T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL)
are aggressive malignancies derived from neoplastic transformation of precursor T
cells. T-ALL accounts for 10–15% of pediatric and 25% of adult ALL cases.
1
Although current treatment with intensive chemotherapy regimens may achieve a cure
rate of 80% in children with T-ALL, treatment of adult patients leads to a lower response
rate.
2
Results from a number of studies have demonstrated a key role for the deregulation
of NOTCH signaling pathways in the oncogenic transformation leading to the development
of T-ALL and T-LBL, providing a rationale for the development of gamma-secretase inhibitors
as a novel targeted therapy for these hematologic malignancies.
3, 4, 5, 6, 7
PF-03084014 is a noncompetitive, reversible, targeted agent that selectively inhibits
gamma secretase in multiple tumor types including leukemia and lymphoma.
8, 9, 10
Treatment with PF-03084014 has demonstrated significant antitumor activity in preclinical
models of lymphoid malignancies and solid tumors.
8, 9, 10
In study A8641014 (approved by the ethics and regulatory committees of the participating
institutions, with signed patient informed consent, and following the Declaration
of Helsinki and good clinical practice guidelines), eight patients with T-ALL or T-LBL
received treatment with PF-03084014 150 mg twice daily in continuous cycles, and all
were evaluable for safety and treatment response as well as pharmacokinetic and pharmacodynamic
analyses. Mean patient age was 31 (range 18–43) years. Six patients were male and
two were female; the majority (75%) was white (Table 1). Five patients had a primary
diagnosis of T-LBL with a mean duration of 2.4 years and three had a primary diagnosis
of T-ALL with a mean duration of 4.8 years. All eight patients had received prior
systemic therapy; most patients (n=7, 87.5%) had been treated with two or three prior
regimens and three (37.5%) had received prior radiation therapy.
Treatment with PF-03084014 was associated with a complete response (CR) in a patient
with T-ALL that lasted for ~3 months, with evidence of full hematologic recovery.
This patient had been heavily pretreated, achieving a CR following induction therapy
with cyclophosphamide, idarubicin, methotrexate, vincristine and dexamethasone, but
not after salvage treatment with nelarabine, vincristine and cyclophosphamide; the
patient also relapsed after a cord blood stem cell transplant performed 8 months before
study entry.
NOTCH1 sequence analysis by conventional Sanger sequencing did not reveal any NOTCH1
mutation in the peripheral blood samples from five patients, including the T-ALL patient
with a CR. Evaluation by the more sensitive deep-sequencing method revealed a known
activating mutation, L1679P, in exon 27 of NOTCH1 in the T-ALL patient with a CR,
which was confirmed in an independent bone marrow sample collected at a different
time point (25% blasts; Table 2). This finding is consistent with the hypothesis that
NOTCH1-activating mutations may have a leukemogenic role in T-ALL and confer sensitivity
to gamma-secretase inhibition. However, deep-sequencing analysis also revealed a known
activating NOTCH1 mutation (V1677D) in bone marrow mononuclear cells from a non-responding
patient with T-LBL. This suggests that mutation status does not consistently predict
response to PF-03084014, in line with prior clinical trials.
3
Further, it may indicate differences in the biology of the disease and in the role
played by NOTCH-mediated signaling pathways in T-LBL versus T-ALL (for example, the
degree of 'NOTCH addiction' in tumor cells) or, alternatively, a resistance to treatment
with gamma-secretase inhibitors in T-LBL cells, mediated by other pathways (for example,
PI3/mTOR kinase signaling).
11, 12
The most common adverse events following treatment with PF-03084014 in patients with
T-ALL/T-LBL were nausea and vomiting. Diarrhea was not a treatment-limiting toxicity
in patients with T-ALL/T-LBL, as previously observed with other investigational gamma-secretase
inhibitors
13, 14
and it was mostly low grade (grades 1 and 2). In contrast with the results obtained
in patients with solid tumors,
15
no rash and hypophosphatemia were reported in patients with T-ALL/T-LBL treated with
PF-03084014, although the duration of treatment was shorter and the number of treated
patients was substantially lower in this population. The causality of the dose limiting
toxicity reported in this study, elevations in liver enzymes, remains unclear as it
was observed in a patient who was receiving concomitant treatment with hepatotoxic
drugs, and had chronic graft-versus-host disease and a suspected hepatic infection
(candidiasis). Furthermore, no hepatic enzyme abnormalities (AST and ALT) and bilirubin
elevations were noted when PF-03084014 administration was restarted at the reduced
dose of 130 mg twice daily and continued for at least 2 months.
Pharmacokinetic analysis of PF-03084014 following single-dose and multiple-dose administration
to patients with T-ALL or T-LBL demonstrated a favorable pharmacokinetic profile.
Steady state was achieved by day 8 of treatment and the mean terminal half-life was
18 h (s.d., 3.6), after repeated daily dosing of PF-03084014.
Treatment with PF-03084014 induced inhibition of HES4 gene expression levels at days
8, 15 and 21 of cycle 1 in the peripheral blood (as surrogate tumor tissue with no
leukemic blast separation) of the majority of patients with T-ALL and T-LBL, thus
providing a biomarker for measuring in vivo modulation of NOTCH pathway-related targets.
Of note, HES4 gene expression levels were inhibited throughout cycle 1 in the responding
patient with T-ALL, with an increase above baseline levels at disease relapse (end-of-treatment
sample).
In conclusion, the anti-T-ALL activity demonstrated by PF-03084014 in this study,
as well as the antitumor activity observed in patients with solid tumors,
15
supports further evaluation of PF-03084014 in patients with T-ALL or T-LBL in an earlier
therapeutic setting to limit the confounding factor represented by the poor prognosis
associated with relapsed or refractory disease.