Category Archives: 13. Malignant Lymphomas

Malignant Lymphomas

 – Christian Hoffmann –

Malignant lymphomas are neoplastic diseases of the lymphatic system that grow rapidly and aggressively, and lead to death within a few weeks or months if left untreated. Hodgkin’s disease (HD) is distinguished from the large group of non-Hodgkin’s lymphomas (NHL). In comparison to the general population, HIV infected patients are affected significantly more frequently by all types of lymphoma (see Table 1). Aggressive non-Hodgkin’s lymphomas of B-cell origin are particularly frequent.

The incidence of lymphomas has been markedly reduced by the introduction of antiretroviral therapy. However, there is evidence that this reduction overall was not as impressive as with KS or most opportunistic infections (COHERE 2009, Franceschi 2010). Thus, the relative proportion of lymphoma among all AIDS-associated illnesses is increasing. The decline of the incidence seems to be greater for lymphoma subtypes that mainly occur in severe immunodeficiency (Kirk 2001, Polesel 2008).

In some HIV cohorts, malignant lymphomas have already overtaken KS as the most frequent malignancy. In the EuroSIDA study, the proportion of AIDS-defined illnesses that were malignant lymphomas increased from less than 4% in 1994 to 16% in 1998 (Mocroft 2000). In France, lymphomas accounted for 11% and 10% of all deaths in HIV patients in 2000 and 2005, respectively (Bonnet 2009). Among the AIDS-related deaths, NHL (28%) was the by far most frequent event (Lewden 2008).

Table 1. Relative risk of different lymphomas in HIV patients in comparison to the normal population (adapted from Goedert 2000)

Malignant NHL total

165

High-grade malignancy NHL

348

Immunoblastic NHL

652

Burkitt’s NHL

261

Not classifiable

580

Primary CNS lymphoma (PCNSL)

> 1,000

Low-grade malignancy NHL

14

Plasmocytoma

5

Hodgkin’s disease 8

 

Malignant lymphomas in HIV-infected patients are also biologically very heterogeneous and differ in several aspects. The frequency and extent of oncogenic mutations or cytokine dysregulation differ, as does the histogenetic origin of the malignant cells (Porcu 2000). In addition, the association with EBV and other oncogenic viruses such as HHV-8 or SV40 is very variable. The extent of immunodeficiency also varies significantly. Burkitt’s lymphoma and Hodgkin’s lymphoma (HL) frequently occur even when the immune status is good. In contrast, immunoblastic and especially primary CNS lymphoma (PCNSL) are almost always associated with severe immunodeficiency. There is now some evidence that some subtypes of malignant lymphoma can be considered as to be “opportunistic” as severe immunodeficiency is required for the development of these entities. For other lymphoma subtypes, chronic B-cell activation, possibly induced by even low HIV viremia, is a prerequisite (Epeldegui 2007, Zoufaly 2009, Regidor 2011).

However, HIV-associated lymphomas – both NHL and HD – have numerous common clinical features. Characteristics include the usually aggressive growth, diagnosis in the advanced stages with frequent extranodal manifestations, poorer response to treatment, high relapse rates and an overall poor prognosis (Levine 2000). Despite a better prognosis during recent years (see below), HIV-infected patients with NHL continue to endure substantially higher mortality compared with HIV-uninfected patients with NHL (Chao 2010).

The treatment of malignant lymphoma remains problematic. Although aggressive chemotherapy is possible in many patients with existing immunodeficiency, it is complicated and requires a close cooperation between HIV clinicians and physicians with experience in hematology/oncology.

The following discusses systemic NHL, PCNSL and HD separately. Multicentric Castleman’s disease will also be mentioned as a distinct entity, although it is not considered a malignant lymphoma. Low-grade (indolent) NHLs are very rare in HIV patients, and will therefore not be discussed here. As there are no data or even recommendations available, the treatment of such cases should follow the recommendations for HIV-negative patients.

 

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Filed under 13. Malignant Lymphomas, Part 3 - AIDS, Systemic Non-Hodgkin lymphomas (NHL)

Systemic Non-Hodgkin lymphomas (NHL)

– 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.

Diagnosis

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
A Asymptomatic
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).

Therapy

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.

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Filed under 13. Malignant Lymphomas, Part 3 - AIDS, Systemic Non-Hodgkin lymphomas (NHL)

Primary CNS lymphoma

– Christian Hoffman –

Primary CNS lymphomas (PCNSL) are a late complication of HIV infection and used to occur in up to 10% of AIDS patients. Large autopsy series in the 1990s showed even higher prevalence rates. The incidence of PCNSL seems to have decreased significantly in the last years in comparison to systemic lymphomas (Polesel 2008). PCNSL are EBV-associated in almost 100% of cases (Camilleri-Broet 1997). Histologically, findings are almost always consistent with diffuse large-cell non-Hodgkin’s lymphomas. In these patients, the CD4 T cells are almost always below 50/μl at the time of diagnosis. In the pre-HAART era, PCNSL had the poorest prognosis of all the AIDS-defining illnesses, with a median survival of less than three months (Fine 1993). In the last years, this bleak picture, often characterized by therapeutic nihilism, has changed significantly. In the HAART-era, survival may be several years and even complete remission has become possible (Hoffmann 2001).

Signs and symptoms

Different neurological deficits occur depending on the localization. Epileptic seizures may be the first manifestation of disease. Personality changes, changes in vigilance, headache and focal deficits such as paresis are also frequent. Fever is usually absent. As patients are almost always severely immunocompromised, constitutional symptoms may mask the actual problem.

Diagnosis

Cranial CT or (better) MRT scan should be performed rapidly. The most important differential diagnosis is cerebral toxoplasmosis. A solitary mass is usually more indicative of PCNSL. However, 2-4 lesions may be present, which are usually fairly large (more than 2 cm in diameter). More than four lesions of a PCNSL are rarely found.

In addition to an updated toxoplasmosis serology, which – if negative – makes toxoplasmosis very unlikely, a recent CD4 T cell count should be available. The better the immune status, the less likely the diagnosis of PCNSL. In our own cohort, less than 20% of patients had more than 50 CD4 T cells/μl at the time of diagnosis. At over 100 CD4 T cells/µl, however, cerebral toxoplasmosis is also less likely.

In addition to the physical examination, a minimal diagnostic program (chest radiography, abdominal ultrasound) should clarify whether the CNS involvement is secondary to systemic lymphoma. This should always include fundoscopy to exclude ocular involvement (up to 20%).

Besides cerebral toxoplasmosis, differential diagnoses include abscesses, glioblastoma and cerebral metastasis of solid tumors. In the absence of increased intracranial pressure, lumbar puncture is advised. If steroids have already been administered, however, the probability of finding malignant cells is diminished. EBV DNA is commonly detected in CSF of HIV-infected patients. Quantitative EBV PCR in the CSF improves the diagnostic specificity, however, the predictive value remains too low for it to be used as an isolated marker for PCNSL (Corcoran 2008).

In most cases, a treatment attempt for toxoplasmosis can be made initially. If this is unsuccessful, PCNSL is more likely. In such cases, stereotactic brain biopsy is essential to secure the diagnosis.

Treatment

For many years, cranial radiation therapy has been the only option for patients with PCNSL, independent of the HIV status. In HIV-negative patients, using the combination of radiation therapy and steroids, a remission of 12-18 months duration is usually achieved. In HIV patients in the pre-HAART era, radiation only improved survival from 0.9 to 3.0 months (Fine 1993). Survival of more than one year was rare.

The prognosis for HIV-negative patients has improved in the last years due to the introduction of methotrexate-based (MTX) chemotherapies (Carraba 2010). Whether these results will be applicable in HIV patients is not clear. In addition, the incidence of PCNSL is now diminishing to such an extent that convincing data on therapy efficacy can hardly be expected in the near future. A clear recommendation for treatment can therefore not be made at this time.

Some clinicians still favor cranial radiation therapy alone in HIV-infected patients (fractionated, 40 Gy total dose). In our experience, before radiation a treatment attempt with intravenous MTX is justified (3 g/m2 every 14 days with leucovorin rescue) – also in order to avoid possible neurological damage from radiation. A small study in HIV patients has shown that this approach is practical (Jacomet 1997).

However, the decisive factor in all cases – independent of the specific therapy chosen – is the best possible immune reconstitution. Under ART, survival of several years has become realistic. Complete remissions have even been described after treatment with ART alone (McGowan 1998, Aboufila 2007). In our own cohort of 29 patients with histologically diagnosed PCNSL, all four patients who experienced an increase in CD4 T cells survived longer than 18 months. Three out of four patients reached complete remission. One patient has now lived for over six years without evidence of relapse (Hoffmann 2001). In a multivariate analysis, combination ART was shown to be the only factor associated with a prolonged survival in addition to cranial radiation therapy. Two of these patients, however, died after about three years of a progressive neurological syndrome, which was probably a long-term sequela of radiation therapy in both cases. In view of the better prognosis for patients today, radiation toxicity should therefore be considered more than in the past. Three further studies from France, the USA and Australia have since shown a survival of several years due to ART (Rigolet 2001, Skiest 2003, Newell 2004).

All patients with PCNSL should therefore be treated intensively with antiretroviral therapy, to achieve the best possible immune reconstitution. If only a moderate immune reconstitution is possible, additional immunomodulatory or antiviral therapies should be evaluated. The partially very positive reports about ganciclovir and interleukin-2 (Raez 1999, Aboulafia 2002) or hydroxyurea (Slobod 2000) should, however, be interpreted with caution. “Between the lines” of these publications, in which either individual or hardly more than 2-4 patients were described, combination ART was almost always a factor.

In all cases with signs of raised intracranial pressure, rapid administration of steroids (e.g. dexamethasone 8 mg tid, decreasing the dose rapidly after resolution of edema) is indicated, even if diagnostic testing is more difficult as a result.

References

Aboulafia DM. Interleukin-2, ganciclovir, and high-dose zidovudine for the treatment of AIDS-associated primary central nervous system lymphoma. Clin Infect Dis 2002, 34: 1660-2.

Aboulafia DM, Puswella AL. Highly active antiretroviral therapy as the sole treatment for AIDS-related primary central nervous system lymphoma: a case report with implications for treatment. AIDS Patient Care STDS 2007;21:900-7.

Camilleri-Broet S, Davi F, Feuillard J, et al. AIDS-related primary brain lymphomas: histopathologic and immunohistochemical study of 51 cases. Hum Pathol 1997, 28:367-74.

Carrabba MG, Reni M, Foppoli M, et al. Treatment approaches for primary CNS lymphomas. Expert Opin Pharmacother 2010, 11:1263-76.

Corales R, Taege A, Rehm S, Schmitt S. Regression of AIDS-related CNS Lymphoma with HAART. XIII International AIDS-Conference, Durban, South Africa, 2000, Abstract MoPpB1086.

Corcoran C, Rebe K, van der Plas H, Myer L, Hardie DR. The predictive value of cerebrospinal fluid Epstein-Barr viral load as a marker of primary central nervous system lymphoma in HIV-infected persons. J Clin Virol 2008, 42:433-6.

DeAngelis LM. Primary central nervous system lymphomas. Curr Treat Options Oncol. 2001, 2:309-18.

Fine HA, Mayer RJ. Primary central nervous lymphoma. Ann Intern Med 1993, 119:1093-1104.

Hoffmann C, Tabrizian S, Wolf E et al. Survival of AIDS patients with primary central nervous system lymphoma is dramatically improved by HAART-induced immune recovery. AIDS 2001, 15:2119-2127.

Jacomet C, Girard PM, Lebrette MG, Farese VL, Monfort L, Rozenbaum W. Intravenous methotrexate for primary central nervous system non-Hodgkin’s lymphoma in AIDS. AIDS 1997, 11:1725-30.

Levine AM. AIDS-related lymphoma: clinical aspects. Semin Oncol 2000, 27:442-53.

McGowan JP, Shah S. Long-term remission of AIDS-related PCNSL associated with HAART. AIDS 1998, 952-954.

Newell ME, Hoy JF, Cooper SG, et al. Human immunodeficiency virus-related primary central nervous system lymphoma: factors influencing survival in 111 patients. Cancer 2004, 100:2627-36.

Patsalides AD, Atac G, Hedge U, et al. Lymphomatoid granulomatosis: abnormalities of the brain at MR imaging. Radiology 2005, 237:265-73.

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.

Raez L, Cabral L, Cai JP, et al. Treatment of AIDS-related primary central nervous system lymphoma with zidovudine, ganciclovir, and interleukin 2. AIDS Res Hum Retroviruses 1999, 15:713-9.

Rigolet A, Bossi P, Caumes E, et al. Epidemiological features and incidence trends of primary cerebral lymphomas observed in 80 HIV-infected patients from 1983 to 1999. Pathol Biol (Paris) 2001, 49:572-5.

Skiest DJ, Crosby C. Survival is prolonged by highly active antiretroviral therapy in AIDS atients with primary central nervous system lymphoma. AIDS 2003, 17:1787-93.

Slobod KS, Taylor GH, Sandlund JT, Furth P, Helton KJ, Sixbey JW. Epstein-Barr virus-targeted therapy for AIDS-related primary lymphoma of the central nervous system. Lancet 2000, 356:1493-94.

Wyen C, Stenzel W, Hoffmann C, Lehmann C, Deckert M, Fatkenheuer G. Fatal cerebral lymphomatoid granulomatosis in an HIV-1-infected patient. J Infect. 2006 Dec 11.

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Filed under 13. Malignant Lymphomas, Part 3 - AIDS, Primary CNS lymphoma

Hodgkin’s disease (HD)

– Christian Hoffmann –

The incidence of HD is elevated in HIV-infected patients by a factor of 5-15 compared to the HIV-negative population. For particular subtypes, such as lymphocyte-depleted and mixed-cellularity HD, the relative risk is presumably much higher (Frisch 2001). Despite this and the growing realization that these subtypes at least are clearly associated with immunodeficiency, HIV-HD is not included as an AIDS-defining illness.

There is growing evidence that the incidence of HIV-HD is increasing in the setting of improved immunity. Several studies reported on an increased incidence during the last years (Clifford 2005, Biggar 2006, Engels 2008, Bohlius 2011). In our own cohort we found significant differences between NHL and HD (Wyen 2008). Whereas the majority of NHL cases was diagnosed in ART naïve patients, HD mainly occurred in subjects receiving a virologically effective ART. In 54% of the patients with HIV-HD, plasma viremia was below the limit of detection at the time of HD diagnosis (NHL: 21%, p <0.001). The reason for this phenomenon is still under debate. As CD4 T cells usually predominate in the tumor microenvironment of HD, it is speculated that immune reconstitution induced by ART provides an appropriate micro-environment allowing adequate growth signals for proliferation and survival of the neoplastic Reed-Sternberg (RS) cells in HD (Gloghini 2007). In addition, CD40/CD40L interactions and EBV infection may contribute to constitutive activation of NFkB which is an antiapoptotic factor in RS cells. Interestingly, patients whose CD4 T cell counts decline despite suppression of HIV-1 replication, are at risk for HD (Bohlius 2011).

An advanced stage of disease at diagnosis is typical, as is frequent extranodal involvement and a trend towards prognostically poorer subtypes (Tirelli 1995, Rapezzi 2001, Thompson 2004). Mediastinal disease is significantly less frequent than in HIV-negative patients. A further difference to HD in seronegative patients is the predominance of cases with RS cells, as well as the clear association with EBV infection, which is 80-100%, depending on the study. EBV infection is therefore seen as an important etiologic factor for development of HIV-HD.

In comparison to HIV-negative HD, which is a highly treatable tumor, the prognosis of HIV-HD was poor in the pre-HAART era. In nearly all cohorts with more than 20 patients, the median survival was only between 15-20 months, respectively (Andrieu 1993, Tirelli 1995, Errante 1999, Levine 2000). The response to chemotherapy was also moderate compared to the normal population. Complete remission rates were between 40-80%, and hematological and infectious complications were frequent. This gloomy scenario has clearly changed since the introduction of combination ART. In our own multicenter cohort of 56 patients, the median survival was 40 months. In patients with adequate ART, the two-year survival rate was 84%, which was very encouraging (Hoffmann 2004). In the meantime, other groups have also reported better prognoses with ART (Ribera 2002, Gérard 2003, Berenguer 2008).

Signs and symptoms

B symptoms occur in the majority of cases. Extranodal and advanced stages are almost always the rule. Lymphomas are firm, immobile or hardly mobile and painless, and the distinction from HIV lymphadenopathy or tuberculous lymphadenitis is not always possible.

Diagnosis

Staging is necessary as for non-Hodgkin lymphomas (see relevant section). Diagnostic lymph node extirpation is even more important here than with NHL, as puncture only rarely allows diagnosis of Hodgkin’s disease. Single accurate diagnostics are better than half-heartedly bothering the patient with repeated punctures and losing time unnecessarily. Surgical extirpation is possible as an outpatient in many centers. As with NHL, specimens should be sent to reference laboratories if possible. Since bleomycine will be administered, a lung function test should always precede the first chemotherapy.

Treatment

Risk adapted treatment strategy in patients with HIV-HD in accordance with standard treatment procedures established for HIV-negative patients with HD is recommended. The achievement of complete remission (CR) is important. In one larger cohort, the only variable independently associated with overall survival was the achievement of CR (Berenguer 2008).

In limited (Ann Arbor I-II, no risk factors) and intermediate (I-II with risk factors) stages, many clinicians still favor the classical ABVD regimen (four double cycles, see Table 4) for HIV infected patients. ABVD is the abbreviation for the combination chemotherapy with the cytostatics adriamycine, bleomycine, vinblastine and DTIC (dacarbazine). Ambulatory treatment is possible.

Table 4: ABVD regimen (4 double cycles, repeat on Day 29)*
Adriamycine (= doxorubicin) Doxo-Cell®, Adriblastin® 25 mg/m2 i.v. Day 1 + 15
Bleomycine Bleomycin Hexal®, Bleo-Cell® 10 mg/m2 i.v. Day 1 + 15
Vinblastine Velbe®, Vinblastin Hexal® 6 mg/m2 i.v. Day 1 + 15
Dacarbazine (DTIC) Detimedac® 375 mg/m2 i.v. Day 1 + 15
* ABVD regimen. Due to strong emetogenicity of dacarbazine, 5HT3-receptor blocker anti-emetics should always be administered, e.g. granisetron, tropisetron or ondansetron.

In HIV-negative patients with advanced stages (as is almost always the case for HIV-HD) the BEACOPP regimen of the German Hodgkin Study Group has been used in the last years, mainly with escalated dosing. This has proven to be significantly more effective, both with regard to response rates and long-term survival. However, the BEACOPP regimen is more toxic. Whether these positive results can be seen in HIV-HD is still not clear. However, based on initial reports and our own experience, BEACOPP seems to be possible (Hartmann 2003). There is also growing experience to date with the Stanford V protocol, for which there have recently been promising reports (Spina 2002).

References

Andrieu JM, Roithmann S, Tourani JM, et al. Hodgkin’s disease during HIV-1 infection: the French registry experience. French Registry of HIV-associated Tumors. Ann Oncol 1993, 4:635-41.

Berenguer J, Miralles P, Ribera JM, et al. Characteristics and outcome of AIDS-related Hodgkin lymphoma before and after the introduction of highly active antiretroviral therapy. J AIDS 2008;47:422-8.

Biggar RJ, Jaffe ES, Goedert JJ, et al. Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood 2006, 108:3786-91.

Bohlius J, Schmidlin K, Boué F, et al. HIV-1-related Hodgkin lymphoma in the era of combination antiretroviral therapy: incidence and evolution of CD4+ T-cell lymphocytes. 4. Blood. 2011 Mar 2. [Epub ahead of print]

Cheung MC, Hicks LK, Leitch HA. Excessive neurotoxicity with ABVD when combined with protease inhibitor-based antiretroviral therapy in the treat-ment of AIDS-related Hodgkin lymphoma. Clin Lymphoma Myeloma Leuk 2010, 10:E22-5.

Clifford GM, Polesel J, Rickenbach M, et al. Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and HAART. J Natl Cancer Inst 2005;97:425-32.

Engels EA, Biggar RJ, Hall HI, et al. Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer 2008;123:187-94.

Errante D, Gabarre J, Ridolfo AL, et al. Hodgkin’s disease in 35 patients with HIV infection: an experience with epirubicin, bleomycin, vinblastine and prednisone chemotherapy in combination with antiretroviral therapy and primary use of G-CSF. Ann Oncol 1999, 10:189-95.

Frisch M, Biggar R, et al. Association of Cancer with AIDS-related immunosuppression in Adults. JAMA 2001, 1736-1745.

Gérard L, Galicier L, Boulanger E, et al.  Improved survival in HIV-related Hodgkin’s lymphoma since the introduction of highly active antiretroviral therapy. AIDS 2003;17:81-7.

Gloghini A, Carbone A. Why would the incidence of HIV-associated Hodgkin lymphoma increase in the setting of improved immunity? Int J Cancer 2007, 120:2753-4.

Hartmann P, Rehwald U, Salzberger B, Franzen C, Sieber M, Wohrmann A, Diehl V. BEACOPP therapeutic regimen for patients with Hodgkin’s disease and HIV infection. Ann Oncol 2003;14:1562-9.

Hoffmann C, Chow KU, Wolf E, et al. Strong impact of highly active antiretroviral therapy on survival in patients with human immunodeficiency virus-associated Hodgkin’s disease. Br J Haemat 2004, 125: 455-462.

Levine AM, Li P, Cheung T, et al. Chemotherapy consisting of doxorubicin, bleomycin, vinblastine, and dacarbazine with granulocyte-colony-stimulating factor in HIV-infected patients with newly diagnosed Hodgkin’s disease: a prospective, multi-institutional AIDS clinical trials group study (ACTG 149). JAIDS 2000, 24:444-50.

Rapezzi D, Ugolini D, Ferraris AM, Racchi O, Gaetani GF. Histological subtypes of Hodgkin’s disease in the setting of HIV infection. Ann Hematol 2001, 80:340-4.

Ribera JM, Navarro JT, Oriol A, et al. Prognostic impact of highly active antiretroviral therapy in HIV- related Hodgkin’s disease. AIDS 2002, 16: 1973-6.

Spina M, Gabarre J, Rossi G, et al. Stanford V regimen and concomitant HAART in 59 patients with Hodgkin disease and HIV infection. Blood 2002, 100:1984-8.

Thompson LD, Fisher SI, Chu WS, Nelson A, Abbondanzo SL. HIV-associated Hodgkin lymphoma: a clinicopathologic and immunophenotypic study of 45 cases. Am J Clin Pathol. 2004, 121:727-38.

Tirelli U, Errante D, Dolcetti R, et al. Hodgkin’s disease and HIV infection: clinicopathologic and virologic features of 114 patients from the Italian Cooperative Group on AIDS and Tumors. J Clin Oncol 1995, 13:1758-67.

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.


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Filed under 13. Malignant Lymphomas, Hodgkin's diesease (HD), Part 3 - AIDS

Multicentric Castleman’s Disease (MCD)

– Christian Hoffmann –

Although rare, multicentric Castleman’s disease is a highly problematic illness for the affected patients – not only due to the (in HIV infection) poor prognosis, but also because many clinicians and pathologists are not very familiar with this entity. The usually severely ill patients are often subjected to diverse diagnostic and therapeutic procedures.

In comparison to the benign, localized hyperplasia of lymphatic tissue, first described by Castleman in 1956, HHV-8-associated multicentric Castleman’s disease, as it occurs in HIV infection, is a malignant lymphoproliferative disease (Oksenhendler 1996). Although HIV-MCD is not classified as a lymphoma or AIDS-defining illness, prognosis is poor. In a prospective study, the median survival was 14 months (Oksenhendler 1996). According to a review on 84 cases with HIV-MCD, life expectancy of the patients seems to have significantly improved in the era of combination ART (mortality rate of only 29% when compared to 75% in the pre-HAART era). During recent years, prognosis further improved, mainly due to the increased use of the monoclonal antibody rituximab (Hoffmann 2011, Michot 2011).

Pathogenesis

The pathogenesis of the disease is not completely understood. There is a close association to HHV-8, and as a result about half of the patients also have KS. Lymph nodes involved by HIV-MCD are often involved by KS (Naresh 2008). HHV-8 encodes a homologue of IL-6 (viral IL-6) that has been shown to be biologically active in several assays and whose activities mirror those of its mammalian counterparts. In particular IL-6 and IL-10 are elevated with close association to the HHV-8 viral load (Oksenhendler 2000). Viral IL-6 mediates its effects through the gp130 signal transducer, but signaling is not dependent on the structurally related IL-6 receptor subunit of the receptor-signal transducer complex (Moore 1996, Li 2001, Suthaus 2010). It is postulated that viral IL-6 thus has a broader spectrum of potential target cells than human IL-6. This may be reflected by the clinically impressive “cytokine storms” which are observed periodically in patients suffering from HIV-MCD. HHV8-infected plasmablasts localise to the mantle zones of the lymphoid follicles (El Daly 2010). Of note, there are reports of MCD cases negative for HHV-8-infection (Seo 2009) but also of an interleukin-6-related systemic inflammatory syndrome in HIV-infected patients with HHV-8 but without MMCD (Uldrick 2010). In these cases, the pathogenesis remains unclear.

It remains also unclear, why only a small proportion of patients with active HIV/HHV-8 coinfection develops HIV-MCD. It should be noted that the extent of immunodeficiency varies significantly in these patients. We and others have seen MCD patients with a normal immune status and low viral load (Powles 2009). Moreover, ART does not appear to protect against HIV-MCD. In our own cohort of 52 patients, the majority of the patients with HIV-MCD were already on ART and had a viral load of less than 400 copies/ml at the time of diagnosis (Hoffmann 2011). It is also of note that HIV-MCD, unlike KS, is not associated with a lack of HHV-8-specific CD8 T cells or limitation of their functional profile (Guihot 2008). There is also evidence that the incidence of HIV-MCD is increasing. It appears to occur more frequently in older HIV-positive individuals with well-preserved immune function (Powles 2009).

Progression to malignant lymphoma (often HHV-8-associated entities such as PEL or plasmablastic subtypes) is frequent. In by far the largest prospective study to date with 60 MCD cases, 14 patients developed malignant lymphoma after a median observation period of 20 months (Oksenhendler 2002). However, in patients treated with rituximab, the lymphoma risk appears to be significant lower than in patients treated with conventional chemotherapies (Hoffmann 2011, Michot 2011).

Signs and symptoms

The main signs are the often significant lymph node enlargements, which are almost always combined with considerable B symptoms including fever, night sweats and weight loss. Almost all patients complain of weakness and severe malaise. There is always massive splenomegaly. Hepatomegaly (70%), respiratory symptoms (65%) and edema with hypoalbuminemia (55%) are also seen in the majority of cases. Lymph nodes, which may be anything from very soft (as with tuberculosis) to rock hard (as with lymphoma) on palpation, can normalize or relapse within weeks without any intervention.

The extent of symptoms is very variable and may fluctuate considerably. Many patients report on “Castleman episodes”, lasting from a few days to one or two weeks. Between these episodes, most patients do again relatively well for weeks or even months. In most patients leaving untreated for HIV-MC, however, the frequency of the episodic flares is increasing over time.

Diagnosis

The diagnosis is made histologically after lymph node extirpation – providing that the pathologist knows what HIV-MCD looks like. The germinal centers of affected lymph nodes have an onion-skin appearance with vascular proliferation. Hyaline-vascular and plasma cell types of Castleman’s disease can be distinguished.

Clinicians should explicitly indicate their suspicion. It is possible that a significant proportion of cases are never correctly diagnosed. In every case of episodic flares of B-symptoms, splenomegaly, lymphadenopathy and elevated CRP the diagnosis of HIV-MCD must be considered.  HIV alone rarely causes such severe illness! In the case of the symptoms described above, the pathological diagnosis of HIV-associated lymphadenopathy should thus not be accepted too easily.

Ultrasound reveals hepatosplenomegaly. Laboratory tests show hypoalbuminemia and hypergammaglobulinemia. There is often significant anemia which may be hemolytic, often reflecting pancytopenia or hemophagocytic syndrome (Stebbing 2009).

In our experience, CRP is a useful parameter for monitoring the activity of HIV-MCD and observing the effectiveness of MCD treatment.. During an episodic flare, CRP levels of more than 100 mg/l can bee seen. Between the episodes, however, CRP is often reaching normal ranges. In some patients, clinical symptoms are preceeded by elevated CRP levels. Treatment success is reflected by sustained decrease of CRP. Determining the HHV-8-DNA level may also be useful in diagnosing and for following up (Marcelin 2007, Stebbing 2011).

Treatment

At present, there is no widely accepted recommendation for a specific treatment for MCD. However, something has to be done quickly as the course of disease can be extremely fulminant. According to newer data, we believe that the use of rituximab is the treatment of choice in HIV-infected patients with MCD (see below). Some experts advocate rituximab monotherapy for good performance status patients without organ involvement and rituximab with chemotherapy for more aggressive disease (Bower 2010). ART should always be given, although it doesn’t always help (Dupin 1997, Lanzafame 2000, Aaron 2002, de Jong 2003, Sprinz 2004). Some cases have even been described to occur after starting ART, leading to the suspicion that the inflammatory component of MCD may be increased by immune reconstitution (Zietz 1999).

Apart from ART, there are numerous, very diverse forms of therapy. However, no option has been tested in randomized, controlled trials. Another problem lies also within the countless case reports, where a probable positive “publication bias” has to be taken into account.

Rituximab: this monoclonal antibody against CD20-expressing cells is also used in B cell lymphomas (see above). It has been speculated that rituximab is effective in HIV-MCD by eliminating or reducing the pool of HHV-8 infected B cells which are localized mainly in the mantle zone of lymph nodes. Rituximab has being tried with success in several patients with HIV-MCD (Corbellino 2001, Marcelin 2003, Casquero 2006). More recently, at least two larger studies came to encouraging results. In a French study, 16/24 patients with HIV-MCD reached a complete remission of clinical symptoms after four cycles of rituximab (Gérard 2006). The overall survival (OS) after one year was 92% and the disease-free survival (DFS) was 74%. In a British study, 20/21 patients achieved a clinical remission with rituximab, and 14/21 patients showed a radiological response (Bower 2007). After two years, OS and DFS were 95% and 79%, respectively. CRP, immune globulins, cytokines such as IL-5, IL-6 or IL-10 and HHV-8-viremia decreased after treatment (Bower 2009). In our cohort, rituximab markedly improved prognosis in HIV-infected patients with MCD, compared to patients receiving chemotherapy only (Hoffmann 2011).

Rituximab is usually given at a dose 375 mg per m2 body surface, once weekly over four weeks. Attention should be paid to a good hydration of the patients. Rituximab is usually well tolerated. The main adverse event seems to be a reactivation of KS, which is seen in up to a third of the cases (Bower 2007).

Rituximab is also effective as retreatment for rituximab pretreated HIV-MCD (Powles 2007). Based on the data published to date and on our own experiences we would consider rituximab to be the first option in patients with HIV-MCD. However, there also some case reports in which rituximab was not successful (Neuville 2005, Buchler 2008). For these cases, other therapeutical approaches are to be discussed in the following briefly.

Valgancyclovir: promising approach as this antiviral agent may act against HHV-8. As shown by a randomized trial, valgancyclovir significantly reduces the frequency and quantity of HHV-8 replication (Casper 2008). More recently, preliminary data suggest that valgancyclovir (combined with high-dose AZT) is active in HIV-MCD. Of 14 patients, 12 had “clinical improvement”, showing a decline of inflammatory markers such as CRP, IL-6 and HHV-8 viremia (Uldrich 2011). However, in our own cohort we were unable to confirm these findings (Hoffmann 2011). According to some experts, valgancyclovir may have a role as maintenance therapy in the future (Bower 2010). In contrast, antiviral therapy with foscarnet or cidofovir had no benefit (Coty 2003, Senanayake 2003, Berezne 2004).

Chemotherapy: well-tolerated chemotherapies such as vincristine (2 mg i.v. as a bolus at 14-day intervals) or oral etoposide (50 mg daily) have proven effective according to several reports as well as our own experience (Scott 2001, Kotb 2006). Even CHOP standard chemotherapy can help, but does not seem to significantly prolong survival.

Splenectomy: may be appropriate in severe cases. It is speculated that IL-6 production is reduced and that a large reservoir of HHV-8 is removed through the splenectomy. In a series of 40 patients, the median survival following splenectomy was 28 versus 12 months (Oksenhendler 2002). According to a US team, the symptoms were improved in 10/10 patients following splenectomy (Coty 2003).

Anti-IL-6 receptor antibodies: In HIV-negative patients, very optimistic data from Japan have been published, in which patients were successfully treated with anti-IL-6 receptor antibodies such as tocilizumab (Nishimoto 2005, Matsuyama 2007). In Europe, tocilizumab has been approved in 2009 for treatment of rheumatoid arthritis. There are no data in patients with HIV-MCD.

Thalidomide: This drug is believed to inhibit cytokine dysregulation as well as the inflammatory component of MCD. Case reports in HIV-MCD exist (Lee 2003, Jung 2004). It should be noted that thalidomide has been associated with venous thrombo-embolic events, including deep venous thrombosis and pulmonary emboli. Anticoagulation during thalidomide administration is mandatory. We have seen two patients developing pulmonary emboli despite anticoagulation. Therefore we would not recommend the use of thalidomide in HIV-MCD.

Other immune therapies: For interferon, there are positive as well as negative examples (Coty 2003, Nord 2003). Steroids have no effect on MCD.

References

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Berezne A, Agbalika F, Oksenhendler E. Failure of cidofovir in HIV-associated multicentric Castleman disease. Blood 2004, 103:4368-9.

Bower M, Powles T, Williams S, et al. Brief communication: rituximab in HIV-associated multicentric Castleman disease. Ann Int Med 2007;147:836-9.

Bower M, Veraitch O, Szydlo R, et al. Cytokine changes during rituximab therapy in HIV-associated multicentric Castleman disease. Blood 2009, 113:4521-4.

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Buchler T, Dubash S, Lee V, et al. Rituximab failure in fulminant multicentric HIV/human herpesvirus 8-associated Castleman’s disease with multiorgan failure: report of two cases. AIDS 2008, 22:1685-7.

Casper C, Krantz EM, Corey L, et al. Valganciclovir for suppression of human herpesvirus-8 replication: a randomized, double-blind, placebo-controlled, crossover trial. J Infect Dis 2008, 198:23-30.

Casquero A, Barroso A, Fernandez Guerrero ML, Gorgolas M. Use of rituximab as a salvage therapy for HIV-associated multicentric Castleman dis-ease. Ann Hematol 2006, 85:185-7.

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Corbellino M, Bestetti G, Scalamogna C, et al. Long-term remission of Kaposi sarcoma-associated herpesvirus-related multicentric Castleman disease with anti-CD20 monoclonal antibody therapy. Blood 2001;98:3473-5.

Coty PC, Astrow A, Gallinson D, et al. A single institution’s experience treating castlemans disease in HIV positive patients. Abstract 2485, 39th ASCO 2003, Chicago, IL/USA

de Jong RB, Kluin PM, Rosati S, et al. Sustained high levels of serum HHV-8 DNA years before multicentric Castleman’s disease despite full suppres-sion of HIV with highly active antiretroviral therapy. AIDS 2003; 17:1407-8.

Dupin N, Krivine A, Calvez V, et al.  No effect of protease inhibitor on clinical and virological evolution of Castleman’s disease in an HIV-1-infected patient. AIDS 1997;11:1400-1.

El-Daly H, Bower M, Naresh KN. Follicular dendritic cells in multicentric Castleman disease present human herpes virus type 8 (HHV8)-latent nuclear antigen 1 (LANA1) in a proportion of cases and is associated with an enhanced T-cell response. Eur J Haematol 2010, 84:133-6.

Gérard L, Bérezné A, Galicier L, et al. Rituximab in Patients with HIV-associated Multicentric Castleman Disease (HIV-MCD). Castlema B-ANRS 117 Trial. Abstract 814, 13th CROI 2006, Denver.

Guihot A, Oksenhendler E, Galicier L, et al. Multicentric Castleman disease is associated with polyfunctional effector memory HHV-8–specific CD8+ T cells. Blood 2008; 111: 1387 – 1395.

Hoffmann C, Müller M, Schmid H, et al. Improved Outcome in Patients with HIV-associated Multicentric Castleman’s Disease during Recent Years: An Effect of Rituximab? Abstract 861, 18th CROI 2011, Boston.

Jung CP, Emmerich B, Goebel FD, Bogner JR. Successful treatment of a patient with HIV-associated multicentric Castleman disease (MCD) with thalidomide. Am J Hematol 2004, 75:176-7.

Kotb R, Vincent I, Dulioust A, et al. Life-threatening interaction between antiretroviral therapy and vinblastine in HIV-associated multicentric Castleman’s disease. Eur J Haematol 2006, 76:269-71.

Lanzafame M, Carretta G, Trevenzoli M, et al. Successful treatment of Castleman’s disease with HAART in two HIV-infected patients. J Inf 2000,40:90-1

Lee FC, Merchant SH. Alleviation of systemic manifestations of multicentric Castleman’s disease by thalidomide. Am J Hematol 2003; 73: 48-53.

Li H, Wang H, Nicholas J. Detection of direct binding of human herpesvirus 8-encoded interleukin-6 (vIL-6) to both gp130 and IL-6 receptor (IL-6R) and identification of amino acid residues of vIL-6 important for IL-6R-dependent and -independent signaling. J Virol 2001, 75:3325-34.

Marcelin AG, Aaron L, Mateus C, et al. Rituximab therapy for HIV-associated Castleman’s disease. Blood 2003, 102:2786-8.

Marcelin AG, Motol J, Guihot A, et al. Relationship between the quantity of Kaposi sarcoma-associated herpesvirus (KSHV) in peripheral blood and effusion fluid samples and KSHV-associated disease. J Infect Dis 2007, 196:1163-6.

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Michot JM , Gérard L, Burcheri S, et al. Impact of Rituximab on Incidence of NHL in Patients with HIV-associated MCD. Abstract 83, 18th CROI 2011, Boston

Moore PS, Boshoff C, Weiss RA, Chang Y. Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV. Science. 1996, 274:1739-44.

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Filed under 13. Malignant Lymphomas, Multicentirc Castleman's Disease (MCD), Part 3 - AIDS