Bone marrow:  a most unique and vital piece of equipment

Bone marrowThere is only one location in your body where new red blood cells (platelets and neutrophils etc.) are created.  And that is your bone marrow.  As CLL patients, we know only too well that lymphocytes (B-cells, T-cells) can multiply in lymph nodes.  Not so red blood cells, platelets and neutrophils.  Each of these crucial blood cell lines need to be created from scratch in the bone marrow, starting from healthy blood stem cells (also called hematopoietic stem cells).

In adults, bone marrow is usually found in the large bones of the skeletal system, namely hip and pelvic bones, ribs and the long bones in thighs.  100% of the bone marrow is active and able to produce new blood cells when we are born.  As we age, more and more of the bone marrow becomes inactive, filled with fatty cells.  The white blobs in the picture above are collections of fat cells. Think of it as moth-balled production capacity.  As you can imagine, a growing child needs to produce a lot more blood cells on a continuous basis than someone who is in his “golden years”, where new blood cells need to be created only to make up for cells lost to general wear and tear.

Here is a quick rule of thumb:  subtract your age from 100%.  That gives the percentage of your bone marrow that is still active.  In other words, a seventy year old man has only 30% of his bone marrow active and available for production of new blood cells.  This is often referred to as “bone marrow cellularity” in lab reports. Sometimes, under duress, the body brings back hitherto mothballed production capacity and this is seen as “hypercellularity” (more cellular bone marrow and less fatty deposits) – always with reference to the age of the patient.

What makes the bone marrow so important?  Active and functioning bone marrow is the only location of “pluripotent hematopoietic stem cells“.  That is quite mouthful, but it is actually quite simple.  “Pluripotent” means capable of doing many things.  “Hematopoietic” refers to blood.  So, pluripotent hematopoieitc stem cells are capable of making all the different types of cells that make up your blood supply.

These blood stem cells are capable of making new blood cells as well as renew their own numbers, thereby keeping a nice supply of blood stem cells for future use.  Below is a chart of how these very important group of stem cells go about their business.  As you can see, depending upon the needs of the body, they first differentiate into either lymphoid or myeloid stem cells.  Lymphoid stem cells can only make B-cells, T-cells and NK cells.  Myeloid stem cells can make red blood cells, platelets, neutrophils and many other vital cell lines.

Hematopoiesis

Damaged blood stem cells

Blood stem cells can get damaged for a variety of reasons.  It could be due to congenital or inherited problems, gene mutations that cause Fanconi’s anemia, for example.  Some viruses can also cause stem cell damage, among them the ever popular Epstein-Barr virus and hepatitis B.  Lack of proper nutrition (folate or vitamin B12 deficiency) can also damage blood stem cell health.  Obviously of importance to us CLL folks, infiltration of the bone marrow by large numbers of CLL cells will also interfere with proper functioning of the stem cells that live there.

Last but not least, many of the chemotherapy agents used to treat CLL and other cancers are quite toxic to blood stem cells. High on the list of drugs that can cause hematopoietic stem cell damage are fludarabine and cyclophosphamide.  I have no doubt that pentostatin (the other purine analog of fludarabine) and chlorambucil (another alkylating agent similar to cyclophosphamide) and bendamustine (the latest darling of the chemotherapy crowd) can also cause blood stem cell damage, to varying degrees.

Consequences of blood stem cell damage can be varied, depending upon the cause of the damage. If it is due to poor nutrition, once the cause is identified, proper use of supplements can correct the deficiency.  If it is due to viral infection, treating the underlying infection can bring out renewed health of the stem cells.  If it is due to CLL infiltration of the bone marrow, therapy targeted at reducing the CLL infiltration can bring out better working conditions for the blood stem cells living there, thereby improving their morale and production output.  If the blood stem cells are lazy and not doing their job because the body is no longer producing the growth factors that are, in essence, marching orders for the production of specific types of blood cells, then using man-made growth factors such as Procrit, Aranesp (red blood cell growth factors) or Neupogen, Neulasta (neutrophil growth factors) will remedy the situation.

But what if the problem is none of the above, the reason for reduced or stopped production of new blood cells (platelets, red blood cells, neutrophils etc) is because too many blood stem cells have been killed, and there are too few around to do the job? People with drastically reduced numbers of blood stem cells cannot make enough red blood cells, platelets, neutrophils etc to make up for the daily losses of these cell  lines due to wear and tear.   Giving them growth factor injections is of no use, since there are not enough blood stem cells present to listen to the marching orders and crank up production. By the way, another good way of killing off stem cells is excessive radiation exposure to the bone marrow.

Cancer Biother Radiopharm. 2002 Aug;17(4):399-403.

Chemotherapy and bone marrow reserve: lessons learned from autologous stem cell transplantation.

Aksentijevich I, Flinn I.

The Johns Hopkins Oncology Center, 1650 Orleans St., Baltimore, MD 21231, USA.

Cytotoxic chemotherapy is often complicated by hematopoietic toxicity. The degree of aplasia and the rapidity of count recovery following chemotherapy are indicative of bone marrow reserve. Patients who generally have a normal bone marrow function will recover from chemotherapy-induced cytopenia relatively rapidly. In contrast, patients that have poor bone marrow reserve will have significantly prolonged period of aplasia. Predicting the hematopoietic toxicity of radioimmunotherapy is an important dosimetry consideration. Unfortunately, there are no good models for predicting toxicity from chemotherapy that could be applied to radioimmunotherapy. However, models used to predict the ability to harvest autologous stem cells for use after high dose chemotherapy may be useful in predicting bone marrow reserve and potential toxicity from radioimmunotherapy. These models indicate that the successful mobilization of stem cells into the peripheral blood is inversely proportional to exposure to stem cell toxic drugs. Establishing criteria that will help predict the amount of myelotoxicity sustained from radioimmunotherapy could lead to improved dosimetry and ultimately to better therapy for patients.

PMID: 12396704

Pancytopenia (reduced capacity for production of multiple cell lines) caused by irreversible loss of blood stem cells is a dangerous situation. Only two approaches remain for patients suffering from drastic loss of blood stem cell reserves.  One is regular transfusions of all the necessary cell lines from blood donors.  Red blood cell and platelet transfusions are quite common.  Neutrophil transfusions are very rare.

This is not as simple as it sounds; becoming transfusion dependent on a long term basis is complicated business that can cause many other problems down the road (iron overload, risk of serious viral infections inherent in using any blood product etc).  The other approach is a stem cell transplant, where the loss of the patient’s own stem cells is corrected by transplantation of blood stem cells donated by a matched donor.  As we know only too well, even with modern improvements, fatality rates and long term complications of stem cell transplants are still too high for comfort.

Aging process

While we have a number of young members of CLL Topics, as a general rule CLL strikes an older segment of our population.  There are some undeniable effects of increasing age that no amount of Botox and plastic surgery can reverse.  One of the downsides of growing older is that the number and production capability of blood stem cells decreases.  Age related anemia and age related deficits of immune function are only too well documented.  This means the smaller numbers of hematopoietic stem cells remaining are all the more precious for our elderly patients.

Oncol Rep. 1998 Mar-Apr;5(2):397-400.
Effect of age on human peripheral blood stem cells.
Egusa Y, Fujiwara Y, Syahruddin E, Isobe T, Yamakido M.
Source
Second Department of Internal Medicine, Hiroshima University School of Medicine, Kasumi 1-2-3, Minami-ku, Hiroshima 734, Japan.
Abstract
We evaluated the correlation between the number of peripheral blood stem cells (PBSCs) and aging by monitoring those of CD34+ cells (PB-CD34+), colony-forming unit granulocyte macrophages (PB-CFU-GM) per 1 ml of peripheral blood in normal volunteers (n=50) including 20 males and 30 females (median age 67, range 20-90). The numbers of PB-CD34+, PB-CFU-GM were monitored by flow cytometry and methylcellulose-based colony assay, respectively. An inverse correlation between the number of PB-CD34+ with age (r=-0.33, p=0.020) was found. Furthermore, the number of PB-CFU-GM also showed an inverse correlation with age (r=-0.58, p=0.003). Based on these results, it is suggested that the number of PBSCs decrease with age.
PMID: 9468566

Oncol Rep. 1998 Mar-Apr;5(2):397-400.

Effect of age on human peripheral blood stem cells.

Egusa Y, Fujiwara Y, Syahruddin E, Isobe T, Yamakido

Second Department of Internal Medicine, Hiroshima University School of Medicine, Kasumi 1-2-3, Minami-ku, Hiroshima 734, Japan.

We evaluated the correlation between the number of peripheral blood stem cells (PBSCs) and aging by monitoring those of CD34+ cells (PB-CD34+), colony-forming unit granulocyte macrophages (PB-CFU-GM) per 1 ml of peripheral blood in normal volunteers (n=50) including 20 males and 30 females (median age 67, range 20-90). The numbers of PB-CD34+, PB-CFU-GM were monitored by flow cytometry and methylcellulose-based colony assay, respectively. An inverse correlation between the number of PB-CD34+ with age (r=-0.33, p=0.020) was found. Furthermore, the number of PB-CFU-GM also showed an inverse correlation with age (r=-0.58, p=0.003). Based on these results, it is suggested that the number of PBSCs decrease with age.

PMID: 9468566

Translating the abstract above into plain English, older people have fewer blood stem cells (CD34 positive cells) and their blood stem cells show less capacity for making new blood cells as well as regenerating themselves.

By now you should have figured out that older CLL patients needing therapy for controlling their CLL are often between a rock and a hard place.  Aggressive chemotherapy regimens such as  FCR and BR (bendamustine + Rituxan) may be nice to get deep and long lasting remissions.  But on the cost side of the equation, you and your physicians should also pay attention to your bone marrow’s status.  After all, it will do you precious little good if the CLL is knocked back into a deep remission, but in the process of getting there you have done a seriously bad number on your precious bone marrow stem cells. Blood transfusions can be kept up only for so long, and age restrictions may shut out stem cell transplant possibility.  This is the reason why new guidelines suggest full strength FCR therapy, all six cycles of it, are contra-indicated for elderly patients.

I have no doubt that down the road the same recommendation will also be made regarding B+R therapy.  Frankly, I am becoming increasingly worried about the new-found fascination with bendamustine.  It is a potent new addition to our collection of bullets, I agree on that.  But it is by no means a kinder and gentler form of chemotherapy.  Younger patients may do fine with it.  But older patients, especially those with other age-related health problems, may be smart to discuss the potential stem cell toxicity of aggressive chemotherapy in their specific situation.  As always, it is a case of weighing the costs versus rewards.

Effective CLL control without excessive stem cell damage

When there is something of importance that the editors of “Blood” wish to highlight, they ask an expert (who is not one of the authors) to write an editorial discussing the article in question.  Here is the link to the editorial piece, titled “Toward chemotherapy-free treatment of CLL“.  An abstract of the article itself is given below.  As always, send me a personal email if you want help locating the full length article for your own reading pleasure.

Blood. 2011 Sep 29;118(13):3489-98. Epub 2011 Jul 1.

Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia.

Badoux XC, Keating MJ, Wen S, Lee BN, Sivina M, Reuben J, Wierda WG, O’Brien SM, Faderl S, Kornblau SM, Burger JA, Ferrajoli A.

University of Texas M. D. Anderson Cancer Center, Houston, TX

The best initial therapy for elderly patients with chronic lymphocytic leukemia (CLL) has not yet been defined. We investigated the activity of lenalidomide as initial therapy for elderly patients with CLL. Sixty patients with CLL 65 years of age and older received treatment with lenalidomide orally 5 mg daily for 56 days, then titrated up to 25 mg/d as tolerated. Treatment was continued until disease progression. At a median follow-up of 29 months, 53 patients (88%) are alive and 32 patients (53%) remain on therapy. Estimated 2-year progression-free survival is 60%. The overall response rate to lenalidomide therapy is 65%, including 10% complete response, 5% complete response with residual cytopenia, 7% nodular partial response, and 43% partial response. Neutropenia is the most common grade 3 or 4 treatment-related toxicity observed in 34% of treatment cycles. Major infections or neutropenic fever occurred in 13% of patients. Compared with baseline levels, we noted an increase in serum immunoglobulin levels across all classes, and a reduction in CCL3 and CCL4 plasma levels was noted in responding patients. Lenalidomide therapy was well tolerated and induced durable remissions in this population of elderly, symptomatic patients with CLL. This study was registered at www.clinicaltrials.gov as #NCT00535873.

PMID: 21725050

Now for the highlights

  • This clinical trial addresses the needs of an often ignored (and yet very large!) group of CLL patients – namely, those 65 years or older.
  • Unlike M. D. Anderson’s usual penchant for aggressive dosing regimens, this clinical trial starts with a carefully modulated dosing schedule.  Patients started off with 5mg/day of lenalidomide (“Revlimid”), and after a month and a half, the dose was gradually increased to a higher limit of 25mg/day – the actual dosing limit being determined by how individual patients tolerated the drug.  This is a sensible way of initiating Revlimid therapy.  Start with a low dose to minimize tumor flare type of adverse effects, and after a significant length of time, when the tumor load is hopefully reduced greatly and the patient has become used to the drug, gradually escalate the dose to a level that is customized to each individual patient.
  • This dosing approach showed a gradual improvement over time.  Perhaps for the first time, we have a therapeutic approach that works better for older patients than good old chlorambucil!
  • Neutropenia continues to be the number one hematological toxicity.  Surprisingly, the number of patients experiencing severe infections was lower than expected – this may have to do with the unique mechanism of Revlimid’s action.  Unlike other standard issue chemotherapy drugs, Revlimid is thought to work by increasing the activity of the patient’s own immune system.  for this reason, it is called an “imid” or immuno-modulatory drug. There is reasonable hope that immunomodulatory drugs do far less damage to hematopoietic stem cells.
  • Much work remains to be done to determine how exactly Revlimid works in CLL.  But this much seems clear: Revlimid causes increased activity of T-cells. Equally important, unlike other chemotherapy drugs, treatment with Revlimid actually increased immunoglobulin levels in patients!
  • Revlimid is thought to interfere with BCR (B-cell receptor) signalling, something that is a very active pathway in unmutated IgVH type CLL patients.  So, and wait for the good news, unmutated IgVH patients may in fact be better candidates of Revlimid therapy than patients with the (good ) mutated version of IgVH!

Other details – such as patient characteristics, overall survival, adverse effects etc – were described in an earlier article I wrote on the same subject, titled “Revlimid for Elderly Patients” and I refer you to it for these details.

Editorial

So, you may fairly ask, why this second review of the same clinical trial?  Very simple.  Reading through my analysis in the earlier article I felt I had not just justice to the importance of preserving bone marrow stem cells and their ability to function properly.  Recently I have heard from more than a couple of our members who now face irreversible bone marrow damage, resulting in across the board pancytopenia and are now transfusion dependent.  Three of the group are also ineligible for mini-allo transplants because of their age.  End of the road.  The common theme among all these folks: somewhat elderly patients and more than a couple of layers of aggressive chemotherapy regimens.

Older patients have fewer of these precious progenitors of blood cells and preserving them is of great importance.  If the remaining level of bone marrow reserves are depleted, you may find yourself in a situation where there are few options left.  Please take seriously the guidance given in recent research suggesting therapy options such as full strength FCR are contra-indicated for older patients.  If your physician suggests B+R instead of FCR, and you happen to be an older patient, it is definitely worth asking your physician about potential damage to bone marrow stem cell reserves.

CLL and its treatment is not yet an exact science.  And there are enough individual differences that almost any rule I may come up with may not be appropriate in a particular case.  All I am suggesting is making the best possible choices, in a sober and informed manner.  It is foolish to bring out the biggest and baddest guns, when you may not be able to withstand therapy related toxicity.  Equally foolish would be to forswear all chemotherapy drugs because they are toxic.  Sure, they are toxic.  And you would be a crazy person to use any of them, except that you also happen to have this incurable cancer called CLL.  As always, think carefully about the risks and rewards, talk it out with your doctors and then make the decision based on what feels right for you.

And once you have made your decision, please do yourself a favor and don’t look back, second guessing and worrying yourself to a fare-thee-well.

weighing choices