Results of a phase II trial of a combination of oral cytarabine ocfosfate (YNK01) and interferon α-2b for the treatment of chronic myelogenous leukemia patients in chronic phase

Article metrics

Abstract

Cytarabine ocfosfate (YNK01) is a prodrug analogue of cytarabine which is resistant to systemic deamination after oral administration. Following initial studies indicating significant anti-tumour activity of YNK01 a phase II trial was initiated in order to assess the tolerability and efficacy of a combination of this agent with interferon α-2b (IFN-α2b) in recently diagnosed chronic phase CML patients (n = 98). The treatment was subdivided into cycles consisting of 4 weeks of continuous administration of IFN-α-2b (3 MU/m2/day 1st week and then 5 MU/m2/day) and 14 days of oral YNK01 (600 mg/day 1st cycle). At the end of each cycle the dose of YNK01 was adjusted according to the blood count observed during the previous 4 weeks. The median time from diagnosis to inclusion in the trial was 2 months (range 6 days to 7.5 months). At 12 weeks, 62 patients (63%; 95% CI, 54–73) achieved a complete hematological response. At 24 weeks, of 98 patients, two achieved a complete cytogenetic response, 14 a partial response (16% major cytogenetic response rate; 95% CI, 9–24) and 34 a minor response; 19 patients were not evaluable for cytogenetic response. During the trial, 20 patients progressed to accelerated (6) or blastic phases (14). The median time to progression was 15 months (range 2–38 months). At 3 years the overall survival was 79% (95% CI, 70–88). Although the complete hematological response rate compared favorably with the 40% response rate previously obtained with the subcutaneous formulation of Ara-c, the cytogenetic response rate was less than expected. Most of the patients experienced side-effects and all permanently stopped YNK01. Although the combination seems attractive the initial dose of 600 mg per day is probably too high and should be reconsidered in further trials.

Introduction

Chronic myelogenous leukemia (CML) is a hemopoietic stem cell disorder which can be cured by allogeneic stem cell transplantation. However, a suitable donor is found in only 15% of the patients. Other current options for treatment of patients with CML include homoharringtonine,1 interferon-α2 and the recently developed 2-phenylaminopyrimidine STI571 (Glivec), a tyrosine kinase inhibitor.3 Interferon-α 2a and 2b (IFN-α) have demonstrated anti-leukemic activity with 60 to 80% of patients achieving complete hematological responses within a period of treatment of 3 to 6 months.4,5,6,7,8 A substantial number of these patients also achieved cytogenetic responses defining a subgroup of patients with significantly better survival.9 However, the proportion of patients who achieved a complete cytogenetic response was still low and it is uncertain whether interferon can ‘cure’ patients. Cytosine-arabinoside (Ara-c) was shown to exhibit a selective activity on CML progenitors cells in vitro.10 Because of its in vitro activity, Ara-c alone has been tested in vivo for the treatment of patients with chronic phase CML. Treatment of several patients resulted in high rates of hematological and cytogenetic remission.11,12 IFN-α combined with Ara-c resulted in a greater cytotoxic effect on leukemic human progenitors cells in vitro13 and uncontrolled observational studies indicated that the addition of low-dose Ara-c to IFN-α for the treatment of chronic phase CML patients who failed to respond to IFN-α resulted in complete hematological and cytogenetic responses.14,15 The superiority of a combination of IFN-α plus Ara-c over IFN-α monotherapy has been demonstrated in large multicenter randomized trials.16,17,18 However, subcutaneous injection of Ara-c resulted in serious side-effects such as mucositis or pain at the site of injection. Thus a substantial number of patients stopped Ara-c.

YNK01 is an Ara-c lipophilic prodrug which, because it is resistant to deoxycytidine deaminase, can be administered orally. YKN01 is absorbed in the distal part of the small intestine and is metabolized in the liver. After oxidation of YNK01, Ara-c is released into the systemic circulation and following administration of a dose of YNK01 of 200–300 mg, plasma levels of Ara-c are comparable to those achieved after low-dose Ara-C (20 mg/m2).19 During the first phase I/II study using YNK01 as monotherapy (at a starting dose of 600 mg/day) partial and complete cytogenetic responses were obtained in previously heavily pretreated patients.20 In a phase I/II pilot study (six patients) a combination of YNK01 (600 mg/day) and IFN-α2b (3 to 5 MU/m2/day) was well tolerated. Therefore, we decided to initiate a phase II trial in order to assess the tolerability and the effectiveness of a combination of IFN-α2b with YNK01 in recently diagnosed CML chronic phase patients.

Patients and methods

Patients

Patients with recently diagnosed Philadelphia (Ph)-positive chronic phase CML (less than 6 months) were eligible if they were between 18 and 75 years old. Other entry criteria were: WHO performance status of 0, 1 or 2; white blood cell count (WBC) less than 20 × 109/l after induction treatment with hydroxyurea; platelet count >100 × 109/l. Exclusion criteria were: CML in accelerated or blastic phase or Ph-negative CML; prior treatment for CML with chemotherapies other than hydroxyurea; cardiac disease, pregnancy or uncontrolled infection; the presence of a contra-indication for treatment with IFN-α (any neuropsychiatric history, developing hepatitis, uncontrolled renal insufficiency).

The study was approved by the ethics committee of Poitou-Charentes Area and all patients gave their written informed consent.

Treatment

The treatment was subdivided into cycles consisting of 4 weeks of continuous administration of IFN-α2b (3 MU/m2/day 1st week and then 5 MU/m2/day) and 14 days of oral YNK01 (600 mg/day 1st cycle). At the end of each cycle the dose of YNK01 was adjusted according to the blood count observed during the previous 4 weeks. The daily dose of YNK01 could be increased with an increment of 300 mg if during the previous cycle the WBC count was higher than 5 × 109/l and/or the platelet count higher than 150 × 109/l. Otherwise the dose of 600 mg was continued and the same rules were applied to subsequent cycles but the maximum daily dose of YNK01 was limited at 1200 mg. Conversely, if during the previous cycle the WBC fell below 3 × 109/l and or the platelet below 100 × 109/l then the daily dose of YNK01 was decreased to 300 mg. IFN-α2b and YNK01 could be stopped if the WBC fell below 2 × 109/l and the platelet count fell below 50 × 109/l and treatment was resumed when the WBC count exceeded 3 × 109/l and the platelet count 100 × 109/l. As a general rule, the YNK01 dosage of the previous cycle was recommended for the following cycle if the WBC count was between 3 × 109/l and 5 × 109/l and the platelet count between 100 × 109/l and 150 × 109/l.

Before starting the study treatment, hydroxyurea (HU) could be given to reduce the WBC to below 20 × 109/l but then had to be permanently discontinued. The dose of IFN-α-2b was adapted according to the rules of our previous CML 91 trial. Briefly, the dose of IFN-α2b was reduced by half when the granulocyte count dropped below 1.5 × 109/l, the platelet count below 100 × 109/l or both and discontinued if the granulocyte fell below 1 × 109/l and/or the platelet count below 50 × 109/l.

Initial assessment and monitoring of the patients

The diagnosis of Ph-positive chronic phase CML was confirmed in all patients, and clinical and laboratory assessments were performed to confirm eligibility. Bone marrow aspiration was performed for cytogenetic and cytologic examination. Chest X-ray, 12-channel ECG and abdominal ultrasonography were performed before entry. FBCs were performed every week for 12 cycles and physical examination had to be repeated every week as long as the spleen was palpable. Assessment at the end of the 3rd cycle, 6th cycle, 9th cycle and 12th cycle included full clinical and laboratory evaluation including bone marrow cytogenetic analysis. Abdominal ultrasonography was mandatory during the 3rd cycle and optional afterwards.

Response and toxicity criteria

Efficacy assessments were based on the WBC count, differential and platelet count, the size of the spleen and the percentage of bone marrow mitosis. Response assessments were scheduled at 12 weeks for hematological response and 24 weeks for cytogenetic response. The criteria for complete hematological response were: disappearance of the signs and symptoms of the disease; normal physical examination including disappearance of the splenomegaly; a WBC count less than 10 × 109/l with normal differential (less than 5% myeloid cells were accepted) and a platelet count less than 350 × 109/l. A complete cytogenetic response was defined as the absence of Ph-positive metaphases; partial cytogenetic responses as 1% to 34% of Ph-positive metaphases; major responses include complete and partial responses; minor cytogenetic responses were defined as 35% to 94% of Ph-positive metaphases. Side effects were defined and graded according to WHO toxicity criteria.

Statistical analysis

This phase II non-randomized multicenter trial sought to evaluate the efficacy and tolerability of a combination of IFN-α2b and a new oral formulation of cytarabine. The designated efficacy end points were the 12 weeks hematological response rate and the 24 weeks cytogenetic response rate. The objective of the trial was to achieve results that would be at least equivalent to those for the previous combination using subcutaneous administration of cytarabine. Equivalence would be confirmed if the 95% confidence interval of the hematological response rates at 12 weeks and of the major response rate at 24 weeks contained the rates observed for the CML 91 study, ie 40 and 31%, respectively.16 Conditionally to the 12 weeks hematological response rate of 40% in the CML 91 protocol, the most unfavorable hypothesis in terms of the number of subjects for this trial would be that the 12 week hematological response rate for the IFN-α2b + YNK01 combination was 50%, ie a necessary number of subjects of 98 patients. Survival distributions, time to response, time to events and duration of treatment were estimated by the Kaplan–Meier method; age comparison between groups was analyzed using Wilcoxon Rank Sum Scores. The analysis used SAS software (SAS Institute, Cary, NC, USA).

Results

Patient characteristics

Between January 1997 and February 1998, 98 patients with newly diagnosed Ph-positive chronic phase CML were included (40 females, 58 males; median age 54 years, range 18–73). At presentation the spleen was enlarged in 43%; median WBC was 80.8 × 109/l (range 9.9–640.0) and 45% of the patients had a low Sokal score (Table 1).

Table 1 Features at presentation

Performance status according to WHO score was 0 for 61%, 1 for 35% and 2 for 4%, respectively.

The median time from diagnosis to inclusion in the trial was 2 months (range 6 days to 7.5 months). Pre-treatment with hydroxyurea was administered to 95 patients for a median period of time of 1 month (range 4 days to 7 months). There were three protocol violations: pre-treatment with hydroxyurea was given for 7 months in one patient and for 7.5 months in 2 patients, respectively. These violations were considered as minor and the patients remained within the analyses.

Hematological and cytogenetic responses (Table 2)

Table 2b Cytogenetic response
Table 2a Hematologic response

Hematological response was assessed at 12 weeks. Out of the 98 patients, 62 (63%; 95% CI, 54–73) achieved a complete response with the study treatment. The rates of complete hematological responses within each Sokal risk category were 80%, 62% and 50% for the low, intermediate and high risk categories, respectively. Out of the 35 failure patients, one achieved an hematological response after autologous stem cell transplantation, three patients initially responded but stopped the study treatment due to side-effects and 31 were resistant patients with the study treatment. One patient was not assessable for the response at 12 weeks. At 24 weeks 68 out of 98 (69%; 95% CI, 60–79) had achieved a complete hematological response. Although all were still receiving IFN-α2b at that time, a substantial number of them had stopped YNK01. The median time to achieve complete hematological response was 1.5 months (range 0–3 months). Two patients received an autologous stem cell transplantation and subsequently achieved hematological response at 24 weeks.

Cytogenetic evaluation was obtained for 79 patients at 24 weeks. At that time two patients achieved a complete cytogenetic response, 14 a partial response (16% of major responses; 95% CI, 9–24) and 34 a minor response. Cytogenetic evaluation was not performed in 19 patients for the following reasons: early adverse event (four cases); early adverse event and failure to achieved hematological response (three cases); primary hematological resistance at 12 weeks (five cases); insufficient number of mitosis (four cases); one death; and in two cases the reason was not reported. One of the patients who received an autologous stem cell transplantation achieved a minor cytogenetic response after the transplant. As of July 2000, 13 patients have obtained a complete cytogenetic response, nine with IFN-α2b alone, two with the combination of YNK01 and IFN-α2b, one with subcutaneous injections of cytarabine and one after autologous stem cell transplantation. Among the eight patients who achieved a partial cytogenetic response, seven obtained such result with IFN-α2b alone and one with subcutaneous injections of cytarabine.

Dose

Out of the 98 patients, 39 stopped the study treatment before six cycles. For these 39 patients for the period of time during which they received both agents, the mean daily dose of IFN-α2b was 6.68 MU (±1.81, range 3–8.86) and the mean daily dose of YNK01 was 543.03 mg (±123.34, range 275.61–840.85). Fifty-nine patients went off study treatment at six cycles or later. For these patients during the first six cycles the mean daily dose of YNK01 and IFN-α2b were 583.21 mg (±197.52, range 283.23–1050) and 7.58 (±2.02, range 3.33–11,36) respectively. After six cycles for those who were still under study treatment the median dose of IFN-α2b and YNK01 were 6 MU total dose per day and 300 mg, respectively. As indicated in Table 3, most patients received the scheduled doses of IFNα-2b and YNK01 during the first six cycles. Although dosage and pharmacokinetics were not performed, given the metabolism of the two drugs, it is assumed that no interaction was expected between them. There was no correlation between the dose of YNK01 or IFN-α2b and the hematological or cytogenetic responses.

Table 3 Median doses and ratio of YNK01 and IFN for each of the first six cycles

Follow-up of the patients

The median follow-up of the living patients is 34 months. During the trial, 20 patients progressed to accelerated phase (six) or blastic phase (14). The median interval to progression was 15 months (range 2–38 months). At 3 years the overall survival was 79% (95% CI, 70–88) (Figure 1) and the survival without progression was 72% (95% CI, 60–83). During the trial 24 haemopoietic stem cell transplants (14 allogeneic and 10 autologous) were performed 2 to 34 months after entry on the protocol, mainly because of failure to achieve a hematological or cytogenetic response. When allogenic patients are censored at the time of allogeneic transplantation the survival at 3 years is 83% (95% CI, 74–92). Nineteen deaths were recorded. Twelve patients died of progression. Five transplant-related deaths were recorded. The reason of death for the last two patients was unrelated to CML (lung cancer and sudden death at home).

Figure 1
figure1

Probability of survival from start of IFN-α2b and YNK01.

Side-effects and discontinuation of the treatment (Tables 4, 5 and 6)

Table 6 Biological side-effects recorded in 71 patients
Table 5 Clinical side-effects recorded in 98 patientsa
Table 4 Discontinuation of YNK01

All patients experienced at least grade 1 toxicity. Although it was sometimes difficult to distinguish between side-effects related to either IFN-α2b or YNK01, flu-like symptoms, neurological changes and psychiatric disorders were related to the use of IFN-α2b; diarrhea, vomiting and mucositis were attributable to YNK01. Most of the patients experienced episodes of asthenia (84 patients) which was considered severe (grade 3 or 4) in 31 patients. No significant relationship was found between age and severe toxicity (31 patients with severe toxicity: median age 54 years, range 25–73; 67 patients without severe toxicity: median age 53 years, range 18–73). Diarrhea and vomiting were severe (grade 3–4) for nine and 11 patients, respectively, and such side-effects could explain grade 3–4 weight loss. Severe psychiatric disorder such as depression was a reason for ending the protocol and thus the contribution of YNK01 for the treatment of CML could not be assessable for these patients. Leukopenia and thrombocytopenia were considered a result of the use of both agents. Grade 3 thrombocytopenia was recorded in seven patients and considered as a possible responsibility of YNK01. However no severe episode of bleeding was recorded. Red cell transfusions were required for seven patients because of symptomatic anemia or because their physician felt that transfusion could improve their medical condition. Such anemia was presumed to have resulted from inhibition of erythropoiesis due to YNK01. There was no clinical evidence of blood loss or laboratory evidence to suggest hemolysis. Transfusions were required for four patients at cycles 1, 2, 3 and 4, respectively, and for three patients at cycle 5. Mean values of white blood cells and platelets are given in Figures 2 and 3, respectively. They were calculated for the first period of 24 weeks during which 59 patients received the study treatment. One patient received the two drugs without discomfort for a period of 30 months and then stopped because of the development of blast crisis. He died 12 months later, still in blast crisis. Another patient achieved a complete hematological response after 1 month and a complete cytogenetic response after 18 months of treatment with the combination of the two drugs. He stopped YNK01 after 27 months of treatment and then relapsed with 48% of Ph-positive metaphases while still receiving IFN-α2b alone.

Figure 2
figure2

Mean values of white blood cells during the first 24 weeks in 59 patients (× 109/l).

Figure 3
figure3

Mean values of platelet during the first 24 weeks in 59 patients (× 109/l).

As of July 2000, all patients had definitively stopped YNK01. Of these, 39 discontinued before six cycles, 31 between six cycles and 1 year, 10 at 1 year and 18 thereafter. Among the 39 patients who definitively stopped YNK01 before six cycles, 32 patients did so because of side-effects, six patients because of hematological failure. A final patient went off study when he switched to another hospital. After six cycles, reasons for discontinuation were hematological failure (nine patients), cytogenetic failure (13 patients), side-effects in relation to the use of YNK01 or the combination of IFN-α2b and YNK01(21 patients). Eight patients discontinued the treatment for personal reasons, and finally, one patient discontinued because of sudden death at home. Seven additional patients stopped YNK01 after they obtained a complete cytogenetic response. During the trial 62 patients stopped the study treatment for toxicity or no compliance after a median period of time of 9 months (95% CI, 7–16) and 28 patients stopped for treatment failure (median period of time not reached). At 12 months, 22% of the patients stopped for treatment failure (95% CI, 13–30) (Figure 4a and b).

Figure 4
figure4

(a) Cumulative rate of treatment discontinuation for toxicity or no compliance. (b) Cumulative rate of treatment discontinuation for treatment failure.

Discussion

Preliminary clinical experience suggested that the combination of IFN-α2b and Ara-C improved on the results seen with IFN-α2b treatment alone.14,15 It has been shown in several randomized trials that IFN-α was more efficacious than chemotherapy such as hydroxyurea or busulfan.2 In several studies, there was an association between achievement of major or complete cytogenetic responses and survival improvement.9 Thus the rationale behind the use of a combination of IFN-α and Ara-c was the expectation that such a combination could increase the cytogenetic response rate and the overall survival. Single arm studies as well as randomized trials suggested that the use of IFN-α and Ara-c resulted in higher cytogenetic response rate and better survival.16,17,18 An update of the French CML 91 trial showed, after a median follow-up of 46 months (range 4–82), the 5 year probability of survival was 58% (95% CI, 51–65) for patients assigned to the IFN-α2b arm and 70% (95% CI, 64–76) for patients assigned to the IFN-α2b + Ara-c arm.21 Significant side-effects of this new modality of treatment, such as weight loss, nausea, vomiting, diarrhea, mucositis and pain at the site of injection were related to the use of Ara-C. In our previous study, half of the patients stopped Ara-C within 12 months because of side-effects. An oral formulation of Ara-c could result in less side-effects and allow more prolonged administration of the anti-leukemic compound which could result in higher cytogenetic response rate and better survival. This phase II trial aimed to assess the toxicity and efficacy of a combination therapy with IFN-α2b and YNK01, a new oral formulation of Ara-c. All the patients were in chronic phase and only pre-treatment with hydroxyurea was permitted. All the patients received the standard dose of IFN-α2b in combination with YNK01 which was administered orally for a period of 14 days each month. The dose of 600 mg per day was selected on the basis of previous phase I/II studies.

The complete hematological response rate at 12 weeks of 63% compared favorably with the 40% response rate previously obtained with the subcutaneous formulation of Ara-c. However, the cytogenetic response rate was less than expected. In the CML 91 study, 31% of the patients who received subcutaneous injections of cytarabine achieved major cytogenetic responses at 24 weeks whereas only 16% (95% CI, 9–24) achieved such a result with YNK01 and IFN-α2b. Such a cytogenetic response rate is similar to the rate that was achieved with IFN-α2b alone in our randomized study. This is not surprising since a large number of patients discontinued YNK01 before 6 months and thus could not have achieved the maximum anti-leukemic effect of the two drugs. However, it should be pointed out that the cytogenetic response rate achieved in our previous trial using subcutaneous injection of cytarabine was high compared to those usually achieved by other groups. The dose of 600 mg per day of YNK01 was selected on the basis of previous pharmacokinetics studies.19 In a phase I/II study, YNK01 was administered by a 14 day cycle with escalating doses, starting with a daily dose of 100 mg/m2 which is equivalent to 40 mg/m2 cytarabine on a molar basis. In this study the maximum tolerated dose was reached at the 1200 mg/m2 dose level with WHO grade 3–4 diarrhea as the main toxicity.19 After administration of YNK01 at a dosage of 100–150 mg/m2, plasma levels of cytarabine were comparable to those achieved after low-dose cytarabine treatment (20 mg/m2). Other studies using YNK01 alone or in combination with IFN suggested that a fixed dose of 600 mg produced significant anti-leukemic effect with acceptable toxicity. The efficacy of a continuous administration of YNK01 in combination with IFN-α2b was evaluated in patients who failed previous IFN-based regimens.22 Dose escalations up to 900 mg were permitted for those patients who failed to response to the initial 300 mg/day dosage. Of the 10 patients enrolled in the study, four achieved complete hematological responses and one a complete cytogenetic response. In this study, seven patients went off protocol because of side-effects. Toxic effects attributed to YNK01 were fatigue, diarrhea and thrombocytopenia. The question of the relationship between doses of YNK01 was considered. Although the number of patients was small, it was suggested that treatment-associated side-effects worsened with dose escalation of YNK01. While YNK01 therapy was stopped in three patients (33.3%) at the low-dose level of 300 mg, two patients at 600 mg (40%) and two patients at 900 mg (100%) discontinued the study treatment due to YNK01-related toxicity. Moreover, dose levels beyond 300 mg were associated with a higher incidence of WHO grade 2 and 3 toxicities. It was concluded that the combination of YNK01 at the dose of 300 mg in combination with IFN could be an effective regimen in pre-treated late chronic phase patients. The preliminary results of the Australia and New Zealand YNK01 CML trial were recently reported.23 The study design was exactly the same as the French study. Forty patients with a recent diagnosis of CML chronic phase were enrolled. Patients were required to complete two cycles of combination therapy to be evaluable for efficacy. Nine patients were considered non-evaluable due to IFN intolerance. Of 21 evaluable patients at 9 months, 43% achieved a major cytogenetic response, the median time to achieve such result being 20 weeks; moreover, five achieved a complete cytogenetic response. Within the limitation of the overall number of patients these results are superior to ours and similar to those achieved previously with the subcutaneous formulation of cytarabine. The question of the modality of administration of cytarabine has been addressed in several trials. It has been suggested that the combination of IFN plus continuous administration of cytarabine could be superior as compared to the intermittent administration of cytarabine in patients with early chronic phase CML.24 The optimal modality of administration of YNK01 is also currently being studied. The Austrian CML study group initiated a phase III trial to compare the efficacy of IFN plus continuous oral YNK01 vs intermittent administration of YNK01 in newly diagnosed Ph-positive CML patients, the dose of YNK01 being 300 mg daily. The French study group has also initiated a dose escalation study comparing intermittent vs continuous administration of YNK01, 100 mg being the initial daily dose.

These studies may provide useful indications for further use of this oral formulation of cytarabine in combination with other drugs. Preliminary in vitro studies have suggested that an additive effect of STI571 and cytarabine could be demonstrated.25 Thus in vivo administration of a combination of YNK01 and STI571 would be of considerable interest.

References

  1. 1

    Kantarjian HM, Talpaz M, Smith TL, Cortes J, Giles FJ, Rios MB, Mallard S, Gajewski J, Murgo A, Cheson B, O'Brien S . Homoharrringtonine and low-dose cytarabine in the management of late chronic-phase chronic myelogenous leukemia J Clin Oncol 2000 18: 3513–3521

  2. 2

    Chronic Myeloid Leukemia Trialists’ Collaborative Group. Interferon alfa versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials J Natl Cancer Inst 1997 89: 1616–1620

  3. 3

    Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL . Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia N Engl J Med 2001 344: 1031–1037

  4. 4

    Ozer H, George SL, Schiffer CA, Rao K, Rao PN, Wurster-Hill DH, Arthur DD, Powell B, Gottlieb A, Peterson BA . Prolonged subcutaneous administration of recombinant alpha-2b interferon in patients with previously untreated Philadelphia chromosome positive chronic-phase chronic myelogenous leukemia: effect on remission durantion and survival: Cancer and Leukemia Group B Study 8583 Blood 1993 82: 2975–2984

  5. 5

    Hehlmann R, Heimpel H, Hasford J, Kolb HJ, Pralle H, Hossfeld DK, Queiber W, Löffler H, Hochhaus A, Heinze B, Georgii A, Bartram CR, Griebhammer M, Bergmann L, Essers U, Falge C, Queiber U, Meyer P, Schmitz N, Eimermacher H, Walther F, Fett W, Kleeberg UR, Käbisch A, Nerl C, Zimmermann R, Meuret G, Tichelli A, Kanz L, Tiggges FJ, Schmid L, Brockhaus W, Tobler A, Reiter M, Perker M, Emmerich B, Verpoort K, Zankovich R, Wussow PV, Prümmer O, Thiele J, Buhr T, Carbonell F, Ansari H the German CML Study Group. Randomized comparison of interferon-α with busulfan and hydroxyurea in chronic myelogenous leukemia Blood 1994 84: 4064–4077

  6. 6

    Allan N, Richard S, Shepherd P . UK Medical Research Council randomised, multicentre trial of interferon-α n1 for chronic myeloid leukemia: improved survival irrespective of cytogenetic response Lancet 1995 345: 1392–1397

  7. 7

    Ohnishi K, Ohno R, Tomonaga M, Kamada N, Onozawa K, Kuramoto A, Dohy H, Mizoguchi H, Miyawaki S, Tsubaki K, Miura Y, Omine M, Kobayashi T, Naoe T, Ohshima T, Hirashima K, Ohtake S, Takahashi, Morishima Y, Naito K, Asou N, Tanimoto M, Sakuma A, Yamada K the Kouseisho Leukemia Study Group. A randomized trial comparing interferon-α with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase Blood 1995 86: 906–916

  8. 8

    The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Long term follow-up of the Italian trial of interferon-α versus conventional chemotherapy in chronic myeloid leukemia Blood 1998 92: 1541–1548

  9. 9

    Talpaz M, Kantarjian H, Kurzrock R, Trujillo JM, Gutterman JU . Interferon alpha produces sustained cytogenetic responses in chronic myelogenous leukemia Ann Intern Med 1991 114: 532–538

  10. 10

    Sokal JE, Leong SS, Gomez GA . Preferential inhibition by cytarabine of CFU-GM from patients with chronic granulocytic leukemia Cancer 1987 59: 197–202

  11. 11

    Sokal JE, Gockerman JP, Bigner SH . Evidence for a selective antileukemic effect of cytosine arabinoside in chronic granulocytic leukemia Leukemia Res 1988 12: 453–458

  12. 12

    Robertson MJ, Tantravahi R, Griffin JD, Canellos GP, Cannistra SA . Hematologic remission and cytogenetic improvement after treatment of stable-phase chronic myelogenous leukemia with continuous infusion of low dose cytarabine Am J Hematol 1993 43: 95–102

  13. 13

    Bezwoda WR, Mansoor N, Seymour L . Combined cytosine arabinoside plus interfron alpha: I. Interferon α potentiates the effect of cytosine arabinoside in HL 60 cells by stimulation of apoptosis. II. Clinical studies in leukemia and lymphoma Int J Oncol 1993 2: 463–467

  14. 14

    Guilhot F, Dreyfus B, Brizard A, Huret JL, Tanzer J . Cytogenetic remissions in chronic myelogenous leukemia using interferon alpha-2a and hydroxyurea with or without low dose cytosine-arabinoside Leuk Lymphoma 1991 4: 49–55

  15. 15

    Kantarjian HM, Keating MJ, Esthey EH, O'Brien S, Pierce S, Beran M, Koller C, Feldman E, Talpaz M . Treatment of advanced stages of Philadelphia chromosome-positive chronic myelogenous leukemia with interferon-α and the low dose cytarabine J Clin Oncol 1992 10: 772–778

  16. 16

    Guilhot F, Chastang C, Michallet M, Guerci A, Harousseau JL, Maloisel F, Bouabdallah R, Guyotat D, Cheron N, Nicolini F, Abgrall JF, Tanzer J . Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia N Engl J Med 1997 337: 223–229

  17. 17

    Guilhot F, Guerci A, Maloisel F, Harousseau JL, Brière J, Ifrah N, Abgrall JF, Guyotat D, Christian B, Bauduer F, Jaubert D, Martin C, Guilhot J, Chastang C . Follow-up of 1047 patients with chronic myelogenous leukemia treated with interferon or interferon with cytarabine Blood 1997 90 (Suppl. 1): 2299a (Abstr.)

  18. 18

    Rosti G, Bonifazi F, De Vivo A, Martinelli G, Russo D, Trabacchi E, Tura S . Cytarabine increases karyotypic response and survival in IFNα treated chronic myelogenous leukemia patients: results of a national prospective randomized trial of the Italian Cooperative Study Group in CML Blood 1999 94 (Suppl. 1): 2669a (Abstr.)

  19. 19

    Braess J, Freund M, Hanauske A, Heil G, Kaufmann C, Kern W, Schüssler M, Hiddemann W, Schleyer E . Oral cytarabine ocfosfate in acute myeloid leukemia and non-Hodgkin's lymphoma phase I/II studies and pharmacokinetics Leukemia 1998 12: 1618–1626

  20. 20

    Guilhot F, Harousseau JC, Fiere D, Rapp MJ, Michallet M, David M, Schuessler M . Phase I/II trial of Ara-c prodrug YNKO1 in chronic myelogenous leukemia patients: hematologic and cytogenetic responses Proc Am Soc Clin Oncol 1996 15: 1402a (Abstr.)

  21. 21

    Guilhot F, Maloisel F, Guyotat D, Vilque JP, Michallet M, Harousseau JL, Bordessoule D, Bouabdallah R, Tertian G, Blanc M, Ifrah N, Audhuy B, Christian B, Bauduer F, Eisenmann JC, Traulle C, Rossanino S, Wetterwald C, Casassus P, Maisonneuve H, Guilhot J, Chastang C . Significant survival improvement with a combination of interferon alpha 2b (IFN) and cytarabine (Ara-C) in chronic myeloid leukemia (CML). Update of randomized trial Proc Am Soc Clin Oncol 1999 18: 23a (Abstr.)

  22. 22

    Kühr T, Eisterer W, Apfelbeck U, Linkesch W, Bechter O, Zabernigg A, Geissler K, Barbieri G, Duba C, Gastl G, Thaler J . Treatment of patients with advanced chronic myelogenous leukemia with interferon-alpha-2b and continuous oral cytarabine ocfosfate (YNKO1): a pilot study Leukemia Res 2000 24: 583–587

  23. 23

    Mollee P, Taylor K, Arthur C, Januszewciz H, Grigg A, Hughes T, Bradstock K, Wolf M, Gibson J, Schwarer T, Spencer A, Browett P, Hawkins T, Seldon M, Herrmann R, Martin N, Shina S, Low C, Nagalingam V, Wright S, Rodwell R, Coulston J, Morton J, Taylor D . A phase II study of interferon alpha (IFN) and intermittent oral cytarabine (YNKO) in the treatment of newly diagnosed chronic myeloid leukemia (CML) Blood 2000 96 (Suppl. 1): 545a (Abstr.)

  24. 24

    Kantarjian HM, O'Brien S, Smith TL, Rios MB, Cortes J, Beran M, Koller C, Giles FJ, Andreef M, Kornblau S, Giralt S, Keating MJ, Talpaz M . Treatment of Philadelphia chromosome-positive early chronic-phase chronic myelogenous leukemia with daily doses of interferon alpha and low-dose cytarabine J Clin Oncol 1999 17: 284–292

  25. 25

    Kano Y, Akutsu M, Tsunoda S, Mano H, Sato Y, Honma Y, Furukawa Y . In vitro cytotoxic effects of a tyrosine kinase inhibitor STI571 in combination with commonly used antileukemic agents Blood 2000 97: 1999–2007

Download references

Acknowledgements

This work was supported by grants from Schering-Plough, USA, the Programme Hospitalier de Recherche Clinique and Ligue Nationale contre le Cancer, France. We are indebted to Doctor Stephen O'Brien for reviewing this manuscript and to Cécile Vignaud-Demer for technical assistance.

Author information

Correspondence to F Guilhot.

Rights and permissions

Reprints and Permissions

About this article

Keywords

  • chronic myelogenous leukemia
  • interferon
  • oral formulation of cytarabine (YNK01)

Further reading