CHRONIC LYMPHOCYTIC LEUKEMIA

The dysfunction within the follicular center of the lymph nodes and the gathering swarm of functionally incompetent (anergic) self-reactive cells within the bone marrow produce poly-reactive autoantibodies creating Chronic Lymphocytic Leukemia (CLL).

CLL affects between 16,000 to 17,000 individuals mostly older ones with a median age of 58 years in the United States. Whites outrank other ethnic origins.

The CLL differentiated clusters of cells mostly include CD 19, CD20, C21, CD23 and CD5. Targeting the largest cohort is the latest game in therapeutics to suppress the wayward lymphocytic cell. Other Surface antigen markers are also listed in references.

·        Stage: From a prognostic point of view CLL had classically been staged based initially on Lymphocytosis. In the Rai model: Stage I: 25% Lymphocytosis. StageII: 50% Lymphocytosis with Nodes. Stage III: Stage II and Lymphocytosis with Nodes and Anemia Hgb less than 11g per deciliter and Platelets of  less than 100,000 per dL. 

Binet created a slightly better system anchoring on the values of Hemoglobin, nodes and platelets. Stage I = Hgb >10 g/dL, Platelets >100/dL and < 3 nodal regions involved. Stage II was essential Stage I with >3 Nodal regions involved. Stage III was Hgb <10g and="" or="" platelet="">3 Nodes. Favorable subsets emerged based on these gradations. However recent data has been able to disambiguate within the stages based upon the molecular nuances.

·         Chromosomal Data:

o   About 50% of CLL patients have 13q14 abnormality and are usually benign.

o   19% have 11q22-23 abnormality and are mostly aggressive

o   15% have 17p13 abnormality and have large nodal disease and aggression.

·         Molecular Data (Overexpression associated with lowering survivals):

o   ZAP70 (Zeta-associated Peptide of 70 kilodaltons) expression is associated with 8 year survival. ZAP70 non-expression CLL has >25 year survival.

o   CD38

o   IgVH (Immunoglobulin Variable Heavy Chain) (un-mutated) immunoglobulin gene. Interestingly high risk patients have low DNA mutation at the IgVH gene region and vice versa.

o   Bcl-2 (Down regulation of miRNA 15a and miRNA 16-1 increases Bcl-2)

o   Beta-2-Microglobulin

o   Lymphocytic doubling Time

·         Current Chemotherapy Regimens:

o   Chlorambucil

o   Fludarabine

Whereas Chlorambucil and Fludarabine PFS were identical at 18 and 19 months respectively, the Overall survival was 64 months and 46 months respectively, but it did not achieve significance.

o   Fludarabine(F) + Cyclophosphamide(C)

o   FC+Mitoxantrone or FCM

o   FC+ Rituxan or FCR

Adding Rituxan to FC improved the PFS significantly although the overall survival was not greatly impacted. It appears that monoclonal antibodies that target specific CD markers have short term increased responses but limited survival benefits. The escape velocity of this recurrence might suggest antibody production against the antibody being used in therapy, methods of dosing, or the CLL cells aggregating newer mutations over time. It is important to note that treatment of early CLL is not indicated as it is harmful through risk of infections and shortening of survival. CLL patients due to their inability to produce functional B humoral antibodies are not able to fight off bacterial infections.

o   CVP (Cyclophosphamide (C) + Vincristine (V or O) + Prednisone(P))

o   CHOP (H = Doxorubicin)

o   Revlimid (Thalidomide analog) was associated with 47% Responses and 9% Complete Remissions with complete elimination of Minimal Residual Disease MRD).

·         Monoclonal Antibodies and Cytolytics:

o   Rituxan (CD20 antibody)

o   Alemtuzumab (Anti CD 52) Effective against the aggressive 17p13 cases.

o   Ofatumumab (Anti CD 20)

o   Obinutumumab (Anti CD 20 cytolytic agent)

o   Ibrutinb (Bruton Tyrokinase Inhibitor) In a small number of cases with BTK mutation Ibrutinib is ineffective. In the RESONATE study Ibrutinib had a 58% response with a tripling of survival 24.2 vs. 5.5 months in previously treated patients.

Unfortunately what has plagued longer term survival is the existence of MRD following therapy. Comparing the newer agent Obinutumumab + Chlorambucil vs. Rituxan + Chlorambucil resulted in 78% vs. 65% Response, 27 months vs. 15 months PFS and the MRD in Blood was 37.7% vs. 3.3%, in the Bone Marrow MRD was 19.5% vs. 2.6%.  

·         Other Therapies:

o   Genetically modified T-Cell to express CD 19 used against CLL resulted in 26 of 59 patients with complete remissions (Proof of Concept study)

o   Allogeneic Bone Marrow Transplants: This therapy is the only known curative therapy known against CLL. It has an inherent risk of mortality as a consequence of the Induction and Conditioning related complications pre transplant and GVHD post-transplant. ABMT is utilized as an option in younger (50-65 years of age) patients with known molecularly determined aggressive disease who can withstand the rigors and risks of such therapy.
o   Duvelisib a dual PI3K gamma/delta inhibitor showed an impressive 98% nodal response noted on CT scan in 43 patients. This drug showed activity in 17p13 cases and at least one Ibrutinib refractory case.
o   Future pipeline include Anti-Bcl-2 drugs to enhance apoptosis in the errant lymphocytic population

Understanding the very nature of malignant biological diseases is the doubling time. A slow growing disease takes longer to accumulate cancer cells, thus the patient (host) survives longer with the disease. Also in most solid malignancies 2/3rds of the disease span is invisible and un-diagnosable due to malignant cell quantity as is depicted on the graphs posing variable doubling time. An aggressive disease grows faster and has a higher mortality lacking effective therapies. You can observe from this graph that the growth explosion occurs in the very late stages of the disease when it becomes (semi)resistant to therapy due to acquired DNA mutations and immune-surveillance blunting modalities.

	Doubling	months	months	months	months
1	2	6	12	18	24
2	4	12	24	36	48
3	16	18	36	72	96
4	256	24	48	144	192
5	65536	30	60	288	384
6	4294967296	36	72	576	768

Will CLL yield to cure other than using ABMT?

Will multimodality therapies improve overall survival of each molecular subsets of the disease spectrum?

References:

 Shanshal, Mohammed; Haddad, Rami Y. (April 2012). "Chronic Lymphocytic Leukemia". Disease-a-Month 58 (4): 153–167. doi:10.1016/j.disamonth.2012.01.009.PMID 22449365.

 Jump up^ National Cancer Institute. "General Information About Chronic Lymphocytic Leukemia". Retrieved 2007-09-04.

 http://www.nature.com/leu/journal/v16/n2/full/2402363a.html#tbl4

Rai, KR; Sawitsky, A; Cronkite, EP; Chanana, AD; Levy, RN; Pasternack, BS (Aug 1975). "Clinical staging of chronic lymphocytic leukemia.". Blood 46 (2): 219–34.

Binet, JL; Auquier, A; Dighiero, G; Chastang, C; Piguet, H; Goasguen, J; Vaugier, G; Potron, G; Colona, P; Oberling, F; Thomas, M; Tchernia, G; Jacquillat, C; Boivin, P; Lesty, C; Duault, MT; Monconduit, M; Belabbes, S; Gremy, F (Jul 1, 1981). "A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis.".Cancer 48 (1): 198–206.
Shanafelt TD, Byrd JC, Call TG, Zent CS, Kay NE (2006).

 "Narrative review: initial management of newly diagnosed, early-stage chronic lymphocytic leukemia". Ann. Intern. Med. 145 (6): 435–47 

Dohner H, Stilgenbauer S, Benner A, "" et al. (2000). "Genomic aberrations and survival in chronic lymphocytic leukemia". NEJM 343 (26): 1910–6 

Mraz, M.; Mraz, M.; Pospisilova, S.; Malinova, K.; Slapak, I.; Mayer, J. (2009). "MicroRNAs in chronic lymphocytic leukemia pathogenesis and disease subtypes".Leukemia & Lymphoma 50 (3): 506–509

 
Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR (2002). "Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study". Blood99 (10): 3554–61. 

 
Urba WJ et al. (2011). "Redirecting T Cells". N. Engl. J. Med. 365 (8): 110810110014063 

Dreger P, Brand R, Hansz J, Milligan D, Corradini P, Finke J, Deliliers GL, Martino R, Russell N, Van Biezen A, Michallet M, Niederwieser D; Chronic Leukemia Working Party of the EBMT (2003). "Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning". Leukemia 17 (5): 841–8. 

http://cll.ucsd.edu/biorepository_links/CLL%20ChiorazziRai.pdf

"GIVE ME THAT MAN..."

Give me that man

That is not passion’s slave

Give me that blanket that comforts and soothes

For in my heart

There was a fighting that would not let me sleep,

Our indiscretion

Sometime serve us well.

In those wakeful moments’

When around a surgeon’s scalpel the blood congeals

And time is spent to heal.

What a piece of work is a man

The quintessence of dust.

What is he

Whose grief bears such emphasis

Such intricate complexity

Of thought and action?

How noble in reason

How infinite in faculties

To quell the cry of pain.

How like an angel

How express and admirable

To drown the misery

And purge the disquiet

Of a thousand natural shocks

That flesh is heir to

And to take arms against a sea of trouble

And by opposing, end them.

Yet within the firmament of that reason

I could be bounded in a nutshell

And count myself a king of infinite space,

Were it not that I have bad dreams.

These dreams, though this be madness

There is method in’t.

The vile mechanism feeds

And eyes without feeling

Feeling without sight,

Cannot chart the course to reason.

The spirit that I have seen, may be a devil

And the devil hath power t’assume a pleasing shape

Cleave the general ear with horrid speech,

Make mad the guilty and appal the free.

These clever studied orphans of untruth

Confound the ignorant and amaze

Indeed the very faculties of eyes and ears.

They forget in their charted hypocrisy;

This above all: to thine own self be true,

And it must follow, as the night the day,

Thou canst not then be false to any man.

The power that exudes such tyranny

Tis dangerous when the baser nature comes between

The pass and fell incensed points of mighty opposites.

They know not what they do

As their power is often fleeting

And the unholy madness, a passing fancy

A man may fish with the worm that hath eat of a king,

And eat of the fish that hath fed of that worm

They thus find permanence in indignity

within houses that last till doomsday.

While chastising nobility, they cry and

Humanity bleeds as one is lost to the many

Eviscerating the noble cause of individuality

The chief good and market of this time

Is left wanting in art and science,

Or somewhere in between.

This warlike paragon of animals

Abuses me to damn me.

As villainy though it have no tongue,

Will speak with most miraculous organ!

One day!

Leaving in its vile dust

This beauty of the world,

This noble of humans

This physician.

In apprehension how like a god,

I will wear him in my heart’s core,

Ay, in my heart of heart

As he grunts and sweats under the weary life

Bringing comfort through his discomfort

To the one of the many!

This poem is a composite of Shakespeare's eloquent words and some of mine. Juxtaposing with the Bard is tantamount to courting disaster, yet I will "screw my courage to the sticking place!"

DICTATING the CURVE of a BANANA

Can you dictate the curve of a banana? Can you?

Quite naturally humans have faced threats of great magnitude and survived. They have the unseen instincts and intuition built into the mechanics of reason, which serve them well. The foreboding that comes with such intelligence is amplified via a magnificent brain design. All the peaks and valleys of the sulci and the gyri in the brain beautifully enfold these luxuries of scale in thought and action to prevent harm to self. When illness or a malady visits upon this “quintessence of dust,” there are doctors who stitch and heal the ripped fabric. Were it not for the doctors, human misery would be manifold, survival would still be languishing and the aging demographics would be a distant hope.

But now this enterprise of medicine largely folded into its doppelganger “healthcare” visits its Sister Souljah moment and everyone in the halls of power and control backs away from what was to how it must be. It must be “patient-centered,” they claim. “They are destroying healthcare!” they claim. But who is it that they point to?

That is where we lay our scene…

The Older Past…

Let us look back a few years to see what was. As a patient you went to see your doctor in his office and there were many such tiny little abodes where a single doctor and his army of one would take care of your malady. The doctor would spend time asking about aunt Melody and uncle Arthur and then delve into the rigor of extracting information about health and well-being. He or she would ask several questions about symptoms and signs that you might have observed or seen and any complicating side effects from the medicines previously prescribed and about any improvement in functionality. He would examine with his hands and use his stethoscope to listen to the inner murmurings of the body. Having satisfied himself to understand the problem fully he would pat the shoulders or she would give you a hug of comfort, a word of advice, a wink of understanding and walk with you to the exit. You felt when you left that you had just seen your best friend, most times.

The Old Past…

That lasted a while until the insurance industry and larger corporate types in the business world waddled in with their pendulous money-bags and gold watches tied to their belts. They created a mini-maze of bureaucracy through the HMOs and mandated a clear and unequivocal chain of command for how the doctor would be paid. There were the usual pre-approvals to reckon with, and authorizations to contend with. All in all the bureaucracy was carefully, through incrementalism, comfortably embedded in that tiny little Hobbit sized office. The doctor’s army of one increased to an army of four suddenly with the demands of those times. The doctors concerns about payroll of his employees and his capacity to maintain the level of service was at odds with the demands of the day. Other agencies came visiting and finding faults that had to be reckoned and made compliant, the enormously large volumes of mandates started taking its toll on the beleaguered physician. Now, as the patient entered the doctor’s office that had transformed from a small place to a modern facility of glass, steel and humming electronics, the doctor would say hello to the patient and then with his eye on his watch and one on the waiting room, where many sat fidgeting with their watches or hand bags delayed from their daily lives, sped through the complaints leaving behind a wrinkle of frustration on his or her patient’s brow. The hint of rush was felt within each conversation as interruptions every 18 seconds by the doctor to get to the bottom of the illness’s mystery was all he or she could care about. Time had become a precious commodity.

The New Present…

And if that was not enough, soon the Mack truck of full blown bureaucracy backed into the facility with tomes of “do this for that.” Failure to follow the legal jargon in those tomes, which said much in little, implied more than a lot and warned of a hellish future for noncompliance broke another rung in the ladder of “wellness” afforded to the patient.  There were computers humming in every room of these expanded facilities. The white coat became just that and no more. The doctor was busy looking at the computer as he asked perfunctory questions that were coded by an 18-year old software designer somewhere far away in some far off land to fulfill the desires of an insurer and its governmental agency that existed behind some heavily fortified impenetrable walls. The rush of the action and the patient’s laments were limited to yes and no while the truth of his malady remained entombed within. There was a rush and ruffle of papers handed to the patient and orders to get this and that done before the next visit. The diagnosis and therapy would have to wait until the results poured in later. The Ct scan would diagnose what the hands and critical thinking did before.

The expanded offices could not keep up with the demands of the verbiage. The doctors first tried to add to their staff, failing which they tried to formalize relationships with other doctors into larger networked groups so they could achieve survival through scale. As the demands increased and the rewards diminished many of these organizations failed to comport themselves to live within their contractual obligations. Other doctors left the Hobbit abodes and their expanded versions and sought refuge within the hospitals under the banner of 9-5 jobs.

The Newer Present…

There was a wrinkle on these greener pastures waiting to unfold. The hospitals now emboldened with their own doctor employees were no longer reliant on the community physicians. The hospitals now called the shots. The business-rooted CEOs up-coded their billings to increase their revenues and to increase their bottom lines as the business in the business of medicine slowly corrupted to the core. Meanwhile the CEOs, CMOs, and the CFOs enjoyed the windfall and all made handsome salaries in the 7 digits.  They preached “Do Less with More,” as they cut hospital staff to a minimum and exploited resources that would bring in the highest dollar. The employee-doctors were told how to code for their services, initially this was merely a suggestion and then through verbal force of threats of expulsion from the brotherhood of “providers,” it became the only game in town.  Meanwhile the patients barely saw the physician. The patient care was rapidly evaluated by other less educated individuals whose actions were rubber-stamped by higher authorities. Education was in full bloom, limit costs, abbreviate a trouble life and help a patient die well.

The Newest Present…

Ask your mother or your grandmother in how they perceived their interactions with their physicians then and now and a whole tale will unfold that might sound like a fairy tale. But you should ask, for there is wisdom in a long life! She will tell you that today it is the corrupted influence of inducement, incentivizing and threats that dehumanizes both the patient and the physician.

We are here… and it is today!

What the future holds is cloudy. I predict that once again the undying traits of liberty encoded within the human DNA. One day that small Hobbit-style office will spring back into action with or without the lust for the “global-public-good” decree. After all we are all patients and we will seek what sings to our souls. Patients will demand and the free-market will provide. We will have finally realized the lust to be like Europe! Yet ours will be different, it will not be due to the middling-many, the intermediaries. The favorable doctor-patient relationship will be achieved, through the individualism, liberty and dignity in the end. The old calling “Life Liberty and the Pursuit of Happiness” is also etched in our history’s 239-year old DNA.

No, I don’t believe that you can dictate the curve of a banana. Not just yet anyway! Maybe after sequencing a banana’s DNA we might find the gene that causes the bananas to curve and which can be knocked out to allow bananas to grow straight. Woe to us if we tamper with nature at that level just to prove a point!

Take note, fawners, facilitators and arbitrators!