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
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.
.jpg)
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:
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.
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