Saturday, February 28, 2015


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.


Will CLL yield to cure other than using ABMT?
Will multimodality therapies improve overall survival of each molecular subsets of the disease spectrum?


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