE+S)|
|IV||Diffuse or disseminated involvement of one or more extralymphatic organs with or without associated lymph node involvement; or isolated involvement of an extralymphatic organ with involvement of distal (non-regional) lymph nodes.|
Table 2b: Every stage is divided into categories A and B
|B||General symptoms:a) unexplained weight loss of more than 10% in the last six months, and/or
b) unexplained persistent or recurring fever with temperatures above 38 °C, and/or
c) drenching night sweats
Basic diagnostic tests for staging include chest radiography; abdominal ultrasound; CT scans of the neck, thorax and abdomen; and bone marrow biopsy; aspiration alone is not enough. In addition to an updated immune status and viral load, the following should be determined at the very least: blood count, ESR, CRP, uric acid, LDH, liver and kidney parameters and electrolytes. ECG and echocardiography are also important beforehand. The possible cardiotoxicity of chemotherapy (anthracyclines) during the course of treatment can only be evaluated if these tests have been performed at the start. Pulmonary function should be tested before treatment with regimens containing bleomycine is initiated.
After two cycles of chemotherapy, a restaging should be performed to evaluate treatment success. This restaging should be oriented according to the original localization of lymphoma. After completion of the protocol, a complete restaging with bone marrow biopsy (if there was initial involvement) and all CT scans are necessary. With a complete remission, restaging is recommended initially at three-monthly intervals. These intervals can be prolonged to six months after one year and to twelve months after two years. Relapses after more than three years are rare.
In advanced stages of the disease (Ann Arbor III-IV), and particularly with ENT involvement, a diagnostic lumbar puncture is necessary before initiating systemic chemotherapy to exclude meningeal involvement. In such cases, 15 mg of methotrexate can be administered intrathecally as prophylaxis. Whether this action, generally accepted by oncologists, actually has any benefit or not, has never been shown in controlled studies. However, newer data suggest that there may be a benefit (Spina 2010).
Due to extremely rapid generalization, even “early stages” are rarely limited. The real stage of the disease is often underestimated – every aggressive HIV-associated lymphoma should therefore be treated primarily with systemic chemotherapy with curative intent. Surgery or radiation therapy alone are not sufficient. Treatment should be started rapidly due to the aggressive nature of these lymphomas. In particular, time should not be wasted on staging. The necessary tests should be completed within a week.
In Europe, diffuse large-cell NHLs have been treated for many years with CHOP-based regimens (usually 4-6 cycles, see table). CHOP is the abbreviation used for the combination chemotherapy with the cytostatics cyclophosphamide, adriamycin (hydroxydoxorubicin), vincristine (Oncovin®) and prednisolone. To date, no other chemotherapy regimen has been shown to have better efficacy. There are no randomized controlled trials comparing CHOP with other regimens such as CDE or EPOCH which have been proposed by several working groups.
In contrast to CDE or EPOCH, CHOP can be administered in ambulatory care and is fairly well tolerated. At least 4-6 cycles should be administered, and – as far as possible – 2 cycles after reaching complete remission (CR).
The standard three-week CHOP regimen (CHOP-21) is shown in Table 3. Following the success of CHOP-14 (one cycle every two weeks) in older HIV-negative patients (Pfreundschuh 2004), CHOP-21 can also be “intensified”: in CHOP-14 the use of the growth hormone G-CSF (e.g. Filgastrim 30-48 million units or Neupogen® 300/480 µg s.c. daily on days 4 to 13) reduces the duration of neutropenia. This approach not only decreases the phase of increased susceptibility to infections, but also increases the dose intensity of chemotherapy. However, there is no comparative data on this for HIV patients. So far, we have had fairly positive experiences – in most HIV patients, it is possible to shorten the interval.
Recently, a study from East Africa reported on a dose-modified oral chemotherapy, consisting in lomustine, etoposide and cyclophosphamide/procarbazine. This pragmatic approach had acceptable remission rates in 49 patients with AIDS-NHL and could be considered as an alternative in resource-poor countries (Mwanda 2009).
Table 3: CHOP regimen (4-6 cycles of 3 weeks each, repeat on Day 22) *
|Cyclophosphamide||Endoxan®||750 mg/m2 i.v. Day 1|
|Doxorubicin||Doxo-CellÒ, Adriblastin®||50 mg/m2 i.v. Day 1|
|Vincristine||Vincristin®||1.4 mg/m2 (maximum 2 mg) i.v. Day 1|
|Prednisolone||Decortin H®||2 tbl. at 50 mg qd p.o., Day 1-5|
|Mesna||Uromitexan®||20% of cyclophosphamide dose at hours 0, 4, 8 (with reference to cyclophosphamide i.v. given as a short infusion or orally)|
* Standard CHOP regimen (“CHOP 21”)
We recommend the administration of co-trimoxazole as an adjuvant therapy, up until one month after completion of the chemotherapy (960 mg three times weekly), independent of the CD4 T cell count. Oral mucous membranes should be treated with mouthwashes and topical amphotericin. Good compliance from the patients is an important factor. During chemotherapy, at least twice weekly monitoring of the patient’s condition, blood count, liver and kidney parameters is necessary. Treatment is usually continued with the full dose according to protocol if leukocytes are above 3,000/mm3 again after nadir and platelets more than 80,000/mm3 on the planned day of treatment. Patients should be advised to carry out daily temperature monitoring and be told to present immediately in case of fever.
Rituximab in HIV infected patients
The introduction of the monoclonal CD20-antibody rituximab (MabThera® or Rituxan®) was one of the biggest advances in oncology in recent years. In numerous lymphomas, this antibody, which binds highly specifically to CD20-positive B cells (CD20 is expressed by most lymphoma cells), has markedly improved the effectiveness and length of response of conventional chemotherapy. A combination of CHOP and rituximab (R-CHOP) is now standard in many lymphomas. Rituximab is usually well tolerated, but often leads to a longer lasting B cell depletion, and occasionally to severe neutropenia (Voog 2003).
It is not clear whether rituximab has a similarly large clinical benefit for HIV infected patients as it has for HIV negative patients with B cell lymphoma. The results from AMC 010, a multicenter prospective and randomized US study, have at least raised doubts (Kaplan 2005). In this study, 143 patients with CD20-positive AIDS-NHL were randomized (1:2) to CHOP or R-CHOP (rituximab in the usual dose of 375 mg/m² on day 1 with a monthly maintenance therapy for 3 months following chemotherapy). In addition to the chemotherapy, all patients also received G-CSF, a co-trimoxazole prophylaxis and an AZT-free ART. Both groups were well matched. The planned CHOP cycles were carried out at the same intensity in both groups, and in both groups only slight dose reductions were necessary.
The main results were disappointing. There was only a trend towards a better response in the R-CHOP arm (complete response rate 58% versus 47%, p=0.15). No differences were found with respect to the length of response, disease-free or total survival. However, neutropenia and incidence of (especially severe) infection were significantly higher in the rituximab group. Out of a total of 15 patients who died from an infection during the study, 14 had received rituximab (14% versus 2%, p=0.035). The cause of death was usually septicemia from various bacteria – both gram-negative and gram-positive were identified. Death occurred in the majority (8/15) during the first two cycles, although six cases happened during the rituximab treatment at the end of the chemotherapy. Fatalities occurred in all centers and were therefore not due to a possible lack of expertise in any one location. A further risk factor for “death from infection” was a low baseline CD4 count – 8/13 patients had less than 50 CD4 T cells/µl. The cause of the high rate of severe infections is still unclear. Pathophysiologically, it is at least possible that in pre-existing T cell defects present in HIV patients, a long-lasting rituximab-induced B cell depletion or hypoglobulinemia has particularly negative effects (Miles 2005). There are also some reports on an elevated risk for PML in patients receiving rituximab (Carson 2009). The reason for this association remains unclear.
In contrast to the results of AMC 010, there are numerous mostly uncontrolled studies which did not find an elevated risk for serious infection with the use of rituximab (Spina 2005, Boue 2006, Ribera 2008, Sparano 2009). In a cohort study of 164 patients with NHL since 2005, treatment with rituximab was not associated with increased mortality from infection. Moreover, rituximab seems to be beneficial even in severely immunosuppressed patients (Wyen 2008).
Following the data which have to be examined, the use rituximab can be considered in all HIV infected patients with CD20 positive NHL. Even a severe immune deficiency (less than 200 CD4 T cells/µl) does not represent a contraindication. However, intensive monitoring and the prophylactic use of co-trimoxazole (and possibly quinolones) may be advisable. In addition, it is imperative that more data is obtained. For this reason, a multicentric cohort study has been set up for Germany starting in 2006, which should incorporate as many patients as possible.
More Intensive Chemotherapy as Standard CHOP
After earlier studies showed that intensive chemotherapy led to a disproportionately high risk of infection and toxic complications (Kaplan 1997), the tendency for a long time was to withhold HIV patients from therapy and often to treat them with reduced-dose regimens. This seems to be changing in the age of combination ART. Several prospective studies have shown that the tolerability of chemotherapy is improved through ART (Powles 2002, Sparano 2004, Bower 2008).
In the past few years, small pilot studies have been repeatedly published in which HIV patients have been treated with CHOP regimens. There are also studies in which doxorubicin has been given as liposomal Caelyx® (Levine 2004) or where the dose of cyclophosphamide was increased (Costello 2004). In addition, CDE, a regimen which, when given for several days as infusions is supposed to overcome the potential chemotherapy resistance of lymphoma cells, is propagated again and again (Sparano 2004). The CR rates in these studies were between 50 and 75%. In our experience, CR rates up to 70% are also possible with ART and standard CHOP. Whether these new attempts, which always cause a stir, are really better than CHOP, remains speculative. In our view, they are not ready for use outside of clinical trials. Even stem cell transplantations are now possible in HIV patients – a scenario that was still unthinkable a few years ago. Very high doses of myeloablative chemotherapy in combination with ART are well tolerated (see below). In HIV patients with Burkitt’s lymphoma, intensive protocols that were originally developed for HIV negative patients are also being successfully employed (see below).
Today, the decisive question regarding more intensive chemotherapy in HIV infected patients is, therefore, not whether it can be used, but who actually needs it or will benefit from an increased dose.
What ART When?
In early studies, the effect of combination ART on the prognosis of HIV-associated NHL was only modest (Levine 2000, Matthews 2000). Over the last years, however, many studies clearly demonstrated that prognosis of patients with NHL is markedly improved with ART (Antinori 2001, Besson 2001, Ratner 2001, Hoffmann 2003). In addition to survival, some studies also showed improved disease-free survival, response rates and even improved tolerability of chemotherapy. Even cases in which ART alone led to a complete remission of lymphoma have been published (Amengual 2008, Baraboutis 2009). There is no doubt that every patient with AIDS-associated lymphoma should start an antiretroviral therapy, even in the setting of a relatively preserved immune function.
In most cases, an already existing, virologically effective ART can be continued during chemotherapy. However, a switch from AZT (myelotoxic) and from d4T/ddI (high risk of polyneuropathy, in particular when given with vinca alkaloids) to other nucleoside analogs or to a nuke-free regimen should be considered. Before switching to abacavir, an HLA-B*5701 genetic screening is recommended. When switching to tenofovir, intensive monitoring of renal function parameters is required.
In naïve patients, the first one or two CHOP cycles can be completed before starting ART. Some clinicians prefer to complete all six cycles out of concern for interactions and cumulative toxicities (Little 2003). In our opinion, this is not necessary, even though data on possible interactions between ART and chemotherapy is limited (review: Mounier 2008). For example, the effect of PIs and NNRTIs on doxorubicin levels seems to be only moderate (Toffoli 2004) and in many studies, the concomitant use of ART and chemotherapy was safe and feasible (Powles 2002, Weiss 2006, Simcock 2007, Bower 2008). However, there have been some reports of patients who experienced severe vinblastine-associated neurotoxicity during concomitant treatment with ritonavir-boosted PIs (Cheung 2010). If PI-containing combinations are used, TDM is recommended.
In ART-naïve patients without pre-existing renal damage, we would favor a combination of tenofovir, FTC and raltegravir. The integrase inhibitor raltegravir has a low risk for interactions and side effects. Moreover, many studies suggest a faster viral decay with this agent compared to other antiretrovirals. During tenofovir, renal function should be monitored carefully.
Special entities of lymphoma
Burkitt’s or Burkitt-like lymphomas: the particularly high proliferative capacity and aggressiveness of Burkitt’s or Burkitt-like lymphomas is a problem even in HIV negative patients. In this case, the CHOP regimen is insufficient (Trümper 2001). Although it is still unclear whether this is also true for HIV infected patients with Burkitt’s lymphomas, many clinicians have in recent years tended to treat such patients more intensively. A modified dose-adapted protocol of the German multicenter study group for adult acute lymphoblastic leukemia (GMALL) is usually used for the treatment of HIV-negative cases of Burkitt-NHL/B-ALL, and consists of four to six short, intensive 5-day polychemotherapy cycles, alternating A and B cycles. A cytoreductive pretreatment with cyclophosphamide and prednisone, each for 5 days, was given before the first cycle. During cycle A, fractionated doses of ifosphamide for 5 days, intermediate- or high-dose methotrexate 500-3,000 mg/m2, VM26, cytarabine (ara-C), vincristine, and dexamethasone are given. During cycle B, ara-C, VM26 and ifosphamide are replaced by doxorubicin and cyclophosphamide (Hoelzer 1996). Preliminary data show better responses than with CHOP (Hoffmann 2006) and rates comparative to those of HIV-negative patients (Oriol 2008). However, the GMALL protocol is a very intensive chemotherapy, which cannot be administered on an outpatient basis. Strict monitoring of patients in hospital for several weeks is very important. Centers without experience in this intensive protocol should not administer it to HIV infected patients.
Other intensive therapies have been also reported (Cortes 2002, Wang 2003). A significant problem with most of the studies is that there is no control group. There is no randomized study. However, there is increasing evidence that conventionally treated patients with Burkitt’s lymphoma continue to have a worse prognosis even in the age of combination ART (Conti 2000, Lim 2005, Spina 2005). Although this has not been confirmed by all study teams (Bower 2005), intensive therapy should be considered for every patient with Burkitt’s lymphoma. A poor immune status or the existence of a concurrent opportunistic infection does not necessarily have to be an obstruction (Lehmann 2005).
Plasmablastic lymphomas: are a relatively “new” entity in HIV infected patients. Plasmablastic lymphomas probably belong to the diffuse large-cell NHLs, but display a completely characteristic immune phenotype, which usually correlates to a post-germinal center cell – markers for the B-cell antigen CD20 are negative, whereas the plasma-cell reactive antibodies VS38c and CD138 are positive (Brown 1998, Teruya-Feldstein 2004).
The oral cavity is the site of involvement (Gaidano 2002), although extra-oral manifestations do occur (Chetty 2003). There is a close association with an HHV-8 infection but also EBV (Castillo 2008, Riedel 2008). Like Burkitt’s lymphoma, plasmablastic lymphomas have a very high rate of proliferation and are extremely aggressive. More recent data shows that the earlier very poor prognosis is markedly improved by ART (Teruya-Feldstein 2004, Lester 2004, Riedel 2008). In a study on 89 NHL, we were able to show that a post germinal center profile, as often occurs in plasmablastic lymphomas, is independently associated with a worse prognosis (Hoffmann 2005). This observation was confirmed by other groups (Dunleavy 2010). It is our opinion that patients should therefore receive other treatments than CHOP-21. These could include bortezomib, which is a selective potent proteasome inhibitor that has been approved for clinical treatment of multiple myeloma and mantel cell lymphoma. There exist at least one case report (Bibas 2010).
Primary effusion lymphoma (PEL): a further therapeutic problem is the relatively rare entity of the so-called primary effusion lymphoma which is also termed body cavity lymphoma (Carbone 1997+2000). These lymphomas are often very difficult to diagnose histologically. A visible tumor mass is usually absent, so that malignant cells can only be found in body cavities (e.g. pleural, pericardial, peritoneal). There are histological similarities to immunoblastic and anaplastic cells with a non-B-, non-T phenotype. Every pleural or pericardial effusion occurring in an HIV patient and containing malignant cells, is suspicious of PEL. The involved pathologist should always be informed about this suspicion. There is a characteristic close association with the herpes virus HHV-8, which can be detected in the malignant cells, and which provides a relatively typical gene expression profile (Simonelli 2005, Fan 2005). Recently, a solitary variant has been reported, which is neither morphologically nor immunophenotypically distinguishable from the classical PEL types (Chadburn 2004).
The response to the CHOP regimen is usually poor and poorer than that of centroblastic NHL (Simonelli 2003). Case studies with complete remission on ART alone have been described (Boulanger 2001, Hocqueloux 2001). We have, however, seen two PEL patients who have also died of progression despite CHOP and ART after only a few months. A small study reported encouraging results with a combined chemotherapy with high dose methotrexate. In at least 3/7 patients a lasting complete remission could be achieved – a notable achievement in view of the otherwise poor prognosis, and an approach that should be followed up (Boulanger 2003). On the other hand, there are reports in which even intensive treatment regimens were unsuccessful (Waddington 2004). A new option may be bortezomib, which is a selective potent proteasome inhibitor. Xenograft models have shown that bortezomib induces PEL remission, providing a rational basis for clinical evaluation (Sarosiek 2010).
Relapse Therapy, Stem Cell Transplantation
At the moment, no general recommendations for relapse therapy of NHL can be given. The prognosis of NHL relapse is poor overall, anyway. A team from the USA reported their positive experiences using the ESHAP protocol (etoposide, methylprednisolone, ara-C and cisplatin) – DHAP appears to have no effect in this case (Bi 2001). The EPOCH-regimen may also be effective. Other salvage monotherapies with mitoguazon or liposomal daunorubicin are well tolerated, but purely palliative (Levine 1997, Tulpule 2001).
It should always be checked whether the affected patient with a relapse of lymphoma qualifies in principle for an autologous stem cell transplant (ASCT). In ASCT, the intensity of the chemotherapy can be markedly increased by the preceding gain of pluripotential stem cells (own cells: autologous; foreign cells: allogenic). Following the myeloablative chemotherapy, the patients are re-infused with the stem cells. Over 200 cases of SCT in HIV-infected patients have been described so far worldwide (Gabarre 2000+2004, Re 2003, Krishnan 2005, Serrano 2005, Spitzer 2008). They have clearly shown that efficacy as comparable to HIV-negative patients (Simonelli 2010, Krishnan 2010). Even a few allogeneic SCT have been reported (Kang 2002, Bryant 2008, Gupta 2009, Oka 2010).
In 2009, one of these cases attracted much intention. German researchers from Berlin transplanted stem cells from a donor who was homozygous for CCR5 delta32 in a patient with acute myeloid leukemia and HIV-1 infection. The patient remained without viral rebound for years after transplantation and discontinuation of ART (Huetter 2009, Allers 2011). There is now doubt that this case offers great hope for potential gene therapies. However, given the high mortality of patients undergoing allogeneic SCT, this treatment would be too risky as a routine treatment for HIV and too difficult to find donors with the right genetic make-up.
The critical problem of autologous SCT in many hematological centers is above all a logistical one, namely the complicated storage of stem cells, which has to conform to strict safety regulations. The storage of potentially infectious HIV material together with stem cells from non-infected patients in the normal cooling tanks is not allowed – an extra (expensive) tank is required.
Allers K, Hütter G, Hofmann J, et al. Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood 2011, 117:2791-9.
Amengual JE, Zhang X, Ibrahim S, Gardner LB. Regression of HIV-related diffuse large B-cell lymphoma in response to antiviral therapy alone. Blood 2008, 112:4359-60.
Antinori A, Cingolani A, Alba L, et al. Better response to chemotherapy and prolonged survival in AIDS-related lymphomas responding to HAART. AIDS 2001, 15:1483-91.
Antiretroviral Therapy Cohort Collaboration (ART-CC). Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal. Clin Infect Dis 2009, 48:1138-51.
Baraboutis IG, Marinos L, Lekakis LJ, et al. Long-term complete regression of nodal marginal zone lymphoma transformed into diffuse large B-cell lymphoma with highly active antiretroviral therapy alone in HIV infection. Am J Med Sci 2009, 338:517-21.
Besson C, Goubar A, Gabarre J, et al. Changes in AIDS-related lymphoma since the era of HAART. Blood 2001, 98:2339-44.
Bi J, Espina BM, Tulpule A, Boswell W, Levine AM. High-dose cytosine-arabinoside and cisplatin regimens as salvage therapy for refractory or relapsed AIDS-related non-Hodgkin’s lymphoma. J AIDS 2001, 28:416-21.
Bibas M, Grisetti S, Alba L, et al. Patient with HIV-associated plasmablastic lymphoma responding to bortezomib alone and in combination with dexamethasone, gemcitabine, oxaliplatin, cytarabine, and pegfilgrastim chemotherapy and lenalidomide alone. JCO 2010, 28:e704-8
Bonnet F, Burty C, Lewden C, et al. Changes in cancer mortality among HIV-infected patients: the Mortalité 2005 Survey. Clin Infect Dis 2009, 48:633-9.
Bonnet F, Lewden C, May T, et al. Malignancy-related causes of death in hiv-infected patients in the era of HAART. Cancer 2004, 101:317-24.
Boue F, Gabarre J, Gisselbrecht C, et al. Phase II trial of CHOP plus rituximab in patients with HIV-associated non-Hodgkin’s lymphoma. J Clin Oncol 2006, 24:4123-8.
Boulanger E, Agbalika F, Maarek O, et al. A clinical, molecular and cytogenetic study of 12 cases of human herpesvirus 8 associated primary effusion lymphoma in HIV-infected patients. Hematol J 2001, 2:172-9.
Boulanger E, Daniel MT, Agbalika F, Oksenhendler E. Combined chemotherapy including high-dose methotrexate in KSHV/HHV8-associated primary effusion lymphoma. Am J Hematol 2003, 73: 143-8.
Bower M, Stebbing J, Tuthill M, et al. Immunologic recovery in survivors following chemotherapy for AIDS-related non-Hodgkin lymphoma. Blood 2008;111:3986-90.
Breen EC, Boscardin WJ, Detels R, et al. Non-Hodgkin’s B cell lymphoma in persons with acquired immunodeficiency syndrome is associated with increased serum levels of IL10, or the IL10 promoter -592 C/C genotype. Clin Immunol 2003, 109:119-29.
Breen EC, Epeldegui M, Boscardin WJ, et al. Elevated levels of soluble CD44 precede the development of AIDS-associated non-Hodgkin’s B-cell lymphoma. AIDS 2005, 19:1711-2.
Breen EC, Fatahi S, Epeldegui M, et al. Elevated serum soluble CD30 precedes the development of AIDS-associated non-Hodgkin’s B cell lymphoma. Tumour Biol 2006, 27:187-94.
Brown RS, Campbell C, Lishman SC, et al. Plasmablastic lymphoma: a new subcategory of HIV-related NHL. Clin Oncol 1998, 10:327-9.
Bryant A, Milliken S. Successful reduced-intensity conditioning allogeneic HSCT for HIV-related primary effusion lymphoma. Biol Blood Marrow Transplant 2008, 14:601-2.
Carbone A, Cilia AM, Gloghini A, et al. Primary effusion lymphoma cell lines harbouring human herpesvirus type-8. Leuk Lymphoma 2000, 36:447-56.
Carbone A, Gaidano G. HHV-8-positive body-cavity-based lymphoma: a novel lymphoma entity. Br J Haematol 1997, 97: 515-522.
Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy following rituximab therapy in HIV negative patients: a report of 57 cases from the Research on Adverse Drug Event and Reports (RADAR) project. Blood. 2009 Mar 5.
Castillo J, Pantanowitz L, Dezube BJ. HIV-associated plasmablastic lymphoma: lessons learned from 112 published cases. Am J Hem 2008, 83:804-9.
Chadburn A, Hyjek E, Mathew S, et al. KSHV-positive solid lymphomas represent an extra-cavitary variant of primary effusion lymphoma. Am J Surg Pathol 2004, 28:1401-16.
Chao C, Xu L, Abrams D, et al. Survival of non-Hodgkin lymphoma patients with and without HIV infection in the era of combined antiretroviral therapy. AIDS 2010, 24:1765-70.
Chetty R, Hlatswayo N, Muc R, et al. Plasmablastic lymphoma in HIV+ patients: an expanding spectrum. Histopathology 2003, 42:605-9.
Cheung MC, Hicks LK, Leitch HA. Excessive neurotoxicity with ABVD when combined with protease inhibitor-based antiretroviral therapy in the treatment of AIDS-related Hodgkin lymphoma. Clin Lymphoma Myeloma Leuk 2010, 10:E22-5.
COHERE Study Group. Incidence and risk factors of HIV-related non-Hodgkin’s lymphoma in the era of combination antiretroviral therapy: a European multicohort study. Antivir Ther 2009, 14:1065-74.
Cortes J, Thomas D, Rios A, et al. Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and highly active antiretroviral therapy for patients with AIDS-related Burkitt lymphoma/leukemia. Cancer 2002, 94:1492-9.
Costello RT, Zerazhi H, Charbonnier A, et al. Intensive sequential chemotherapy with hematopoietic growth factor support for non-Hodgkin lymphoma in patients infected with the human immunodeficiency virus. Cancer 2004, 100:667-76.
Dunleavy K, Little RF, Pittaluga S, et al. The role of tumor histogenesis, FDG-PET, and short course EPOCH with dose-dense rituximab (SC-EPOCH-RR) in HIV-associated diffuse large B-cell lymphoma. Blood. 2010 Feb 3. [Epub ahead of print]
Epeldegui M, Breen EC, Hung YP, Boscardin WJ, Detels R, Martínez-Maza O. Elevated expression of activation induced cytidine deaminase in peripheral blood mononuclear cells precedes AIDS-NHL diagnosis. AIDS 2007, 21:2265-70.
Fan W, Bubman D, Chadburn A, et al. Distinct subsets of primary effusion lymphoma can be identified based on their cellular gene expression profile and viral association. J Virol 2005, 79:1244-51.
Franceschi S, Lise M, Clifford GM, et al. Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study. Br J Cancer 2010, 103:416-22.
Gabarre J, Azar N, Autran B, Katlama C, Leblond V. High-dose therapy and autologous haematopoietic stem-cell transplantation for HIV-1-associated lymphoma. Lancet 2000, 355:1071-2.
Gabarre J, Marcelin AG, Azar N, et al. High-dose therapy plus autologous hematopoietic stem cell transplantation for HIV-related lymphoma: results and impact on HIV disease. Haematologica 2004, 89:1100-8.
Gaidano G, Cerri M, Capello D, et al. Molecular histogenesis of plasmablastic lymphoma of the oral cavity. Br J Haematol 2002,; 119: 622-628.
Gérard L, Meignin V, Galicier L, et al. Characteristics of non-Hodgkin lymphoma arising in HIV-infected patients with suppressed HIV replication. AIDS 2009, 23:2301-8.
Goedert JJ. The epidemiology of AIDS malignancies. Semin Oncol 2000, 27:390-401.
Grulich AE, Wan X, Law MG, et al. B-cell stimulation and prolonged immune deficiency are risk factors for non-Hodgkin’s lymphoma in people with AIDS. AIDS 2000, 14:133-40.
Gupta V, Tomblyn M, Pedersen TL, et al. Allogeneic hematopoietic cell transplantation in human immunodeficiency virus-positive patients with hematologic disorders: a report from the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 2009, 15:864-71.
Hocqueloux L, Agbalika F, Oksenhendler E, Molina JM. Long-term remission of an AIDS-related primary effusion lymphoma with antiviral therapy. AIDS 2001, 15:280-2.
Hoffmann C, Repp R, Schoch R, et al. Successful autologous stem cell transplantation in a severely immunocompromised patient with relapsed AIDS-related B-cell Lymphoma. Eur J Med Res 2006, 11:73-6.
Hoffmann C, Tiemann M, Schrader C, et al. AIDS-related B-cell lymphoma (ARL): correlation of prognosis with differentiation profiles assessed by immunophenotyping. Blood 2005, 106:1762-9.
Hoffmann C, Wolf E, Fatkenheuer G, et al. Response to highly active antiretroviral therapy strongly predicts outcome in patients with AIDS-related lymphoma. AIDS 2003, 17:1521-9.
Hoffmann C, Wolf E, Wyen C, et al. AIDS-associated Burkitt or Burkitt-like lymphoma: short intensive polychemotherapy is feasible and effective.Leuk Lymphoma 2006, 47:1872-80.
Hütter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med 2009, 360:692-8.
Kang EM, de Witte M, Malech H, et al. Nonmyeloablative conditioning followed by transplantation of genetically modified HLA-matched peripheral blood progenitor cells for hematologic malignancies in patients with AIDS. Blood 2002, 99:698-701.
Kaplan LD, Lee JY, Ambinder RF, et al. Rituximab does not improve clinical outcome in a randomized phase III trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin’s lymphoma: AIDS-malignancies consortium trial 010. Blood 2005, 106:1538-43.
Kaplan LD, Straus DJ, Testa MA, et al. Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin’s lymphoma associated with HIV infection. N Engl J Med 1997, 336:1641-8.
Kirk O, Pedersen C, Cozzi-Lepri A, et al. Non-Hodgkin lymphoma in HIV-infected patients in the era of HAART. Blood 2001, 98: 3406-3412.
Krishnan A, Molina A, Zaia J, et al. Durable remissions with autologous stem cell transplantation for high risk HIV-associated lymphomas. Blood 2005, 105:874-8.
Krishnan A, Palmer JM, Zaia JA, Tsai NC, Alvarnas J, Forman SJ. HIV status does not affect the outcome of autologous stem cell transplantation (ASCT) for non-Hodgkin lymphoma (NHL). Biol Blood Marrow Transplant 2010, 16:1302-8.
Landgren O, Goedert J, Rabkin C, et al. Risk of AIDS Non-Hodgkin’s Lymphoma is strongly predicted by elevated levels of circulating immunoglobulin-free light chains. Abstract 29, 16th CROI 2009, Montréal.
Lehmann C, Wyen C, Hoffmann C, Fatkenheuer G. Successful administration of aggressive chemotherapy concomitant to tuberculostatic and highly active antiretroviral therapy in a patient with AIDS-related Burkitt’s lymphoma. HIV Med 2005, 6:51-3.
Lester R, Li C, Galbraith P, et al. Improved outcome of human immunodeficiency virus-associated plasmablastic lymphoma of the oral cavity in the era of HAART: a report of two cases. Leuk Lymphoma 2004, 45:1881-5.
Levine AM, Seneviratne L, Espina BM, et al. Evolving characteristics of AIDS-related lymphoma. Blood 2000, 96: 4084-4090.
Levine AM, Tulpule A, Espina B, et al. Liposome-encapsulated doxorubicin in combination with standard agents (cyclophosphamide, vincristine, prednisone) in patients with newly diagnosed AIDS-related non-Hodgkin’s lymphoma: results of therapy and correlates of response. JCO 2004; 22:2662-70.
Levine AM, Tulpule A, Tessman D, et al. Mitoguazone therapy in patients with refractory or relapsed AIDS-related lymphoma: results from a multicenter phase II trial. J Clin Oncol 1997;15:1094-103.
Levine AM. AIDS-related lymphoma: clinical aspects. Semin Oncol 2000, 27:442-53.
Lewden C, May T, Rosenthal E, et al. Changes in causes of death among adults infected by HIV between 2000 and 2005: The “Mortalité 2000 and 2005” surveys (ANRS EN19 and Mortavic). J AIDS 2008, 48:590-8.
Lim ST, Karim R, Nathwani BN, 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, 23:4430-8.
Little RF, Pittaluga S, Grant N, et al. Highly effective treatment of AIDS-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood 2003, 101:4653-9.
Matthews GV, Bower M, Mandalia S, et al. Changes in AIDS-related lymphoma since the introduction of HAART. Blood 2000, 96:2730-2734.
Miles SA, McGratten M. Persistent panhypogammaglobulinemia after CHOP-Rituximab for HIV-related lymphoma. JCO 2005;23:247-8.
Mocroft A, Katlama C, Johnson AM, et al. AIDS across Europe, 1994-1998: the Eurosida study. Lancet 2000, 356:291-296.
Mounier N, Katlama C, Costagliola D, Chichmanian RM, Spano JP. Drug interactions between antineoplastic and antiretroviral therapies: Implications and management for clinical practice. Crit Rev Oncol Hematol 2008 Dec 11. [Epub ahead of print]
Mwanda WO, Orem J, Fu P, et al. Dose-modified oral chemotherapy in the treatment of AIDS-related non-Hodgkin’s lymphoma in East Africa. J Clin Oncol 2009, 27:3480-8.
Oka Y, Tashiro H, Mizutani-Noguchi M, et al. Successful unrelated bone marrow transplantation for a human immunodeficiency virus type-1-seropositive acute myelogenous leukemia patient following HAART. Int J Hematol 2010, 91:140-5.
Oriol A, Ribera JM, Bergua J, et al. High-dose chemotherapy and immunotherapy in adult Burkitt lymphoma : comparison of results in human immunodeficiency virus-infected and noninfected patients. Cancer 2008.
Pfreundschuh M, Trumper L, Kloess M, et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004, 104:634-41.
Polesel J, Clifford GM, Rickenbach M, et al. Non-Hodgkin lymphoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy. AIDS 2008;22:301-6.
Porcu P, Caligiuri MA. AIDS-related lymphomas: future directions. Sem Oncology 2000, 4:454-62.
Powles T, Imami N, Nelson M, Gazzard BG, Bower M. Effects of combination chemotherapy and HAART on immune parameters in HIV-1 associated lymphoma. AIDS 2002, 16:531-6.
Purdue MP, Lan Q, Martinez-Maza O, et al. A prospective study of serum soluble CD30 concentration and risk of non-Hodgkin lymphoma. Blood 2009,114:2730-2.
Ratner L, Lee J, Tang S et al. Chemotherapy for HIV-associated non-Hodgkin’s lymphoma in combination with HAART. J Clin Oncol 2001, 19: 2171-8.
Re A, Cattaneo C, Michieli M, et al. High-dose therapy and autologous peripheral-blood stem-cell transplantation as salvage treatment for HIV-associated lymphoma in patients receiving HAART. JCO 2003, 21:4423-7.
Re A, Michieli M, Casari S, et al. High-dose therapy and autologous peripheral blood stem cell transplantation as salvage treatment for AIDS-related lymphoma: long-term results of the Italian Cooperative Group on AIDS and Tumors (GICAT) study with analysis of prognostic factors. Blood 2009, 114:1306-13.
Regidor DL, Detels R, Breen EC, et al. Effect of highly active antiretroviral therapy on biomarkers of B-lymphocyte activation and inflammation. AIDS 2011, 25:303-14.
Ribera JM, Oriol A, Morgades M, et al. Safety and efficacy of cyclophosphamide, adriamycin, vincristine, prednisone and rituximab in patients with human immunodeficiency virus-associated diffuse large B-cell lymphoma: results of a phase II trial. Br J Haematol 2008;140:411-9.
Riedel DJ, Gonzalez-Cuyar LF, Zhao XF, Redfield RR, Gilliam BL. Plasmablastic lymphoma of the oral cavity: a rapidly progressive lymphoma associated with HIV infection. Lancet Infect Dis 2008;8:261-7.
Sarosiek KA, Cavallin LE, Bhatt S, et al. Efficacy of bortezomib in a direct xenograft model of primary effusion lymphoma. Proc Natl Acad Sci U S A 2010, 107:13069-74.
Serrano D, Carrion R, Balsalobre P, et al. HIV-associated lymphoma successfully treated with peripheral blood stem cell transplantation. Exp Hematol 2005, 33:487-94.
Simcock M, Blasko M, Karrer U, et al. Treatment and prognosis of AIDS-related lymphoma in the era of highly active antiretroviral therapy: findings from the Swiss HIV Cohort Study. Antivir Ther 2007;12:931-9.
Simonelli C, Spina M, Cinelli R, et al. Clinical features and outcome of primary effusion lymphoma in HIV-infected patients: a single-institution study. J Clin Oncol 2003, 21:3948-54.
Simonelli C, Tedeschi R, Gloghini A, et al. Characterization of immunologic and virological parameters in HIV-infected patients with primary effusion lymphoma during antiblastic therapy and highly active antiretroviral therapy. Clin Infect Dis 2005, 40:1022-7.
Simonelli C, Zanussi S, Pratesi C, et al. Immune recovery after autologous stem cell transplantation is not different for HIV-infected versus HIV-uninfected patients with relapsed or refractory lymphoma. Clin Infect Dis 2010, 50:1672-9.
Sparano JA, Lee JY, Kaplan LD, et al. Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated, B-cell non-Hodgkin’s lymphoma. Blood. 2009 Dec 29. [Epub ahead of print]
Sparano JA, Lee S, Chen MG, et al. Phase II trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with HIV-associated non-Hodgkin’s lymphoma: an Eastern Cooperative Oncology Group Trial (E1494). J Clin Oncol 2004, 22:1491-500.
Spina M, Chimienti E, Martellotta F, et al. Phase 2 study of intrathecal, long-acting liposomal cytarabine in the prophylaxis of lymphomatous meningitis in human immunodeficiency virus-related non-Hodgkin lymphoma. Cancer. 2010 Jan 27. [Epub ahead of print]
Spina M, Jaeger U, Sparano JA, et al. Rituximab plus infusional cyclophosphamide, doxorubicin and etoposide (R-CDE) in HIV-associated non-Hodgkin’s lymphoma: pooled results from three phase II trials. Blood 2005, 105:1891-7.
Spina M, Simonelli C, Talamini R, Tirelli U. Patients with HIV with Burkitt’s lymphoma have a worse outcome than those with diffuse large-cell lymphoma also in the highly active antiretroviral therapy era. J Clin Oncol 2005, 23:8132-3.
Spitzer TR, Ambinder RF, Lee JY, et al. Dose-reduced busulfan, cyclophosphamide, and autologous stem cell transplantation for HIV -associated lymphoma: AMC study 020. Biol Blood Marrow Transplant 2008;14:59-66.
Stebbing J, Mandalia S, Palmieri C, Nelson M, Gazzard B, Bower M. Burkitt’s lymphoma and previous AIDS-defining illnesses are not prognostic factors in AIDS-related non-Hodgkin’s lymphoma. J Clin Oncol 2005, 23:8538-40.
Teruya-Feldstein J, Chiao E, Filippa DA, et al. CD20-negative large-cell lymphoma with plasmablastic features: a clinically heterogenous spectrum in both HIV-positive and -negative patients. Ann Oncol 2004, 15:1673-9.
Toffoli G, Corona G, Cattarossi G, et al. Effect of highly active antiretroviral therapy (HAART) on pharmacokinetics and pharmacodynamics of doxorubicin in patients with HIV-associated non-Hodgkin’s lymphoma. Ann Oncol 2004, 15:1805-9.
Trümper L, Möller P, Neubauer A. Non-Hodgkin-Lymphome. Lehrbuch der Klinischen Onkologie (Hrsg. Hiddemann W, et al), Springer Verlag.
Tulpule A, Rarick MU, Kolitz J, et al. Liposomal daunorubicin in the treatment of relapsed or refractory non-Hodgkin’s lymphoma. Ann Oncol 2001;12:457-62.
Voog E, Morschhauser F, Solal-Celigny P. Neutropenia in patients treated with rituximab. N Engl J Med 2003, 348:2691-4.
Waddington TW, Aboulafia DM. Failure to eradicate AIDS-associated primary effusion lymphoma with high-dose chemotherapy and autologous stem cell reinfusion: case report and literature review. AIDS Patient Care STDS 2004, 18:67-73.
Wang ES, Straus DJ, Teruya-Feldstein J, et al. Intensive chemotherapy with cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for HIV-associated Burkitt lymphoma. Cancer 2003, 98: 1196-205.
Weiss R, Mitrou P, Arasteh K, et al. AIDS-related lymphoma: simultaneous treatment with combined cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy and HAART is safe and improves survival–results of the German Multicenter Trial. Cancer 2006;106:1560-8.
Wyen C, Faetkenheuer G, Oette M, Plettenberg A, Rockstroh J, van Lunzen J, Mayr C, Esser S, Hentrich M, Hoffmann C. Treatment of AIDS-related lymphoma: rituximab may be beneficial even in severely immunosuppressed patients. Abstract 1026, 14th CROI 2008, Boston.
Ziegler JL, Drew WL, Miner RC, et al. Outbreak of Burkitt’s-like lymphoma in homosexual men. Lancet 1982, 2:631-3.
Zoufaly A, Stellbrink HJ, Heiden MA, et al. Cumulative HIV viremia during highly active antiretroviral therapy is a strong predictor of AIDS-related lymphoma. J Infect Dis 2009, 200:79-87.