Decitabine Maintenance in Elderly Acute Myeloid Leukemia Patients

The median age of patients with AML at presentation is between 65 to 70 years (Peterson
1977, Brincker 1985, Baudard 1994) and the incidence of AML increases with advancing age
(Wingo 1995). Given this, increased attention should be focused on adult patients 60 years
or older with this disease. Treatment strategies in younger patients are well established
however therapy in the elderly deserves particular thought (Foon 1981, Sebban 1998,
Lowenberg 1998). Also progress in the treatment of AML in the elderly population is not near
progress that has been made in the treatment of the younger population (Stone 2002,
Kantarjian 2006). Poor tolerability and questionable treatment benefit have left older adult
patients with AML often without effective treatment options or with best supportive care.
According to Medicare records, only 30% of a cohort of 2657 AML patients older than 65 years
were provided chemotherapy treatment (44% in patients 65 to 74 years, 24% in patients 75 to
84, and 6% in patients 85 and above). The mortality was 86% at 1 year and 94% at 2 years
following the diagnosis. The overall survival in this cohort was only 2 months (Menzin
2002). The study could not distinguish between intensive induction chemotherapy and
palliative therapy.

Despite modest improvements in outcomes for younger patients with AML, adults over 55 years
of age (the majority of patients with AML) continue to do poorly (Tallman 2005).

In patients over 60 years response rates have ranged from 40% to 55% and in patients over 70
years have ranged from 24% to 33% (Buchner 2009, Estey 2007, Lowenberg 1998, Rowe 2004).
Patient and leukemia related factors could explain the poor result of older patients with
AML (Harry 2007, Gupta 2005). Also in patients over 60, with adverse cytogenetics the
response rates range from 26% to 34%; with antecedent hematologic disorder they range
between 28% and 46%; and with Eastern Cooperative Oncology Group (ECOG) performance status
(PS) 2 it is around 26%. (Grimwade 2001, Rowe 2004, Appelbaum 2006).

For the past several decades, standard induction chemotherapy for acute myeloid leukemia
(AML) has consisted of the "7+3" regimen of cytarabine plus an anthracycline. Standard
consolidation chemotherapy has consisted of high dose cytarabine for 3-4 cycles. Few trials
have randomized older patients with AML to receive standard remission induction (i.e.,
anthracycline-containing) chemotherapy versus either palliative therapy or less intensive
chemotherapy. The median survival of older adults with AML treated with cytarabine plus an
anthracycline on the "7+3" schedule is 8 to 12 months (Estey 2007, Rowe 2004). Less than 10%
of patients remain in remission for more than 3 years. (Lowenberg 1998, Godwin 2003, Roboz
2007).

The European Organization for the Research and Treatment of Cancer (EORTC) conducted a trial
on 60 patients and randomized them to intensive chemotherapy (daunorubicin 30 mg/m2/day
intravenously [IV] for 3 days, vincristine 1 mg/m2/day IV on Day 2, cytarabine 100 mg/m2/day
IV for 7 days with 50 mg/m2/day IV bolus every 12 hours for 7 days) or a "watch and wait"
approach (supportive care alone with hydroxyurea 3 g PO on Days 1 and 4 and LDAC
(subcutaneous cytarabine) 100 mg/m2 every 12 hours SC on Days 2, 3, 5, and 6 administered
only when leukemia-related symptoms occurred). All patients were more than 65 years old, but
had to have preserved organ function and performance status. The patients who received
induction chemotherapy had a higher complete remission (CR) rate (58% vs. 0%), lower
incidence of early mortality (3/31 vs. 18/29 patients), longer median survival (21 weeks vs.
11 weeks) and greater chance of survival at 2.5 years (17% vs. 0%). The median duration of
hospitalization did not statistically differ between the two groups.

In the study performed by Tilly et al (Tilly 1990) in patients >65 years old, 87 patients
were randomized to receive either LDAC 10 mg/m2 SC every 12 hours for 21 days or standard
chemotherapy induction with rubidazone (a daunorubicin-derived agent) 100 mg/m2 IV for 4
days plus cytarabine 200 mg/m2 IV for 7 days. The combination chemotherapy arm was
associated with a 31% early death rate compared with10% in the lower dose arm. There was a
higher CR rate in the rubidazone/cytarabine arm (52% versus 32%), but only a trend toward
improved survival favoring this arm (12.8 months versus 8.8 months) was reported.

Repetitive cycles of high dose Cytarabine (HiDAC- 3 g/m2 ARA-C twice a day on days 1, 3, 5)
is an effective consolidation regimen for AML patients based on the CALGB in 1994 (Mayer
1994). In patients younger than 60, this protocol produced a high rate of continuous CR.
However in patients older than 60, a high rate of neurotoxicity was reported using this
regimen (Mayer 1994). A follow up study modified this protocol by using Intermediate Dose
Cytarabine (IDAC) (1 g/m2 ARA-C twice a day on days 1, 3, 5) and applied the regimen to a
group of elderly patients (≥60 years) with de novo AML. This protocol (IDAC) was found to be
an effective and well-tolerated consolidation regimen for elderly patients (Sperr 2004).
Based on this study the median overall survival, disease-free survival, and continuous CR
were 10.6, 15.5, and 15.9 months, respectively (Sperr 2004).

Thus, from the data obtained in these studies, chemotherapy in some form is superior to best
supportive care alone or best supportive care with chemotherapy initiated after evidence of
disease progression. However no single treatment approach appears adequate and can be
considered the standard of care for elderly AML patients. Thus, improved treatment
strategies and more suitable chemotherapy regimens are needed (Harry 2007). Additionally, it
is not clear how best to administer chemotherapy with currently available drugs, taking into
account induction and consolidation treatments.

Several different categories of new therapies are under development, including multidrug
resistance (MDR) reversal agents, immunomodulatory therapies, and signal transduction
targeting. Table 1 shows examples of targets and agents developed and being developed. Given
the lack of standards in the treatment of elderly AML, of the use of these newer agents in
treating AML is justified.

Table 1: Targets for New Agents for Acute Myelogenous Leukemia (Medscape.com) Targets Agents
CD33 Gemtuzumab ozogamicin CD45 131I-anti-CD45 MDR1/Pgp Cyclosporine, PSC-833 Angiogenesis
and/or VEGF Thalidomide, SU-5416, bevacizumab antibodies Hypermethylated chromatin
Decitabine Histone deacetylase Phenylbutyrate trichostatin A, trapoxin Bcl-2 Bcl-2 antisense
S-phase checkpoint UCN-01 20S proteasome PS-341 Tyrosine kinase (c-kit receptor) STI-571
Flt-3 kinase CEP-701 Farnesyl transferase BMS-214662, R115777

A sizeable percentage of older adults attain a complete remission with induction
chemotherapy, but almost all of these patients will relapse within a median of four to eight
months unless given additional cytotoxic therapy (Cassileth 1999). Even with post-remission
therapy, relapses are common. Furthermore, post-remission therapy in older adults is
complicated by high rates of treatment related toxicity.

To address the problem of post-remission therapy, the Nordic MDS group performed a phase II
multicenter study, which studied long-term maintenance with azacitidine. They studied
patients with high-risk MDS and AML arising from MDS. The mean age of the group was 68
years. Patients who achieved CR after induction received low dose azacitidine sq 5 out of 28
days until relapse. They noted a median CR duration of 13.5 months and noted very mild side
effects (Grovdal 2008).

In another phase II trial Decitabine was used for untreated AML patients older than 60 who
were not candidates for intensive chemotherapy (or who refused it). PS was ECOG <3. All pts
received induction with Decitabine at 20mg/m2 IV on days 1-10 of a 4 week cycles. Patients
with persistent AML at the end of a cycle received a repeat of the 10 day course, but
responding patients received maintenance with shortened courses of 3-5 days depending on the
degree and duration of neutropenia. Forty two percent of patients achieved CR. Median OS has
not yet been reached; median f/u of 19 surviving patients was 8 months. The median number of
cycles received till the date of publication was five (Blum 2009).

One retrospective study studied 141 elderly AML patients in first CR after 7+3 induction
chemotherapy. In patients aged 60-70 year, consolidation ± maintenance therapy improved
outcomes (DFS and OS). In patients older than 70 and with WBC < 30 x109/l maintenance
therapy without consolidation improved outcomes. In patients older than 70 and with WBC < 30
x 109/l consolidation therapy worsened outcomes. In patients older than 70 and with WBC > 30
x 109/l, both consolidation and/or maintenance therapy did not improve outcomes (Corre
2005).

The purpose of this study is to determine whether it is feasible to use maintenance
treatment (prolonged treatment over several months) with Decitabine in elderly patients with
AML after they have obtained a remission with standard chemotherapy. The study also aims at
obtaining preliminary results on whether this approach prolongs the period of remission
after standard chemotherapy. The study group will include elderly (≥60 years of age), Acute
Myeloid Leukemia (AML) patients who can tolerate an aggressive therapy.

Inclusion Criteria:

1. Patients with AML (excluding Acute Promyelocytic Leukemia) according to the WHO
classification, including de novo and secondary AML. Patient must be in complete
remission after 1 cycle of induction therapy consisting of cytarabine (100 mg/m2 as a
24 hour infusion for 7 consecutive days) and idarubicin (12 mg/m2 as a slow
intravenous push daily for 3 days), and 2 cycles of consolidation therapy (each
consisting of cytarabine at a dose of 1 g/m2 given intravenously over 3 hours every
12 hours on days 1,3,and 5).

2. Patients who maintain morphologic complete remission as documented by a bone marrow
aspirate/biopsy after consolidation therapy will be eligible to receive Decitabine
maintenance therapy. Maintenance therapy should be started as soon as feasible after
recovery from the last consolidation cycle but no sooner than 29 days after start of
the last consolidation cycle and no later than 60 days after recovery from the last
cycle of consolidation therapy.

3. Age ≥ 60 years

4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1

5. Informed consent, personally signed and dated to participate in the study

6. Be able to comply with study procedures and follow-up examinations

7. Be non-fertile or agree to use birth control during the study through the end of last
treatment visit

8. Adequate renal and hepatic function as indicated by all of the following: Total
bilirubin ≤ 1.5 institutional Upper Limit of Normal (ULN); and Aspartate
aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 ULN; and Serum
creatinine ≤ 1.5 mg/dL

9. Adequate cardiac function as measured by at least 1 of the following: Left
ventricular ejection fraction (LVEF) ≥ 50% on multigated acquisition (MUGA) scan,
similar radionuclide angiographic scan, or echocardiogram

Exclusion Criteria:

1. Diagnosis of acute promyelocytic leukemia (APL, WHO classification of APL with
t(15;17)(q22;q12)

2. Prior diagnosis and treatment for AML, including hematopoietic stem cell transplant
(HSCT)

3. Previous therapy with a hypomethylating agent including decitabine or azacitidine
(i.e. for an antecedent myelodysplastic syndrome)

4. Any prior therapy for AML except for hydroxyurea for the control of blood counts

5. Psychiatric disorders that would interfere with consent, study participation, or
follow-up

6. Cardiac Disease: Heart failure NYHA class 3 or 4; unstable coronary artery disease
(MI more than 6 months prior to study entry is permitted); serious cardiac
ventricular arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin
are permitted)

7. Chronically impaired renal function (creatinine clearance < 30 ml / min)

8. Inadequate liver function (ALT and AST ≥ 2.5 x ULN) if not caused by leukemic
infiltration

9. Total bilirubin ≥ 1.5 x ULN if not caused by leukemic infiltration

10. Known HIV and/or hepatitis C infection

11. Evidence or history of severe non-leukemia associated bleeding diathesis or
coagulopathy

12. Evidence or recent history of CNS disease, including primary or metastatic brain
tumors, seizure disorders

13. Clinical evidence suggestive of central nervous system (CNS) involvement with
leukemia unless a lumbar puncture confirms the absence of leukemic blasts in the
cerebrospinal fluid (CSF)

14. Any other severe concurrent disease, or have a history of serious organ dysfunction
or disease involving the heart, kidney, liver, or other organ system that may place
the patient at undue risk to undergo therapy on this protocol

15. Systemic fungal, bacterial, viral, or other infection not controlled (defined as
exhibiting ongoing signs/symptoms related to the infection and without improvement,
despite appropriate antibiotics or other treatment)

16. Diagnosis of another malignancy, unless the patient has been disease-free for at
least 5 years following the completion of curative intent therapy with the following
exceptions: Patients with treated non-melanoma skin cancer, in situ carcinoma, or
cervical intraepithelial neoplasia, regardless of the disease-free duration, are
eligible for this study if definitive treatment for the condition has been completed.
Patients with organ-confined prostate cancer with no evidence of recurrent or
progressive disease based on prostate-specific antigen (PSA) values are also eligible
for this study if hormonal therapy has been initiated or a radical prostatectomy has
been performed

17. History of organ allograft

18. Any severe concomitant condition, which makes it undesirable for the patient to
participate in the study or which could jeopardize compliance with the protocol

19. Patients who have an indication for and can undergo a non-myeloablative transplant
procedure