Carl Sagan and Myelodysplastic Syndrome: Understanding a Bone Marrow Cancer

What was reported at the time

The Cornell Chronicle announced on December 20, 1996, that Carl Sagan had died in Seattle "after a two-year battle with a bone marrow disease." He was 62. The cause of death was pneumonia.

He was at the Fred Hutchinson Cancer Research Center when he died. Cornell reported that he had received a bone marrow transplant there in April 1995 for the treatment of myelodysplasia, which it described as a pre-leukemic syndrome. CNN reported the same, quoting a center spokeswoman.

Cornell added that he continued to supervise undergraduate and graduate students and to do research while recovering, and had returned unexpectedly to the Seattle hospital that month.

That is the documented record. This article does not go past it, and it draws no lesson from his treatment. What follows is what myelodysplastic syndrome is understood to be.

What MDS actually is

Bone marrow is the factory for blood. It makes red cells that carry oxygen, white cells that fight infection, and platelets that stop bleeding.

In myelodysplastic syndromes, that factory produces cells that never mature properly. NCI describes immature cells that fail to become healthy blood cells, dying in the marrow or shortly after reaching the bloodstream. The result is a shortage of one or more blood cell types, which doctors call a cytopenia.

MDS is not one disease but a group. NCI reports slightly more than 10,000 people diagnosed in the United States each year, an age-adjusted rate of roughly 4.4 to 4.6 per 100,000. It is more common in men. It occurs mainly in people over 60, and the median age at diagnosis is about 70.

Most cases have no known cause. NCI lists risk factors including past chemotherapy or radiation therapy for another cancer, exposure to tobacco smoke, pesticides, fertilizers, solvents such as benzene, and heavy metals such as mercury or lead.

Why it is called pre-leukemic

The label CNN and Cornell used in 1996 reflects a real feature of the disease. MDS can progress into acute myeloid leukemia.

The dividing line is a count. Immature marrow cells are called blasts, and NCI states that by convention MDS is reclassified as acute myeloid leukemia when blasts in blood or marrow reach or exceed 20 percent.

But that transition is not the whole story, and NCI is careful about it. Many patients die of the complications of low blood counts, meaning infection or bleeding, before ever reaching that stage. The shortage of healthy cells is dangerous in its own right.

The subtypes carry different odds. In refractory anemia, marrow blasts stay under 5 percent, progression to leukemia is rare, and NCI reports median survival of 2 to 5 years in most series. This form accounts for 20 to 30 percent of cases. Refractory anemia with excess blasts, split into two grades by whether marrow blasts run 5 to 9 percent or higher, makes up roughly 40 percent of cases and carries a greater risk of transformation.

Signs, and why they get missed

NCI states that MDS often causes no early symptoms and may be found during a routine blood test. When it does declare itself, the signs are the ones NCI lists:

• Shortness of breath.
• Weakness, or feeling tired.
• Skin that is paler than usual.
• Easy bruising or bleeding.
• Petechiae, meaning flat, pinpoint spots under the skin caused by bleeding.

Each maps onto a missing cell type. Breathlessness, pallor, and fatigue come from too few red cells. Bruising and petechiae come from too few platelets. Repeated infections come from too few working white cells.

When to get checked

Ask a doctor to look further if:

• Breathlessness or fatigue has been building over weeks or months with no clear cause.
• You bruise from knocks that would not have marked you a year ago.
• Pinpoint red or purple spots appear on the skin, most often on the lower legs.
• Infections keep returning or take much longer than usual to clear.
• A blood count has come back abnormal, especially a low count that is still low when repeated.

One specific pattern is worth naming. NCI describes macrocytic anemia, meaning anemia with red cells that are larger than normal, as a feature of refractory anemia, and lists vitamin B12 and folate among the blood chemistry tests used in the workup. Large red cells usually point to B12 or folate deficiency. When those levels come back normal and the anemia persists, the marrow itself needs investigation.

There is no screening test for MDS in people without symptoms. The complete blood count that finds most cases is nearly always ordered for another reason.

Diagnosis and risk scoring

Blood tests come first, including a complete blood count with differential. The diagnosis is confirmed in the marrow, sampled by needle, where a pathologist looks for the abnormal cell shapes that define the disease and counts blasts.

Chromosome testing, called cytogenetics, follows. NCI states that prognosis is directly related to three things: the number of blast cells in the marrow, particular chromosome abnormalities, and how severe the shortages of blood cells are.

Those three inputs feed formal scoring systems. The International Prognostic Scoring System, or IPSS, combines blast percentage, number of cytopenias, and cytogenetic risk group. The revised version, IPSS-R, gives more weight to chromosome findings and to how severe the cytopenias are. Both are applied only at diagnosis. A third system, the WHO Prognostic Scoring System, is dynamic, so a person can be reassigned to a different category as the disease changes.

What treatment involves

NCI groups treatment into supportive care, drug therapy, and chemotherapy with a stem cell transplant.

Supportive care is not a placeholder. For lower-risk disease it may be the whole plan, using transfusions and infection management to keep blood counts workable.

Among drugs, NCI reports that in higher-risk disease azacitidine has been shown to improve survival. Lenalidomide has FDA approval for lower-risk, transfusion-dependent patients whose cells carry a chromosome change called del(5q). In the study supporting that approval, 148 transfusion-dependent patients were treated, and 67 percent became independent of transfusions, with a median time to response of 4 to 5 weeks. NCI also notes the drug's limits, since it can push neutrophil and platelet counts down.

A stem cell transplant remains the only approach that can cure MDS, and it is demanding enough that age, fitness, and risk score all weigh on the decision.

Every figure above describes a group of patients studied at a point in time. None of them predicts what will happen to one person, and treatment for this disease has changed considerably since 1996.

Sources

• https://www.cancer.gov/types/myeloproliferative/hp/myelodysplastic-treatment-pdq
• https://www.cancer.gov/types/myeloproliferative/patient/myelodysplastic-treatment-pdq
• https://news.cornell.edu/stories/1996/12/carl-sagan-cornell-astronomer-dies-today-dec-20-seattle
• https://www.cnn.com/US/9612/20/sagan/