Page 989 - Hematology_ Basic Principles and Practice ( PDFDrive )

872 Part VII Hematologic Malignancies

traditional chemotherapeutic agents, radiation, and other antitumor to its lower affinity to Bcl-XL. Early clinical experience with venetoclax
treatments. is very promising, with remarkable efficacy in a patient population
with relapsed or refractory CLL with high ORR (75%–79%) and
Bcl-2 Antisense impressive CR rates (22%–29%) and clearance of MRD even in
Liposomal antisense Bcl-2 oligonucleotide (Bcl-ASODN) has been the high-risk subsets of patients with the adverse-risk del(17p) chro-
created and shown to cause apoptosis of many types of cancer and mosomal abnormality associated with p53 mutation/dysfunction,
leukemia cells. Bcl-2-ASODN also sensitized tumor cells in vitro and an unmutated immunoglobulin heavy chain gene (IGHV), and
in vivo to chemotherapeutic drugs. The most promising agent to those with disease refractory to fludarabine in a phase I trial. The
target Bcl-2 is Genasense (oblimersan sodium; G3139), an 18-mer early clinical trials of venetoclax were suspended initially because
phosphorothioate oligodeoxynucleotide antisense compound. Clini- all patients treated developed tumor lysis syndrome (TLS), which
cal studies suggest safety and efficacy in solid and hematologic led to two deaths. That led to modification of the clinical protocol
malignancies. In a phase III trial, 241 patients were randomly assigned with a gradual dose escalation of venetoclax on a 2–3-weekly basis
to receive oblimersen 3 mg/kg/day as a 7-day continuous infusion in up to the target dose of 400 mg daily with stringent monitoring and
addition to fludarabine–cyclophosphamide versus fludarabine– aggressive prophylaxis and management of TLS. Although laboratory
cyclophosphamide. This study met its primary objective by demon- evidence of TLS remain highly prevalent in patients with CLL treated
strating a significantly superior CR or nodular partial remission (CR/ with venetoclax, no deaths due to TLS have been observed after
nPR; 17% vs. 7%; p = .025); however, no significant differences in adoption of these modifications. ORR rates as high as 61% have been
ORRs as well as TTP were found. However, at 5-year follow-up a reported in a mixed cohort of patients with relapsed NHL in com-
significant improvement in survival was noted, with a hazard ratio of bination with bendamustine and rituximab with no added toxicity.
0.6 for those treated with oblimersen. Results of another phase III The responses were few in patients with relapsed DLBCL; however,
study were reported in which the addition of oblimersan to high-dose responses (37.5%) were seen in patients with indolent lymphomas.
dexamethasone did not improve OS or TTP in myeloma patients. A phase III clinical trial is in progress in patients with relapsed/
refractory CLL comparing venetoclax and rituximab to bendamus-
BH3 Peptide/Mimetics or Bcl-2/Bcl-XL Small-Molecule tine and rituximab. Venetoclax has received approval for relapsed/
Antagonists refractory CLL with del(17p) based on impressive clinical activity.
Another strategy to create Bcl-2 inhibitors has focused on developing However, the risk of TLS may be prohibitive to limit its use to clini-
small molecules that mimic the action of the endogenous Bcl-2- cians with expertise in management of hematological malignancies
binding death agonists. Compounds that mimic the BH3-only class and TLS.
of death agonists such as Bad inhibit the survival proteins Bcl-2 and
Bcl-x L but do not appear to have independent proapoptotic activity.
Two classes of novel small-molecule cell-permeable inhibitors of the Cyclin-Dependent Kinase Inhibitors
Bcl-x L -BH3 domain (BH3I) have been identified. Studies have
demonstrated that BH3Is induce apoptosis by preventing BH3 Orderly progression through the cell cycle is regulated by the coor-
domain-mediated interaction between proapoptotic and antiapop- dinated expression of a variety of genes and proteins, and effected by
totic members of the Bcl-2 family. Two natural products have been the interactions between cyclins, CDKs 1–9 and endogenous CDK
suggested to antagonize the antiapoptotic function of Bcl-2 or Bcl-x L . inhibitors (e.g., p21 CIP1 , p27 KIP1 , and p57 KIP2 ; see Fig. 57.1). CDK1,
Tetrocarcin A was reported to inhibit mitochondrial functions of in association with cyclins A and B, is involved in G 2 M progression;
Bcl-2 and suppress its antiapoptotic activity. In another report, CDK2, CDK4, and CDK6, in association with cyclins A, D, and E,
Antimycin-A was shown to mimic activity of BH3 peptides and are involved in G 1 S progression. Activation of CDKs results in
selectively induce apoptosis in cell lines overexpressing Bcl-x L . Certain phosphorylation of the pRb, which leads to its dissociation from the
green tea catechins and black tea theaflavins were identified as potent E2F transcription factor. Once freed, E2F triggers the transcription
inhibitors (K i in the nanomolar range) of the antiapoptotic Bcl-2 of diverse genes involved in cell cycle progression (thymidylate syn-
family of proteins. On the basis of the high-resolution three- thase and dihydrofolate reductase, among numerous others). Endog-
dimensional structure of the target receptor, small organic molecules enous small-molecule CDK inhibitors such as P21 CIP1 and P27 KIP1
that bind to this interface have been designed. ABT-737 is a BH3 bind stoichiometrically to CDKs and inhibit their activity. CDK
mimetic that binds to Bcl-2, Bcl-xL, and Bcl-w with high affinity (K i activity can also be regulated through inhibitory or activating phos-
<1 nM) but not to Mcl-1. Preclinical data demonstrate cytotoxic phorylation. Interference with the activation of CDKs results in
activity in B lymphoid tumor cell lines, human follicular lymphoma, dephosphorylation of pRb, leading in turn to binding and inactiva-
myeloma, and CLL cells, as well as synergism with other chemothera- tion of E2F and inhibition of cell cycle progression.
peutic agents. Also, ABT-737 effectively kills AML blast, progenitor, Cell cycle dysregulation is a cardinal characteristic of cancer. A
and stem cells without disturbing normal hematopoietic cell develop- classic example of this phenomenon is the association of increased
ment. However, the clinical utility of ABT-737 is limited, as it expression of cyclin D 1 in MCL. Regulation of the cell cycle has been
undergoes rapid metabolism and is not orally bioavailable. Targeted found to be closely related to apoptosis, and disruption of normal
modifications of ABT-737 led to synthesis of navitoclax (ABT-263), cell cycle transit has been shown to be a potent cell death stimulus.
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an orally bioavailable BH3 mimetic. In the initial phase I trial more A corollary of this observation is that agents that interfere with the
than half of patients had a decrease in their lymphocytosis, with 35% cell cycle, in addition to blocking cell cycle progression, can be potent
achieving partial remission. The main toxicity was dose-dependent inducers of programmed cell death. Cell cycle inhibitors can be
thrombocytopenia, which occurred early in the treatment cycle (days subdivided into several categories. For example, they can act directly,
2–5 of a 21-day cycle). Neutropenia occurred at higher dose levels. as in the case of CDK inhibitors, or indirectly, as in the case of HDIs,
Other adverse events included gastrointestinal side effects and fatigue. compounds that block cell cycle progression by inducing endogenous
The remarkable activity of this agent in early trials validated Bcl-2 as cell cycle inhibitors such as P21 CIP1 . The latter agents are discussed
a target for the treatment of CLL. The clinical development of navi- later in this chapter. CDK inhibitors can also be classified as specific
toclax was suspended because of thrombocytopenia; which is an (i.e., directed against a particular CDK, such as CDK2) or those that
off-target effect due to inhibition of Bcl-XL. nonspecifically inhibit most CDKs (e.g., flavopiridol).
Venetoclax (Abt-199) was subsequently developed to replace
navitoclax as a highly selective, orally available small-molecule Bcl-2
family protein inhibitor that binds with high affinity (K i <0.10 nM) Flavopiridol
to Bcl-2 and with lower affinity to other Bcl-2 family proteins Bcl-XL
and Bcl-w (>480-fold and >2000-fold lower affinity than to Bcl-2, Flavopiridol (L86-8275) is a semisynthetic flavonoid derived from
respectively). Thrombocytopenia is less frequent with venetoclax due the Indian plant rohitukine. It was the first CDK inhibitor to enter