Page 973 - Hematology_ Basic Principles and Practice ( PDFDrive )

856 Part VII Hematologic Malignancies

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1000 mg/m , with myelosuppression and gastrointestinal toxicity 10% and 17% at 4–6 years for myeloma patients treated with mel-
(including severe watery diarrhea) being the most common side phalan and between 2% and 10% at 7–10 years in patients with
effects. Hodgkin lymphoma. Alkylating agent-associated T-AML has also
Temozolomide represents an imidazotetrazinone. It differs from been recognized in patients with breast and colon cancer.
DTIC in that it is chemically degraded to the monomethyl triazine,
MTIC, at neutral pH and does not require P450 enzymatic demeth-
ylation. Compared with DTIC, temozolomide has much more Antimicrotubule Agents
consistent pharmacokinetic parameters, including peak serum con-
centrations, volume of distribution and clearance, and conversion to The antimicrotubule drugs include the vinca alkaloids (e.g., vincris-
MTIC. Clinical studies documented considerable activity in acute tine, vinblastine, vinorelbine and vindesine), taxanes (e.g., paclitaxel
leukemias. The dose-limiting toxicity was thrombocytopenia and, less and docetaxel), and epothilones (ixabepilone).
frequently, neutropenia, with maximum tolerated doses of 1000 mg/
2
m given over 5 days on a daily or twice-daily regimen. Nausea and
vomiting were the other common side effects, easily controlled with Molecular Targets
antiemetics.
The vinca alkaloids are naturally occurring (vincristine and vinblas-
tine) or semisynthetic (vinorelbine) nitrogenous bases derived from
Bendamustine the pink periwinkle plant, Catharanthus roseus. Paclitaxel was origi-
nally isolated from the bark of the Pacific yew, Taxus brevifolia. Pacli-
Bendamustine is comprised of a 2-chloroethylamine nitrogen mustard taxel can also be isolated from other members of the Taxus genus and
alkylating group, a benzimidazole ring, and a butyric acid side chain. from a fungal endophyte that grows on the Pacific yew. Docetaxel is
Its mechanism of action is unknown but appears to be different to derived semisynthetically from 10-deacetyl-baccatin III, which is
other alkylating agents, causing DNA damage that is repaired pre- obtained from the needles of the European yew, Taxus baccata.
dominantly by the base-excision repair system and has activity against The vinca alkaloids bind to the protein tubulin at a site distinct
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lymphoid cell lines resistant to alkylating agents. Myelosuppression from that of the taxanes and, at low concentrations, inhibit microtu-
with leukopenia and thrombocytopenia is the most frequent side bule dynamics. At higher concentrations, these vinca alkaloids disrupt
effect, with mild nonhematologic side effects including nausea, microtubules and mitotic spindle, resulting in cell cycle mitotic arrest
fatigue, constipation and diarrhea. Phase III studies comparing and apoptosis of cells (see Fig. 57.3). In contrast, after binding to
standard treatment with bendamustine and rituximab in front-line α-tubulin, taxanes kinetically stabilize microtubule dynamics at their
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treatment of CLL and indolent lymphomas (see Chapter 77) have plus ends and shift the equilibrium toward tubulin polymerization
established this combination as first-line treatment. Bendamustine is into microtubule bundles. This also causes mitotic arrest and apop-
also active against MM, and combinations with steroids and bortezo- tosis of cells. The mitotic arrest caused by antimicrotubule drugs is
mib or the immunomodulatory agents thalidomide and lenalidomide associated with phosphorylation of the B-cell lymphoma (BCL2)
have been reported to result in high response rates in patients with protein and increased intracellular levels of the BCL2-associated X
relapsed or refractory disease. protein (Bax), which promote apoptosis.
As natural products, overexpression of the efflux pump multidrug
resistance gene-1 (MDR-1) and the ABCB-1 transporter mediate
Alkylating Agent–Induced Leukemias resistance. Intracellular resistance to mitotic spindle and microtubule
formation is mediated by numerous pathways and proliferative
Alkylating agents induce dose-limiting myelosuppression and cause signals including MYC, nuclear factor kappa-B (NFκB) and AKT.
sublethal DNA damage to hematopoietic progenitors, causing muta- Antimicrotubule agents, particularly the vinca alkaloids, are used
tional events that lead to malignant transformation to preleukemic in the management of lymphomas and leukemias, and continue to
and leukemic states. A concern exists about the use of hematopoietic be used in the mainstay of clinical chemotherapeutic regimens.
growth factors after exposure to alkylating agents (see Chapter 59). Because of their mechanism of action, they are best used in multi-
There is evidence of increased cytotoxicity to hematopoietic progeni- agent combinations, in which potentiation of efficacy with other
tors during simultaneous exposure to these agents and growth factors. classes of agents, such as antimetabolites and DNA-damaging agents,
Treatment-related AML (T-AML) accounts for approximately 15% provide better therapeutic responses and well-tolerated treatments.
of all adult AML. Approximately 50% of T-AML patients have a
preleukemic phase compared with only 10% of patients with de novo
AML. CRs are achieved in 15%–30% of patients with T-AML and Inhibitors of Nucleotide Synthesis
a mean remission duration of 2 months. Chromosomal abnormalities
and gene mutations characteristic of T-AML establish this as a distinct Within this class are two important agents used for hematologic
disease requiring novel therapeutic approaches. Loss or deletion of all malignancies, hydroxyurea and methotrexate. They both serve to
or part of the long arm [q] of chromosomes 5 or 7 is common, as disrupt nucleotide synthesis, and slow or stop DNA and RNA
are trisomy 8 and deletions of the short arm of chromosomes 12, 17, synthesis.
and 21.
Historically, patients with Hodgkin lymphoma treated with Hydroxyurea
mechlorethamine and procarbazine in the MOPP regimen or with Hydroxyurea inhibits ribonucleotide diphosphate reductase, blocking
CCNU were at the highest risk if exposed to radiation as well as an de novo synthesis of purines and pyrimidines. S-phase arrest is com-
alkylating agent combination. Patients with polycythemia vera treated monly observed. Given this exquisite cell cycle specificity, resting and
with chlorambucil were at much higher risk than patients treated quiescent cells are rarely affected and there is virtually no hematopoi-
with phlebotomy alone, which can contribute to a shift in treatment etic stem cell toxicity. As a consequence of disruption of nucleotide
strategy. Patients with myeloma and ovarian cancer have developed synthesis and direct binding to telomere binding factors, telomere
T-AML, especially after prolonged exposure to alkylating agents. synthesis and function are compromised in leukemic cells. In cells
Patients treated with alkylating agents for benign diseases such as arrested in S phase, apoptosis and senescence are observed.
nephritis, lupus, psoriasis, rheumatoid arthritis, and Wegener granu- Hydroxyurea is used in the treatment of myeloproliferative neo-
lomatosis also have an increased risk of T-AML. The mean latency plasms including essential thrombocythemia, polycythemia vera and
between exposure and T-AML from alkylating agents is 4–5 years, in myelofibrosis (Chapters 68–70). It may also be used for acute cyto-
contrast to T-AML from etoposide, which has a latency period as reduction prior to induction therapy of AML and for management
short as 1 year. The cumulative risk of developing T-AML is between of chronic myelomonocytic leukemia. It is commonly used for