Juvenile myelomonocytic leukemia (JMML)

JMML is usually suspected in a baby or toddler with a swollen spleen, low platelets and a high white count with many monocytes. Children’s blood cancer doctors (pediatric hematologist-oncologists) lead the tests. They start with a complete blood count and a look at the blood under a microscope. For JMML, the monocyte count is at least 1,000 per microliter. The team also checks carefully for infections, because some viruses can look like JMML.

A bone marrow sample (aspirate and biopsy) shows whether blasts are under 20 in every 100 cells. That separates JMML from acute myeloid leukemia (AML). Chromosome tests look for monosomy 7, found in about 1 in 5 children with JMML. Gene tests look for changes in the RAS pathway genes PTPN11, KRAS, NRAS, NF1 and CBL. These tests now make a gene-based diagnosis possible in nearly every child. Other tests rule out the BCR::ABL1 gene of chronic myeloid leukemia. A high level of fetal hemoglobin (hemoglobin F) for the child’s age can add another clue.

Teams also test a sample of normal tissue, such as a cheek swab, and sometimes a small skin sample. This shows whether the gene change was present from birth (germline) or only in the leukemia cells. The answer matters, because in some children with an inherited change the illness settles on its own.

For most children with JMML, a donor (allogeneic) stem cell transplant is the main treatment that can cure it. Before the transplant, a medicine called azacitidine, which the FDA has approved for children with newly diagnosed JMML, or other treatment may be used to control the disease. The child’s gene results and overall health guide the plan.

A small group of children, whose JMML is lower risk or tends to settle on its own, may be watched closely instead. Specialists work out which children these are, and which children need a transplant planned quickly.

After the transplant, blood and gene tests check that the donor cells have taken hold and that JMML is under control. JMML can still come back. If it does, options may include changing the medicines that calm the immune system, extra immune cells from the donor, a second transplant or a clinical trial.

When a transplant from a donor is planned, the team usually tests brothers and sisters first. Each full sibling has about a one in four chance of being a full match.

Most patients do not have a matched relative. In the words of NMDP, the U.S. registry, “75% of patients don’t have a fully matched donor in their own family.” The team then searches registries of volunteer donors around the world and banks of donated cord blood. In some transplants, a half-matched parent, child or sibling can also be the donor.

Matching depends on inherited tissue markers called HLA, so a patient is most likely to match someone who shares their ancestry. Every person who joins makes the search a little more likely to succeed, especially for patients from groups that are underrepresented on registries.

JMML is serious, and for most children a donor transplant is what offers a cure. Before transplants were used, more than 9 in 10 children with JMML died despite chemotherapy. With transplant, survival of about 1 in 2 children was reported. A more recent French study found that about 3 in 4 children were alive five years after transplant.

Several things shape how JMML goes. Children younger than 2, with a platelet count above 33,000 and a lower hemoglobin F level for their age, tend to do better. Having two or more gene changes, or a highly methylated DNA pattern, is linked with a harder course. In the French study, waiting more than 6 months from diagnosis to transplant was linked with lower survival. On the other hand, some children with Noonan syndrome or an inherited CBL change see the illness settle without transplant.

The disease coming back (relapse) is the main risk after transplant. In studies summarized by the National Cancer Institute, it happened in 30 to 40 in 100 children. In the French study, it was about 25 in 100 at five years. About half of children who relapse can still be treated successfully with a second transplant. Azacitidine can help control JMML before transplant. Trametinib, a MEK inhibitor, is being studied for JMML that returns or resists treatment. These numbers describe groups of children. They cannot say what will happen to one child.