ALK-negative anaplastic large cell lymphoma

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

It is called ALK-negative because a laboratory stain on the biopsy does not find the ALK protein. Its counterpart, ALK-positive disease, makes that protein because of a rearrangement between two chromosomes.

That single stain separates two diagnoses that look alike. This form tends to affect older adults, typically between 40 and 65, and slightly more men than women. The ALK-positive form affects children and young adults.

It is the less common of the two. Lymphoma Action puts it at around three in every ten cases of anaplastic large cell lymphoma, out of fewer than 200 UK diagnoses a year — though that source does not state which year the count comes from, or whether it includes the skin-only and breast-implant-associated forms.

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

No cause is established.

The NCI describes two genetic findings within the lymphoma cells that carry meaning for how the disease is expected to behave: rearrangements of a gene called DUSP22, which are associated with a better outlook, and changes in TP63, which are associated with a worse one. Both are properties of the tumour rather than things anyone could have avoided.

None of the sources we read describes an inherited cause, a lifestyle cause or an environmental exposure.

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 sites beyond the lymph nodes: the gut, the chest, the bone marrow, the skin. Most people are at stage 3 or 4 when it is found.

It grows quickly, so symptoms tend to develop over weeks rather than months and treatment starts soon after diagnosis.

The NCI places outcomes in this form below those of ALK-positive disease. We have not put a number on that, because the source gives the comparison without a denominator, a region or a year behind it.

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

Early-stage disease may also involve radiotherapy.

For people who reach a first complete remission, a transplant using their own cells may be offered as consolidation. This is one of the conditions the evidence for that was actually built on.

How strong that recommendation is depends on where you look, and the honest answer is that it is not settled. EBMT’s own table grades a first-remission transplant here as a clinical option to be weighed case by case, rather than as something generally indicated. The NCI describes the evidence behind it as anecdotal, drawn from small and backward-looking studies rather than from a trial designed to answer the question.

Even so, it is not the default. In the trial that defined modern first-line treatment, fewer than a quarter of people in either arm actually received a consolidation transplant.

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 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 decide a great deal: CD30, which determines whether the targeted drug can be used, and ALK, which determines which of the two diagnoses this is.

Treatment runs as multiple cycles of chemotherapy — six or eight in the trial behind the current approach.

If consolidation is planned, stem cells are collected from the bloodstream in advance, high-dose chemotherapy follows, and the stored cells are given back. It means an inpatient stay with very low blood counts. There is no donor search and no waiting for a match.

None of the sources we read reports on quality of life, diagnostic delay or fertility for this condition. We would rather name that gap than fill it with something plausible.

On the path most people with this diagnosis are on, a donor plays no part. The transplant discussed after a first remission uses the person’s own cells, and EBMT states that a donor transplant is not an indication as first-line consolidation for this group of lymphomas.

A donor matters later, and genuinely. If the lymphoma comes back and responds to further treatment, a transplant from a matched sibling or a well-matched unrelated donor is graded as generally indicated in suitable people. EBMT describes a donor transplant as the one treatment able to cure people whose disease is refractory or has relapsed, where they are fit enough for it.

One study of 182 people with relapsed or refractory anaplastic large cell lymphoma who had a donor transplant found 41% free of progression at five years. That study included both forms of the disease and found 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 here — for the minority whose disease relapses or does not respond, and not at diagnosis.