The Effect of Imatinib Mesylate on Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia with Secondary Chromosomal Aberrations

Vol. 9, 1333–1337, April 2003 Clinical Cancer Research 1333

The Effect of Imatinib Mesylate on Patients with Philadelphia Chromosome-positive Chronic Myeloid Leukemia with Secondary Chromosomal Aberrations

Anwar N. Mohamed,1 Pamela Pemberton, require therapy additional to imatinib mesylate for maximal ؉ Jeffrey Zonder, and Charles A. Schiffer eradication of the Ph leukemic cells. Department of Pathology and the Division of Hematology/Oncology, Karmanos Cancer Institute, Wayne State University School of INTRODUCTION Medicine, Detroit, Michigan 48201 CML2 is a clonal myeloproliferative disorder of pluripotent hematopoietic progenitor cells characterized by massive proliferation and accumulation of myeloid cells that differentiate ABSTRACT normally (1, 2). The cytogenetic hallmark of CML is the Ph Purpose and Experimental Design: The acquisition of chromosome that results from a reciprocal t(9;22)(q34;q11.2) secondary chromosomal aberrations in chronic myeloid leu- translocation or its variants t(V;9;22) (3). The molecular conse- kemia (CML) patients with Philadelphia chromosome-posi- quence of this translocation is the formation of the BCR/ABL tive (Ph؉) karyotype signifies clonal evolution associated gene fusion usually located on the Ph chromosome (4, 5). The with disease progression to accelerated/blastic phase. There- BCR/ABL encodes a chimeric protein of Mr 210,000, the pre- fore, these aberrations are of clinical and biological impor- dominant fusion protein in CML (6). Whereas the native c-abl tance. We identified 58 cases with secondary abnormalities protein is mainly nuclear and has tightly regulated kinase activ- in addition to t(9;22)(q34;q11.2) or its variants in a review of ity, the chimeric bcr/abl oncoprotein is localized in the cyto- 137 CML patients treated with imatinib mesylate (STI571). plasm and has a constitutively activated tyrosine kinase. Similar Clinically 13 patients were in chronic phase, 24 in acceler- to other kinases, the bcr/abl functions by binding to ATP and ated phase, and 21 in blastic phase. transfers phosphaste from ATP to tyrosine residues, activating Results: More than 50% of cases showed the major multiple signal transduction pathways. The latter causes exces- -routes of CML clonal evolution [؉8, i(17q), ؉Ph, and/or sive cellular proliferation, arrests apoptosis, and decreases cel ؉19]. The remainder exhibited minor routes of secondary lular adhesion. It has been shown that the enhanced tyrosine -abnormalities with ؊17/17p؊, 11p؊/rearr(11p), and ؊7/ kinase activity of bcr/abl protein is essential for CML patho rearr(7) as the most frequent abnormalities. Of particular genesis and is likely to represent the initiating event (7). interest, one case developed an inv(16)(p13q22) as a second- Clinically, CML progresses through three distinct phases: a ary anomaly during blastic transformation. The bone mar- chronic phase that is easily controlled followed by an ill-defined row was consistent with myelomonocytic morphology with unstable accelerated phase, leading to a terminal blastic phase. eosinophilia. Cytogenetic responses to imatinib mesylate oc- The latter phase resembles acute leukemia and is highly refractory to chemotherapy with Յ20% response rate and a median curred in 15 of 58 (26%) patients; 12 achieved complete survival of 3–6 months (8). The majority of CML patients show cytogenetic remission, 2 had a major response, and 1 had a the Ph chromosome as the sole change throughout the chronic minor response, with most responses noted within 3–6 phase. As CML transforms to advanced phases, the Phϩ cells months. Seven patients remain in remission >17–30 months, acquire new karyotypic abnormalities, most often a second copy 2 patients relapsed between 12 and 19 months on therapy, of the Ph chromosome, i(17q), and trisomy 8 and 19. The and 1 patient was treated by bone marrow transplantation. increased genetic instability of the Phϩ leukemic clone facili- Conclusions: Although some Ph؉ CML patients with tates the emergence of subclones with highly malignant pheno- clonal evolution can have a complete cytogenetic response to types (9, 10). imatinib mesylate, responses tend to be brief, and such Most CML patients express the bcr/abl protein making it an patients may benefit from subsequent stem cell transplan- ideal target for therapy. Recently, STI571 was designed specif- tation. Therefore, CML patients with clonal evolution may ically to inhibit the tyrosine kinase activity of the bcr/abl protein (11). This agent functions by blocking the binding of ATP to the kinase domain of the bcr/abl protein (12, 13). Preclinical studies have shown that in vitro STI571 inhibited proliferation of cell Received 6/3/02; revised 10/24/02; accepted 10/25/02. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 2 The abbreviations used are: CML, chronic myeloid leukemia; Ph, 1 To whom requests for reprints should be addressed, at Cytogenetics Philadelphia; imatinib mesylate, signal transduction inhibitor 571 Laboratory, Hutzel Professional Building, 4727 St. Antoine Boulevard, (STI571); KCI, Karmanos Cancer Institute; CCR, complete cytogenetic Suite #411, Detroit, MI 48201. Phone: (313) 745-9676; Fax: (313) 993- response; MCR, major cytogenetic response; FISH, fluorescence in situ 0677; E-mail: [email protected]. hybridization; CR, cytogenetic response.

lines expressing bcr/abl and in vivo was also successful in Table 1 Characteristics of the 58 Patients eradicating bcr/abl-containing tumors in nude mice (12–14). Characteristic Values Furthermore, initial clinical trials with STI571 demonstrated Phase promising results in all phases of CML (15–17). In this study, CPa 13b we evaluated the effects of STI571 (Novartis, Pharma AG) AP 24b therapy on CML patients with additional cytogenetic changes BP 21b superimposed on the Ph chromosome as part of Phase II inter- Sex Male 30b national clinical trials conducted at the KCI. Female 28b Age Median 50c MATERIALS AND METHODS Range 22–78c Patients. Patients were enrolled into three Phase II clin- WBC, baseline Median 133,200d ical trials of STI571 for the treatment of CML in chronic phase Range 1,300–265,000d after IFN-␣ failure, accelerated phase, and blastic phase. Some Platelet counts baseline of these patients were treated on protocols of which the clinical Median 533,000d d results have been described recently, whereas others were Range 10,000–1,056,000 treated on subsequent “expanded access” studies at the KCI. a CP, chronic phase; AP, accelerated phase; BP, blastic phase. b No. of cases. Briefly, male or female patients were eligible for the studies if c they were Ն18 years of age and had a diagnosis of CML. The Years. d Cells/mm3. patients were required to be positive for Ph chromosome t(9; 22)(q34;q11.2) or its variant t(V;9;22). CML patients who were Ph negative but BCR/ABL gene fusion-positive were also eligible. The chronic phase of CML was defined by the presence and every 3 months thereafter to monitor the size and progres- ϩ of Ͻ15% blasts, Ͻ20% basophils, and Ͻ30% blasts plus pro- sion of the Ph clone. CRs were determined by the percentage myelocytes in the peripheral blood and marrow, and a platelet of metaphase cells that were negative for the Ph chromosome. count of at least 100,000/mm3. In addition to the above criteria, On the basis of analysis of 20 metaphase cells, CRs were ϭ ϭϾ CML patients were eligible for the chronic phase trial if they classified as: CCR all cells normal, MCR 65% of cells ϭ were resistant or refractory to a regimen containing IFN therapy. normal, and minor CR 1–65% of cells normal. A failure of treatment with IFN was defined as lack of complete FISH was performed using LSI BCR (spectrum green)/ hematological response despite Ͼ6 months of IFN-␣ therapy ABL (spectrum orange) extra signal DNA probe (Vysis, Inc., (hematologic resistance), lack of CR (Ͼ65% Phϩ) after 1 year Downers Grove, IL). The probe is useful for the detection of of therapy (cytogenetic resistance), or hematological or cytoge- t(9;22)(q34;q11.2) or its variant in metaphase and interphase ϩ netic relapse. Patients with severe intolerance to IFN-␣ were cells. In a Ph cell, the hybridization produces one fused yellow also eligible. Accelerated phase CML was defined by at least signal, two orange signals (native ABL and residual ABL), and 15% to Ͻ30% blasts, Ն30% blasts plus promyelocytes in pe- one green signal (native BCR). The normal control produces ripheral blood or marrow, at least 20% peripheral basophils, or two green and two orange signals. All of the details concerning thrombocytopenia defined as platelet counts of Ͻ100,000/mm3, pretreatment of slides and hybridization were carried out ac- unrelated to therapy. CML in blastic phase was defined by at cording to instructions accompanying the probes. The chromo- Ј least 30% blasts in peripheral blood or marrow, or the presence somes were counterstained with 4 ,6-diamidino-2-phenylindole of extramedullary disease other than liver or spleen enlarge- and viewed with Zeiss Axioskop fluorescence microscope using ment. Patients with karyotypic evolution without other criteria triple excitation/emission bandpass filters. At least 200 nuclei of advanced disease were treated on chronic phase trials. All of and 10 metaphase cells were analyzed from each specimen. The Ͼ the patients gave written informed consent to participate in the cutoff value of this probe was 1%. studies, and the studies were reviewed and approved by our Institutional Clinical Research Review Board. CML patients in RESULTS chronic phase received 400 mg of STI571 p.o. once a day, We have identified 58 cases Phϩ CML with secondary whereas patients in accelerated phase and blastic phase were abnormalities in a review of 137 CML patients treated with given 600 mg p.o. once a day. Patients were treated as long as STI571 at KCI as part of multicenter Phase II clinical trials. The they continued to respond. characteristics of the patients are summarized in Table 1. Cytogenetic Analysis. Cytogenetic studies were per- Chromosome Analyses. Chromosome analysis of the 58 formed on metaphase cells derived from short-term unstimu- patients revealed the presence of the classic Ph chromosome, lated bone marrow aspirate or peripheral blood cultures. Briefly, t(9;22)(q34;q11.2), in 50 patients (86%). In 5 patients, the Ph colcemid was added to culture (0.05 ␮g/ml) for 1 h. After chromosome originated through a complex variant translocation incubation in hypotonic solution for 30 min (0.075 M KCL), involving chromosomes 9 and 22, and a third chromosome. cells were fixed with a mixture of 3 parts methanol to 1 part Three patients were lacking the Ph chromosome, but FISH glacial acetic acid. Metaphase cells were Q- or G-banded, and testing revealed BCR/ABL gene fusion located on the normal- karyotypes were interpreted according to the 1995 International looking 22q. In addition to the Ph chromosome, all 58 of the System for Human Cytogenetic Nomenclature (18). Chromo- cases demonstrated additional secondary numerical and/or some analysis was performed before imatinib mesylate therapy structural abnormalities at the time of entry on these trials.

Table 2 Cytogenetics and BCR/ABL FISH analyses on 15 CML patients with cytogenetic responses Case no. Phase Prior to ST1571 3m Ph:Na 6m Ph:N 9m Ph:N 12m Ph:N 15m Ph:N CR Survival 1 CP t(9;15;22),ϩ8 4:16 3:17 0:20 0:20 0:20 CCR A 30mϩ BCR:ABLϪ 2 CP t(9;22),t(9;11) 0:20 0:20 0:20 BCR:ABLϪ BCR:ABLϪ CCR A 24mϩ BCR:ABLϪ 3 CP t(9;22),ϩ21 0:20 BCR:ABLϪ BCR:ABLϪ BCR:ABLϪ CCR A 30mϩ 4 CP t(9;22),14qϩ 4:16 4:16 BCR:ABLϪ BCR:ABLϩ 20:0 CCR A progressed 12m 5 CP t(9;22),inv(11) 20:0 2:18 6:14 12:8 0:20 CCR A 30mϩ BCR:ABLϪ 6 CP t(9;22),ϩ8,ϩ19 8:12 3:17 20:0 MCR D 13m 7 AP t(9;22),ϩ8,ϩPh 0:20 0:20 BCR:ABLϪ CCR A19mϩ BCR:ABLϪ 8 AP t(9;22),i(17q) 5:15 0:20 0:20 0:20 2:18 CCR A progressed 19m BCR:ABLϪ BCR:ABLϪ 9 AP t(9;22),i(Ph) 20:0 0:20 0:20 0:20 Hypocellular CCR D 18m BCR:ABLϪ 10 AP t(9;22),ϩPh 9:11 BCR:ABLϪ CCR A17mϩ 11 AP BCR:ABLϩ,i(17q) BCR:ABLϪ BCR:ABLϪ BCR:ABLϪ CCR D 18m 12 AP t(9;22),ϩ8,8pϪ 0:20 0:20 BCR:ABLϪ BCR:ABLϪ CCR A 30mϩ 13 BP t(9;22),ϩ8,6qϪ 12:8 mCR D 7m 14 BP t(9;22),13qϪ 6:14 0:20 7:13 CCR D 14m 15 BP t(9;20;22),ϩ8 6:14 MCR A 8m Post BMT a Ph:N, ratio phϩ:normal based on analysis of 20 metaphases. BCR:ABLϩ, BCR:ABL fusion positive; BCR:ABLϪ, BCR:ABL fusion negative; AP, accelerated phase; BP, blastic phase; CP, chronic phase; CR, cytogenetic response; CCR, complete CR; MCR, major CR; mCR, minor CR; D, dead; A, alive; m, month.

These secondary abnormalities appeared exclusively in the Phϩ hand, 30 of 43 (70%) non-CR cases had 2 or more additional clone in all of the patients, a sign of clonal evolution. Most of abnormalities. the cases showed the major pathways of CML karyotypic evo- Of those 15 CR patients, 12 patients achieved a CCR. lution including an extra copy of the Ph chromosome in 25 Three of the 12 patients with CCR had advanced disease, and 1 cases, trisomy 8 in 21 cases, trisomy 19 in 7 cases, trisomy 21 was in accelerated phase after relapse from allogeneic bone in 7 cases, and isochromosome 17q in 5 cases. Other less marrow transplantation (Table 2, case 11). CCRs were achieved frequent abnormalities observed in our cases were loss of 17p in as early as 3 months and as late as 15 months after the initiation 4 cases, rearrangement of 17q in 4 cases, ϩ17 in 2 cases, loss/or of therapy. Eleven of the 12 patients who had a CCR tested rearrangement of chromosome 7 in 5 cases, rearrangement of negative for BCR/ABL gene fusion by FISH (Table 2). Three chromosome 11 (mostly 11p) in 6 cases, and 5qϪ in 2 cases. Of patients showed partial CRs, 2 major responses, and 1 minor particular interest, 1 patient had a pericentric inversion of chro- response. Seven of 15 CR patients continue on STI571, in mosome 16, inv(16)(p13q22), as a secondary abnormality dur- remission, with follow-up ranging from 17 to 30 months. Four ing blastic transformation of the disease. The bone marrow was of these 7 patients remain PhϪ or BCR/ABLϪ by FISH after 30 morphologically and phenotypically consistent with my- months of follow-up. Two patients relapsed between 12 and 19 elomonocytic (M4) differentiation and eosinophilia. The karyo- months on therapy but are still alive. Five patients died from type of another case displayed a t(15;17)(q22;q25) translocation disease progression between 7 and 18 months after initiation of as an extra abnormality. Additional evaluation with FISH using STI571 therapy. One patient (#15) underwent mini-allogeneic the dual color PML/RARA DNA probes (Vysis Inc.) revealed transplantation 8 months after STI571 therapy. The bone mar- that the PML gene was translocated to chromosome 17, but not row of the latter patient was negative for Ph chromosome as fused with the RARA gene, indicating that the t(15;17) in this well as BCR/ABL fusion 9 months after transplant. case differed from the usual form associated with acute promy- elocytic leukemia. Of the 58 cases, 34 had more than one secondary aberration, and various combinations were seen at DISCUSSION variable frequencies. The role of Ph chromosome in the development and patho- CRs. CRs were observed in 15 of 58 (26%) CML pa- genesis of CML is well documented. Early in the chronic phase tients with secondary chromosomal abnormalities who were of CML, the Ph chromosome is likely the sole genetic event in treated with STI571. These 15 patients included 6 of 13 CP, 6 of the majority of patients (9, 10). Because BCR/ABL alone is 24 AP, and 3 of 21 BP patients. Their cytogenetic data are sufficient to initiate CML, one might assume that STI571 is an summarized in Table 2. A single additional abnormality was ideal therapy to block this genetic defect. Results from clinical observed in 11 of 15 (74%) CR cases and 2 additional abnor- trials have revealed that STI571 therapy is able to induce he- malities in the other 4 cases. As seen in Table 2, none of the 15 matological remission in the vast majority of newly diagnosed CR cases had chromosome 7 or 5 abnormality. On the other CML patients and those in CP for whom previous IFN therapy

was either not successful or limited by toxicity (16, 19). The rate proliferate as a consequence of the secondary genetic abnormal- of MCR in patients with chronic-phase CML in whom treatment ities arising within the Phϩ clone. These secondary genetic with IFN-␣ had failed was ϳ60%. Among those patients, the changes may provide alternative pathway signals to enhance IFN-intolerant subgroup responded most favorably to STI571, proliferation despite effective targeting of BCR/ABL by possibly because some of these patients had previously had CRs STI571. An alternative possibility is that the Phϩ leukemic cells from the IFN therapy (19, 20). The CCR rate is even higher, are a heterogeneous population, and STI571 promotes selection ϳ70%, in newly diagnosed CML patients (21). However, in of an STI571-resistant clone that eventually becomes predomi- later-stage CML, the Phϩ clone of most cases acquires addi- nant. Both BCR/ABL and the other secondary genetic changes tional molecular and/or cytogenetic aberrations, driving the dis- might drive the proliferation of this resistant clone. ease to more aggressive phenotypes (9, 10). Thus, MCR was The issue of resistance to STI571 has become a subject of observed in only 24% of patients in accelerated phase and 16% intense interest and study (25–27). In a recent study by Gorre et in blastic phase (17, 22, 23). Moreover, the remissions, partic- al. (27), it was found that resistance to STI571 therapy was ularly in blastic phase, were not durable, because most patients associated with reactivation of BCR/ABL signal transduction in relapsed within a few months. all of the cases examined, caused either by gene amplification of Is imatinib mesylate effective as a single agent in CML BCR/ABL or point mutations in the BCR/ABL kinase domain. with additional cytogenetics changes? Our results suggest that Later the same investigators found that mutations of BCR/ABL there is a small subset of patients whose Phϩ leukemic cells gene were common in both acquired and de novo-resistant CML remain sensitive to imatinib therapy despite the presence of (28). Other mechanisms of STI571 drug resistance have been additional abnormalities. Fifteen of the 58 (26%) patients in this suggested to include plasma sequestration of drug via ␣ 1 acid study demonstrated CRs, of whom 7 maintained a complete glycoprotein, multidrug resistance pathways, involvement of remission with a follow-up ranging from 17 to 30 months. Other other protein kinases, and reentry of the bcr/abl protein in the studies have reported similar CRs in accelerated and blastic cellular cytoplasm (29–31). On the basis of these findings, the phases defined by hematological criteria, a patient population mechanisms of STI571 resistance appear to be complex and with a high frequency of secondary cytogenetic abnormalities possibly multifactorial. However, the observation that continued (17, 22, 23). Of considerable interest is the subgroup of patients BCR/ABL signaling was present in most imatinib-resistant pa- in chronic phase clinically and hematologically but with clonal tients (27) suggests that alternative strategies directed at de- evolution. These patients are often faced with the decision about creasing BCR/ABL should be pursued in such patients. The heat the advisability of immediate allogeneic transplantation versus shock protein 90 inhibitor, 17-allylamino-demethoxygeldana- awaiting the results of a trial with imatinib. Only 6 of 13 such mycine, has been shown to increase BCR/ABL catabolism in patients had CRs in our series, and 2 of these responders have vitro, perhaps synergizing with imatinib in this regard, and since had progressive disease. O’Dwyer et al. (24) reported studies evaluating this agent in combination with imatinib are recently on 15 patients in chronic-phase CML with clonal evo- planned (32). lution noting CCRs in 9 of 15 patients (60%), which have been In conclusion, the impact of additional genetic abnormal- sustained for the relatively short follow-up of 1 year. Although ities on clinical response to STI571 therapy in CML has impor- it is possible that some secondary changes might remain more tant clinical and biological implications. Our study suggests that responsive to imatinib than others, this is difficult to discern in CML patients with secondary chromosomal abnormalities, from these relatively small patient numbers. CRs were noted in STI571 therapy was capable to eradicate the Phϩ clone in a patients with an additional copy of the Ph chromosome as well small subset of patients. Those patients may benefit from sub- as in some individuals with complex additional abnormalities. sequent stem cell transplantation (33). However, in many pa- However, based on both of these series, it is clear that a tients, STI571 failed to induce cytogenetic remission suggesting sustained response in chronic-phase patients with clonal evolu- that the Phϩ clone genetically evolved and escaped the depend- tion is far from certain and that such individuals who are ency on bcr/abl kinase for proliferation. The limited activity of transplant candidates should be monitored closely for response STI571 on CML patients with advanced genetic changes raises should they elect an initial trial of imatinib. 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