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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 787-795
Treatment of Refractory and Relapsed Acute Myelogenous Leukemia
With Combination Chemotherapy Plus the Multidrug Resistance
Modulator PSC 833 (Valspodar)
By
Ranjana Advani,
Hussain I. Saba,
Martin S. Tallman,
Jacob M. Rowe,
Peter H. Wiernik,
Joseph Ramek,
Kathleen Dugan,
Bert Lum,
Jenny Villena,
Eric Davis,
Elisabeth Paietta,
Manuel Litchman,
Branimir
I. Sikic, and
Peter L. Greenberg
From Stanford University Medical Center, Stanford, CA; VA Medical
Center, Palo Alto, CA; Moffitt Cancer Center, Tampa, FL; Northwestern
University Medical Center, Chicago, IL; University of Rochester School
of Medicine and Dentistry, Rochester, NY; Albert Einstein Cancer
Center, Bronx, NY; and Novartis Pharmaceuticals, E Hanover, NJ.
 |
ABSTRACT |
A potential mechanism of chemotherapy resistance in acute myeloid
leukemia (AML) is the multidrug resistance (MDR-1) gene product
P-glycoprotein (P-gp), which is often overexpressed in myeloblasts from
refractory or relapsed AML. In a multicenter phase II clinical trial,
37 patients with these poor risk forms of AML were treated with PSC 833 (Valspodar; Novartis Pharmaceutical Corporation, East Hanover, NJ), a
potent inhibitor of the MDR-1 efflux pump, plus mitoxantrone,
etoposide, and cytarabine (PSC-MEC). Pharmacokinetic (PK) interactions
of etoposide and mitoxantrone with PSC were anticipated, measured in
comparison with historical controls without PSC, and showed a 57%
decrease in etoposide clearance (P = .001) and a 1.8-fold
longer beta half-life for mitoxantrone in plasma (P < .05).
The doses of mitoxantrone and etoposide were substantially reduced to
compensate for these interactions and clinical toxicity and in Cohort
II were well tolerated at dose levels of 4 mg/m2
mitoxantrone, 40 mg/m2 etoposide, and 1 g/m2 C
daily for 5 days. Overall, postchemotherapy marrow hypoplasia was
achieved in 33 patients. Twelve patients (32%) achieved complete remission, four achieved partial remission, and 21 failed therapy. The
PK observations correlated with enhanced toxicity. The probability of
an infectious early death was 36% (4 of 11) in patients with high PK
parameters for either drug versus 5% (1 of 20) in those with lower PK
parameters (P = .04). P-gp function was assessed in 19 patients using rhodamine-123 efflux and its inhibition by PSC. The
median percentage of blasts expressing P-gp was increased (49%) for
leukemic cells with PSC-inhibitable rhodamine efflux compared with 17%
in cases lacking PSC-inhibitable efflux (P = .004). PSC-MEC
was relatively well tolerated in these patients with poor-risk AML, and
had encouraging antileukemic effects. The Eastern Cooperative Oncology
Group is currently testing this regimen versus standard MEC
chemotherapy in a phase III trial, E2995, in a similar patient population.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
PATIENTS WITH ACUTE myeloid leukemia
(AML) who have relapsed or are refractory to conventional chemotherapy,
as well as those whose disease develops after antecedent chemotherapy or prior myeloid stem cell disorders have poorer prognoses and responses to chemotherapy compared with those with de novo
AML.1-3 Overexpression of the multidrug resistance
(MDR-1) gene product P-glycoprotein (P-gp)4-6 is
one of the mechanisms associated with poor responses of these forms of
AML. A number of adverse prognostic variables such as age, CD34
expression, cytogenetic pattern, or secondary leukemia (because of
prior cytotoxic therapy or an antecedent myelodysplastic syndrome) have
also been linked to P-gp overexpression.7-10 Cells that
overexpress MDR-1 are cross-resistant to several important
antileukemia drugs including anthracyclines and epipodophyllotoxins
(eg, mitoxantrone and etoposide). Cells with the MDR phenotype are
characterized by lower intracellular drug accumulation11,12
concomitant with reduced sensitivity to these agents.7,8,13
Several agents capable of modulating and decreasing MDR-1 in
vitro, such as quinine, tamoxifen, calcium channel blockers, cyclosporine, and its analogue PSC 833 (PSC; Valspodar; Novartis Pharmaceutical Corporation, East Hanover, NJ) have been used
clinically, including evaluation in preliminary studies for treating
poor-risk AML.6,14-18 The mechanism of MDR modulation of
cyclosporine (cyclosporin A) differs from its immunosuppressive
action.19 PSC is a more potent inhibitor of P-gp than
cyclosporine, without the immunosuppression or renal toxicity of the
parent compound.20 We report herein the results of a
multicenter phase II trial evaluating PSC, in combination with
mitoxantrone, etoposide, and cytarabine (PSC-MEC) for the treatment of
AML patients with poor prognostic features. In this trial, we also
evaluated the pharmacokinetics of mitoxantrone and etoposide in the
presence of PSC, and the level of AML blastic MDR-1 expression,
using functional as well as flow cytometric analyses.
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MATERIALS AND METHODS |
Patients.
This study was an open-label phase II multicenter trial initiated in
June 1995 and closed to accrual in February 1997. The protocol was
approved by the Institutional Review Boards and Human Subjects
Committees of all participating institutions. Eligibility criteria
included patients with a diagnosis of AML by the
French-American-British classification,21 with the
following characteristics: (1) early relapse, ie, 6 months after first
complete remission (CR); (2) refractory to chemotherapy, either to
initial induction or at first relapse; (3) relapse after autologous or
allogeneic bone marrow transplantation (BMT); (4) second or greater
relapse; (5) secondary AML or AML evolving from myelodysplastic
syndromes (MDS) or myeloproliferative disorders (MPD) (not chronic
myeloid leukemia). Patients were also required to have a left
ventricular ejection fraction of  50%, Eastern Cooperative Oncology
Group (ECOG) performance status of 0 to 2, hepatic and renal function
tests  2 × normal, age of 18 to 70 years, and no evidence of
active infection or central nervous system leukemia.
Chemotherapy treatment.
The chemotherapy regimen is based on a modification of a prior MEC
regimen,22 using reduced mitoxantrone and etoposide doses because of anticipated pharmacokinetic (PK) interactions related to
coadministration with PSC.6,18,23 PSC (Valspodar) was administered as a pretreatment loading dose at 2 mg/kg over 4 hours,
with a concomitant continuous infusion at 10 mg/kg/d for 120 hours (5 days). Chemotherapy began immediately after completion of a 4-hour
loading dose of PSC. Two dose levels of chemotherapy were used. In
cohort I, patients received mitoxantrone 5 mg/m2/d
intravenous (IV) bolus, days 1 to 5; etoposide 50 mg/m2/d,
days 1 to 5; and cytarabine 1 g/m2/d, days 1 to 5 administered IV as a short infusion over 1 hour. Because of excess
toxicity in this cohort as described below, in cohort II, the dose of
mitoxantrone was reduced to 4 mg/m2 and etoposide to 40 mg/m2. A bone marrow aspirate and biopsy was performed
between days 8 to 10 (3 to 5 days after completion of chemotherapy) to
assess adequacy of marrow hypoplasia. Hematopoietic growth factor
support with granulocyte-macrophage colony-stimulating factor (GM-CSF, Sargramostim; Immunex, Seattle, WA) or granulocyte colony-stimulating factor (G-CSF, Neupogen; Amgen, Thousand Oaks, CA)
administered daily after marrow hypoplasia was recommended
but not required in the protocol. Twenty-nine patients received growth
factor support (11 with GM-CSF, 13 with G-CSF). Five patients received
both of these drugs as they were crossed over at the individual
investigator's discretion. If residual leukemia was present in the
marrow at this time, the induction course was repeated for 3 to 5 days
depending on residual blastic cellularity (% of blasts relative to the
overall cellularity calculated as the product of % cellularity and
fraction of blasts). Treatment was administered for 5 days at identical doses as in the first course if the blastic cellularity was 10%, and
for 3 days if it was 5% to 10%. A maximum of two induction cycles was
permitted to achieve bone marrow hypoplasia (ie, <5% blastic
cellularity). If disease persisted thereafter, the patient discontinued
the treatment protocol and was considered to have failed to respond.
Patients who achieved CR were scheduled to receive consolidation
treatment with PSC-MEC for one cycle. Toxicity was assessed and graded
using the ECOG Leukemia Common Toxicity Criteria.24
Measurement of response.
Previously established response criteria were used.25 CR
required adequate marrow cellularity with <5% blasts documented at
the preconsolidation evaluation, no peripheral blasts, an absolute neutrophil count 1,500/µL, platelet count
100,000/µL, and no evidence of extramedullary
leukemia. Partial remission (PR) required all criteria as in CR except
that the bone marrow may have contained 5% to 25% blasts, or the bone
marrow had <5% blasts, in the presence of moderate thrombocytopenia
(50 to 100,000/µL). Failure was defined as leukemia-associated or
caused by early death (ie, within 30 days of completion of treatment).
Leukemia-related causes of failure were refractory disease (inability
to achieve hypoplasia despite two cycles of chemotherapy) and regrowth
resistance, a term used to indicate cases in which >25% bone marrow
blasts were noted on recovery despite adequate marrow hypoplasia having
been achieved.26
P-gp expression of leukemic blasts.
Leukemic blast cells from bone marrow or peripheral blood were
evaluated for P-gp expression and function at the study's central laboratory (Dr Elisabeth Paietta, Albert Einstein Cancer Center, NY).
Monoclonal antibody 4E3.16 to a P-gp-specific cell surface peptide
epitope (provided by Dr R. Arceci, Children's Hospital, Cincinnati,
OH) was tested on mononuclear cells. Cells were incubated with 4E3.16
for 30 minutes at 4°C in the presence of 6% heat-inactivated serum
to reduce nonspecific antibody binding, followed by staining with goat
anti-mouse antibody conjugated to fluorescein isothiocyanate. Gating of
the leukemic blasts on the flow cytometer was based on linear forward
angle light scatter and right angle side scatter and validated using an
extensive diagnostic antibody panel.27 The absolute
percentages of "P-gp expressing" gated leukemia cells were
compared between cases and used in the statistical
analysis.28,29
P-gp function of leukemic blasts.
To test for P-gp function, the uptake and efflux of rhodamine-123 was
monitored by flow cytometry in leukemic cells gated according to
scatter properties and antigen profile.28,29 Cells were
prestained with phycoerythrin (PE)-labeled antibody to CD34, or CD33 if
the cells did not express CD34, and then incubated with 2 µg/mL
rhodamine-123 for 30 minutes at 37°C in the dark. In control
experiments, neither the anti-CD34 nor other antibodies used in these
double-labeling studies interfered with P-gp function. Subsequently,
rhodamine release was measured over a period of 60 minutes at 37°C
in the absence and presence of PSC 833 (10 µmol/L) or cyclosporine A
(15 µmol/L). Our preliminary time-course studies of rhodamine release
over a range from 30 to 120 minutes at 37°C had established that
optimal sensitivity of the assay was achieved at the 60-minute time
point. Cell lines used for standardizing P-gp detection and function
were the resistant 8226/Dox6 myeloma cells and their sensitive parent
line, 8226/s (both provided by Dr W. Dalton, Moffitt Cancer Center,
Tampa, FL). To quantitate P-gp function, the relative change of the
maximum mean rhodamine fluorescence channel over the 60-minute time
period was recorded selectively in the double-stained
(rhodamine/PE-antibody) cell population. Measurable rhodamine efflux
was defined as a channel shift of 20%. This parameter was based on
our experience in de novo AML patients that a mean channel shift of
<20% was not reversible by PSC 833 or cyclosporine in vitro and was
invariably associated with low P-gp expression levels.28-30
Pharmacological and PK studies.
For PSC levels, samples of venous blood were obtained before the start
of the PSC infusion and just before the mitoxantrone doses on days 3 and 5. For mitoxantrone and etoposide, baseline venous blood samples
were obtained before mitoxantrone administration on the 5th day of
chemotherapy, then at the end of the etoposide infusion (1.1 hours),
and 2, 6, 8, and 12 hours after the start of mitoxantrone infusion.
Whole blood PSC concentrations were determined by radioimmunoassay
(ANAWA Laboratories, Zürich, Switzerland). Etoposide and mitoxantrone were analyzed by modifications of previously published high performance liquid chromatography
methods.31-33
Noncompartmental PK analyses of etoposide concentration-time data were
performed using the XLPHARM M-IND program (VKPharmacokinetics, Turnhout, Belgium). PK data for the PSC-MEC patients were compared with
a historical database of 20 patients treated with etoposide alone in
other trials at Stanford University.31-32 The sampling times for mitoxantrone in this study were not sufficient for
characterization of the alpha (distribution) and gamma (terminal
elimination) phases but did allow for characterization of the second
(beta) elimination phase, T1/2 . These data were compared
with those previously published for mitoxantrone.34
Statistical considerations.
One-tailed Wilcoxon rank tests35 were used for statistical
analysis of age-related clinical responses and for the comparison of
immunophenotype and PSC inhibitable function. P values of .05 were considered significant. Remission duration was defined as time to
relapse or death from the date of CR. Overall survival was measured
from the initiation of induction treatment until death from any cause.
Overall survival and remission duration were estimated by the method of
Kaplan and Meier.36 PK analyses of etoposide and
correlations with patient clinical data were tested for normal
distribution using the Wilk-Shapiro statistic.37 Differences in PK parameters for etoposide between the PSC-MEC and
historical groups were compared using the Mann-Whitney U test with an a priori level of significance of P = .05 (two-sided). For mitoxantrone, 95% confidence intervals for the T-values were calculated for the PSC-MEC group and compared with that of the previously published trial.34 Nonoverlapping 95%
confidence intervals indicated a statistical significance at P
< .05.38
| |
RESULTS |
Thirty-nine patients were entered into the trial, of whom 37 patients
were evaluable for response. Two patients were ineligible and removed
from the study (1 patient was diagnosed with active tuberculosis after
protocol entry but before starting treatment and another developed
hypotension within an hour of the PSC infusion and did not receive MEC
chemotherapy). Pretreatment patient characteristics are shown in
Table 1. Disease categories of the 37 evaluable patients entered were early relapse (n = 11), second relapse
(n = 5), secondary/post MDS-MPD (n = 10), refractory AML (n = 7), and
relapse after BMT (n = 4). The median patient age was 54 years (range,
27 to 70 years).
Chemotherapy responses.
Cohort I doses of chemotherapy were used to treat the first 6 patients.
All six patients developed marrow hypoplasia. Among these patients
three early deaths occurred (ie, within 30 days) because of severe
mucositis and infection with prolonged marrow hypoplasia in 5 of the 6 patients. Therefore, for cohort II patients (n = 31), the doses of
mitoxantrone and etoposide were reduced 20%, as described in Materials
and Methods. Twenty-three patients received one cycle and 14 received
two cycles of chemotherapy. Thirty-two of 35 patients (2 were not
evaluated for hypoplasia) who had postchemotherapy bone marrow
examinations achieved adequate marrow hypoplasia. Twenty-one of the 37 patients achieved marrow hypoplasia with one cycle of treatment (4 of 6 in cohort I, 17 of 31 in cohort II).
Overall, 12 patients (32%) achieved a CR and four achieved a PR. The
treatment failed in twenty-one patients
(Table 2). The responses and failures were
evenly distributed between disease categories and occurred within both
cohorts (Tables 2 and 3). Three of 13 patients (23%) over 60 years old achieved CRs compared with 9 of 24 patients (38%) 60 years old. In the group of 6 patients in cohort I
there was only one CR whereas in cohort II, 11 of 31 patients (36%)
achieved CRs. The median time to document achievement of CR after
starting chemotherapy was 52 days (range, 20 to 77 days). For patients
treated with one cycle of chemotherapy this was slightly shorter (51 days; range, 20 to 77 days; n = 7) compared with those who required two
cycles of treatment (59 days; range, 51 to 72 days; n = 5).
Nine patients in CR received consolidative therapy, including six with
consolidation chemotherapy (four with PSC-MEC, one with fludarabine
plus cytarabine, and one high-dose cytarabine). Overall, five patients
have undergone BMT, four in CR (two allogeneic, two autologous) and one
in PR from a matched unrelated donor. The median remission duration for
patients achieving CR was 6 months (range, 0.7 to 13 months) with a
median survival of 8.3 months (range, 5 to 18+ months). The overall
median survival was 6.0 months (range, 0 to 18+ months).
Twenty-one patients failed to respond to therapy, as summarized in
Table 4. Twelve patients died during the
hypoplastic period, eight patients had leukemic regrowth resistance,
and one patient had leukemia that was refractory to treatment.
Toxicity.
Grade 3 or 4 mucositis occurred in 3 of 6 (50%) patients in cohort I
and in only 6 of 31 (19%) patients in cohort II. Other significant
toxicities included transient mental status changes and transient
peripheral neuropathy in 1 patient each. No ataxia was reported.
Transient hyperbilirubinemia was an anticipated side effect of PSC
therapy, as previously reported6,39; bilirubin levels of
1.5 mg/dL occurred in 34 of 37 (92%) patients in cycle 1 and in 12 of
14 (89%) patients in cycle 2. The median peak serum bilirubin levels and peak times to reach this level after starting each
course of chemotherapy were similar for those requiring one or two
courses of induction treatment: median 2.6 mg% (range, 1.5 to 27.7 mg%) on median day 5.5 (range, 2 to 23 days). The hyperbilirubinemia
was transient in 27 of the 33 patients in whom follow-up values were
available, and resolved in a median of 10 days (range, 4 to 19 days).
The 6 patients with persistent hyperbilirubinemia had contributing
factors in addition to PSC administration, such as infections, sepsis,
and hepatitis. Clinical responses were not related to the bilirubin
level or time course of bilirubin elevations.
One patient developed a possible allergic reaction to PSC (hypotension
within 1 hour of the PSC infusion despite premedications) and was taken
off study before receiving chemotherapy. Twelve deaths occurred on
study, 3 of 6 in cohort I and 9 of 31 in cohort II (Table 4). Nine of
the 12 deaths were caused by infection (cohort I, 3 of 6 patients;
cohort II, 6 of 31 patients) and were unrelated to the number of
induction cycles. However, the infectious deaths correlated with PK
parameters as discussed below. One death was caused by an arrhythmia
secondary to severe hypokalemia, one myocardial infarction occurred in
the setting of a hemolytic anemia, and one patient died of a subdural
hemorrhage related to thrombocytopenia.
Results of P-gp and CD34 analyses.
P-gp expression/function and CD34 expression were evaluated in all
patients for whom adequate bone marrow sample quality and volume were
obtained. Detailed data are presented in
Table 5 and a collated summary in
Table 6. In 19 patients, rhodamine efflux
was measured as an index of P-gp function, and is listed as the % mean
channel shift in Table 5. Rhodamine efflux was detected in 15 cases.
Ten of these cases had relatively increased P-gp expression (27% to
96% of the leukemic blasts stained with the 4E3.16 antibody) (Tables 5
and 6). In 8 of these 15 patients, the efflux of rhodamine was
inhibitable by PSC with the extent of inhibition of function ranging
from 45% to 100%. In these 8 patients the median proportion of blasts
expressing P-gp was increased, 49% (range, 27% to 96%) compared with
17% (range, 1% to 40%) in the 7 patients with PSC noninhibitable
P-gp function, P = .004 (Table 6).
Figure 1 shows P-gp expression and the
corresponding rhodamine-123 efflux activity in two representative
patients. CD34 expression was also higher in the PSC-inhibitable versus PSC noninhibitable blasts (median 95% v 51%, P = .02), Table 6. In 4 patients no measurable rhodamine efflux function
was noted, associated with low 4E3.16 and CD34 expression on the blasts
(Table 5). No patient had appreciable P-gp expression without rhodamine efflux. Also, none of the patients with CD33-positive/CD34-negative blast cells showed classical PSC 833 inhibitable rhodamine efflux activity.
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Table 5.
P-gp Expression and Function in Leukemic Blasts From 19 Patients in Whom P-gp Expression, Rhodamine Accumulation, and
Inhibition of Rhodamine Efflux by PSC 833 Were Measured
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| Fig 1.
P-gp expression and the corresponding rhodamine-123
efflux activity. The two left flow cytometer contour plots (a) reflect
P-gp expression as measured by staining of blast cells with antibody
4E3.16. Cells in the lower right quadrant are positive for 4E3.16,
whereas cells in the left lower quadrant are negative for 4E3.16
because they lack fluorescence above background. The two right flow
cytometer cytograms (b) show cellular rhodamine-123 fluorescence after
1 hour of cell incubation at 37°C in CD34-positive blast cells. A
shift of rhodamine-123 fluorescence from the right upper to the left
upper quadrant reflects cellular efflux of rhodamine-123. Patient #1
showed P-gp expression in a small subpopulation of blast cells and
lacked measurable rhodamine-123 efflux activity despite CD34
expression. In patient #2, P-gp was detected on >90% of blast cells
and these blast cells showed marked rhodamine-123 efflux activity,
which was inhibitable by PSC 833 (data not shown).
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No correlation was shown between P-gp expression and response to
therapy in these small groups of patients. In the patients with
PSC-inhibitable rhodamine efflux there were 2 CRs, 1 PR, and 5 failures, whereas all 7 patients with noninhibitable efflux failed
therapy. Two responses were observed in the 4 patients with no
rhodamine efflux (1 CR and 1 PR).
In addition to the 19 patients for whom sufficient material was
available for P-gp functional studies (Table 5), 7 patients had flow
cytometric measurements of P-gp and 10 for CD34 expression. Among these
26 patients having P-gp expression studies, 14 (54%) had 20% blasts
positive for P-gp, 4 (15%) had 10% to 19% positive blasts, and 8 (31%) had 10% positive blasts. The median % of CD34-positive cells
in the 29 patients tested was 76% (range, 2% to 98%), and 25 of
these 29 patients had >20% CD34-positive blast cells.
PK data.
Whole blood PSC levels >1,000 ng/mL, which correspond to serum PSC
levels of 1,500 to 2,000 ng/mL, were achieved in all 33 patients. These
levels of PSC are known to substantially inhibit P-gp in
vitro.40 Median whole blood PSC levels were 3,070 ng/mL on
the 5th day of infusion (range, 1,390 to 10,460 ng/mL).
PK variables of etoposide during 30 courses of PSC-MEC in 23 patients
were significantly different from etoposide without PSC in a historical
control group.31,32 These data show a 57% decrease in
clearance of etoposide, from 1.17 to 0.50 L/h/m2
(P = .001). During 30 PSC-MEC courses in 28 patients,
the mean T1/2 for mitoxantrone was 3.6 hours (95%
confidence intervals 3.3 to 4.0 hours), which is 1.8-fold longer than
previously reported for mitoxantrone in the absence of PSC (mean, 2.03 hours; 95% confidence intervals 1.4 to 2.7 hours; P < .05).34,41 PK data for patients in cohort I (n = 3)
showed a 1.4-fold higher mean mitoxantrone area under the curve (AUC)
and a 1.6-fold higher mean etoposide AUC when compared with cohort II
(n = 28). PK parameters correlated with toxicity. Early deaths caused
by infections occurred in 9 patients. Patients with PK studies, 4 of 11 (36%) who had high AUC values (etoposide >80 µg × h/mL and mitoxantrone >160 ng × h/mL) versus
1 of 20 (5%) with lower AUCs, had infectious early deaths, (P = .004). The mean plasma AUC for mitoxantrone in patients with
infectious early death was 253 ng × h/mL compared with 105 ng × h/mL for the remaining patients (P = .031). The mean etoposide
level in this latter group was 96 µg × h/mL compared with 60 µg × h/mL, P = .66. No correlation was observed between PK
values and remission rates.
| |
DISCUSSION |
This study showed encouraging antileukemic effects and acceptable
tolerance of the PSC-MEC regimen in patients with poor prognosis AML.
Recently, Estey et al42 have proposed placing poor-risk AML
patients in four categories that correlated their responses to
conventional treatment with presenting clinical features. These patients were categorized as being in one of four prognostic risk groups, based on their background treatment history. Group 1 had expected CR rates of approximately 70% (patients with a first CR
lasting >2 years being treated with conventional therapy); Group 2 had expected CR rates of approximately 40% (patients with a first CR
duration of 1 to 2 years being treated with conventional treatment);
Group 3 patients had expected CR rates of approximately 10% to 20%
(patients with a first CR lasting <1 year, or with no initial CR, who
were receiving their initial salvage attempt with conventional
treatment); and Group 4 patients had expected CR rates of <1%
(patients with an initial CR <1 year, or with no initial CR, who were
receiving a second or subsequent salvage regimen, having not responded
to a first salvage attempt with conventional drugs). Virtually all of
our patients (26 of 27 patients with de novo AML) are categorized as
being in the very poor prognostic risk Groups 3 and 4 (Table 1). The
remaining 10 patients in our study had poor-risk features related to
their having developed secondary AML after an antecedent hematologic
disease (Table 1).
Despite these poor-risk features, antileukemic effectiveness of PSC-MEC
was shown, with 12 CRs (32%) being achieved among the 37 patients
treated (Table 2). Responses occurred in all subgroups of patients
entered in the study (Table 3). The overall early mortality rate of
30% (12 of 37) is comparable with that occurring in patients receiving
other salvage protocols.43-45 Most of the deaths (9 of 12)
were secondary to infections during the period of hypoplasia (Table 4).
This complication was unrelated to whether the patient received one or
two cycles of PSC-MEC induction therapy but correlated with the
described PK parameters.
The median time to achieve a CR was relatively long (52 days). This
slow hematopoietic recovery (despite use of GM-CSF or G-CSF in 29 patients) was likely multifactorial, ie, related to the specific drug
regimen itself, plus to the patients' prior therapy, relatively
elderly ages and secondary types of AML, all of which may contribute to
prolonged postchemotherapy cytopenias.43-47 These data
indicate the need for some delay during the period of recovery before
determining response, as well as the need for prolonged postinduction
supportive care in patients receiving this treatment regimen.
For these poor-risk patients, an important therapeutic aim of such a
salvage regimen was to enable the option of BMT, which was performed in
5 patients. After achievement of CR, 9 of the 12 patients received
consolidative therapy, including 4 with BMT. The median remission and
survival duration of patients achieving a CR were 6 and 8.3 months,
respectively. The median overall survival for all the 37 patients was
6.0 months. These values are comparable with prior studies with similar
patients.22,48
PSC is 2- to 10-fold more potent than its parent compound cyclosporine
for modulating MDR in vitro and in vivo in animal
models.19,20 In this study, target blood levels of PSC
capable of in vitro P-gp modulation were achieved in all patients and
were maintained for the 5 days of administration of this drug. This
finding, plus the tolerability of the drug, indicated effective dosing
of PSC with this regimen. Anticipating substantial PK interaction
between PSC and the MDR-modulated agents used for treatment of
leukemia, the doses of mitoxantrone and etoposide used for cohort I
were significantly reduced compared with the doses used for these drugs without PSC.6,18,22,23 These doses were also lower than those previously used for MEC in combination with
cyclosporine.48 Despite reduction of the mitoxantrone and
etoposide doses, the initial six patients treated (cohort I)
experienced substantial hematologic and gastrointestinal toxicity.
Therefore, for cohort II, the doses of mitoxantrone and etoposide were
further reduced by 20%. With these lower doses of mitoxantrone and
etoposide, adequate marrow hypoplasia was achieved and the drugs were
relatively well tolerated, even in elderly patients. Transient
reversible hyperbilirubinemia attributable to PSC blockade of bilirubin
excretion16,39 was observed in most patients.
Our PK analyses showed a 57% decrease in clearance of etoposide
compared with historical controls without PSC.31,32 For mitoxantrone, the mean T1/2 was 1.8-fold longer than
previously in the literature for patients treated in the absence of
PSC.34,41 These findings for mitoxantrone are likely an
underestimation of the effect of PSC on mitoxantrone PKs, because our
sampling times did not allow determination of the characteristically
long terminal gamma elimination phase for mitoxantrone.34
Our observations are in concert with the previous observations of the
effect of PSC on etoposide or mitoxantrone PKs.40,49 These
PK interactions of these drugs are also consistent with clinical,
laboratory, and animal model observations,50,51 and
corroborate the need for dose reduction of mitoxantrone and etoposide
when they are combined with PSC. Correlative evaluation further
suggests that early deaths were PK related, particularly in patients
with high mitoxantrone AUCs. These PK data have been separately
reported in detail.32
The expression of P-gp in de novo AML blast cells is generally lower
than that occurring at relapse or in patients whose disease was
refractory to chemotherapy or post-MDS/MPD.11,13,52,53 The
predictive value of P-gp as an independent marker for treatment failure
in AML is controversial, with most7,54,55 but not all17,48 studies showing that P-gp expression is correlated with a poor prognosis. Prior studies have suggested the importance of
measuring the efflux of rhodamine to assess the function of P-gp and
its potential blockade by modulators.28,29,54,56 In the
report herein, the median level of P-gp expression (using the
monoclonal antibody 4E3.16) was higher in blasts from patients with
PSC-inhibitable rhodamine efflux than in those whose blasts lacked this
effect (49% v 17%, P = .004; Table 6). It should be
noted that no consensus has been reached in the First MDR Detection Methods Workshop.57 There is currently no published
agreement as to the extent of rhodamine-123 efflux which is predictive
for clinically relevant P-gp function.
In this study, all 10 patients whose leukemia cells were positive for
P-gp with 27% to 96% staining by 4E3.16 also showed efflux of
rhodamine. In addition, there were 5 patients with low P-gp expression
and high rhodamine efflux, indicating the possibility of another
rhodamine transporter in these leukemias. Rhodamine efflux in these 5 cases was not inhibitable by PSC. It has previously been shown that
drug efflux mechanisms unrelated to P-gp exist in a subgroup of AML
patients.58 Among the 10 leukemias expressing high levels
of P-gp, two showed noninhibitable efflux, suggesting the coexpression
of one of these non-P-gp rhodamine transporters. The expression level
of P-gp in patients with noninhibitable P-gp function was significantly
lower than that found on blast cells from patients with inhibitable
function. Correlation between P-gp expression and response to treatment
in this study could not be made in this relatively small group of
patients. However, none of the 7 patients with noninhibitable rhodamine
efflux achieved a remission.
A recent preliminary report of a randomized study using quinine as an
MDR modulator plus intensive chemotherapy for AML post-MDS and
high-risk MDS patients indicated that quinine increased the CR rate and
disease-free survival in patients considered to be P-gp positive, but
not in those who were P-gp negative.59 Other recent
preliminary investigations using PSC plus chemotherapy for
relapsed and refractory AML have also shown encouraging
results.60,61 In contrast, a recent study not showing a
benefit of PSC plus chemotherapy had a differing experimental design
and marked regimen-related toxicity, which may have contributed to the
relatively poor clinical outcomes of those patients.49
There is increasing evidence that mechanisms in addition to P-gp
contribute to the MDR resistance phenotype in human
malignancies.62-67 These include the MDR-related
protein,68,69 the lung-resistance protein,67
and the transporter of antigenic peptides.70 These mechanisms, like P-gp, may cause increased efflux of drugs (and surrogate markers like rhodamine) and/or intracellular
redistribution of drugs. The bcl-2 family of proto-oncogenes,
which are critical regulators of apoptosis, may also play a role in
drug resistance in leukemias.71 Altered topoisomerase II
expression may contribute to resistance to anthracyclines, etoposide,
and mitoxantrone in leukemias.72 These other mechanisms of
resistance may limit the efficacy of P-gp modulators either by their
coexpression at the outset of therapy or by their emergence after the
elimination of P-gp-positive tumor cells. Development of
multifunctional MDR modulators or combined blockade of more than one
resistance mechanism may be necessary to effectively circumvent MDR in
hematologic malignancies.
Prevention of the emergence of drug resistance has been shown in
preclinical experiments in which drug-sensitive cancer cells are
treated with MDR-related cytotoxins together with P-gp
modulators.73-75 The suppression of MDR1 expression
in these models suggests that MDR modulation could be considered early
in the course of the disease, before the emergence of either P-gp or
other mechanisms of drug resistance.
The study reported herein suggests that MDR-modulating agents such as
PSC plus chemotherapy are potentially useful for treating poor-risk AML
patients. However, the determination of the relative contribution of
PSC to clinical responses in this setting will require phase III
randomized trials comparing this regimen with equitoxic control
regimens without an MDR-modulator. Such a study of PSC-MEC versus MEC
chemotherapy (E2995), based on this phase II trial, has recently been
activated within the ECOG in a similar subgroup of patients.
| |
ACKNOWLEDGMENT |
We are grateful to Dr Robert Arceci (Children's Hospital, Cincinnati,
OH) for providing the 4E3.16 antibody.
| |
FOOTNOTES |
Submitted February 6, 1998; accepted September 28, 1998.
Supported in part by by National Institutes of Health grants R-01 CA
52168 (B.I.S.), U-01 CA 21115 (Eastern Cooperative Oncology Group), and
M-01 RR 00070 (General Clinical Research Center, Stanford University
School of Medicine); and by research funds from Novartis Pharmaceuticals, Bristol-Myers Squibb, and Immunex Corporations.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Presented in part at the American Society of Hematology meeting held in
San Diego, CA, December 1997.
Address reprint requests to Peter L. Greenberg, MD, Room S-161,
Hematology Division, Stanford University Medical Center, Stanford, CA
94305-5112; e-mail: peterg{at}leland.stanford.edu.
| |
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Top
Abstract
Introduction