Imatinib has marked antileukemic activity in advanced Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), but secondary resistance develops rapidly, reflecting the limitations of single-agent therapy. Experimental data suggest that interferon-α (IFN-α) enhances the antileukemic activity of imatinib. We therefore examined combined imatinib and low-dose IFN-α in six patients with Ph+ALL who were ineligible for stem cell transplantation. All patients had received imatinib for 0.5–4.8 months prior to IFN-α, for relapsed (n=3) or refractory (n=1) Ph+ALL or as an alternative to chemotherapy following severe treatment-related toxicity (n=2). Five patients were in hematologic remission (CR) with minimal residual disease (MRD+), one patient was refractory to imatinib. Four of the five MRD+ patients are alive in CR after a median treatment duration of 20 (11–21) months. Two of these patients are in continuous CR 21 months after imatinib was initiated, while the other two patients experienced an isolated meningeal relapse that was successfully treated with additional intrathecal chemotherapy. Sustained molecular remissions were achieved in three patients and are ongoing 13 and 10.5 months after central nervous system (CNS) relapse and 6 months after starting concurrent IFN-α and imatinib, respectively. Marrow relapse occurred in one of the five MRD+ patients. Combination treatment was associated with a complete marrow response of 5 months duration in the imatinib-refractory patient. Imatinib combined with low-dose IFN-α may achieve prolonged hematologic and molecular remissions in a subset of patients with advanced Ph+ALL, who are not candidates for allogeneic SCT. CNS prophylaxis is necessary and may enhance the antileukemic activity of imatinib and IFN-α.
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is the largest cytogenetically defined subgroup among adult ALL and carries the worst prognosis.1,2,3,4 Its incidence is 20–30% overall but increases with age, approximately to 50% in patients with B-precursor ALL who are above 50 years of age.5 Although current induction regimens induce complete remission in 60–80% of younger patients,2,6,7,8 the high incidence of relapse results in a 3-year disease-free survival (DFS) of approximately 13%.5 In patients failing first-line therapy, salvage chemotherapy has limited efficacy and rarely induces prolonged responses, despite considerable toxicity.9,10,11 Allogeneic stem cell transplantation (allo-SCT) performed in CR1 is potentially curative, but treatment-related mortality and rate of disease recurrence are substantial.12,13 In patients undergoing SCT in second or subsequent CR or primary induction failure (PIF), 2-year overall survival (OS) of 17% (CR2/3) and 5% (PIF) have been reported, due to substantial transplant-related mortality and relapse.14,15 Overall, only a subset of patients actually undergoes allo-SCT because of older age, comorbidity, lack of a compatible donor or disease progression before SCT can be performed.
Imatinib mesylate (Glivec™, formerly STI571), a tyrosine kinase inhibitor selective for the ABL, KIT and PDGF-R kinases,16,17 has shown considerable antileukemic activity in chronic myeloid leukemia (CML) as well as in relapsed or refractory Ph+ALL.18,19,20 Imatinib suppresses the p210 and p190 BCR-ABL protein kinases and thereby functionally inactivates BCR-ABL, which has been causally implicated in the development of Ph+ leukemias.21,22
Clinical trials of imatinib in relapsed or refractory Ph+ALL demonstrated a high antileukemic potential with initial response rates of 60–70% and remarkably low toxicity.19,20 Primary resistance to imatinib is observed in 25–30% of patients.23 Secondary resistance to imatinib occurs a median of 2.2 months after starting treatment,20 largely as a result of point mutations in the ATP-binding domain of the BCR-ABL oncogene.24,25 These results demonstrate that imatinib as a single agent is not sufficient treatment of advanced Ph+ALL. Moreover, imatinib affords inadequate protection against central nervous system (CNS) leukemia, apparently due to poor penetration of the blood–brain barrier.26,27
Combination strategies will have to consider the patient's ability to tolerate further cytotoxic chemotherapy and should compromise the favorable toxicity profile of imatinib as little as possible. Additive or even synergistic effects of imatinib and cytotoxic agents or IFN-α have been demonstrated in vitro, suggesting that these combinations may be active in Ph+ leukemia at the cellular level.28,29
Low-dose IFN-α therapy has shown efficacy in maintaining long-lasting morphological and cytogenetic remissions in patients with Ph+ALL after autologous SCT or chemotherapy with standard maintenance. Since minimal residual disease (MRD) was detected in a subset of these patients, IFN-α was suggested to facilitate disease control rather than its elimination.30 Recently, Visani et al31 reported a maintained reinduction of a complete morphological, cytogenetic and molecular remission in a patient with third relapse of Ph+ALL by combining imatinib at a dose of 600 mg/day with low-dose subcutaneous IFN-α (3 × 1 MU/week).
Taken together, these data suggest that imatinib in conjunction with IFN-α may have clinical activity in patients with Ph+ALL, particularly in the setting of MRD. Neither the efficacy of this drug combination in Ph+ALL nor the tolerability and safety of simultaneous imatinib and IFN-α in terms of hematologic and nonhematologic toxicity have yet been established. We therefore examined the clinical effect of the combination treatment in six patients with Ph+ALL who were not eligible for SCT (n=4), had relapsed after previous allo-SCT (n=1) or in whom SCT was not possible in a timely manner (n=1).
Patients and methods
Imatinib therapy and definition of response
The six patients described in the present report are a subset of 68 consecutive patients with relapsed or refractory Ph+ALL who were referred to our center to receive imatinib within phase II trials (Novartis study codes CSTI571 109 and 114). Details of study procedures are provided elsewhere.20 Patients received imatinib at a single daily oral dose of 600 (n=5) or 400 mg (n=1; due to prior liver toxicity) for either relapsed (n=3) or refractory (n=1) Ph+ALL, or due to grade 3–4 nonhematologic toxicity during standard induction therapy precluding further chemotherapy regimens (n=2). The median age was 63 years (range 47–74 years). Patients’ characteristics are summarized in Table 1.
A complete hematologic response (CHR) was defined according to conventional criteria as a reduction of marrow blasts to <5% with no blasts in peripheral blood, hematopoietic recovery with absolute neutrophil counts (ANCs) and platelet counts ⩾1.5 × 109/l and ⩾100 × 109/l, respectively, and no evidence of extramedullary disease. A complete marrow response (marrow-CR) was defined as a reduction of marrow blasts to <5% with no blasts in peripheral blood, no evidence of extramedullary involvement but incomplete hematopoietic recovery, as reported previously.20 Partial response was defined as the reduction of bone marrow (BM) blasts to 6–25%. Relapse and refractoriness were defined by conventional criteria. Time to progression (TTP) was calculated as the time from the start of imatinib treatment until relapse after initial response; OS was calculated from the start of imatinib.
Low-dose subcutaneous IFN-α was added in patients receiving single-agent imatinib therapy who were either in complete remission (CHR or marrow-CR), but remained MRD positive by quantitative PCR (pt. nos. 1–5) or were refractory to imatinib (pt. no. 6). IFN-α-2a (Roferon®) was administered via pen containing vials with 18 MU. All patients gave prior informed consent.
IFN-α was started at 1 MU three times a week with dose escalation to a target dose of 3 MU three times a week as rapidly as tolerated. The previously transplanted patient (pt. no. 4) received IFN-α at 3 × 1 MU/week without further dose increase. In patient no. 6, who was refractory to a 2-week course of imatinib, IFN-α was started at a dose of 5 MU/day 7 × /week, with subsequent reduction as described under results.
Detection of MRD by quantitative real-time RT-PCR
Quantitative real-time PCR was performed primarily using Taqman technology, as described previously.32 The sensitivity of the method was 10−5 as determined by diluting defined numbers of patient cells in PB and BM MNC of healthy volunteer donors.
Efficacy and outcome
In five patients (pt. nos. 1–5), IFN-α was added to ongoing imatinib of 3.4–4.8 months (median 3.8 months) duration during hematologic remission (CHR or marrow-CR) but with evidence of MRD (Table 2). In four of these patients, IFN-α doses were escalated to 3 × 2.5–3 MU/week as rapidly as clinically tolerated. One patient (no. 4) who had previously undergone allo-SCT received 3 × 1 MU/week with no further dose increase. The median duration of combined imatinib and IFN-α therapy is 15.7 (range 1–18) months. Two patients remain in uninterrupted remission 18 and 16 months after start of combination therapy (nos. 1 and 2, Figure 1a and b). These patients experienced a prolonged and sustained decline in BCR-ABL levels (no. 1) and conversion to MRD negativity by quantitative RT-PCR (no. 2), respectively. Two patients (nos. 3 and 4) experienced an isolated CNS relapse during combination therapy (no. 4) or within 3 weeks of discontinuation in a patient who interrupted therapy on his own accord (no. 3). Combined therapy was subsequently reinstituted. Neither of these two patients had received prophylactic cranial irradiation during induction therapy. Treatment of CNS relapse consisted of repeated intrathecal (i.t.) triple chemotherapy given parallel to imatinib and IFN-α. Both patients subsequently received additional cranial and optic nerve irradiation, respectively. In both patients, bcr/abl transcripts became undetectable 9 (no. 3) and 14 weeks (no. 4) after CNS relapse, and both patients are in molecular remission (MRD negative) after 15 and 17 months of combination therapy (Figure 1c and d). Patient no. 5 relapsed 1 month after starting IFN-α. In this case, initiation of IFN-α coincided with a pronounced increase of MRD levels (Figure 1e), indicating rapidly evolving relapse.
Patient no. 6 started combination therapy in the setting of refractory disease after 14 days of imatinib. IFN-α was added at 5 MU 7 × /week and reduced to 3 MU 3 × /week 1 week later. Although BM cytology still showed 90% marrow blasts after 2 weeks of combination therapy, imatinib and IFN-α were continued because of slightly reduced cellularity and the lack of other treatment options. After 6 weeks of combined therapy, BM blasts were reduced to less than 5%. BCR-ABL fusion signals detected in BM by FISH decreased from 52 to 20 and 1.4% after 2 and 6 weeks of combination therapy, respectively. Grade 4 neutropenia and thrombocytopenia were present when imatinib was initiated; after achieving a complete marrow response, neutropenia improved to grade 2 and thrombocytopenia to grade 3. BM relapse occurred 5 months after IFN-α was added (Table 2, Figure 1f).
Grade 1–2 nonhematologic toxicity consisting of fatigue and bone pain developed in two patients after IFN-α was added. One patient (no. 4) experienced intermittent headaches, visual disturbances and bilateral papillary edema about 4 weeks after starting IFN-α. These symptoms were initially attributed to IFN-α, leading to discontinuation of the drug, but were subsequently shown to be prodromi of CNS relapse diagnosed 2 weeks later by demonstration of blasts in the cerebrospinal fluid. Hematologic toxicity in nontransplanted patients starting combination therapy for persisting MRD was mild. Two patients experienced grade 1–2 neutropenia and thrombocytopenia. One patient developed intermittent grade 3 neutropenia and thrombocytopenia that reversed after IFN-α dose reduction. Patient no. 4, who had received previous allo–SCT, developed grade 3 thrombocytopenia after start of single-agent imatinib and remained thrombocytopenic thereafter.
The rapid development of secondary resistance in patients with relapsed or refractory Ph+ALL initially responsive to single-agent imatinib19,20 indicates that combination therapy is required in those patients not eligible for potentially curative allo-SCT. Older age, comorbidity or previous allo-SCT preclude allo-SCT in a sizeable proportion of patients with relapsed or refractory Ph+ALL. Moreover, even when allo-SCT is attempted, resistance to imatinib frequently develops before transplantation can be performed, resulting in an extremely poor outcome.33 Based on experimental and preclinical data showing additive or synergistic effects of imatinib and IFN-α on Ph+ cells,29,30 we investigated whether combined treatment with imatinib and low-dose subcutaneous IFN-α may benefit Ph+ALL patients who were not candidates for timely allo-SCT.
When IFN-α was combined with imatinib in the setting of MRD, bcr/abl transcript levels declined continuously in four patients, with three patients eventually achieving a sustained molecular remission and one maintaining low MRD levels close to the detection threshold. Only one of the patients starting combination therapy while in hematologic remission experienced a systemic relapse, although an intercurrent isolated CNS relapse occurred in two patients. This was successfully treated with additional i.t. chemotherapy followed by cranial and orbital irradiation, respectively. Imatinib has been shown previously to penetrate the blood–brain barrier poorly,26,27 apparently due to P-glycoprotein-mediated drug efflux.34 Taken together, these results emphasize the need for CNS prophylaxis in addition to imatinib and IFN-α, particularly in patients who had not received prior prophylactic cranial irradiation.
Overall, our clinical findings involving concurrent imatinib and interferon, with four of six patients surviving and in CR 19–21 months after starting imatinib and 15–18 months after starting combination therapy, are far superior to any previously reported results with imatinib not involving allo-SCT. TTP with imatinib monotherapy is only 2 months in Ph+ALL patients who fail first-line (or subsequent) therapy, and OS is approximately 6 months.19,20 Even in the subset of patients achieving a complete hematologic remission or marrow response, the median time to relapse was only 5.4 and 2.9 months, respectively,23 and the median OS was 8–9 months.20 Long-term survival has so far been observed only in patients who were transferred to allo-SCT while still in CR,23 in rare patients (n=2) who were transplanted previously20 or those receiving additional IFN (n=1).31
It is particularly intriguing that three patients achieved a sustained molecular remission. Single-agent imatinib given outside of an allo-SCT setting has so far not been shown to induce sustained molecular remissions in patients with Ph+ALL, and essentially all nontransplanted patients who remained MRD positive have relapsed unless transferred to allo-SCT or given additional IFN, as shown in this paper and a recent case report by Visani et al.31
Interestingly, both patients with an isolated CNS relapse achieved MRD negativity after i.t. chemotherapy was given in addition to imatinib and IFN-α, suggesting a synergistic systemic antileukemic effect between these agents and i.t. administered methotrexate, cytosine arabinoside and corticosteroids. Taken together, CNS prophylaxis incorporating prophylactic CNS irradiation and/or repeated i.t. chemotherapy should thus be an integral part of a therapeutic strategy involving imatinib-based combination therapy.
The clinical efficacy of concomitant imatinib and low-dose IFN-α is further supported by the prolonged remission and survival (ongoing 20.5 and 20.8 months after starting imatinib) observed in two elderly patients whose previous treatment comprised only induction chemotherapy followed by 3.5–4.8 months of imatinib monotherapy, without achieving MRD negativity. With standard multiagent induction chemotherapy and subsequent consolidation cycles, OS in patients with de novo Ph+ALL is less than 9 months.5 In elderly patients with high-risk ALL, including presence of the Philadelphia chromosome, the CR rate is only 34% and survival of responding patients is only 7 months (Gökbuget et al, unpublished), results that are substantially inferior to the outcome of the comparable patients described in this report.
Our observation that the additional administration of IFN-α in an imatinib-refractory patient (no. 6, Table 1) induced a complete cytologic response is consistent with a recent report describing induction of molecular remission by low-dose IFN-α in a patient with p190Bcr/Abl-positive ALL and secondary resistance to imatinib alone,31 although the response kinetics in these patients differed, with a more protracted (6 weeks) response in our patient. The conclusion that combination therapy was indeed responsible for this patients' response is supported by a considerable body of evidence that delayed responses to imatinib are exceedingly uncommon, if they occur at all, in Ph+ALL,20 in contrast to CML. Moreover, we have recently shown that the lack of a BM response after 2 weeks is highly predictive of subsequent nonresponse to imatinib monotherapy and accordingly a dismal treatment outcome.23
The mechanisms by which IFN-α may augment the antileukemic efficacy of imatinib either in CML or in Ph+ALL remain to be resolved. We and others have demonstrated that the development of secondary resistance is associated with point mutations in the ATP binding domain or activation loop of the BCR-ABL oncoprotein. These mutations block binding of imatinib to the ATP binding site of the ABL kinase and consequently result in loss of antileukemic activity.24,25 Mutations have been detected prior to imatinib therapy only rarely and at a very low frequency in Ph+ALL.35 Thus, one mechanism by which IFN-α prolongs imatinib-induced remissions may involve suppression of clonal evolution, including development and selection of point mutations, for example, due to its antiproliferative activity. Alternatively, IFN-α may stimulate an immune response to BCR-ABL expressing leukemic blasts,36 although Ph+ALL is generally considered to be poorly responsive to immunological interventions.
Our finding that the combination of imatinib at a daily dose of 400–600 mg with IFN-α at doses ranging from 1 MU 3 × /week to 3 MU 3 × /week were well tolerated is important in view of the fact that many of the patients who are candidates for this type of therapy will not be able to tolerate toxic regimens. In general, hematologic and nonhematologic toxicity were mild (grades 1–2) and did not necessitate treatment discontinuation or prolonged interruptions. We restricted the IFN-α dose to a maximum of 3 × 1 MU/week in the patient who had previously undergone allo-SCT, because higher doses have been shown to induce myelosuppression and/or severe graft-versus-host disease frequently.37,38,39,40 The low-dose level used in our patient was well tolerated, but experience with larger numbers of patients is required to permit a definite assessment of the safety of this combination, particularly regarding its potential for inducing or aggravating graft-versus-host disease.
In conclusion, low-dose IFN-α in combination with imatinib and CNS prophylaxis is a promising, well-tolerated treatment option for adult patients with advanced Ph+ALL who are not candidates for aggressive treatment approaches such as allo-SCT. Prolonged hematologic and molecular remissions may be achieved in a subset of patients, but future studies with larger cohorts of Ph+ALL patients are needed to determine the impact of this combination on DFS and to elucidate optimal dosing and scheduling.
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This work was supported by BMBF Competence Network Leukemias (01GI9971), the Adolf-Messer Foundation and by a grant from Novartis.
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