Bone Marrow Biopsy (BMB

The issue here is not the use of BMB but of the need to do two at a time (one in each hip). Many malignancies are "focal" in the sense that they are not evenly distributed throughout the marrow space so that it is possible - even likely - that a single biopsy might miss a diagnostic area. Probably the best example of this is multiple myeloma in which it is possible to miss a place totally involved by the myeloma and pick up cells that appear to be perfectly normal and free of disease.
I believe that what is being said here is that multiple same day biopsies do not provide any additional information and that saving pain/aggravation/time/money/etc. is justified in CLL
 

Bone Marrow Infiltration

When you were first diagnosed, a bone marrow wasn't really necessary since the presence of the abnormal clone of cells could be identified from the peripheral blood. Now that you can apparently cleared your blood and perhaps lymph nodes of these cells, the question is where to check to make sure that this remission is a good one.
Leukemias arise in the marrow so it makes sense to see what is going on there. As a test, PCR can be done on any bodily specimen except red cells (they have no nucleus). One of the other advantages of the marrow specimen is that you get a LOT of cells to test so the chances of missing one or two "baddies" is much lower than if you used a smaller number of cells.
 

There are two different procedures that might be referred to. Bone marrow
aspirate means some bone marrow is sucked out of the bone - usually from the
pelvic bone at the back, but still sometimes taken from the breast bone - and
smeared on a slide and stained just like a blood film. Bone marrow trephine
means a marrow core of bone marrow is cut from the bone and sectioned and
stained like any other biopsy. The first is quick and easy and gives good
information about the size and shape of the blood cells, but in truth very little
more information than a blood film. It is useful for research studies, because
there is quite a lot of evidence that marrow cells behave differently from
blood cells (they are more likely to be CD38 positive, for example) and give
more information on the nature of the leukemic process.

Bone marrow trephine allows the pathologist to recognise 4 patterns of
involvement: nodular, interstitial, mixed nodular and interstitial, and diffuse.
Only diffuse involvement has prognostic value - the prognosis is worse than
with any of the other three patterns.

Other information can be picked up from the bone marrow: it may help in
diagnosing ITP or AIHA or pure red cell aplasia, which sometimes occur as
complications of CLL and rarely will uncover a coexisting myelodysplastic syndrome.

BMB in CLL is no longer recommended except in clinical trials. Diagnosis is made by immunophenotyping. Previously, it was necessary to have at least 30% lymphocytes in teh bone marrow to make the diagnosis, but that is an archaic requirement.

BMB was then recommended for prognosis. there were four patterns of involvement: diffuse - sheets of CLL cells replacing the normal marrow architecture; nodular - nodules of CLL cells outside the normal structure of bone marrow; interstitial - strings of CLl cells within the normal structure, between the normal fat cells; and mixed interstitial and nodular. Only diffuse had prognostic value (worse), but with teh modern prognostic markers like VH gene mutations, ZAP-70 and FISH, BMB is no longer of significance.

BMB can be useful for checking on the normal cells in the marrow. The old adage that cellularity should be 100% minus your age is not much use when you have infiltrating lymphocytes. But it is possible to asses whether there is any normal marrow presnt (this might be helpful to determine whether red cells, platelets or neutrophils are actually being produced (and so rule out ITP, immune neutropenia, or pure red cell aplasia, not to mention aplasia caused by chemotherapy.

Everybody with CLL has bone marrow involvement, so it is perfectly possible to be Rai stage 0 and have significant marrow replacement. Only when the Hb or platelet count falls do you move into stage III or IV, or the lymph nodes enlarge for stage I and the spleen for stage II.

BMB does not necessarily track stage.

You can distinguish CLL cells from normal lymphocytes in the marrow, but this is not normally done in a BMB. It requires immunophenotyping or PCR.

I think I should give a fuller answer on why bone marrow biopsies are done.

A bone marrow biopsy is taken from the hip, usually with the patient on his or her side. A long, thin, hollow needle is inserted into the bone where it cuts a core of tissue, in the same sort of way that you would core an apple. The needle is then withdrawn containing the core, which is then sliced up and the thin slices examined on a microscope slide.

This is a painful procedure, and it is quite difficult to get the angle of insertion right, so it requires a lot of practice from the operator. The best results are produced by operators who do a lot of biopsies every day. MD Anderson have an enviable reputation for doing BMBs painlessly and quickly (they do over 60 a day), but other centers can get very good at it. Essential to good practice is proper local anesthesia. This means waiting until the anesthetic takes effect. Nowadays when I don't do very many I always use midazolam intravenously. This is a short term sedative. Patients who have it remember nothing of the procedure that follows.

A bone marrow aspirate can be taken from either the hip or the breast bone (sternum). Sedation isn't needed, but local anesthetic is. When the marrow is sucked out there is a strange pain that is over in a second. The local anesthetic doesn't help this, but although it is unpleasant, most patients do not find it a deterrent to having another aspirate if it is necessary.

What is the purpose of a bone marrow?

First for diagnosis. In CLL is the disease is in the blood, then it must be in the marrow. The diagnosis of CLL is best made by immunophenotyping the cells in the blood. The only circumstance that a marrow would be needed for diagnosis is where the disease is not in the blood - SLL for instance, and getting tissue from the marrow to immunophenotype is an easier proposition than biopsying a lymph node. If, however, you are ill and the doctors do not know what is wrong then a bone marrow is often done as a fishing expedition. SLL or other lymphomas can occasionally be diagnosed in this way.

Second for staging. None of the staging systems demand a bone marrow, but the pattern of bone marrow involvement - diffuse, nodular, interstitial or nodular and interstitial has some prognostic value. However, this has been superseded by VH gene mutations, ZAP-70, FISH and CD38.

Third to define a complete remission. NCI guidelines demand a normal bone marrow in order to call a remission complete. So if you are in a trial and a complete remission endpoint needs to be defined, then a marrow is necessary. For those not in a trial, then a treatment decision may be based on whether the marrow is clear - for example, whether to give Campath or follow up with a transplant.

Fourth to investigate a complication of CLL or its treatment. Anemia or thrombocytopenia may be due to autoimmunity, or swamping of the marrow with leukemia or ablation of the marrow by chemotherapy or MDS. A BMB and aspirate will help to sort out which.

All of these REASONS for a BMB are sensible. But what I think is wrong is to do a BMB for no reason. Just to fill in boxes on a chart or because it fulfils a particular protocol or for 'completeness'. So my advice is if you are offered a BMB by your physician ask him why he wants one. There may be a very good reason, but often the answer may be obtainable in a less painful way.

Patients who have stable disease, who are stage 0 or 1, seldom need a bone marrow.

There was a discussion about BMB at the meeting in Brooklyn. The consensus
was that although it is not necessary for diagnosis and its prognostic value
has been superceded, it should be performed before each round of treatment in
order to give a baseline and to check for other complications. My own opinion
is  that a Coombs test should be done before embarking on a course of therapy.
 Autoimmune neutropenia is a rare complication. My guess is that your problem
is  marrow infiltration, so get a BMB to be sure.