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BRIEF REPORT
From the Arizona Cancer Center, Tucson.
Chronic myeloid leukemia blast phase (CML-BP) cells commonly
express the multidrug transporter, P-glycoprotein (Pgp). To determine whether Pgp inhibition improves treatment outcome in CML-BP, the Southwest Oncology Group performed a randomized, controlled trial testing the benefit of the Pgp modulator, cyclosporin A (CsA). Seventy-three eligible patients were assigned to treatment with cytarabine and infusional daunorubicin with or without intravenous CsA.
Treatment with CsA yielded no improvement in treatment outcome as
measured by the frequency of induction resistance (68% vs 53%), rate
of complete remission or restored chronic phase (CR/CP, 8% vs 30%),
and survival (3 vs 5 months). Blast expression of Pgp (63%) and LRP
(71%) was common, whereas only Pgp adversely impacted the rate of
CR/CP (P = .025). We conclude that Pgp has prognostic relevance in CML-BP but that the modulation of Pgp function with CsA as
applied in this trial is ineffective.
(Blood. 2002;100:1910-1912) Blast transformation of chronic myeloid leukemia
(CML-BP), the terminal phase of the disease, remains an important
therapeutic challenge. Attempts to induce remission or to restore
chronic phase with chemotherapy regimens active in acute myeloid
leukemia (AML) are generally ineffective, yielding median overall
survival (OS) of 2 to 4 months.1,2 Resistance to cytotoxic
therapy in CML-BP extends to high-dose chemoradiotherapy conditioning with allogeneic stem cell rescue, offering a potential for extended survival rate that rarely exceeds 10%.1 The bcr/abl
fusion gene product is singularly responsible for the hematologic
manifestations of chronic phase CML3 and contributes to
cellular resistance to cytotoxic therapy by the up-regulation of
antiapoptotic molecules and other survival signals.4-8 In
CML-BP, however, chemotherapy resistance is multifactorial and cannot
be ascribed solely to bcr/abl. Although the bcr/abl-specific tyrosine
kinase inhibitor, imatinib mesylate (Gleevec; Novartis, Basel,
Switzerland), has shown promising activity in patients with CML-BP,
responses in CML-BP are short-lived because of the acquisition of
alternative mechanisms of resistance that contribute to treatment
failure.9,10
P-glycoprotein (Pgp) is a highly conserved plasma membrane glycoprotein
that functions as an ATP-dependent multidrug exporter with broad
specificity for natural product-derived
antineoplastics.11-13 In adult AML, the overexpression of
Pgp is associated with reduced cellular accumulation and in vitro
resistance to anthracyclines that can be overcome by concurrent
exposure to competitive Pgp antagonists such as cyclosporin A
(CsA).14-16 Indeed in AML, Pgp overexpression is
associated with a lower rate of complete remission and with inferior
rates of disease-free and overall survival in patients receiving
conventional anthracycline-containing induction and consolidation
regimens.17-20 Southwest Oncology Group trial SWOG-9126
showed that adding CsA to a chemotherapy regimen containing infusional
daunorubicin (DNR) significantly reduces induction resistance in
patients with high-risk AML and prolongs the duration of
remission and survival, implicating Pgp as an important cellular mechanism of resistance in myeloid leukemia.21 Pgp
expression is demonstrable in myeloblasts in as many as 70% of
patients with CML-BP.22-24 To determine whether the
inhibition of Pgp export function improves survival in CML-BP, the SWOG
conducted a randomized trial in adults (18-70 years old) with CML in
previously untreated BP (SWOG-9032) comparing treatment with the same
induction and consolidation regimen containing infusional DNR and
high-dose cytarabine (HDAC) used in SWOG-9126, with or without the
addition of CsA. Patients were required to have serum bilirubin levels lower than 1.5 times the institutional upper limit of normal, adequate
cardiac function, and performance status of 0 to 2 by SWOG criteria.
Among 82 patients with previously untreated CML-BP registered
between September 1992 and January 1998, 5 were ineligible because of
prior treatment intended to restore chronic phase or to control leukocytosis 7 days or less before registration (3 patients), performance status 3 (1 patient), or unwillingness to accept
randomization (1 patient). All 73 eligible patients with centrally
reviewed pretreatment cytogenetics had the Philadelphia chromosome
(Ph). Randomization between the HDAC/DNR (40 patients) and HDAC/DNR+CsA (37 patients) arms was stratified by age (younger than 55 vs 55 or
older) and blast lineage (myeloid vs lymphoid vs undifferentiated). Blast expression of Pgp, multidrug resistance protein-1 (MRP1), the
major vault protein lung resistance protein (LRP), and Pgp dye efflux
capacity were assessed by flow cytometry as previously described.20,21
Characteristics of the eligible patients were generally similar in
the CsA and control arms, except that CsA patients had higher
leukocyte and peripheral blast counts (Tables
1-4).
Expression of Pgp and LRP were slightly more common in the CsA arm, but
CsA-inhibitable DiOC2 efflux and expression of MRP1 were
not. Among 75 eligible patients evaluable for induction toxicity, 8 (21%; 95% confidence interval [CI], 10%, 37%) of 38 controls died
of induction toxicity compared with 7 (19%; 95% CI, 8%, 35%) of 37 CsA patients (one-tailed test, P = .48). Grade 4 hyperbilirubinemia was more frequent with CsA (P < .0001;
14 [38%] HDAC/DNR+CsA vs 1 [3%] HDAC/DNR).
Twelve controls (30%; 95% CI, 17%, 47%) achieved complete response
(CR; 7 patients) or restored chronic phase (CP; 5 patients) compared
with 3 CsA patients (8%; 95% CI, 2%, 22%; 2 CRs, 1 CP). Twenty-one
controls (53%; 95% CI, 36%, 68%) had resistant disease compared
with 25 (68%; 95% CI, 50%, 82%) CsA patients. All responses (CR or
restored CP) were achieved with one course of induction therapy. Twelve
of 15 responding patients (2 CsA, 10 controls) had cytogenetic
follow-up, and 3 of these (2 with CR and 1 with restored CP, all
controls) achieved cytogenetic CR.
Estimated median OS time was 5 months (95% CI, 4-7 months) in
the control arm versus 3 months (95% CI, 2-5 months) in the CsA arm
(one-tailed test, P = .77). Because the CsA-treated cohort had higher leukocyte and peripheral blast counts and higher Pgp expression, additional analyses were performed to assess whether such
differences confounded the treatment comparison. In unstratified proportional hazards (PH) regression models, survival decreased with
increasing WBC (2-tailed test, P = .074) or absolute blast count (P = .19), but it varied little in relation to level
of Pgp expression (P = .47) or efflux
(P = .14). However, in multivariate analysis, the absence
of benefit of CsA was not explained by confounding effects of these
factors (results not shown).
To determine whether pretreatment multidrug resistance phenotype has
prognostic relevance in CML-BP, we examined the relation between blast
expression of Pgp and other drug resistance proteins to treatment
outcome in univariate analysis. With both treatment arms combined,
response to treatment (CR, CR/CP, or RD) was significantly associated
with Pgp expression and function (Table
5), whereas neither MRP1 nor LRP
expression adversely influenced induction outcome. As in the analysis
of OS, the lack of benefit of CsA could not be explained by confounding
effects of drug resistance protein expression or efflux.
This controlled trial was designed so that the survival comparison between treatment arms would have 91% statistical power if the true CsA:control mortality hazards ratio was 0.5 (one-sided test at critical level, 5%), and this level of power was achieved. Therefore, the results of this study provided compelling evidence that the addition of CsA to an HDAC/DNR-containing induction and consolidation regimen offers no survival benefit of practical importance over chemotherapy alone in patients with CML-BP. We cannot exclude the possibility that failure to achieve blood concentrations of CsA sufficient for Pgp blockade impacted the results of this trial. However, the analogous regimen studied in patients with high-risk AML (SWOG-9126) consistently yielded CsA blood concentrations exceeding 1500 ng/mL and significantly improved survival in Pgp-positive patients.21 Our data indicate that Pgp expression and function represent adverse prognostic variables impacting induction outcome in CML-BP, analogous to the data reported for AML. The negative results of this study do not exclude the potential benefit of more potent, so-called second-generation Pgp antagonists in CML-BP, but they raise the notion that Pgp expression reflects an alternative antigenic marker of a primitive blast phenotype that, in this disease, represents only one of many redundant cell defense mechanisms or survival signals. Indeed, recently characterized large genomic deletions on the derivative chromosome 9 adjacent to the t(9;22) breakpoint identify a subgroup of CML patients with particularly poor prognosis and inferior survival, independent of clinical prognostic variables.25 Strategies to inhibit Pgp function may merit further study in CML-BP when combined with the bcr-abl tyrosine kinase inhibitor, imatinib mesylate, and conventional cytotoxics.26 Imatinib mesylate interrupts the constitutive kinase-induced antiapoptotic signals to yield additive cytotoxicity or synergy with many antineoplastics.27 Indeed, Pgp has been implicated as an important cellular mechanism contributing to in vitro resistance to imatinib mesylate. The farnesyl transferase inhibitor SCH66336, a downstream inhibitor of ras-mediated signaling by BCR-ABL, directly inhibits Pgp transport function with a potency comparable to that of CsA.28-30 Inhibition of Pgp might accentuate cytotoxicity by augmenting imatinib mesylate and antineoplastic cellular accumulation and, as a consequence, potentially limit the molecular adaptation to BCR-ABL recognized with extended imatinib mesylate treatment.31
Submitted October 4, 2001; accepted January 2, 2002.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Alan F. List, Southwest Oncology Group (SWOG-9126), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217.
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© 2002 by The American Society of Hematology.
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Abstract
Introduction