Page 994 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 877

activity with manageable toxicity in patients with relapsed classical treatment permits a broad integration into currently approved che-
Hodgkin lymphoma, four patients died during the study, of which motherapy regimens. A variety of HDIs synergistically enhance the
two may have been treatment-related deaths. As a result, this study has growth inhibition and apoptosis of DNA-damaging agents and
been terminated. Entinostat is another Class I selective HDI and is well irradiation. This occurs, in part, through a HDI-mediated increase
tolerated either as a single agent or in combination with other drugs. A in chromatin accessibility and downregulation of DNA repair. A
phase I trial tested entinostat in patients with refractory solid tumors small phase I study examined the MTD of vorinostat with standard-
and lymphomas. Prolonged disease stabilization was seen in some dose CHOP chemotherapy in 14 patients with untreated PTCL. The
patients, and the drug was well tolerated and demonstrated antitumor MTD of vorinostat was 300 mg daily. The combination was toler-
activity. ated, with diarrhea being the most common toxicity observed, and
with a 2-year PFS and OS of 79/70% and 81/75% in the two dosing
Cyclic Tetrapeptide Histone Deacetylase Inhibitors schedules tested, respectively. Synergy between HDI and proteasome
The principal members of this class of agents are depsipeptide (romidep- inhibitors has been demonstrated in preclinical and clinical studies
sin). Romidepsin has recently been approved by the FDA as an IV agent in myeloma. The most well-characterized model of synergy between
for the treatment of patients with relapsed or refractory CTCL. It is a proteasome inhibitors and HDIs are the dual inhibition of the protea-
potent HDI that exerts in vitro antitumor effects at nanomolar levels some and aggresome pathways. Targeting both the proteasome with
against several cancer cell types. It also induces apoptosis of human bortezomib and the aggresome with HDAC6 inhibitors in tumor
acute leukemia and CLL cells. It is a natural product derived from cells induces greater accumulation of polyubiquitinated proteins,
Chromobacterium violaceum, a bacterium isolated from Japanese soil resulting in increased cellular stress and apoptosis. More specifically,
samples. Additionally, romidepsin was shown to exert antiangiogenic proteasome inhibition drives the formation of aggresomes, which are
effects by modulating the expression of genes involved in angiogenesis. dependent on the interaction of HDAC6 with tubulin and dynein
FDA approval for rhomidepsin in relapsed/refractory CTCL is based complex. Moreover, the proteasome inhibitor (bortezomib) and
on two large phase II studies: a multi-institutional study based at the HDAC6 inhibitors (tubacin or panobinostat) lead to increased
NCI in the United States (71 patients), and an international study (96 hyperacetylation of tubulin and generation of polyubiquitinated
patients). The treatment schedule was identical across both studies and proteins, thus increasing cellular stress response (i.e., c-Jun N-terminal
the ORR was 34% in both studies. Romidepsin also induced complete protein kinase activation) and leading to apoptosis, which is, in part,
and durable responses in patients with relapsed or refractory PTCL dependent on caspase activity. The addition of panobinostat to
across all major PTCL subtypes, regardless of the number or types of bortezomib improved PFS by about 3 months in a recent randomized
prior therapies, with an objective response rate of 25%, which led to phase III trial of 768 patients with relapsed/refractory myeloma that
the approval of single-agent romidepsin for the treatment of relapsed led to FDA approval. Clinical trials are ongoing to test the combina-
or refractory PTCL in the United States. Similarly, a phase II trial tions of HDI with hypomethylating agents, mTOR inhibitors, and
enrolling 47 patients with PTCL of various subtypes including PTCL other proteasome inhibitors.
not otherwise specified, angioimmunoblastic, ALK-negative anaplastic
large-cell lymphoma, and enteropathy-associated T-cell lymphoma also
showed an ORR of 38%. A phase I study of romidepsin in patients Denileukin Diftitox
2
with CLL and AML at a dosage of 13 mg/m IV on days 1, 8, and
15 of a 4-week cycle showed antitumor activity in several patients, Denileukin diftitox (DD) or DAB389IL-2 (Ontak) is a fusion
although no CRs or PRs were observed. Response was greater in protein in which the receptor binding domain of diphtheria toxin
patients with CLL than AML. There were no life-threatening toxicities, has been exchanged for that of the IL-2 molecule. Because of the
but constitutional symptoms characteristic of HDAC inhibition were specificity of the IL-2 domain, the DT-mediated cytotoxic activity
observed in the majority of patients. will predominately affect cells that express the IL-2 receptor (IL-2R).
Depsipeptide shows substantial activity against CTCL and it has The IL-2R is selectively expressed on activated T-lymphocytes, B cells,
been approved by the FDA for treatment of CTCL patients who have and NK cells. It has been shown that IL-2 fusion toxin is cytotoxic
received at least one prior line of systemic therapy at a dose of 14 mg/ against in vitro T-cell lines. It has been estimated that approximately
2
m IV over 4 hours on days 1, 8, and 15 of a 28-day cycle. Another 50% of CTCL cases express the IL-2R (CD25), as demonstrated
phase II study of depsipeptide as a single agent has shown an encour- by immunohistochemical staining. DD was approved by the FDA
+
aging 38% response rate in PTCL. In relapsed myeloma, no objective for the treatment of relapsed or persistent, CD25 CTCL based on
responses have been observed. demonstrated efficacy in a placebo-controlled multinational dose-
+
ranging study that enrolled 144 patients with CD25 stages Ia–III
Toxicity of Histone Deacetylase Inhibitors in CTCL. Patients who had three or fewer prior therapies were randomly
assigned to receive an IV infusion of either DD at 0.018 mg/kg or
Clinical Trials 0.009 mg/kg on days 1–5 of a 21-day cycle (maximum eight cycles)
or saline placebo. The ORR for patients receiving the 0.018 mg/kg
The most common grade 3 and 4 adverse events observed with the dose was 46%, with a median response duration of 220 days. The
use of HDIs were thrombocytopenia, neutropenia, anemia, fatigue, ORR for patients receiving the 0.009 mg/kg dose was 37%, with a
and diarrhea. In some cases, HDI-induced thrombocytopenia can be median response duration of 277 days. Patients receiving the saline
rapidly reversible upon withdrawal of the drug. Nausea, vomiting, placebo had an ORR of 16% and median response duration of 81
anorexia, constipation, and dehydration were also seen in patients days. Significant improvements of PFS at both doses of DD was
receiving HDIs. Deaths have been reported in clinical studies involv- noted (hazard ratio: 0.27 comparing 0.018 mg/kg vs. placebo, p =
ing HDIs. For example, when mocetinostat was tested in patients .0002; hazard ratio: 0.42 comparing the 0.009 mg/kg vs. placebo, p
with relapsed Hodgkin lymphoma four patients died, of which two = .02). Treatment-emergent adverse events that occurred in at least
were treatment-related deaths. Similarly, deaths were also reported in 20% of patients in the 0.018 mg/kg group, and more frequently
clinical trials involving vorinostat, givinostat, and many other HDIs. than in the placebo arm, were fever, nausea, rigors, fatigue, vomiting,
headache, peripheral edema, diarrhea, anorexia, rash, and myalgia.
Combinations of Histone Deacetylase Inhibitors Serious adverse events in patients receiving DD included infusion
reactions, capillary leak syndrome, and loss of visual acuity, includ-
With Other Agents ing loss of color vision. Laboratory abnormalities reported included
hypoalbuminemia and hepatic transaminitis. Both bexarotene and
With an increased understanding of the function of HDIs, rational alitretinoin were shown to increase the expression of CD25 in
combinations of chemotherapies and HDI inhibitors have been the CTCL cell line. Cells that were subsequently exposed to DD
investigated. The acceptable toxicity profile associated with HDI showed a 50%–70% decrease in protein synthesis. This observation