HIV and lymphoma

Guest writer Matt Sharp updates HTU on a group of cancers that still cause premature deaths in people with HIV, though cure rates are improving.

The 'C' word

Tim Horn is now president of aidsmeds.com, a US-based HIV information website. In 1997, he was very unwell. He soon discovered he had a type of cancer called lymphoma.

“I’d had night sweats, low-grade fevers and diarrhoea, which felt totally out of the ordinary. Blood tests showed sharp elevations in two markers: uric acid and lactate dehydrogenase.

“My doctor had the good sense not initially to say the ‘C’ word, but I figured he was looking for something sinister when he arranged an immediate CT scan. Forty-eight hours later, he called and said that there were two masses near my large intestine and that I should definitely see an oncologist [cancer specialist]. After several more investigations, I was diagnosed with non-Hodgkin’s lymphoma.”

In the beginning of the AIDS epidemic, lymphoma often showed up in those with very late-stage HIV and was usually terminal. Non-Hodgkin’s lymphoma (NHL), the AIDS-defining variety, was responsible for one-in-six AIDS deaths.¹ Today, antiretroviral drugs, chemotherapy and other new treatments help to make this a disease that can be overcome. It’s important from the start, however, to acknowledge that lymphoma is still a life-threatening illness: the sooner it’s diagnosed and treated, the better.

Definitions

Lymphoma means cancer of the lymphocyte cells of the immune system, and usually shows up in the lymph nodes first (in contrast to other immune-system cancers like leukaemia), although other parts of the body may also be affected. It is a complicated malignancy to diagnose and treat, and expertise in both HIV and lymphoma are important in achieving the best outcomes.²

There are a number of different types of lymphoma, differentiated by the type of cells affected, the type of cancer cells they develop into, and the way the cancer spreads.

Hodgkin’s lymphoma (or Hodgkin’s disease) is characterised by the development of cancer cells called Reed-Sternberg cells, which normally develop from the B-lymphocytes, the cells originating in the bone marrow that secrete antibodies. Hodgkin’s tends to spread slowly through the lymph vessels from one lymph node to the next and doesn’t present in non-lymphatic organs till very late-stage illness (which is, unfortunately, when it is sometimes diagnosed). Hodgkin’s lymphoma is not an AIDS-defining illness.

Every lymphoma that isn’t Hodgkin’s lymphoma is classed as non-Hodgkin’s lymphoma (NHL). Eighty per cent of this category consists of a type of cancer called diffuse large B-cell lymphoma. But it includes several rarer cancers such as Burkitt’s lymphoma, avery aggressive lymphoma, which occurs in 16% of cases of NHL in people with HIV, as opposed to 2% in the general population.

It also includes primary central nervous system lymphoma, an often quickly lethal form of brain tumour. This used to occur in up to 10% of people with AIDS, usually at a CD4 count of less than 50, but the incidence has dropped off significantly, even compared to other lymphomas, in recent years and it is now a rare AIDS-defining illness.

Up to 30% of NHL types are still to be named; categories are based on what reference laboratories have been able to identify thus far and not all lymphomas fit comfortably into a type.

What causes lymphoma?

Epstein-Barr virus (EBV), the same virus that causes infectious mononucleosis (glandular fever) causes the majority of NHL and all cases of Hodgkin’s lymphoma occurring in people living with HIV. There’s little point in trying to avoid EBV: 95% of adults have been infected with it at some point, usually without symptoms. High concentrations of EBV are found in lymphoma cells.

EBV used to be known as human herpes virus 4 (HHV-4). A similar virus, HHV-8, also known as KSHV, is the virus that causes the AIDS-defining cancer Kaposi’s sarcoma and is also very occasionally the cause of NHL in people living with HIV.

Current research is studying lymphoma pathogenesis, why it is a continuing problem, even in otherwise healthy HIV-positive people, and why EBV triggers cells to become cancerous in some people but not others.

How common is it?

NHL in people with HIV has become less common in the era of combination therapy, although its incidence has not declined as fast as other AIDS-defining cancers, so it is responsible for a higher proportion of deaths than it used to be. A Swiss HIV Cohort study from 2008³ found that the annual incidence of NHL had declined from 1.36% before combination therapy to 0.18% a year in 2002-2006 (one case per 555 patients a year). It is still 23 times more common in people with HIV than in the general population.

In contrast, Hodgkin’s lymphoma has become more common in people with HIV. In one US cohort study, the annual incidence of Hodgkin’s lymphoma was 0.5% a year in people diagnosed with AIDS (as opposed to HIV) between 1996 and 2006 and was actually less common in people with low CD4 counts than in people with high CD4 counts.⁴ Its incidence rate increased threefold during this time and it is about ten times more common in people with HIV than in the general population.⁵

Prognosis

Tim Horn wondered how he could be diagnosed with an AIDS-defining illness with a CD4 count of 450.

“[I was] devastated because I knew that NHL survival in people with HIV was a coin toss in the late ‘90s - a 50% chance of death within a year - compounded by a rather cinematic idea of what cancer illness and treatment would be like.”

NHL is cured in 40 to 50% of cases with standard chemotherapy. One study of incidence and mortality due to lymphoma since HIV combination therapy was introduced in 2006⁶ found that more than half (59%) of HIV-positive patients with NHL died within two years of diagnosis, compared with 29% of HIV-negative NHL patients; having HIV was associated with a nearly six-fold increase in two-year mortality.

Antiretroviral therapy has had a substantial impact on NHL specifically, and is recommended today as a part of the overall treatment and management of both diseases, but NHL remains a serious illness.

The addition of newer anti-cancer agents such as rituximab (Rituxan or MabThera), however, has increased two-year survival rates to 75% or more.⁷ Hodgkin’s lymphoma is generally less aggressive, with a two-year survival rate of one group of patients of 81%.⁸

Fifty-four per cent of people with HIV and Hodgkin’s lymphoma have an undetectable viral load. It is speculated that the immune reconstitution caused by HIV treatment may actually provide the particular kind of immune stimulus for EBV to proliferate and/or for lymphoma cells to grow and become cancerous in response to its proliferation.

A European study (COHERE) followed people with HIV to see how many would develop Hodgkin’s lymphoma despite antiretroviral therapy. Hodgkin’s incidence was similar in people who were either on or off antiretroviral drugs, but CD4 cells dropped sharply before the diagnosis of Hodgkin’s in people on therapy, despite their having an undetectable viral load. This may be a useful indicator to watch for. Conversely, people diagnosed with NHL did not experience such a decrease in CD4 cells prior to diagnosis.

Symptoms

Most often, lymph node swelling is the main symptom in the majority of lymphomas. The node will be hard, immobile or barely mobile, and painless.

B-symptoms are a group of classic symptoms that may be present in people with lymphoma, typical of many other infections because they are a part of the immune response. These include fever, night sweats and weight loss, and are found in 60 to 80% of cases. Weakness, tiredness and rapid physical deterioration are common.

Non-Hodgkin’s lymphoma is more likely to produce systemic (non-local) symptoms than Hodgkin’s lymphoma.

Every part of the body may be involved, but the gastrointestinal tract, liver and bone marrow are affected frequently so bone pain, internal bleeding and abdominal pain may be involved. Headache without fever is the primary symptom with central nervous system involvement. A combination of many of these symptoms may be expected in all types of lymphomas.

Diagnosis

It’s important to follow up any suspicion of lymphoma as soon as possible, as earlier detection leads to better outcomes. A lymph node biopsy should be performed as soon as possible, done by a specialised lab with experience in identifying lymphomas. This is a small operation, usually done under a general anaesthetic.

Patients will generally have blood tests and a chest X-ray as well, in part to check on their general health. If the biopsy shows the presence of a lymphoma, there will be further tests to see if the disease has spread to other parts of the body. These could include scans, ultrasound examinations and bone-marrow biopsy.

Diagnosis of a lymphoma should include identifying its subtype, to determine how the particular cancer cells multiply and the markers that are expressed on the cells. All this information is needed for an appropriate treatment recommendation.

In any cancer, staging is crucial to determine how far along the tumour has progressed. The Ann Arbor classification system for lymphomas rates stages from I to IV (I being the least progressed), and there is a subdivision of categories known as symptomatic and asymptomatic.

Abdominal ultrasounds, CT scans and bone marrow biopsies are all important diagnostic tools. In people with HIV, CD4 count, viral load, blood counts, inflammation markers, uric acid, liver and kidney markers, and electrolyte levels must also be assessed. Cardiac function must also be checked because some chemotherapy agents are toxic to the heart.

Treatment and new directions

Tim’s treatment was aggressive.

“Treatment for me began with a bang. As I wasn't on HIV treatment, I needed to start immediately which was bad enough by itself at the time. I had to start two different types of chemotherapy: a month of spinal infusions of cytarabine [see glossary] to treat the (possible) cancer in my bone marrow and to prevent it from migrating to my brain, and full-dose CHOP [see glossary], delivered in 21-day cycles.”

Hard-hitting and early treatment is necessary since lymphomas often progress rapidly. It can sometimes take too long to determine the stage of the illness to wait for this information before starting treatment. Every HIV lymphoma should be treated first with chemotherapy with the intention of achieving remission (halting or reversal of the progression of cancer). Surgery or radiation alone are not sufficient.

Treatment for NHL

In Europe, CHOP chemotherapy is recommended [see glossary]. Antibiotics are usually added as chemotherapy reduces white blood cells, key to fighting infections. Chemotherapy can cause a sore mouth; mucous membranes in the mouth can be treated with mouthwashes and the antifungal drug amphotericin prescribed for topical use if a patient develops fungal thrush. Filgrastim (G-CSF) can be prescribed to avoid developing dangerously low white blood cell levels (neutropenia).

Three out of the four CHOP drugs have to be administered by drip but patients can be trained to hook themselves up at home, or have visits from a cancer nurse from an organisation like Macmillan to help. EPOCH [see glossary] may be considered as an alternative, but the additional drug, etoposide, needs to be administered to patients in hospital as it may cause sudden falls in blood pressure if administered too fast.

There is a distinct trade-off between toxicity and effectiveness in many of these regimens. Most of the side-effects of CHOP and other lymphoma regimens are generic to cancer chemotherapy: hair loss, nausea (sometimes intense), skin irritation, pain at the infusion site, and increased vulnerability to other infections. This is because drugs that stop cancer cells growing are blunt instruments and will tend to damage healthy immune-system cells too.

In people living with HIV who are then diagnosed with NHL, there is no question that they should start antiretroviral therapy as soon as possible, if they are not already on treatment: in one study from 2001, the two-year survival rate of patients with HIV treated with antiretrovirals and CHOP was 75% compared with 34% of patients on CHOP alone.⁹

Mortality rates are still higher amongst HIV-positive patients with non-Hodgkin’s lymphoma than in HIV-negative people with the cancer, but having a higher CD4 count (and not having had a previous AIDS-defining illness) reduces the risk of death.¹⁰ Several studies show positive outcomes and there are cases in which complete remission is seen, even without chemotherapy.¹¹ Some ARV drugs should be avoided, especially AZT, as they can damage bone marrow and create immune suppression itself.

Rituximab (Rituxan or MabThera) is a drug that is becoming more common in lymphoma chemotherapy. It adds effectiveness and length of response compared to conventional chemotherapy and is commonly administered in conjunction with standard chemotherapy. Rituximab is an antibody that attaches itself to and destroys only the B-cells that are the ones that become cancerous in most types of lymphoma, but because it also attacks healthy B-cells and may cause a longer-lasting B-cell depletion, it may lead to severe deficiency of a type of immune cell called neutrophils. One randomised controlled study of rituximab in patients with HIV who were also given EPOCH and therapies to control side-effects achieved a two-year remission rate of 75% compared with 55% without rituximab.¹²

Burkitt’s lymphoma is so challenging that more intensive regimens are tried. These are often highly toxic and may require hospital monitoring. Poorer immune status or opportunistic infections do not necessarily need to impede treatment. Aggressiveness is key since standard chemotherapy usually fails. At the 2011 Conference on Retroviruses and Opportunistic Infections (CROI), a study was presented showing a two-year remission rate of 81% in patients in Spain and Germany, using chemotherapy based on methotrexate, one of the oldest cancer chemotherapy drugs, in combination with rituximab, cytarabine and another anti-cancer drug, ifosfamide.¹³ However, methotrexate is a hard-to-tolerate drug, and patients experienced considerable toxic effects including profound immune suppression, bleeding and painful inflammation of the mucous membranes.

Treatment for Hodgkin's

In Hodgkin’s lymphoma, different chemotherapy regimens are recommended. Most commonly, either a regimen known as ABVD is used (adriamycin, bleomycin, vinblastine and dacarbazine, an intravenous infusion), or ChlVPP (a combination of chlorambucil, vinblastine, procarbazine and prednisolone - the vinblastine is given intravenously, and the remainder of the drugs as tablets to be taken at home). Some oncologists are using a different chemotherapy strategy known as BEACOPP, developed by the German Hodgkin Study Group, although it is more toxic.

One of the most radical treatments tried for lymphoma is autogenic stem cell transplantation.Before cancer chemotherapy, stem cells from the patient’s bone marrow are harvested and grown in culture. They are then reintroduced after chemotherapy, with the hope that they will grow and mature to become a cancer-free population of lymphatic cells. In one study, 56% of HIV-positive patients who had had lymphoma were alive and with no signs of relapse nearly three years after diagnosis.¹⁴ This technique is similar to the technique used to cure HIV in the ‘Berlin patient’ case we have covered in previous issues of HTU, though in this case the stem cells re-introduced are the patient’s own, not someone else’s.

Conclusion: life after lymphoma

A lot of this may sound scary and grim but, as with a lot of cancers, survival rates after most kinds of lymphoma have improved markedly even since Tim Horn had his own brush with the disease and, with many new cancer therapies under investigation, will continue to do so. We’ll leave the last words to Tim:

“Though I wouldn’t wish the experience on anybody I do know two things.

“First, lymphoma is survivable, and we’ve come a very long way in treating it and managing side-effects since I was diagnosed in 1997.

“Second, forget about what you think you know about what it means to be diagnosed and treated for any type of cancer. It is a disease, like so many others, that can be managed for years and, fortunately, cured in a number of cases.

“In the event of a cancer diagnosis, draw upon what you already probably know as a person living with HIV. Put yourself first; fight for dignified, expert and professional health care; understand your treatment; draw upon the support of friends and family; and live every day like it matters.”

Glossary

Lymphatic system A system of vessels in the body that regulate the fluid in tissue, distribute fats to cells, and act as the main transporters on immune-system cells – and cancer cells in people with cancer.

Lymph nodes A set of small bean-shaped organs found throughout the body that filter foreign matter, analyse it for possible harm, and serve as garrisons and training grounds for immune cells.

Lymphoma Cancer of the lymphatic system and especially the lymph nodes, in which the immune cells within become cancer cells.

Hodgkin’s lymphoma (or Hodgkin’s disease) A specific kind of lymphoma usually restricted to the lymph nodes, characterised by a particular kind of cancer cell, and spreading slowly from one node to the next. Not AIDS-defining.

Non-Hodgkin’s lymphoma (NHL) All other kinds of lymphoma: characterised by different cells becoming cancerous, and involvement of other parts of the body, which may be widely separated. AIDS-defining in people with HIV.

Cytarabine Cytosine arabinoside, a nucleoside analogue drug used to fight NHL.

CHOP A regimen of four anti-cancer drugs used as standard therapy for lymphoma: cyclophosphamide, adriamycin (hydroxydaunorubicin), vincristine (Oncovin), and prednisolone. It is given in four to six cycles of three to six weeks each. All are administered intravenously, except prednisolone.

EPOCH CHOP plus one other drug, etoposide.

Filgrastim Also called G-CSF (granulocyte colony stimulating factor), this is a naturally-occurring immune stimulant protein which can now be manufactured artificially and is used to strengthen parts of the immune system damaged by cancer chemotherapy.

Rituximab A monoclonal antibody drug now used as an addition to CHOP and EPOCH, it seeks out and destroys cancer cells expressing a particular growth signal.