The Myelodysplastic Dilemma: Pre-Cancer, Cancer or None of the Above?

As the American population ages and the sophistication and commonality of micro-sample, multi-test, atomated blood screening with computerized instant analysis & reporting, continues apace , we are sure to encounter more cases of primary myelodysplastic syndromes (MDS). This  will increase demand for information for patient education, best clinical practices advisory, and  current awareness of basic sciences advances in stem cell biology.

Primary MDS  represents   a family of diseases, most prevalent in those over the age of 50 to 60, that involve unwanted variations in the function of the bone marrow in  its role as the storehouse and processing center of the stem cells that ultimately turn into blood cells. These  MD syndromes are called primary because they do not develop after a patients has been  treated aggressively for cancer by radiation or chemotherapy which are known to cause MDS  as a secondary, or side-effect. Nor do primary MDS patients have a known long-term exposure to hematologically carcinogenic chemicals like benzene, which can bring on MDS and leukemia.

Some Common Symptoms in Primary MDS

Primary MDS is hard to diagnose because so many other diseases and conditions can be blamed for its usual symptoms:

·         If you are in your fifties and taking care of both teenagers and your elderly parents, you might very well feel very tired.

·         Likewise, a certain pallor is easily written off as the result of working long hours indoors, and not being able to get outside.

·         Shortness of breath is often attributed to being out of shape, scarcely a novelty among people this age.

·         But, bleeding from the gums and/or   exaggerated bruising generally are the first warning signs that drive patients to seek help when the other symptoms above seem no longer able to be explained away.

·         Likewise, an exaggerated propensity to catch infectious diseases and endure high fevers, is another hallmark of the disease that can spur action.

·         Early lab tests in a general practitioner's office will almost always indicated anemia, and after some milder forms of treatment for other causes of anemia do not work, more sophisticated tests are then ordered that will eventually uncover MDS.

Do I have cancer? Will I get Leukemia?

After a preliminary diagnosis is made,  the central issue for both patient and physician is whether or not the particular type of MDS that a patient has, is one that will progress to leukemia. At a time not too far distant  in the past, it was thought that most would do so, and the disease was curiously termed a “pre-cancer”, or more frankly,  a kind of “smoldering” leukemia. There is still a great deal of justification for calling it a cancer because the cell forming processes that go awry do so in a manner common to many cancers. 

Yet there is far from unanimity on terminology. Most health insurance policies that are specifically designed to cover cancer, will not define it as a cancer, and therefore will not pay out cancer benefits, yet some other health policies that exclude new policy-holders who have had a prior cancerous condition, do exclude patients with MDS on the basis that MDS is, according to their guidelines, a form of cancer.

Today it is clear that while all but a small percentage of asymptomatic cases of myleodysplastic syndromes are serious, not all are a direct road to cancer (almost always leukemia is the cancer mentioned ). Nor are all of them a sentence to death in a matter of months or even years. Nonetheless a discerning literature search will ironically discloses that the most productive centers for MDS  research and treatment clearly have names that will put the fear of cancer into the hearts of any patient, perhaps even if  they have been told that their particular type is not likely to progress quickly to leukemia, if at all.  Centers with great paper trails in the MDS field include the  M.D. Anderson Cancer Center in Houston TX, the H. Lee Moffitt Cancer Center in Tampa FL, the James P. Wilmot Cancer Center in Rochester, and the Taussig Cancer Center of the Cleveland Clinic OH. This impression is definitely reinforced when one finds the large number of oncology journals included in this entry’s bibliography.

Bone Blast Biology & Categories of Resulting Blood Cells

The site of most new blood cell initiation and launching is the bone marrow. The biggest bones (thighs, pelvis, and sternum) tend to have the most marrow, and therefore are generally more important centers of blood cell production (hematopoiesis) . In the marrow are stem cells in various stages of development, called “blasts,”   which will eventually become one of five major types of blood cell whose nomenclature typically  involves having suffixes of “cytes” of one sort or another. These distinctions are important because different forms of MDS are characterized by abnormalities in one or more of the  categories of maturing blasts or cytes.

All blood cells “cytes” begin their particular transformation process starting with the most primitive stem cell,  the hemocytoblast. Hematoblasts have two jobs. First, they reporoduce themselves. Second, a portion of the reproduced blasts ideally produces mature blood cells or cytes.  Depending on a combination of genetic and epigenetic ------epigenetic=internal biology environmental  influences that affect the way a cell turns out but may not be included in the cell’s DNA----- these hemocytoblasts do produce an assortment of all cyto types,  but some subtly  different populations of blasts, despite sharing the same marrow, nonetheless slightly favor the production of  one or more of the resulting cytes in the assortment of cytes they produce. This imbalance or bias  in production  is not of itself, likely to cause disease, and can be found in blasts and cyte samples taken from entirely healthy volunteers. It can be offset by the opposing bias in other blasts in their marrow.

The biggest worry about blasts is two-fold. First, a blast that has acquired a genetic defect will always continue to multiply that genetic defect. Second, blasts might escape into the blood supply before turning into well-functioning mature blood cells.

The list of healthy, different blast-to-cyte production lines follows:

• There is the red blood cell production line: hemocytoblasts turn into preoerythroblasts, which turn into polychromatic erythroblasts, which turn into erythrocytes (“erythro”  is Greek for red) better known as red blood cells.

• White blood cells (leukocytes,  “leuko”  is Greek for white) have a three-way path of transformations from the hemocytoblast; one for granulocytic cell production---- called  “granulocytic  because they have granules within the cells that are visible with special staining under a microscope---- and two for agranulocytic cell production------ called “agranulocytic” because no granules are visible with staining under a microscope.

• In the granulocytic white blood cell production line, the hemocytoblast turns into a progranulocyte; then the  progranulocyte turns into one of the three of the mature granulocytic white blood cells: basophil, eosinophil, and neutrophil.   

• In the first agranulocytic white blood cell production line, the hemocytoblast turns into a lymphoblast, which turns into a lymphocyte.

• In the second agranulocytic white blood cell production line the hemocytoblast turns into a monoblast, which turns into a monocyte.

• Finally, there is the blood clotting, or thrombocytic (“thrombos”  is Greek for clot) cell production line.  The hemocytoblast turns into a giant megakaryocyte, which fragments into thromboyctes.

Myelodysplastic syndromes typically involve breakdowns or malfunctioning of one or more of the following production lines: the erythrocytic, granulocytic, and the megakaryocytic.  What do these breakdowns involve?

·         The relative spatial or  microscopic  “neighborhood zoning” ” of blast precursors within the overall bone marrow population can go seriously out of balance. There can be take-overs of the space in the marrow by one or more over-producing type of blast or cyte.

·         The speed rates of the differing blast-to-cyte maturation and subsequent ejection of cytes into the blood stream can go out of kilter, causing too low a supply (a cytopenia) or an oversupply of a given category. (Acute Myelogenous Leukemia, for example typically features an oversupply of granulocytic cells, many of which may be immature, and dysfunctional, and which almost always crowd out erythrocytes and thrombocytes.

·         One or more category of cytes may not die off at the time that is expected according to the body’s plan of “apoptosis”. In particular, some cells will live long enough to crowd out or imbalance the other cells that do die off according to plan, with the imbalance growing all the time because the cells that do not undergo predicted apoptosis continue to hang around.

Sorting out the types of Primary MDS:

More Tools, More Categories, & More Accurate Prognoses

It seems that every new diagnostic technology tends to disclose new subtypes of MDS. While this may seem frustrating to those patients who are trying to self-educate on their disease, the results of this sophistication tends to be a better understanding of their prognosis and better planning of a customized treatment. 

The usual tools today for diagnosis include microscopic examination of the circulating blood using stains that selectively point out certain blast or cell types. Bone marrow biopsies are similarly teased apart using microscopic examination, with some marrow blasts or cells being cultured to determine if they have accumulated genetic abnormalities. In flow cytometry, individual abnormal cells so reliably tagged by immunologically binding surface markers that they can be counted exactly by computer as they stream across a microscopic detector.

All of the diagnostic results are then used to assign a category (the most common schemes of categories are the old French, American and British or “FAB” system, and the newer WHO or World Health Organization schemes. They are then scored using the International Prognostic Scoring System (IPSS). The following are among the possible diagnostic categories along with what a typical IPSS would say about the patient’s likelihood for progression to the most dreaded leukemia for primary MDS patients: Acute Myelogenous Leukemia or AML.

• Refractory ( not responsive to the usual treatments) anemia is the mildest forms of MDS.  Only about 5%, and sometimes less, of their red blood cells are actually erythroblasts that did not make it to maturity. They rarely get leukemia and may live 10 years or more, depending on the age at which they developed MDS, and their overall health.

• Refractory anemia with ringed sideroblasts.  The special feature here is that a microscopic examination shows that the blasts that will eventually turn into  red blood cells have circular deposits or rings of iron inside. These are usually detected after a bone marrow biopsy. The likelihood of longer term survival and the avoidance of leukemia are about as favorable as those with refractory anemia alone.

• Refractory cytopenia (shortage of cells)  with dysplasia (malformations)  in two or more types of blood cells.  This is more serious, and has about a 10% chance of turning into leukemia, about double the two previous categories, with less the half of the expected life span.

• Refractory cytopenia with dysplasia in two or more cell types as well as ringed sideroblasts.  The outlook for this combination of abnormalities is about as good or bad as those immediately above.

• Refractory anemia with excess blasts (10%-20%) in the blood supply. This represents a significantly worse situation. About a quarter of these patients will develop acute myeloid leukemia, and life expectancy may be only a few years.

• Unclassified MDS-U. This is an unexpectedly mild  combination with little chance for progression to leukemia.  The numbers of blasts in the blood is fairly low (5% or less) and either the leukocytes or the megakaryoctyes appear abnormal. Lifespans are up to a decade.

• MDS with a Chromosome 5 deletion. These people have a nicked  number 5 chromosome, but for some reason, this seems to protect them from having their anemia and MDS progress to leukemia. A long life span is typical.

Progression to MyeloProliferative Disease and Leukemias

It now appears that, instead of a direct progression to Acute Myleoid Leukemia, some patients will move on an intermediate level of disease, residing somewhere between MDS and AML, known as Chronic Myelomoncytic Leukemia (CML). While CML features, among other things, the high leukocyte (actually mostly monocyte) blood count found in most leukemias, and has an elevated blast percentage (but still less than 20%), one of its more obvious and uncomfortable features is a grossly enlarged spleen.

Treatments for MDS and its Related Diseases & Complications

·         First Approach: Bolster the numbers of mature, productive blood cells, through blood transfusions and/or erythropoietin (red blood-production-stimulating) and one or more G-factor (Granulocyte production stimulating) injections. Watch for problems of blood iron overload (akin to hematochromosis) seen in some patients.

·         Second Approach: Reduce the chances of progression to AML by using anti-methylating agents, such as Vidaza™ or Dacogen™.  The first of these is now in an open label trial for its newer oral form of administration.

·         Third Approach; Immunomodulation. Rivlimid,™ an analogue of the historically birth-defects-inducing drug thalidomide, is showing promise, alone or as part of a combination therapy, in restoring bone marrow to a semblance of normalcy for months to years, and in particular, seems to reduce significantly the inflammation associated with the disease.

·         The Ultimate Approach is a bone marrow transplant.  This is very much an age-and-stage-dependent strategy and requires a certain level of donor compatibility. The younger the patient is, the less aggressive the level of MDS is, and the greater the match, the better the potential for results lasting for years.

In closing, we as librarians are in the center of this syndrome. Even as we met and support more patients seeking MDS  literature who are feeling desperately uncertain because they cannot get a firm categorization in the short run from their hematologist/oncologist or who fear a disease progression, we also get to meet and support the clinical investigators and basic scientists who are, even now, tackling this disease with increasing insight, brought on, in part, by integrating the evidence we curate into their efforts.

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