ALK-positive anaplastic large cell lymphoma

It is a lymphoma of mature T cells in which the cells look large and abnormal under the microscope — that is what "anaplastic" describes — and carry a surface protein called CD30.

What makes it ALK-positive is a rearrangement between two chromosomes that causes the lymphoma cells to make a protein called ALK. That protein can be seen on a laboratory stain of the biopsy, and the stain is what separates this disease from its ALK-negative counterpart.

That distinction is not a technicality. The two forms affect different age groups and behave differently enough that they are treated as separate diagnoses in this library.

This is the more common of the two forms. Lymphoma Action describes it as usually affecting children and young adults, commonly people in their thirties, and about three times as many males as females. Both halves of that matter — it is not only a childhood cancer.

Systemic anaplastic large cell lymphoma is a different disease from the skin-only form and from the form associated with breast implants. Nothing on this page applies to either of those.

The NCI describes the disease as arising from a rearrangement between chromosomes 2 and 5 that produces the ALK fusion protein. That change is found in the lymphoma cells.

It is not described as inherited, and none of the sources we read describes anything a person did that could have caused it.

No lifestyle cause, environmental exposure or family risk appears in these sources.

The most common first sign is one or more painless swollen lymph nodes in the neck, armpit or groin, usually with B symptoms — drenching night sweats, fevers, and unexplained weight loss.

It commonly involves places outside the lymph nodes: the gut, the chest, the bone marrow, the skin. Most people are at stage 3 or 4 when it is found.

And here is the thing that is genuinely counterintuitive about this disease. The NCI notes that people whose lymphoma expresses ALK are usually younger and may have systemic symptoms, disease outside the lymph nodes and advanced-stage disease — and still have a more favourable survival rate than people with ALK-negative disease.

In other words, how alarming it looks at presentation is not what predicts the outcome here. That is worth knowing, because a stage 4 diagnosis in a young person reads as catastrophic and in this particular lymphoma it is not the whole story.

We have not put a survival percentage on this page. The NCI’s statement that outcomes are better in ALK-positive disease comes without a denominator, a region or a year behind it, so it establishes a direction rather than a number.

First-line treatment is combination chemotherapy. Because these lymphoma cells display CD30, one of the drugs can be replaced by brentuximab vedotin — an antibody that carries a cell-killing drug and delivers it into CD30-bearing cells. That combination is approved for previously untreated systemic anaplastic large cell lymphoma.

Early-stage disease may also involve radiotherapy.

In children and adolescents, treatment is chemotherapy, and nearly all are cured with it. Only a small number are ever transplant candidates — those with disease remaining after further treatment, or an inadequate response or relapse.

A transplant using the person’s own cells is discussed after a first remission in this family of lymphomas generally. It is important to be precise about what that does and does not mean for this particular diagnosis, and that is in the next section.

CAR T-cell therapy is graded as generally not recommended for this group of lymphomas at every stage of disease.

If the lymphoma comes back, brentuximab vedotin on its own has been studied in relapsed systemic anaplastic large cell lymphoma. In a study of 58 people followed for a median of just under five years, 57% were free of progression at five years and 79% were alive. Fifty-eight is a small number, and the study did not report results split by ALK status.

Diagnosis means a lymph node biopsy with laboratory staining. Two stains do most of the work: CD30, which decides whether the targeted drug is available, and ALK, which decides which of the two diagnoses this is.

Treatment is multiple cycles of chemotherapy — six or eight in the trial that defined the current approach.

For children and adolescents, chemotherapy is usually the whole of it, and a transplant of any kind is uncommon.

Because this diagnosis often lands on someone in their twenties or thirties, questions about fertility, work and study are pressing. None of the sources we read reports on any of those, and we would rather say so than write something that sounds plausible.

A donor plays no part in the treatment most people with this diagnosis receive. It is treated with chemotherapy, and in children and adolescents nearly all are cured with chemotherapy alone.

There is something specific to say about the first-remission transplant here, and it is a point of accuracy that most sources blur. The evidence for consolidating a first remission with a transplant in this family of lymphomas was built without this disease in it. The randomised trial excluded ALK-positive disease. The registry analysis of up-front autologous transplant covered only the other three conditions. The transplant analysis in the main first-line trial excluded its handful of ALK-positive patients.

So we are not going to tell anyone with this diagnosis that a consolidation transplant is the expected next step. There is no evidence base behind that claim for this particular lymphoma.

Where a donor does become relevant is in the small group whose disease does not respond adequately or comes back. In children and adolescents, EBMT names an inadequate response or relapse of ALK-positive anaplastic large cell lymphoma as one of the few situations in which a transplant is considered at all. In adults with relapsed or refractory disease, a study of 182 people who had a donor transplant found 41% free of progression at five years — and noted that despite ALK positivity being a favourable factor generally, outcomes after a donor transplant did not differ significantly by ALK status.

A donor transplant is not a safer or gentler option than the alternative, and it would be dishonest of us to imply it. In a randomised trial of 104 people with this group of lymphomas, 31% of those who had a donor transplant died of graft-versus-host disease — the donor’s immune cells attacking the recipient’s own tissues. The NCI’s summary of that trial is that the benefit of the donor immune system attacking the lymphoma was cancelled out by deaths from the transplant itself.

When a donor transplant is the right route and no relative matches, the donor comes from a registry. That is the real and narrow place where joining one matters to someone with this diagnosis.