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Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Azacitidine, an inhibitor of DNA methyltransferase, is reported to have antileukemic efficacy and is approved for the treatment of myelodysplastic syndromes in Western countries. We have conducted a Phase I/II study of azacitidine in Japanese patients with myelodysplastic syndromes to evaluate its pharmacokinetics, efficacy, and safety. In all, 53 patients received 75 mg/m2 azacitidine subcutaneously or intravenously once daily for seven consecutive days on a 28-day cycle. The Cmax following intravenous administration was approximately 3.7-fold higher than that following subcutaneous administration, whereas the area under the plasma concentration–time curve from time zero to infinity was comparable for subcutaneous and intravenous administration. The bioavailability of azacitidine following subcutaneous administration was 91.1%, indicating that azacitidine is nearly completely absorbed after subcutaneous administration. The hematologic improvement and hematologic response rates were 54.9% (28/51) and 28.3% (15/53), respectively, and there were no differences between the two routes of administration. Azacitidine was generally well tolerated and clinically manageable in Japanese patients with myelodysplastic syndromes. Adverse events occurred in ≥20% of patients included hematologic toxicity, gastrointestinal events, and general disorders, such as malaise. Grade 3/4 adverse events that occurred in ≥50% of patients were all due to hematologic toxicity. The safety profile of azacitidine was generally similar for both routes of administration, with the exception of injection site reactions observed following subcutaneous administration. These results indicate that azacitidine can be expected to be a useful therapeutic agent in Japanese patients with myelodysplastic syndromes. (Cancer Sci 2011; 102: 1680–1686)

Myelodysplastic syndromes are hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral blood cytopenias and, in many patients, there is a risk of progression to AML.(1,2) Peripheral blood cytopenias, anemia, neutropenia, and thrombocytopenia are the hallmark symptoms of MDS,(3) often resulting in death due to complications such as infection and hemorrhage.

Although no clear association has been identified between genetic aberrations and the pathogenesis of MDS, the presence and expansion of malignant clones of pluripotent hematopoietic stem cells have been detected. Epigenetic alterations, such as hypermethylation of DNA, have been associated with the pathogenesis of MDS.(4,5) Marked methylation of the promoter domain of a tumor-suppressor gene encoding a cell cycle-regulating factor decreases the expression of the gene and induces abnormal cell proliferation.

Azacitidine is a cytidine nucleoside analog, the activity of which against abnormal hematopoietic cells may be mediated by demethylation of DNA and cytotoxic effects. In a Phase III study conducted by the CALGB, azacitidine yielded significantly higher response rates in all types of MDS classified according to the FAB classification(6) compared with best supportive care.(7,8) In addition, in a recently reported international multicenter Phase III study (the AZA-001 study), azacitidine significantly prolonged survival in patients with higher-risk MDS compared with conventional care regimens.(9) Azacitidine is the first drug that has been demonstrated to alter the natural history of MDS.(7,9)

Pharmacokinetic evaluation of azacitidine is limited(10,11) and has not been performed in Japanese patients. Although azacitidine is currently approved for s.c. and i.v. administration in the US, no clinical trial has compared the PK, safety, and efficacy of azacitidine administered s.c. and i.v. Thus, we undertook the present study, an open-label, multicenter study, to evaluate the PK, efficacy, and safety of azacitidine following s.c. and i.v. administration in Japanese patients with MDS.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Patient selection.  Patients aged between 20 and 79 years who had been diagnosed with an MDS subtype (e.g. RA, RARS, RAEB, or RAEB-T), according to FAB classification,(6) were enrolled in the present study. Patients with secondary (treatment-related) MDS with RAEB-T were excluded from the study. Other enrollment criteria included an Eastern Cooperative Oncology Group performance status of 0 or 1,(12) an estimated life expectancy ≥12 weeks, adequate hepatic function (total bilirubin ≤1.5-fold the ULN, aspartate aminotransferase or alanine aminotransferase levels ≤2-fold the ULN), adequate renal function (serum creatinine ≤1.5-fold the ULN, serum carbonates ≥19 mEq/L), and ≥4 weeks since the most recent treatment for MDS, such as immunosuppressive drugs or androgens (patient who had received chemotherapy or radiotherapy were excluded from the study). Patients with RA or RARS needed to meet at least one of the following criteria: (i) hemoglobin <10 g/dL requiring red blood cell transfusion for at least 3 months before study entry; (ii) platelet count <5 × 104/mm3 or significant clinical hemorrhage; and/or (iii) absolute neutrophil count <1000/mm3, with susceptibility to infection requiring treatment with antibiotics. The Institutional Review Board of each participating hospital approved the study protocol and the study was conducted in accordance with Good Clinical Practice for Trials of Drugs and the Declaration of Helsinki. All patients provided written informed consent.

Study design.  Azacitidine was administered at 75 mg/m2 once daily for 7 days on a 28-day cycle either s.c. or i.v. (10-min infusion). For s.c. administration, azacitidine suspension was prepared at a final concentration of 25 mg/mL. For doses >100 mg (4 mL), the dose was divided equally between two syringes and injected into two separate sites. A serotonin 5-HT3 receptor antagonist was administered approximately 30 min prior to azacitidine to prevent nausea and vomiting.

The study was divided into three parts: a Phase I part, a Phase II part, and an extended administration part. Patients were alternately assigned to receive s.c. or i.v. administration in order of their enrollment in the study. In the Phase I part of the study, PK and safety were examined after the administration of two cycles of azacitidine with a cross-over design for route of administration (s.c. to i.v. or i.v. to s.c.) to evaluate PK. In the Phase II part of the study, azacitidine was administered for a minimum of four cycles and its safety and efficacy were evaluated. Patients who received azacitidine for two cycles in the Phase I part of the study continued with azacitidine for an additional two cycles in the Phase II part of the study. In the extended administration part of the study, treatment was continued for patients who met the criteria of PR or HI in the Phase II part of the study as long as they continued to benefit, or until disease progression, for a maximum of 18 cycles.

During the study, the dose of azacitidine could be adjusted (either delayed or decreased) at the beginning of any cycle on the basis of hematologic laboratory results (nadir counts), renal function, serum electrolytes (serum bicarbonate, blood urea nitrogen, and serum creatinine), and the occurrence of Grade 3/4 non-hematologic toxicity. If no HI was evident by Cycle 2 and if no Grade 3/4 non-hematologic toxicity occurred (other than nausea or vomiting), the dose of azacitidine could be increased by 100 mg/m2 for the next cycle.

A change in the route of administration was allowed only at the discretion of the investigator depending on the patient’s condition (but not during the administration period). Patients who met the criteria of CR received azacitidine for an additional three cycles and were then followed-up off treatment.

Pharmacokinetics.  The PK of azacitidine was evaluated on Day 1 in each cycle of the Phase I part of the study. Blood samples were taken before administration and then 15 and 30 min and 1, 2, 3, 4, and 8 h after s.c. administration. For i.v. administration, blood samples were taken before administration and then at 5, 10, and 30 min and 1, 2, 3, 4, and 8 h after administration. Plasma concentrations of azacitidine were measured by LC/MS/MS. The lower limit of quantification was 1.0 ng azacitidine/mL plasma.

The following PK parameters were calculated for each patient for both routes of administration, when applicable. Both Cmax and tmax were determined from observed values. The elimination rate constant (β) was estimated by linear regression of the logarithm of the terminal plasma concentrations as a function of time from at least three data points showing the highest correlation coefficient and t½,β was calculated as 0.693/β. A linear trapezoidal rule area was used to calculate the AUC0–t. Extrapolation to infinity was obtained as Ct/β and this area was added to the AUC0–t to provide an estimate of AUC0–∞. The systemic bioavailability (%) after s.c. administration was calculated from the ratio of the s.c. geometric mean AUC0–∞ to the i.v. geometric mean AUC0–∞. The PK parameters were calculated using WinNonlin Professional v. 5.2.1 (Pharsight, Mountain View, CA, USA).

Efficacy evaluation.  The primary and secondary efficacy endpoints in the present study were the HI and HR rates, respectively, determined according to IWG 2006 criteria.(13) The primary endpoint of HI included evaluation of HI-E, HI-P, and HI-N. Furthermore, HI was defined as the presence of HI in at least one cell line. The secondary endpoint of HR included evaluation of CR, PR, and mCR, defined as marrow improvement evidenced by ≤5% myeloblasts and a ≥50% decrease in myeloblasts over the pretreatment period without an improvement in cytopenias. Efficacy was evaluated after completion of Cycle 4 and after completion of the last cycle, and the best response was defined as the best HI or HR achieved during the study period. The HI was evaluated in patients with abnormal pretreatment values defined according to IWG 2006 response criteria.(13) Transfusion independence was also evaluated in patients who were blood transfusion dependent at baseline. A patient was considered to be transfusion independent at baseline if the patient had had no transfusions during the 56 days prior to and including the first day of treatment. Otherwise, the patient was considered to be transfusion dependent. A patient was considered to be transfusion independent during the study period if the patient had no transfusions over the course of ≥56 consecutive days during the study period.

Safety evaluation.  The occurrence of AE was monitored from the first administration of azacitidine to Day 29 of the last cycle. Furthermore, the occurrence of AE was monitored until just before any change in treatment in cases in which treatment was discontinued or changed to other treatment due to progression of MDS or for other reasons. The AE were classified according to the Medical Dictionary for Regulatory Activities, Japanese edition (MedDRA/J v. 12.0, http://www.pmrj.jp/jmo/php/indexj.php, accessed 22 Jun, 2011), whereas the severity of the AE was evaluated according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, v. 3.0 (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf, accessed 22 Jun, 2011).

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Patient characteristics.  In all, 54 patients were enrolled in the present study and 53 received azacitidine (10 in the Phase I part of the study and 43 in the Phase II part). One patient dropped out of the study before initiation of treatment because of the discovery of a serious complication (emphysema) after enrollment. Thirty-four patients (64.2%) continued on treatment in the extended administration part of the study. The baseline characteristics of the 53 patients are given in Table 1 and were generally similar for patients in the s.c. and i.v. groups. Nine patients (17.0%) had AML based on the WHO classification.(14) All patients had de novo MDS.

Table 1.   Patient characteristics
Patient characteristicsPhase I (= 10)No. patients in the Phase I and II studies (%)
All (= 53)Subcutaneous administration (= 26)Intravenous administration (= 27)
  1. AML, acute myelogenous leukemia; ECOG, Eastern Cooperative Oncology Group; FAB, French–American–British; IPSS, International Prognostic Scoring System; MDS-U, myelodysplastic syndromes, unclassifiable; RA, refractory anemia; RAEB, refractory anemia with excess blasts; RAEB-1, refractory anemia with excess blasts-1; RAEB-2, refractory anemia with excess blasts-2; RAEB-T, refractory anemia with excess blasts in transformation; RARS, refractory anemia with ringed sideroblasts; RCMD-RS, refractory cytopenia with multilineage dysplasia and ringed sideroblasts; WHO, World Health Organization.

Sex
 Male836 (67.9)17 (65.4)19 (70.4)
 Female217 (32.1)9 (34.6)8 (29.6)
Age (years)
 Median64656466
 Range58–7735–7737–7735–77
ECOG performance status
 0633 (62.3)16 (61.5)17 (63.0)
 1420 (37.7)10 (38.5)10 (37.0)
FAB classification
 RA416 (30.2)7 (26.9)9 (33.3)
 RARS13 (5.7)1 (3.8)2 (7.4)
 RAEB420 (37.7)11 (42.3)9 (33.3)
 RAEB-T114 (26.4)7 (26.9)7 (25.9)
WHO classification
 RA39 (17.0)6 (23.1)3 (11.1)
 RCMD15 (9.4)1 (3.8)4 (14.8)
 RARS0000
 RCMD-RS13 (5.7)1 (3.8)2 (7.4)
 RAEB-1211 (20.8)6 (23.1)5 (18.5)
 RAEB-2214 (26.4)8 (30.8)6 (22.2)
 MDS-U0000
 del (5q)02 (3.8)02 (7.4)
 AML19 (17.0)4 (15.4)5 (18.5)
IPSS
 Low0000
 Intermediate-1523 (43.4)10 (38.5)13 (48.1)
 Intermediate-2315 (28.3)10 (38.5)5 (18.5)
 High215 (28.3)6 (23.1)9 (33.3)
Bone marrow blasts (%)
 <5520 (37.7)9 (34.6)11 (40.7)
 5–10213 (24.5)8 (30.8)5 (18.5)
 10–20212 (22.6)6 (23.1)6 (22.2)
 20–3018 (15.1)3 (11.5)5 (18.5)
 Median4.98.58.458.8
 Range0.0–23.00.0–29.90.0–29.90.0–28.6
Cytogenetic abnormalities
 −619 (35.8)10 (38.5)9 (33.3)
 +434 (64.2)16 (61.5)18 (66.7)
Karyotype risk
 Good624 (45.3)12 (46.2)12 (44.4)
 Intermediate313 (24.5)6 (23.1)7 (25.9)
 Poor116 (30.2)8 (30.8)8 (29.6)
Cytopenia
 0/118 (15.1)3 (11.5)5 (18.5)
 2/3945 (84.9)23 (88.5)22 (81.5)
Time since original diagnosis (years)
 <1422 (41.5)10 (38.5)12 (44.4)
 1–219 (17.0)5 (19.2)4 (14.8)
 2–316 (11.3)3 (11.5)3 (11.1)
 ≥329 (17.0)6 (23.1)3 (11.1)
 Unknown27 (13.2)2 (7.7)5 (18.5)

The median number of cycles of azacitidine administered was 7 (range 1–18). Forty-two of 53 patients (79.2%) received four or more cycles, 32 (60.4%) received six or more cycles, 15 (28.3%) received 12 or more cycles, and eight (15.1%) completed 18 cycles of treatment. Of the 32 patients who received six or more cycles, 20 (62.5%) remained on 75 mg/m2 azacitidine throughout the study period with no dose adjustments.

On the basis of hematology laboratory values (nadir counts), the next cycle was delayed for 30 patients (56.6%) and, of these, 18 (60.0%) had their dose reduced. The dose of azacitidine was not increased above 75 mg/m2 for any of the patients.

The route of administration was changed for seven patients during the study period. Four patients were changed from s.c. to i.v. due to injection site reactions (= 3) and hemorrhagic event (purpura; = 1), whereas three patients were changed from i.v. to s.c. administration owing to difficulties in securing a route of access because of small blood vessels (= 2) and extravasation (= 1).

Pharmacokinetics.  The time course of plasma concentrations of azacitidine after s.c. or i.v. administration are shown in Figure 1 and the PK parameters are give in Table 2. Of 10 patients, one discontinued s.c. administration in the second cycle and another had the i.v. dose reduced to 25 mg/m2 azacitidine on the basis of hematology laboratory values (nadir counts) in the second cycle. The bioavailability of azacitidine in the remaining eight patients receiving at 75 mg/m2, s.c., azacitidine was 91.1%. The Cmax for i.v. administration was approximately 3.7–fold higher than for s.c. administration, whereas the AUC0–∞ was comparable between the two routes of administration.

image

Figure 1.  Time-course of mean plasma concentrations of azacitidine (= 9) following s.c. (bsl00001) or i.v. (○) administration. The 8-h plasma concentrations were not plotted because they were measurable in three patients only (s.c. administration) or were below the limit of detection in all patients (i.v. administration). Data show the mean ± SD.

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Table 2.   Pharmacokinetic parameters for azacitidine after subcutaneous and intravenous administration
Route of administrationnDose (mg/m2)Cmax (ng/mL)tmax (h)AUC0–∞ (ng × h/mL)t½,β (h)BA† (%)
  1. Unless noted otherwise, data are given as the mean ± SD. †= 8. –, not calculated; Cmax, maximum plasma concentration; tmax, time to maximum concentration; AUC0–t, area under the plasma concentration–time curve from time zero to the last measurable time point; AUC0–∞, area under the plasma concentration–time curve from time zero to infinity; t½,β, half-life in the beta-phase; BA, bioavailability.

Subcutaneous9751120 ± 2100.361 ± 0.2531180 ± 2501.05 ± 0.6191.1
Intravenous9754170 ± 18500.158 ± 0.0281440 ± 5200.441 ± 0.041
Intravenous125 9530.0833 4550.389

Efficacy.  The best responses obtained in the present study are listed in Table 3. The HI rate was 54.9% (28/51) and the median time to reach the criterion for any improvement was 53.5 days (range 20–217). The HR was 28.3% (15/53) and the median time to reach the criterion for any remission was 113 days (range 49–247). All CR patients had two or three cell line cytopenias at baseline, as defined by the IPSS classification.(15) In addition, of the seven mCR patients, six had two or three cell line cytopenias at baseline, four achieved trilineage HI and one achieved bilineage HI. Subgroup analyses of best response among FAB, IPSS classifications, or route of administration are given in Table 4. There were no marked differences within each subgroup.

Table 3.   Best response
ResponseNn%95% CI
  1. †International Working Group 2006 response criteria(13) define the cases subject to evaluation of hematologic improvement (HI) as follows: baseline hemoglobin <11 g/dL for erythroid improvement (HI-E), baseline platelet count <10 × 104/mm3 for platelet improvement (HI-P), and baseline absolute neutrophil count <1000/mm3 for neutrophil improvement (HI-N). ‡Hematologic responses were not evaluated in the four patients who dropped out of the study during the first cycle of azacitidine treatment. HR, hematologic response; CR, complete remission; PR, partial remission; mCR, marrow complete remission.

Any HI†512854.940.3–68.9
HI-E462145.7
HI-P332266.7
HI-N291448.3
Progression/relapse after HI5335.7
Any HR531528.316.8–42.3
CR53815.1
PR5300
mCR53713.2
Stable disease532649.1
Failure5300
Relapse after CR or PR5300
Disease progression53815.1
Not evaluable‡5347.5
Table 4.   Subgroup analysis of best response
Response% (n/N)
All subjectsFAB classificationIPSSRoute of administration†
RARARSRAEBRAEB-TInt-1Int-2HighSubcutaneousIntravenous
  1. †The route of administration for each patient was defined as the route via which the patient received most cycles of azacitidine treatment (there were several patients in whom the route of administration changed during the treatment period). ‡A patient was considered red blood cell (RBC) transfusion independent at baseline if he or she had undergone no RBC transfusions during the 56 days prior to and including the first day of treatment. The patient was otherwise considered RBC transfusion dependent. A patient was considered RBC transfusion independent during the treatment period if he or she did not undergo any RBC transfusions over a period of ≥56 consecutive days during the treatment period (e.g. Day 1–Day 56, Day 2–Day 57 etc.). HI, hematologic improvement; E, erythroid; P, platelet; N, neutrophil; HR, hematologic response; CR, complete remission; PR, partial remission; mCR, marrow complete remission; RA, refractory anemia; RAEB, refractory anemia with excess blasts; RAEB-T, refractory anemia with excess blasts in transformation; RARS, refractory anemia with ringed sideroblasts; FAB, French–American–British; IPSS, International Prognostic Scoring System; Int-1, intermediate-1; Int-2, intermediate-2.

Any HI54.9 (28/51)50.0 (8/16)100 (3/3)57.9 (11/19)46.2 (6/13)60.9 (14/23)46.2 (6/13)53.3 (8/15)53.8 (14/26)56.0 (14/25)
HI-E45.7 (21/46)40.0 (6/15)100 (3/3)50.0 (9/18)30.0 (3/10)47.6 (10/21)41.7 (5/12)46.2 (6/13)54.5 (12/22)37.5 (9/24)
HI-P66.7 (22/33)46.2 (6/13)50.0 (1/2)100 (9/9)66.7 (6/9)62.5 (10/16)71.4 (5/7)70.0 (7/10)68.8 (11/16)64.7 (11/17)
HI-N48.3 (14/29)60.0 (3/5)0 (0/1)50.0 (8/16)42.9 (3/7)30.0 (3/10)55.6 (5/9)60.0 (6/10)40.0 (6/15)57.1 (8/14)
Any HR28.3 (15/53)18.8 (3/16)33.3 (1/3)35.0 (7/20)28.6 (4/14)21.7 (5/23)33.3 (5/15)33.3 (5/15)26.9 (7/26)29.6 (8/27)
CR15.1 (8/53)18.8 (3/16)33.3 (1/3)15.0 (3/20)7.1 (1/14)17.4 (4/23)13.3 (2/15)13.3 (2/15)11.5 (3/26)18.5 (5/27)
PR0000000000
mCR13.2 (7/53)0020.0 (4/20)21.4 (3/14)4.3 (1/23)20.0 (3/15)20.0 (3/15)15.4 (4/26)11.1 (3/27)
RBC transfusion independent‡55.6 (15/27)55.6 (5/9)100 (3/3)46.2 (6/13)50.0 (1/2)66.7 (10/15)33.3 (2/6)50.0 (3/6)60.0 (9/15)50.0 (6/12)

Of the 27 patients who were RBC transfusion dependent at baseline, 55.6% became transfusion independent during the study period and the proportion of such patients did not differ markedly with FAB or IPSS classifications (Table 4). Transfusion independence on platelet transfusion was not evaluable, because only two patients were platelet transfusion dependent at baseline.

The HI rates following s.c. and i.v. administration were 53.8% (14/26) and 56.0% (14/25), respectively, whereas the corresponding HR rates were 26.9% (7/26) and 29.6% (8/27), respectively (Table 4). There was no difference in efficacy between s.c. and i.v. administration of azacitidine.

The time course of mean values in three hematopoietic lineages in the patients evaluable for HI is shown in Figure 2. Hemoglobin, platelet, and absolute neutrophil counts all increased progressively until Cycle 5 or 6 and were maintained until Cycle 10.

image

Figure 2.  (a) Hemoglobin concentrations, (b) platelet count, and (c) absolute neutrophil count following azacitidine treatment over 18 cycles. Data are the mean ± SEM. n, number of patients evaluable for hematologic improvement at each cycle.

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Safety.  The AE that occurred in ≥20% of patients included hematologic toxicity, gastrointestinal events, and general disorders, such as malaise (Table 5). Grade 3/4 AE, which occurred in ≥50% of patients, were all due to hematologic toxicity. Most Grade 3/4 hematologic toxicities were manageable by dose delay or dose reduction. The median time to onset of nadir hematology values across all cycles was 17 days for hemoglobin and platelets, and 25 days for absolute neutrophil counts.

Table 5.   All adverse events occurring in at least 20% of the 53 patients administered azacitidine
Preferred term†n (%)
NCI-CTC gradeRoute of administration
SubcutaneousIntravenous
1–434Cycle 1 (= 27)Cycle 4 (= 21)Cycle 1 (= 26)Cycle 4 (= 22)
  1. †Adverse events occurring at a frequency of 20% or more are listed. Adverse events are tabulated according to route of administration in each cycle because there were several cases in which the route of administration changed between cycles. NCI-CTC, National Cancer Institute Common Terminology Criteria; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; LDH, lactate dehydrogenase.

Hematologic
 Thrombocytopenia46 (86.8)9 (17.0)25 (47.2)20 (74.1)11 (52.4)21 (80.8)7 (31.8)
 Leukopenia45 (84.9)19 (35.8)22 (41.5)16 (59.3)12 (57.1)18 (69.2)12 (54.5)
 Neutropenia44 (83.0)3 (5.7)40 (75.5)20 (74.1)14 (66.7)19 (73.1)12 (54.5)
 Hemoglobin decreased39 (73.6)7 (13.2)31 (58.5)17 (63.0)8 (38.1)14 (53.8)9 (40.9)
 Erythropenia36 (67.9)7 (13.2)18 (34.0)16 (59.3)8 (38.1)12 (46.2)8 (36.4)
 Hematocrit decreased32 (60.4)5 (9.4)15 (28.3)14 (51.9)6 (28.6)9 (34.6)8 (36.4)
 Lymphopenia29 (54.7)12 (22.6)5 (9.4)10 (37.0)9 (42.9)8 (30.8)6 (27.3)
 Febrile neutropenia16 (30.2)16 (30.2)05 (18.5)04 (15.4)0
Non-hematologic
 Constipation39 (73.6)1 (1.9)011 (40.7)6 (28.6)17 (65.4)11 (50.0)
 Malaise28 (52.8)0010 (37.0)3 (14.3)7 (26.9)1 (4.5)
 Pyrexia24 (45.3)4 (7.5)09 (33.3)1 (4.8)4 (15.4)4 (18.2)
 ALT increased23 (43.4)2 (3.8)011 (40.7)6 (28.6)7 (26.9)2 (9.1)
 Diarrhea23 (43.4)007 (25.9)1 (4.8)6 (23.1)1 (4.5)
 Blood albumin decreased21 (39.6)3 (5.7)08 (29.6)2 (9.5)7 (26.9)2 (9.1)
 AST increased21 (39.6)2 (3.8)09 (33.3)4 (19.0)6 (23.1)3 (13.6)
 Injection site reaction21 (39.6)0018 (66.7)7 (33.3)1 (3.8)0
 Anorexia20 (37.7)3 (5.7)09 (33.3)1 (4.8)5 (19.2)1 (4.5)
 Rash20 (37.7)006 (22.2)2 (9.5)5 (19.2)2 (9.1)
 Blood ALP increased19 (35.8)004 (14.8)6 (28.6)3 (11.5)5 (22.7)
 Nausea18 (34.0)1 (1.9)06 (22.2)07 (26.9)3 (13.6)
 Protein urine present17 (32.1)004 (14.8)2 (9.5)3 (11.5)1 (4.5)
 Blood glucose increased16 (30.2)3 (5.7)006 (28.6)3 (11.5)3 (12.6)
 Blood bilirubin increased16 (30.2)1 (1.9)03 (11.1)4 (19.0)5 (19.2)1 (4.5)
 Blood LDH increased15 (28.3)1 (1.9)05 (18.5)3 (14.3)2 (7.7)1 (4.5)
 Protein total decreased15 (28.3)1 (1.9)08 (29.6)1 (4.8)2 (7.7)1 (4.5)
 Blood urine present15 (28.3)001 (3.7)2 (9.5)3 (11.5)2 (9.1)
 Blood phosphorus decreased13 (24.5)10 (18.9)03 (11.1)03 (11.5)1 (4.5)
 Nasopharyngitis13 (24.5)001 (3.7)1 (4.8)1 (3.8)0
 Injection site erythema13 (24.5)006 (22.2)3 (14.3)01 (4.5)
 Stomatitis11 (20.8)002 (7.4)2 (9.5)2 (7.7)1 (4.5)
 Pruritus11 (20.8)005 (18.5)2 (9.5)3 (11.5)3 (13.6)
 Back pain11 (20.8)002 (7.4)2 (9.5)00

There were no Grade 4 non-hematologic AE and The Grade 3 non-hematologic AE occurring in ≥10% of patients were limited to pneumonia (11.3%; 6/53) and a decrease in blood phosphorus (18.9%; 10/53). Most AE tended to be more pronounced during the first or second cycles of treatment than during later cycles. There were no AE that appeared to increase in frequency over time, suggesting that there were no delayed or cumulative toxicities. There were no relevant differences in the AE profile when analyzed according to FAB or IPSS classifications.

The incidence of AE was comparable between the s.c. and i.v. administration groups, with the exception of injection site reactions, which occurred more frequently following s.c. administration (Table 5). The injection site-related AE observed in the present study were all Grade 2 or lower, and no patients discontinued or interrupted their participation in the study owing to injection site reactions.

A total of 40 SAE was observed in 18 patients (34.0%). The SAE observed in two or more patients included febrile neutropenia (= 7), pneumonia (= 4), sepsis (= 2), neutropenic infection (= 2), thrombocytopenia (= 2), and pericarditis (= 2). With the exception of gastric cancer observed in a 74-year-old patient with RA, the seriousness criterion for SAE was “requiring or prolonging hospitalization.” None of the patients died during the study period; however, one patient died 59 days after the last dose of azacitidine during the follow-up period for AE due to progression of MDS.

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

This is the first report evaluating the PK, efficacy, and safety of azacitidine administered s.c. or i.v. in Japanese patients with MDS. In the Phase I portion of the study, the bioavailability of azacitidine following s.c. administration was 91.1%, indicating that azacitidine is nearly completely absorbed after s.c. administration, with negligible degradation or metabolism prior to entry into the circulation. The PK profile for azacitidine in Japanese patients was similar that seen in Caucasian patients with MDS,(10) suggesting that there are negligible ethnic differences in the PK of azacitidine.

The HI and HR rates were 54.9% and 28.3%, respectively. In the present study, better efficacy was observed than in the CALGB9221 study conducted in a cohort of MDS patients similar to those in the present study,(8) although it is difficult to compare the results between the two studies owing to differences in the response criteria. In the present study, the HR rates in higher-risk MDS patients were 32.4% (11/34) in RAEB and RAEB-T and 33.3% (10/30) in Intermediate-2 and High. Although overall survival was not evaluated in the present study, the favorable efficacy results in higher-risk MDS patients suggests that a prolongation of survival in Japanese patients, similar to the results reported in the AZA-001 study,(9) could be expected. The HI rates in lower-risk MDS patients were 57.9% (11/19) in RA and RARS and 60.9% (14/23) in Intermediate-1. Furthermore, two-thirds of the lower-risk MDS patients who were blood transfusion dependent at baseline became transfusion independent during the study period. These findings indicate that azacitidine treatment results not only in a reduction in the risk of infection and hemorrhage due to cytopenias (leukocytopenia and thrombocytopenia), but also an improvement in the quality of life by eliminating the need for blood transfusions in lower-risk MDS patients.

In Western countries, azacitidine is administered as long as the patient continues to benefit. In the present study, patients who achieved HI required additional treatment cycles to achieve HR. In addition, the HI and HR rates were higher at completion of the last cycle of azacitidine than at completion of Cycle 4 (data not shown). Therefore continued treatment with azacitidine appears to be appropriate not just for Western patients, but also for all patients with MDS, including Japanese patients, as long as the patients continue to benefit from treatment. Hematology laboratory values in three hematopoietic lineages tended to decrease with time in and after Cycle 11 (Fig. 2). In the present study, patients who met the criteria for CR received azacitidine for an additional three cycles and were then followed-up off treatment. Because the median number of cycles in eight CR patients was 7.5 (range 5–11), the removal of these patients was considered to be one of the reasons for the observed decreases in laboratory values.

There was no difference in the efficacy of azacitidine between s.c. and i.v. administration. Because the dosing volume was larger (4 mL maximum) for s.c. administration, there was a high incidence of injection site reactions in patients who received azacitidine s.c. and some of these patients had difficulty continuing with s.c. administration. Furthermore, s.c. administration was difficult in patients who had a low platelet count due to MDS and who were at risk of s.c. hemorrhage, whereas i.v. administration was problematic in patients in whom it was difficult to secure an i.v. route of administration due to small blood vessels or in those who had vascular disorders. In the present study, the route of administration of azacitidine was changed in seven patients. Selection of an alternative route of administration depending on patient condition is clinically significant not only in terms of enabling treatment with azacitidine, but also in terms of continuing it.

Azacitidine was well tolerated and clinically manageable in Japanese patients with MDS. The AE that occurred were generally associated with the known effects of azacitidine and were manageable with symptomatic therapy and/or dose delays, dose reductions, or dose discontinuation. With the exception of the injection site reactions observed following s.c. administration, the AE profile was generally similar between the s.c. and i.v administration groups. The safety profile of azacitidine in the Japanese patients in the present study was comparable to that reported previously in Caucasian patients.(7–9)

In conclusion, our findings demonstrate that the PK, efficacy, and safety of azacitidine are comparable in Japanese and non-Japanese patients, with no marked differences in the safety or efficacy profiles of azacitidine between s.c. and i.v. routes of administration. The risk–benefit ratio of azacitidine in Japanese patients with MDS was comparable to that in non-Japanese patients, indicating that this drug is a promising therapeutic agent for Japanese MDS patients.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

The authors thank all of investigators, physicians, nurses, and clinical research coordinators who contributed to or assisted with the present study. The authors are particularly grateful to Drs K. Toyama (Tokyo Medical University, Tokyo, Japan), H. Mizoguchi (Tokyo Women’s Medical College, Tokyo, Japan), and Y. Ariyoshi (Aichi Cancer Center, Aichi Hospital, Aichi, Japan) for their critical review of the clinical data as members of the Independent Data Monitoring Committee.

Disclosure Statement

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Azacitidine was provided by Nippon Shinyaku Co., Ltd. The authors have no potential conflicts of interest to report.

Abbreviations
AE

adverse events

AML

acute myelogenous leukemia

AUC0–∞

area under the plasma concentration–time curve from time zero to infinity

AUC0–t

area under the plasma concentration–time curve from time zero to the last measurable time point

CALGB

Cancer and Leukemia Group B

Cmax

maximum plasma concentration

CR

complete remission

Ct

final concentration observed

FAB

French–American–British

HI

hematologic improvement

HI-E

erythroid response

HI-N

neutrophil response

HI-P

platelet response

HR

hematologic response

HSCT

hematopoietic stem cell transplantation

IPSS

International Prognostic Scoring System

i.v.

intravenous

IWG

International Working Group

LC/MS/MS

high-performance liquid chromatography with tandem mass spectrometry

mCR

marrow complete remission

MDS

myelodysplastic syndromes

PK

pharmacokinetics

PR

partial remission

RA

refractory anemia

RAEB

refractory anemia with excess blasts

RAEB-T

refractory anemia with excess blasts in transformation

RARS

refractory anemia with ringed sideroblasts

RBC

red blood cell

SAE

serious adverse events

s.c.

subcutaneous

t½,β

half-life in the β phase

tmax

time to maximum concentration

ULN

upper limit of the institutional normal range

WHO

World Health Organization

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  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References
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