Interferon-{alpha}-2b and oral cytarabine ocfosfate for newly diagnosed chronic myeloid leukaemia

P. Mollee1,*, C. Arthur2, T. Hughes3, H. Januszewicz4, A. Grigg5, K. Bradstock6, M. Wolf4, J. Gibson7, A. P. Schwarer8, A. Spencer8, P. Browett9, T. Hawkins9, M. Seldon10, R. Herrmann11, A. Watson12, J. F. Seymour4, N. Martin13, S. Shina14, C. Low14, S. Wright13, R. Rodwell13, J. Coulston13, J. Morton13, H. Blacklock15, D. Taylor13 and K. M. Taylor13

1 Princess Alexandra Hospital, Woolloongabba, Queensland; 2 Royal North Shore Hospital, St Leaonards, NSW; 3 Royal Adelaide Hospital, Adelaide, SA; 4 Peter MacCallum Cancer Institute, Melbourne, Victoria; 5 Royal Melbourne Hospital, Melbourne, Victoria; 6 Westmead Hospital, Sydney, NSW; 7 Royal Prince Alfred Hospital, Camperdown, NSW; 8 The Alfred Hospital, Melbourne, Victoria, Australia; 9 Auckland Hospital, Auckland, New Zealand; 10 Mater Hospital Newcastle, Newcastle, NSW; 11 Royal Perth Hospital, Perth, WA; 12 Townsville General Hospital, Douglas, Queensland; 13 Mater Hospital Brisbane, Brisbane, Queensland; 14 Schering-Plough, Australia; 15 Middlemore Hospital Auckland, Auckland, New Zealand

* Correspondence to: Dr P. Mollee, Haematology Department, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland 4102, Australia. Tel: +61-7-324023961; Fax: +61-7-32407042; Email: peter_mollee{at}health.qld.gov.au


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: Treatment with interferon and subcutaneous cytarabine produces superior cytogenetic responses in chronic myeloid leukaemia (CML) than treatment with interferon alone, but at the expense of greater toxicity. Cytarabine ocfosfate (YNK01) is an oral precursor of cytarabine that may overcome some of the inconvenience and toxicities associated with subcutaneous cytarabine administration.

Patients and methods: We studied the efficacy and tolerability of combination therapy with interferon-{alpha}-2b and YNK01 in patients with newly diagnosed, untreated CML. Forty patients were treated with interferon-{alpha}-2b (5 MU/m2/day) plus monthly courses of YNK01 (600 mg/day for 10 days) for 1 year.

Results: The 6-month complete haematological response rate was 63% and the 1-year major cytogenetic response rate was 30%, with 10% of cytogenetic responses being complete. With a median follow-up of 57 months, the estimated 5-year overall survival was 86% (95% confidence interval 70% to 94%). Treatment tolerability was poor, with toxicity leading to discontinuation of one or both drugs in 60% of cases. The median daily dose of interferon {alpha}-2b was 7.75 MU and the median dose of YNK01 was 600 mg/day for each 10-day treatment cycle.

Conclusions: Interferon-{alpha}-2b and YNK01 produce cytogenetic responses comparable to those achieved with interferon-{alpha}-2b and parenteral cytarabine, although toxicity was excessive. Alternate dosing strategies may enhance the tolerability of YNK01.

Key words: chronic myeloid leukaemia, cytarabine ocfosfate, interferon


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
There are currently a number of therapeutic options for patients with newly diagnosed chronic myeloid leukaemia (CML). For a minority of patients who are appropriate candidates with a suitable donor, allogeneic stem cell transplantation can achieve complete molecular remissions and cure [1Go]. Recently, imatinib has induced impressive cytogenetic remissions and reduced risk of disease progression, but long-term outcome data are still pending [2Go, 3Go]. Interferon-{alpha} has been demonstrated in several randomised controlled trials [4Go–8Go] to suppress the Philadelphia positive (Ph+) malignant clone and to provide prolonged survival compared with standard chemotherapy. The use of interferon and intermittent parenteral cytarabine has been assessed in two randomised trials [9Go, 10Go]. This combination increases the cytogenetic response rate further, and in one trial [9Go] also improved overall survival compared with interferon alone.

However, subcutaneously administered cytarabine has some disadvantages. Following parenteral administration it rapidly undergoes systemic deamination by the ubiquitous enzyme deoxycytidine deaminase, which results in a relatively short serum half-life [11Go]. It also requires a daily subcutaneous injection to deliver the drug and is associated with upper gastrointestinal symptomatology, especially mucositis and nausea [9Go]. Cytarabine ocfosfate (YNK01) is an oral pro-drug analogue of cytarabine that overcomes some of the drawbacks of the parenterally administered compound. Following oral administration it is metabolised in the liver to active ara-C, and then is released into the circulation, resulting in plasma levels comparable to those achieved after low-dose parenteral cytarabine [12Go].

We explored the combination of interferon-{alpha}-2b and YNK01 in the setting of patients with newly diagnosed CML in a schedule mimicking the cytarabine arm of the French randomised controlled trial [9Go], with 10 days of YNK01 substituting for the parenteral cytarabine.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Adults <75 years of age with newly diagnosed (within 12 months) Ph+ CML were eligible for study. Patients had received no prior therapy with the exception of preliminary hydroxyurea or leukopheresis. Those with additional cytogenetic abnormalities at baseline, features of accelerated disease (according to criteria of the International Bone Marrow Transplant Registry) or blast crisis [13Go] were not eligible, nor were those with poor performance status (WHO grade 3/4) or significant psychiatric, cardiovascular, renal or hepatic disorders. The study was conducted according to the principles outlined in the latest version of the Declaration of Helsinki. Informed consent was obtained according to the guidelines of each local institutional ethics committee.

Therapy
Hydroxyurea was initially administered to patients with a white cell count (WCC) >20 x 109/l as a daily dose of up to 50 mg/kg depending on the WCC. Once the WCC was <20 x 109/l, hydroxyurea was discontinued and not reintroduced while the patients remained in the study.

Interferon-{alpha}-2b (Intron A, supplied by Schering-Plough, Australia) was initiated at a dose of 3 MU subcutaneously daily, once the WCC was <20 x 109/l and then escalated to 5 MU/m2 daily (maximum 10 MU daily) according to tolerance over 4–6 weeks. Once the maximal tolerated dose of interferon-{alpha}-2b was achieved, YNK01 (supplied by Schering-Plough) was administered at 600 mg daily on days 1–10 of every 28-day cycle for 1 year of combination therapy. If a complete haematological response was not achieved after 4 months of combination therapy, then the total dose of YNK01 could be increased by changing to a continuous schedule of daily administration throughout the 28-day cycle.

Dose adjustments
Study drug dosages were adjusted to haematological tolerance according to rules established in the study protocol, with the goal of maintaining the absolute neutrophil count >1 x 109/l and the platelet count >50 x 109/l. In cases of haematological toxicity or non-haematological toxicity of uncertain attribution, the YNK01 dose was reduced while maintaining the maximal tolerated interferon dose, since conservation of the interferon dose had priority over that of the YNK01. For example, if the day 29 platelet count was <50 x 109/l or the absolute neutrophil count was <1 x 109/l, therapy was withheld until the blood counts recovered above these levels and the daily dose of YNK01 was reduced by 200 mg, with the interferon recommencing at the previously established dose. For non-haematological toxicity grade >2, drugs were withheld until resolution to grade 1 and the next cycle's dose of YNK01 or interferon was reduced by 50%.

Blood counts were performed weekly during the initial interferon dose escalation phase and the first month of combination therapy. Thereafter, blood tests were performed on days 1 and 22 of each 28-day cycle. Bone marrow aspirates and cytogenetic studies were performed every 3 months in the first year and then every 6 months at the physician's discretion.

After 12 months of treatment, patients in complete cytogenetic remission (CCR) continued on interferon alone. Those with major or minor cytogenetic responses could continue on combination therapy with YNK01 (provided by Schering-Plough on a compassionate release basis) and interferon. Patients with no haematological or cytogenetic response after 12 months of combination therapy were managed at the discretion of their treating physician.

End points
The primary end point was the achievement of a major cytogenetic response (MCR) after 12 months of combination therapy. Other efficacy end points included the 6-month complete haematological response rate (CHR) and overall survival. A CHR required disappearance of all signs and symptoms of the disease (including palpable splenomegaly), a WCC <10 x 109/l with a normal differential and a platelet count <400 x 109/l. Cytogenetic responses were based on the percentage of Ph+ cells in at least 20 metaphases from bone marrow samples. Cytogenetic responses were defined as follows: complete, 0% Ph+ cells; partial 1% to 34% Ph+ cells; minor 35% to 95% Ph+ cells; and major responses included both partial and complete responses. Patients discontinuing treatment due to toxicity without having achieved a cytogenetic response and not assessable at 1 year were considered to have not achieved any cytogenetic remission.

Safety and toxicity of the regimen was assessed using the National Cancer Institute Common Toxicity Criteria.

Statistical methods
The calculations for the study sample size were based on the reported MCR of 24% for interferon compared with 41% for the combination of interferon and subcutaneous cytarabine [9Go]. Assuming a response rate of 41% for the interferon and YNK01 combination, an {alpha} of 0.05 and a power of 0.8, at least 32 patients would be required to be 95% certain that the true response rate exceeded 23% (i.e. the MCR observed in a historic cohort treated with interferon alone).

All statistical analyses were performed on an intention-to-treat basis. The influence of pretreatment characteristics on the achievement of a MCR was assessed by the Wilcoxon rank sum test for continuous variables and Fisher's exact test for categorical variables. Overall survival curves were derived by the method of Kaplan and Meier, with survival measured from the date of diagnosis until death from any cause. Continuous variables are reported as medians with ranges in brackets. Statistical analysis was performed using STATA (University of Texas Statistical Software Package).


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Forty-four patients with newly diagnosed CML were enrolled in the study from December 1997 to March 2000. Four patients did not meet the inclusion criteria due to the presence of additional cytogenetic abnormalities (n=1), concurrently diagnosed coeliac disease with the potential to interfere with study drug absorption (n=1), the presence of a human leukocyte antigen-identical sibling with patient preference for transplantation (n=1) or only 10% Ph+ metaphases at study entry (n=1). Thus, a total of 40 patients were eligible for study. Patient characteristics are detailed in Table 1.


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Table 1. Patient characteristics

 
Response
Table 2 details the haematological and cytogenetic responses. Twenty-five (63%) patients achieved a CHR by 6 months, with the median time to achieve a CHR being 2 months. The probability of achieving MCR and CCR at 1 year was 30% and 10%, respectively. The overall response (major and minor responses) at 1 year was 60%. The median time to a MCR and CCR was 5 months (range 3–10) and 4.5 months (range 3–7), respectively. While 38% of patients achieved a MCR at some time during the first year of therapy, the MCR at 1 year was less, mainly due to interferon intolerance necessitating dose reduction or cessation with subsequent loss of cytogenetic response. There was no significant difference in MCR between those with low risk compared with non-low risk Sokal (35% versus 26%; P=0.7) and Hasford (38% versus 21%; P=0.3) scores.


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Table 2. Haematological and cytogenetic responses

 
Six patients who failed to achieve a CHR by 4 months were switched to continuous dosing of YNK01. Of these, four failed to respond and two achieved CHR, one subsequently achieving MCR and the other CCR. Only one patient in the entire cohort without evidence of any cytogenetic response at 3 months went on to achieve MCR, this being one of the aforementioned patients who received continuous dosing of YNK01.

Follow-up
With a median follow-up of 57 months, the estimated overall survival is 86% (95% confidence interval 70% to 94%) at 5 years. One patient was lost to follow-up 18 months post-study entry. Eleven patients proceeded to allogeneic stem cell transplantation following interferon intolerance (n=7) or failure (n=4). Two of these 11 patients have died from transplant-related causes, six are alive in ongoing remission and three have relapsed and commenced imatinib. Twenty-seven other subjects have gone on to receive imatinib, of whom three have died from progressive disease. No patients commenced imatinib during the study period. One patient remains on interferon in CCR.

Compliance and toxicity
All patients received interferon. During the 12-month study period, the median interferon dose was 7.75 MU/day (range 1.75–10). Two patients came off the study due to interferon toxicity prior to receiving any dose of YNK01. Twenty-two patients achieved the target dose of 5 MU/m2, but only 12 patients maintained this dose for >4 months and only six patients completed 1 year of combination therapy without further dose reduction. The median number of courses of YNK01 in the first year was seven (range zero to 13), with the median daily dose administered being 600 mg (range 100–700) for the 10 days of treatment. Only one patient had a median YNK01 dose >600 mg, with therapy ceasing after two cycles due to interferon intolerance at a dose of 2 MU/day. Five patients completed 1 year of combination therapy with YNK01 at 600 mg for 10 days and three patients completed 1 year of combination therapy with YNK01 at a reduced dose. Of the six patients who switched to continuous dosing of YNK01, the median dose was 350 mg/day with four patients completing 1 year of combination therapy. Six of those discontinuing YNK01 were able to continue on interferon alone.

Overall, 60% of patients experienced an adverse event leading to the discontinuation of combination therapy prior to 1 year. Of these, 13 were primarily related to interferon toxicity, four related mainly to YNK01 and seven had cytopenias related to both drugs. Two patients ceased treatment after 8 and 11 months due to disease progression, and two discontinued treatment due to non-compliance.

Side-effects are detailed in Table 3. Toxicity was significant but manageable. While the toxicities of YNK01 and interferon were sometimes difficult to differentiate, YNK01 seemed to be associated with gastrointestinal toxicity (altered taste, mucositis, abdominal pain and diarrhoea), skin exanthema and more severe thrombocytopenia.


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Table 3. Side-effects of interferon and cytarabine ocfosfate (YNK01) therapy in 40 patients with newly diagnosed chronic-phase chronic myeloid leukaemia

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The association between the achievement of cytogenetic responses and improved overall survival in patients with CML treated with interferon [14Go] provided the rationale to study interferon and cytarabine used in combination to improve cytogenetic response rates and thus impact favourably on survival. Two randomised trials have demonstrated increased cytogenetic responses in those treated with the combination compared with those treated with interferon alone [9Go, 10Go], although improved overall survival was only demonstrated in one trial. This survival benefit in the French trial has persisted long-term, with 5-year overall survival being 58% versus 70% for the interferon and combination arms, respectively [15Go]. Significant toxicity resulted from the addition of cytarabine in this study, however, with 50% of patients discontinuing treatment due to adverse events. Side-effects related to the cytarabine included mucositis, nausea, vomiting, weight loss and the inconvenience and discomfort of an additional subcutaneous injection. As an oral formulation of cytarabine may overcome some of these drawbacks, we explored the effectiveness and tolerability of combination therapy with interferon-{alpha}-2b and YNK01 in patients with newly diagnosed CML.

We report a CHR at 6 months of 63%, which compares favourably with other trials of interferon and intermittent cytarabine (Table 4). The MCR of 30% at 1 year is in keeping with prior reports of interferon and subcutaneous cytarabine, as well as recent similar trials of interferon and intermittent YNK01 [16Go, 17Go]. These latter two trials by the French and Italian CML study groups had a similar design and therapeutic plan, with the exception of the YNK01 being delivered for 14 days every month compared with 10 days every month in our study. The reduced cytogenetic response rate in the French trial [16Go] (16% MCR at 6 months) was thought to reflect the inability to deliver effective anti-leukaemic doses of the YNK01, mostly because of treatment discontinuation in 63% of patients due to toxicity. A further 22% of patients had discontinued treatment at 1 year due to disease progression, in comparison with 5% in our series. It is possible that the lesser cumulative dose of YNK01 in our study was responsible for greater tolerability and thus improved effective drug delivery, but the small numbers involved preclude any firm conclusion. The Italian study of interferon and YNK01 [17Go] demonstrated a 1-year MCR of 28%, with 48% of patients discontinuing therapy due to toxicity (25%), progression (13%) or other reasons (9%).


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Table 4. Comparison of published trials of interferon and intermittent cytarabine ocfosfate (YNK01) for chronic myeloid leukemia (CML)

 
A substantial proportion of our patients also had to discontinue therapy due to toxicity (60%) or non-compliance (5%). This is similar to the French trial of interferon and subcutaneous cytarabine, where 50% of patients discontinued therapy due to toxicity (Table 4). While it is difficult to differentiate accurately between the adverse effects of YNK01 and interferon, YNK01 appeared to cause more gastrointestinal events such as altered taste, mucositis, nausea and diarrhoea, in addition to more pronounced thrombocytopenia than expected with interferon alone.

These toxicities prompt questions about the optimal dose and scheduling of YNK01 administration. Following the high rates of toxicity in the French trial, the investigators returned to a phase I study to determine the maximum tolerated dose of YNK01 when given with interferon in both intermittent and continuous schedules [18Go]. The maximum tolerated dose of the 14-day intermittent schedule was 500 mg (total 7000 mg/month), with dose-limiting toxicities being abdominal pain, diarrhoea and thrombocytopenia. This total monthly dose was similar to that of our trial, where the cumulative dose was 6000 mg/month. Interestingly, the maximum tolerated dose of the continuous schedule was 200 mg/day (total 5600 mg/month), with dose-limiting toxicity being thrombocytopenia. This suggests that use of the continuous schedule may abrogate much of the gastrointestinal toxicity. Continuous administration of YNK01 would also expose the leukaemic cells to the effect of cytarabine for a longer period, and may further improve disease response, as demonstrated in studies of interferon and continuous subcutaneous cytarabine [19Go].

Interferon-based therapies have now been superseded by the introduction of imatinib, a drug that has revolutionised the management of CML. It is thus unlikely that the interferon-{alpha}-2b and YNK01 combination will have a significant role in initial treatment strategies. YNK01 may, however, have a role in combination therapy with imatinib. Imatinib therapy produces dramatic response rates and prolongs time to treatment failure, but complete molecular remissions are uncommon and disease progression is still seen [3Go]. Combination therapy is likely to be required to overcome these problems, and in vivo data suggest that cytarabine and imatinib may have synergic activity [20Go] and that cytarabine may overcome imatinib resistance [21Go]. The availability of cytarabine in an oral preparation makes YNK01 and imatinib an attractive combination to test clinically in chronic- or advanced-phase CML. The toxicity profile of YNK01 demonstrated in our study suggests that an intermittent schedule of administration is not sustainable. Continuous administration of YNK01 may prove more tolerable in this setting, and merits further investigation in studies of sequential or combination therapy with imatinib.


    Acknowledgements
 
The authors gratefully acknowledge the financial and strong support to this study provided by Schering-Plough, Australia.

Received for publication December 31, 2003. Revision received May 27, 2004. Accepted for publication July 8, 2004.


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 Introduction
 Patients and methods
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