– 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
||Involvement of a single lymph node region (I) or involvement of a single extralymphatic organ or site (IE)
||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)
||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)
||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
||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) *
||750 mg/m2 i.v. Day 1
||50 mg/m2 i.v. Day 1
||1.4 mg/m2 (maximum 2 mg) i.v. Day 1
||2 tbl. at 50 mg qd p.o., Day 1-5
||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.
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