Page 1531 - Hematology_ Basic Principles and Practice ( PDFDrive )

1358 Part VII Hematologic Malignancies

A phase “II–I–II” study of pralatrexate in patients with relapsed structure, leading to access by transcription factors and thus tran-
or refractory NHL established the maximum tolerated dose as 30 mg/ scriptional activation. Conversely, HDACs facilitate deacetylation of
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m weekly for 6 of 7 consecutive weeks of treatment. The dose- chromatin, which leads to a closed chromatin structure and transcrip-
limiting toxicity was determined to be mucositis, which was largely tional silencing. Although the modulation of chromatin structure has
controlled with the addition of folic acid and vitamin B 12. These data been long postulated as one of the key mechanisms for HDACI
revealed an ORR of 31% among the entire population of patients activity, it is now widely recognized that these drugs are more appro-
with both B- and T-cell lymphoma (n = 48 evaluable), of which eight priately recognized as more general protein deacetylase inhibitors. In
patients obtained a CR. Among the 20 evaluable patients with B-cell this capacity, it is also recognized that HDACIs may functionally
lymphoma, the ORR was 5%, of which there were no CRs. Among affect tumor cell growth and survival by modulating the posttransla-
the 26 evaluable patients with T-cell lymphoma, the ORR was 54%, tional state of different proteins, which leads to activation or inactiva-
of which there were eight CRs. All the CRs, many of which were very tion of various tumor suppressor genes or oncogenes. While it is not
durable and included patients who had responded to prior metho- precisely known how or why this class of drugs work consistently in
trexate, were seen exclusively in patients with PTCL. PTCL, overexpression of HDAC1, HDAC2, and HDAC6, as well
These data gave rise to a pivotal study of pralatrexate in patients as acetylated histone 4 (H4) have been seen in select subtypes of the
with most subtypes of relapsed or refractory PTCL. The Pralatrexate disease.
in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma To date, three HDAC inhibitors have been approved for the
(PROPEL) study was an international, open-label, single-arm trial in treatment of cancer, including: (1) vorinostat for the treatment of
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which pralatrexate was administered at a dose of 30 mg/m weekly relapsed or refractory CTCL; (2) romidepsin approved for relapsed
for 6 of 7 consecutive weeks. At the time, it was the largest study ever or refractory CTCL and PTCL; and (3) belinostat approved for the
conducted in this patient population. Of 115 patients enrolled, 111 treatment of relapsed or refractory PTCL. The first HDACI approved
were treated with pralatrexate. Overall, the patient population was for the treatment of cancer was vorinostat, or SAHA. Vorinostat is a
very heavily pretreated, with the median number of prior therapies hydroxamic acid derivative known to be a potent class 1–2 inhibitor
being 3, with a range of 1 to 12. Twenty percent of patients in of HDAC. Early developmental clinical studies performed with both
PROPEL had received more than five lines of prior chemotherapy. intravenous and oral vorinostat demonstrated that the drug could
Of all the new drug studies that have emerged recently, the PROPEL inhibit HDACs, leading to accumulation of acetylated H3/H4.
study accrued the greatest diversity of patients with PTCL including These studies also demonstrated that the drug was well tolerated for
patients with blastic NK/T-cell lymphoma, ATLL, and transformed extended periods of time, with dose-limiting toxicities of fatigue,
mycosis fungoides (MF), which are variably excluded from other diarrhea, and anorexia for the oral formulations, and myelosuppres-
studies. In addition, the PROPEL population was, to date, the most sion for the intravenous formulations. Expanded phase II experiences
heavily treated population of the studies reported. The RR among with vorinostat confirmed single-agent activity in HL-transformed
the 109 evaluable patients was 29%, which included 12 CRs (11%), lymphomas and CTCL. These data gave rise to pivotal studies in
with an updated median duration of response of over 121 months. CTCL, leading to FDA approval in 2006.
The most common grade 3 or 4 toxicities included thrombocytopenia Romidepsin is a potent macrolide HDAC inhibitor isolated from
and mucositis. These data led to pralatrexate becoming the first drug Chromobacterium violaceum. An early phase I–II trial demonstrated
ever approved by the United States Food and Drug Administration that romidepsin exhibited marked single-agent activity in patients
(FDA) for PTCL, receiving accelerated approval in late 2009. with relapsed or refractory CTCL and PTCL. In fact, among 47
Detailed population pharmacokinetic and pharmacodynamics patients with relapsed or refractory PTCL, excluding patients with
studies have demonstrated that two variables had the greatest impact transformed MF and HTLV-1 ATL, which were included in the
on the risk of mucositis from pralatrexate, including: (1) area under PROPEL study, an ORR of 38% was noted, including eight patients
the curve of exposure; and (2) pretreatment methylmalonic acid and who attained a CR. The most common toxicities were very similar
homocysteine levels. These observations have given rise over the past to those reported for vorinostat and included nausea, fatigue, and
few years to several modifications of drug administration. The first transient thrombocytopenia. The median duration of response was
has involved the incorporation of leucovorin into the standard roughly 8.9 months, and responses were seen in most of the PTCL
administration of pralatrexate. Given the profoundly greater affinity subtypes studied. These data gave rise to an international, open-label,
of pralatrexate for the reduced folate carrier, risks of mitigating effi- pivotal phase II study of romidepsin in patients with relapsed or
cacy with coadministration seem to be far less. Albeit early, these refractory PTCL who had received at least one line of prior therapy.
evolving experiences suggest that leucovorin after and prior to prala- Of the 131 patients enrolled, 130 had histologically confirmed
trexate can markedly reduce the risk of mucositis, and in some cases PTCL. The median number of prior therapies was 1, with a range of
allows for higher doses of the drug to be tolerated, at least in preclini- 1 to 8. The ORR was 25%, which included 19 (15%) CRs, and the
cal models. Similarly, the contribution of idiosyncratic AUC drug median duration of response was 17 months. These data led to a
exposure has been addressed with a titrated dose-escalation approach conditional approval of romidepsin in patients with relapsed or
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(10 mg/m week 1; 20 mg/m week 2; and 30 mg/m week 3, on a refractory PTCL by the FDA in June of 2011.
4-week dosing basis), allowing for a tailoring of the dose to the In 2014 belinostat became the third HDAC inhibitor approved
idiosyncratic disposition of the drug in a given patient. These for the treatment of cancer, specifically patients with relapsed or
approaches, while preliminary in nature, are being studied in larger refractory PTCL. Belinostat is a hydroxamic-based pan class I and II
populations of patients. HDAC inhibitor. It is currently approved for patients with relapsed
Probably the greatest advances in recent years with not just pra- or refractory PTCL who have received at least one line of prior
latrexate, but all these agents emerging in PTCL, has been the therapy. The original phase II (CLN-6) trial included patients with
emergence of both preclinical and clinical data confirming marked various subtypes of T-cell lymphomas (TCLs; n = 24), and produced
synergy with pralatrexate and other drugs, including gemcitabine, an ORR of 25% in relapsed/refractory PTCL. This activity was the
bortezomib, histone deacetylase (HDAC) inhibitors (HDACIs) such basis for initiating the BELIEF study, where 129 patients with
as romidepsin, and belinostat. Much of this preclinical experience has relapsed and refractory disease received belinostat. The median
now been translated into early proof-of-principal clinical studies. number of prior therapies was 2. The ORR was 26% (11% CR; 15%
PR), with a PFS and OS of 1.6 and 7.9 months, respectively, and a
median duration of response of 13.6 months. Forty-six percent of
Histone Deacetylase Inhibitors patients with AITL experienced a response.
Recent data have now suggested that pralatrexate potently syner-
The HDACIs appear to exhibit a consistent pattern of activity in gizes with other HDAC inhibitors in models of T-cell lymphoma.
T-cell neoplasms, with little to no activity in B-cell lymphoid malig- These data are now being used as a rationale to support a multicenter
nancies. Acetylation of histone proteins facilitates an open chromatin phase I study that will define the maximum tolerated dose of this