Azacytidine for acute myeloid leukemia in elderly or frail patients: a phase II trial (SAKK 30/07)

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Article

Reference

Azacytidine for acute myeloid leukemia in elderly or frail patients: a phase II trial (SAKK 30/07)

PASSWEG, Jakob, et al.

Abstract

This phase II trial treated elderly or frail patients with acute myeloid leukemia (AML) with single-agent subcutaneous azacytidine at 100 mg/m(2), on 5 of 28 days for up to six cycles.

Treatment was stopped for lack of response, or continued to progression in responders. The primary endpoint was response within 6 months. A response rate ≥ 34% was considered a positive trial outcome. From September 2008 to April 2010, 45 patients from 10 centers (median age 74 [55-86] years) were accrued. Patients received four (1-21) cycles. Best response was complete response/complete response with incomplete recovery of neutrophils and/or platelets (CR/CRi) in eight (18%; 95% confidence interval [CI]: 8-32%.), 0 (0%) partial response (PR), seven (16%) hematologic improvement, 17 (38%) stable disease. Three non-responding patients stopped treatment after six cycles, 31 patients stopped early and 11 patients continued treatment for 8-21 cycles. Adverse events (grade ≥ III) were infections (n = 13), febrile neutropenia (n = 8), thrombocytopenia (n = 7), dyspnea (p = 6), bleeding (n = 5) and anemia (n = 4). Median overall survival was 6 [...]

PASSWEG, Jakob, et al . Azacytidine for acute myeloid leukemia in elderly or frail patients: a phase II trial (SAKK 30/07). Leukemia and Lymphoma , 2014, vol. 55, no. 1, p. 87-91

DOI : 10.3109/10428194.2013.790540 PMID : 23547838

Available at:

http://archive-ouverte.unige.ch/unige:37153

Disclaimer: layout of this document may differ from the published version.

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ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2013.790540

Correspondence: Prof. Jakob R. Passweg, Hematology Division, Basel University Hospital, Petersgraben 4, 4031 Basel, Switzerland. Fax: ⫹ 41613654450.

E-mail: jpassweg@uhbs.ch

(Received 19 December 2012 ; revised 12 March 2013 ; accepted 18 March 2013 )

ORIGINAL ARTICLE: CLINICAL

Azacytidine for acute myeloid leukemia in elderly or frail patients:

a phase II trial (SAKK 30/07)

Jakob R. Passweg

¹

, Thomas Pabst

²

, Sabine Blum

³

, Mario Bargetzi

⁴

, Qiyu Li

⁵

, Dominik Heim

¹

, Georg Stussi

⁶

, Michael Gregor

⁷

, Leda Leoncini

⁸

, Sandrine Meyer-Monard

⁹

, Peter Brauchli

⁵

& Yves Chalandon

¹⁰

;

for the Swiss Group for Clinical Cancer Research (SAKK)

1 Universit ä tsspital Basel, Basel, Switzerland, ² Inselspital, Bern, Switzerland, ³ CHUV, Lausanne, Switzerland,

4 Kantonsspital Aarau, Aargau, Switzerland, ⁵ SAKK Coordinating Center, Bern, Switzerland, ⁶ Universit ä tsspital Z ü rich, Z ü rich, Switzerland, ⁷ Luzerner Kantonsspital, Luzern, Switzerland, ⁸ IOSI (Istituto Oncologico della Svizzera Italiana), Bellinzona, Switzerland, ⁹ ICHV (Institut Central des H ô pitaux Valaisans), Sion, Switzerland and

10 H ô pital Universitaire de Gen è ve, Geneva, Switzerland

have improved outcomes for younger patients [1,2]. AML is, however, a disease of older adults, with an annual incidence of approximately 15 in 100 000 in those 60 years of age or older, representing more than two-thirds of all reported cases [3]. Older patients do not tolerate intensive chemotherapy, and even if chemotherapy is given, rates of complete remission are low and very few survive long-term [4].

Poor outcome in older patients with AML is due to unfavor- able characteristics of the leukemia, as well as comorbidities, poor performance status or organ dysfunction, limiting treatment options. AML in older patients may be the result of transformation from myelodysplastic syndrome, confer- ring a poor prognosis, and is more likely to present with poor-risk cytogenetics [5].

No standard of care is established in these patients. Low dose subcutaneous cytosine arabinoside has been shown in a trial by the medical research council (MRC) to prolong survival compared to hydroxyurea. In this trial the complete response (CR) rate on low dose cytosine arabinoside was 18%, and survival increased. It was mainly patients with low and intermediate risk disease who benefi ted from this treatment [6]. Numerous new substances have been tested for activity in AML, but in young patients anthracyclines and cytosine arabinoside remain the standard of care. In older patients all new treatment approaches have to be measured against either best supportive care, or low dose subcutaneous cytosine arabinoside [7 – 9].

Th e cytidine nucleoside analog azacytidine, a hypomethylating agent, has recently been shown to improve survival in patients with myelodysplastic syndrome (MDS) [10,11]. Azacytidine was also associated with signifi cant improvements in other clinically relevant outcomes, including reductions in transfusion need, hospitalization and intravenous antimicrobial use [12]. Th is improved outcome Abstract

This phase II trial treated elderly or frail patients with acute myeloid leukemia (AML) with single-agent subcutaneous azacytidine at 100 mg/m ² , on 5 of 28 days for up to six cycles.

Treatment was stopped for lack of response, or continued to progression in responders. The primary endpoint was response within 6 months. A response rate ⱖ 34% was considered a positive trial outcome. From September 2008 to April 2010, 45 patients from 10 centers (median age 74 [55 – 86] years) were accrued. Patients received four (1 – 21) cycles. Best response was complete response/complete response with incomplete recovery of neutrophils and/or platelets (CR/CRi) in eight (18%;

95% confi dence interval [CI]: 8 – 32%.), 0 (0%) partial response (PR), seven (16%) hematologic improvement, 17 (38%) stable disease. Three non-responding patients stopped treatment after six cycles, 31 patients stopped early and 11 patients continued treatment for 8 – 21 cycles. Adverse events (grade ⱖ III) were infections ( n ⴝ 13), febrile neutropenia ( n ⴝ 8), thrombocytopenia ( n ⴝ 7), dyspnea ( p ⴝ 6), bleeding ( n ⴝ 5) and anemia ( n ⴝ 4). Median overall survival was 6 months. Peripheral blood blast counts, grouped at 30%, had a borderline signifi cant association with response ( p ⴝ 0.07). This modifi ed azacytidine schedule is feasible for elderly or frail patients with AML in an outpatient setting with moderate, mainly hematologic, toxicity and response in a proportion of patients, although the primary objective was not reached.

Keywords: Myeloid leukemias and dysplasias , chemotherapeutic approaches , cytogenetics

Introduction

Acute myeloid leukemia (AML) in the elderly is diffi cult to treat. Combination chemotherapy and stem cell transplant Leuk Lymphoma Downloaded from informahealthcare.com by University of Geneva on 03/01/14 For personal use only.

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88 J. R. Passweg et al.

has also been seen in patients with MDS hitherto classifi ed as MDS RAEBt (refractory anemia with excess blasts in transformation), and according to the 2008 World Health Organization (WHO) classifi cation of tumors of hematological or lymphoid tissues as AML with a blast count of 20 – 30% [13]. Th e mechanism of action of azacytidine is thought to be through incorporation into both DNA and RNA. DNA incorporation decreases DNA hypermethyla- tion, allowing the re-expression of previously silenced genes that may include tumor suppressor genes [14]. We present here the results of a phase II trial treating elderly or frail patients with AML not eligible for intensive chemotherapy with subcutaneous azacytidine.

Patients and methods

Th is open-label single-arm phase II trial evaluated the effi - cacy of 5-azacytidine in newly diagnosed patients with AML not suitable for induction type chemotherapy due to age, comorbidities or unwillingness to undergo chemotherapy, with a WHO performance status ⱕ 3. Patients had to have ⱖ 20% blasts in the blood or bone marrow, or extramedullary disease; AML diagnosis classifi ed by WHO criteria; de novo AML or AML secondary to prior hemato- logical disease or secondary to cytotoxic treatment. Trial therapy consisted of azacytidine 100 mg/m ² injected sub- cutaneously on 5 consecutive days every 28 days for up to six cycles, stopping at six cycles if no response higher than or equal to hematological improvement (HI) was observed, stopping early in the case of progression or complications, and continuing beyond 6 months for responding patients.

Th e trial (Clinical Trial number: NCT00739388) was con- ducted in accordance with the Declaration of Helsinki, and was approved by Swissmedic and the ethics committees of the participating centers. Written informed consent was obtained from all patients.

Endpoint and statistical consideration

Th e primary endpoint of this phase II trial was defi ned as best response (defi ned as complete response/complete response with incomplete recovery of neutrophils and/or platelets [CR/CRi] or partial response [PR]) within 6 months of starting treatment. CR was defi ned as morphologic leukemia-free state and absolute neutrophil count (ANC) ⱖ 1.0 ⫻ 10 ⁹ /L, platelet count ⱖ 100 ⫻ 10 ⁹ /L ( ⱖ 3 days after the last transfusion); CRi was defi ned as CR with incomplete recovery of the ANC and/or platelet count ( ⱖ 3 days after the last transfusion); PR was defi ned as ANC ⱖ 1.0 ⫻ 10 ⁹ /L, platelet count ⱖ 100 ⫻ 10 ⁹ /L ( ⱖ 3 days after the last transfusion) and blasts in the bone marrow should have decreased by ⱖ 50% (relative to baseline) and reached a value of ⱕ 25%.

Secondary endpoints were time to response, response duration, time to and duration of HI as defi ned in the revised response criteria [15], event-free survival defi ned as the time from trial registration until progression, relapse or death from any cause, whichever occurred fi rst, overall survival, adverse events and time spent in the hospital. Time-to-event endpoints were analyzed by the Kaplan – Meier method.

Median follow-up time was calculated using the inverse Kaplan – Meier method.

Th e exact single-stage phase II design by A ’ Hern was used to calculate the required sample size for the primary endpoint. A response rate of ⱕ 15% was considered uninteresting to pursue this treatment approach further, and a response rate of ⱖ 34% was considered promising. With a signifi cance level of 0.05 and a power of 90%, 43 patients were to be included. At the fi nal analysis, if ⱕ 10/43 (23%) patients showed a response, the trial treatment should be considered as uninteresting, otherwise promising.

Results

From September 2008 to April 2010, 47 patients were accrued across 10 centers in Switzerland. Two patients were not evaluable: they did not receive trial medication and had early disease-related death, leaving 45 patients with a median follow-up of 26 months for analysis. Median age of the 45 evaluable patients was 74 (range: 55 – 86) years, 27 (60%) were male and 34 (76%) patients had performance status 0 – 1. Details of the patient population are shown in Table I.

Patients received a median number of 4 (range: 1 – 21) cycles.

Th ree patients stopped treatment after six cycles because of lack of response. Eleven patients continued treatment to 8 – 21 cycles and stopped for progressive disease or relapse (10 patients) or refusal (one patient). Th irty-one patients had stopped treatment without completing the six cycles because of toxicity in four (9%), patient refusal in two (5%), Table I. Patient characteristics.

Characteristic ( n ⫽ 45) Frequency Percent (%)

Gender (male) 27 60.00

Age (median, range) 74 (55 – 86)

WHO classifi cation of AML

AML with recurrent genetic anomalies [inv(16)]

1 2.22

AML with recurrent genetic anomalies (11q23)

2 4.44

AML following MDS 16 35.56

AML with multilineage dysplasia 2 4.44

AML therapy related, alkylating agent type 2 4.44

AML NOS minimally diff erentiated 2 4.44

AML NOS without maturation 5 11.11

AML NOS with maturation 3 6.67

AML NOS myelomonocytic 5 11.11

AML NOS monoblastic 4 8.89

AML NOS megakaryoblastic 1 2.22

AML NOS 2 4.44

Treatment associated AML 5 11.11

Extramedullary disease 4 8.89

Karyotype

46XX/46XY 15 33.33

⫺ 7 2 4.44

5q 2 4.44

11q23 2 4.44

⫹ 8 3 6.67

Other 3 6.67

Complex 10 22.22

NA 8 17.78

WHO performance status

0 9 20.00

1 25 55.56

2 8 17.78

3 3 6.67

WHO, World Health Organization; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; NOS, not otherwise specifi ed; NA not available.

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persistent or progressive disease in 15 (33%) and death with leukemia in 10 (22%). Of these 10 dead patients the immediate cause of death was leukemia in four, infection in four, cardiac failure in one and bleeding in one.

Among all 45 patients, eight (18%; 95% confi dence interval [CI]: 8 – 32%) achieved a CR/CRi, no patients achieved a Table II. Results.

Frequency Percent (%) Best response within 6 months

CR/CRi 8 17.78

PR 0 0.00

Hematologic improvement 7 15.56

Stable disease 17 37.78

Progressive disease 7 15.56

NA (2 withdrawal, 3 death ∗ , 1 unacceptable toxicity)

6 13.33

Time to CR (months, median, range) 4 (2 – 6) Response duration (months, median,

range)

8 (4 – 21) Treatment cycles received (median, range) 4 (1 – 21) Hospital stay

No. of patients hospitalized 35 77.78

Duration (days, median, range) 23 (1 – 80) No. of patients hospitalized fi rst cycle

of treatment

27 60.00

Duration during fi rst cycle (days, median, range)

13 (1 – 30) CR/CRi, complete response/complete response with incomplete recovery of neutrophils and/or platelets; PR, partial response; NA, not available.

∗ Cause of death: subdural hematoma (1), pneumonia (1) and cardiac failure (1).

Figure 1. (a) Overall survival of all 45 patients, (b) event-free survival, (c) response duration in patients achieving CR/CRi and (d) response duration in patients achieving HI.

PR, seven (16%) had HI and 17 (38%) patients had stable disease as best response within 6 months. Details are shown in Table II. In these eight responding patients, treatment was terminated after 4 – 21 cycles for relapse/progression (fi ve patients), death (one patient), refusal (one patient) and other reason (one patient). Median response duration in patients achieving CR/CRi was 8 (range: 4 – ⬎ 21) months.

Figure 1(a) – 1(d) show overall survival, event-free survival, response duration in patients achieving CR/CRi and response duration in patients achieving HI. Th e median hospital stay in 27 patients admitted during the fi rst treatment cycle was 13 days (1 – 30). Th irty-nine (87%) patients died. Median overall survival was 6 months (95% CI: 3.4 – 7.8).

Age, gender and cytogenetic risk group had no statistically signifi cant impact on response, but there was a borderline association between absence of response and higher peripheral blood blast counts when patients were grouped by blast count at diagnosis ( ⬎ 30% vs. ⱕ 30%, p ⫽ 0.07) but not when blast counts were counted by marrow cytology ( p ⫽ 0.17) (12 of 13 responders had blast counts ⬍ 30% in the peripheral blood, 8/13 had blast counts ⬍ 30% by marrow cytology).

Toxicities of the treatment appeared to be manageable, and most reported adverse events were attributable to marrow failure in association with the disease or with infections.

Seventy-three serious adverse events (SAEs) were reported

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90 J. R. Passweg et al.

considered to be of clinical importance was not reached, there were eight patients (18%) who achieved a CR/CRi and an additional seven patients with HI, thus totaling some clinical benefi t at 17/45 patients (38%), although this was short-lived in many. We could not identify factors clearly associated with response, with the possible exception of blast count at diagnosis. Patients with lower blast counts were more likely to achieve a response, although a statistical signifi cance was not reached. Finally, the small number of patients did not allow us to draw conclusions on which cytogenetic and/or molecular defi ned subgroup of patients with AML might preferentially benefi t from azacytidine treatment.

Side eff ects of this treatment were moderate. Reported severe adverse events were more likely to be associated with the disease than caused by the treatment. Th is trial administered azacytidine in a schedule and dose slightly diff erent from what has been approved in patients with myelodysplastic syndrome, i.e. 100 mg/m ² for 5 days instead of 75 mg/m ² for 7 days, the cumulative monthly dose being almost identical. Th is schedule was chosen to facilitate outpatient administration on weekdays without requiring drug to be given over the weekend. Among the unexpected side eff ects, one patient had worsening renal function and one patient had retinal detachment. It is, however, diffi cult to determine in these patients whether there was any relationship with the trial drug or whether these eff ects could be attributed to infection and/or leukemia.

Other investigators have studied hypomethylating agents such as azacytidine and decitabine in patients with AML in 36 patients. Most frequently reported adverse events of

grade III or higher were infections in 13, febrile neutropenia in eight, thrombocytopenia in seven, dyspnea in six, neutropenia in six, bleeding in fi ve and anemia in four patients, and are shown in Table III.

Discussion

Best treatment options for older patients with AML remain poor. Th ere is controversy about how to treat these patients, given the heterogeneous disease presentation and unfavor- able outcome. Older patients with AML have a poor prognosis, with a median survival time of less than 1 year. Treat- ment by supportive care alone is still a serious consideration.

With the exception of low dose subcutaneous cytosine arabinoside, no drug has been shown to be eff ective in comparison to supportive care alone [6]. AML in the elderly is a heterogeneous disease, and age, comorbidities and tumor biology exemplifi ed by cytogenetic risk groups are prognostic factors [5]. New therapeutic approaches are needed, par- ticularly with improved toxicity, for administration in elderly patients.

Th is open-label phase II trial studied the subcutaneous administration of azacytidine to treat unselected elderly patients with AML not eligible for intensive chemotherapy.

Based on data in patients with MDS and on data from patients with MDS RAEBt, which has been reclassifi ed by WHO as AML with low blast counts, we considered a response rate of 35% or more to be promising enough to continue further with this approach, and a response rate of 15% or less to be uninteresting. While the response rate

Table III. All adverse events grade ⱖ III during treatment cycles. ∗

Category Adverse event

No. of patients

(%) ( n ⫽ 45) No. of cycles (%) ( n ⫽ 249)

General Anorexia 1 (2.22) 1 (0.40)

Constipation 1 (2.22) 1 (0.40)

Decubitus 1 (2.22) 1 (0.40)

Dyspnea 6 (13.33) 12 (4.82)

Fatigue 2 (4.44) 3 (1.20)

Heart failure 1 (2.22) 1 (0.40)

Hypertension 1 (2.22) 1 (0.40)

Mucositis 1 (2.22) 1 (0.40)

Pain 2 (4.44) 3 (1.20)

Pleural eff usion 1 (2.22) 1 (0.40)

Retinal detachment 1 (2.22) 4 (1.61)

Secondary malignancy 1 (2.22) 1 (0.40)

Syncope 1 (2.22) 1 (0.40)

Hematologic Anemia 4 (8.89) 7 (2.81)

Bleeding 5 (11.11) 6 (2.41)

Neutropenia 6 (13.33) 27 (10.84)

Pancytopenia 1 (2.22) 1 (0.40)

Th rombocytopenia 7 (15.56) 21 (8.43) Th romboembolic

complications

1 (2.22) 2 (0.80)

Infectious Febrile neutropenia 8 (17.78) 16 (6.43)

Infection 13 (28.89) 17 (6.83)

Pneumonitis 3 (6.67) 4 (1.61)

Laboratory anomalies Increased GGT 1 (2.22) 1 (0.40)

Hyperglycemia 1 (2.22) 1 (0.40)

Most frequently reported SAE No. of patients (%) ( n ⫽ 45) Fatal (all associated with leukemia progression or infection) 8 (17.78)

GGT, gamma-glutamyl transpeptidase; SAE, serious adverse event.

∗ Per patient within each cycle only the highest grade ⱖ III per event type is reported. Note: one non-evaluable patient without taking any treatment drug but having one documented infection with grade V is not included in this table.

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[16 – 22]. Of importance are comparisons with studies using hypomethylating agents as single-agent treatment for AML.

Th ese studies confi rmed responses in a minority of patients as comparable to those shown in the present study, and dif- ferences may be explained by diff erences in patient risk profi les.

Th e present results show that the modifi ed azacytidine schedule as tested here is a feasible option for elderly or frail patients with AML in an outpatient setting with moderate, mainly hematologic, toxicity and response in a small proportion of patients, although the predetermined level of expected effi cacy was not reached. Th e overall survival of the patient cohort does not appear to be very diff erent from experience in similar patients, and it does not appear that single-agent azacytidine has a major impact on the outcome of AML in the elderly. Whether the dosing choice for this study had an impact on the rather low response rate cannot be determined. Further studies will need to address diff erent treatment schedules and the use of azacytidine in combination with other drugs and a comparison with standard treatment approaches such as low dose subcutaneous cytosine arabinoside.

Acknowledgements

Th is trial was sponsored by the Swiss Group for Clinical Cancer Research (SAKK) and supported in part by the Swiss State Secretariat for Education and Research (SER) and by Celgene GmbH Ltd., B ä ndliweg 20, Postfach 1828, CH-8048 Z ü rich.

Potential confl ict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

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