Open Access

Persistent molecular remission of refractory acute myeloid leukemia with inv(16)(p13.1q22) in an elderly patient induced by cytarabine ocfosfate hydrate

  • Masahisa Arahata1Email author,
  • Yukihiro Shimizu1,
  • Hidesaku Asakura2 and
  • Shinji Nakao3
Journal of Hematology & Oncology20158:5

https://doi.org/10.1186/s13045-014-0100-6

Received: 27 December 2014

Accepted: 27 December 2014

Published: 6 February 2015

Abstract

The prognosis of relapsed acute myeloid leukemia (AML) in elderly patients is dismal, even if the AML exhibits a good prognostic karyotype, such as inv(16)(p13.1q22). We present a 72-year-old female with AML with inv(16)(p13.1q22) who suffered five episodes of relapse with temporary complete remission. Maintenance chemotherapy with oral cytarabine ocfosfate hydrate eventually produced persistent molecular complete remission of her AML that had not been induced by conventional regimens including intensive chemotherapy and low dose cytarabine therapy. The high level of tolerability to oral cytarabine ocfosfate hydrate may offer elderly patients with this type of AML a good chance for a cure.

Keywords

Cytarabine ocfosfate hydrateAcute myeloid leukemiaInv(16)(p13.1q22)RefractoryElderly

Introduction

Acute myeloid leukemia (AML) with inv(16)(p13.1q22) is characterized by a favorable prognosis and good response to treatment with cytarabine [1]. The strategy of treatment for AML with inv(16)(p13.1q22) is based on a series of intensive chemotherapy, which is considered more curable than prolonged maintenance chemotherapy with low-dose anti-leukemic agents even in the elderly [2-4]. On the other hand, low-dose cytarabine therapy (LDAC) is recommended for elderly patients with AML who are not considered suitable for intensive chemotherapy [5-8], but LDAC can rarely induce persistent remission [9]. Once they relapse, their prognosis is usually dismal, even if the AML is associated with inv(16)(p13.1q22) [10,11].

Case presentation

In December 2006, a 72-year-old female was admitted to our hospital presenting with general malaise and dyspnea. A physical examination revealed anemic palpebral conjunctiva and purpura of the extremities. The complete blood count indicated severe anemia and thrombocytopenia as well as mild leukocytosis with 22.5% blast cells (Additional file 1). A bone marrow examination showed a total nucleated cell count of 41,000/μL with 67.0% blasts (Additional file 2: Figure S1A). A cytogenetic analysis of the bone marrow cells with G-banding showed 46,XX,inv(16)(p13.1q22) in all 20 dividing cells (Additional file 2: Figure S1B). Based on these findings, the patient was diagnosed as having AML with inv(16)(p13.1q22).

The patient achieved complete remission (CR) after one course of induction chemotherapy comprising behenoyl cytarabine and daunorubicin according to a study protocol [12] (Table 1). However, the AML relapsed four months after the completion of the last cycle of consolidation therapy. Re-induction chemotherapy using the same regimen as the first induction induced a second CR. Thereafter, the patient suffered four further episodes of relapse with temporary remission (Figure 1). The failure to achieve durable remission even with high-dose consolidation therapy and its toxicities prompted us to select palliative care with LDAC at the third relapse. After achieving the sixth CR, the patient declined further treatment with LDAC due to toxicity. Therefore, oral cytarabine ocfosfate hydrate (SPAC) was started in order to maintain remission in November 2011. The SPAC therapy was not associated with any significant toxicity. The CBFB-MYH11 fusion mRNA in the peripheral blood became negative after twelve courses of SPAC therapy, which was terminated in October 2013. The patient has since remained in molecular remission without chemotherapy (Figure 1).
Table 1

Chemotherapy regimens and adverse events in the present case

 

Chemotherapy

No.

Regimen

PS

BI

Grade of adverse event*

BW

(kg)

Complications

Neutropenia

FN or infecton

Anemia

Thrombocytopenia

Anorexia

Weight loss

Onset to 1st CR

Induction

1

BHAC 200 mg/m2 IV day 1-8

3

100

4

3

4

4

3

1

44.4

 

DNR 40 mg/m2 IV day 1-3

Consolidation

2

BHAC 200 mg/m2 IV day 1-5

2

100

4

3

4

4

3

1

41.6

Sepsis

MIT 7 mg/m2 IV day 1-3

 

3

BHAC 200 mg/m2 IV day 1-5

1

100

4

3

3

3

3

1

40.8

 

DNR 25 mg/m2 IV day 1-2

ETP 100 mg/m2 IV day 1-3

4

BHAC 200 mg/m2 IV day 1-5

1

100

4

3

2

2

2

1

40.5

 

ACR 10 mg/m2 IV day 1-5

1st relapse to 2nd CR

Induction

5

BHAC 200 mg/m2 IV day 1-8

4

55

4

3

4

3

3

2

39.0

Osteoporotic lumbar compression fracture Pulmonary Aspergillosis

DNR 40mg/m2 IV day 1-3

Consolidation

6

BHAC 200 mg/m2 IV day 1-6

2

100

4

3

3

2

2

2

38.5

 

DNR 40 mg/m2 IV day 1-3

 

7

Ara-C 1 g/m2 IV x2 day 1-5

1

100

4

3

4

3

3

3

36.9

 

2nd relapse to 3rd CR

Induction

8

LDAC day 1-14 with M-CSF day 15-28

3

100

4

3

3

4

3

3

36.5

 
 

9

LDAC day 1-14 with M-CSF day 1-14

2

100

4

None

3

4

3

3

34.9

 

Consolidation

10

Same as # 9

1

100

3

None

3

3

3

3

35.2

 
 

11

Same as # 9

1

100

3

None

3

3

3

3

36.4

 
 

12

Same as # 9

1

100

3

None

4

3

3

3

36.4

 
 

13

Same as # 9

1

100

2

None

3

3

3

2

37.5

 

3rd relapse to 4th CR

Induction

14

LDAC day 1-14 with M-CSF day 1-14

1

100

4

3

3

4

3

2

37.5

 

VPA 600 mg/day PO

15

LDAC day 1-12 with M-CSF day 1-14

1

100

3

None

3

3

3

   

VPA 600 mg/day PO

Consolidation

16

Same as # 15

1

100

3

None

3

3

3

1

41.3

 

17

LDAC day 1-10 with M-CSF day 1-14

1

100

3

3

2

3

3

2

39.1

 

VPA 600 mg/day PO

18

Same as # 17

1

100

3

3

2

3

3

2

39.4

 

19

Same as # 17

1

100

3

None

3

3

3

1

40.6

 

4th relapse to 5th CR

Induction

20

LDAC day 1-10 with M-CSF day 1-14

3

95

4

3

4

4

3

1

42.4

 

21

SPAC 200 mg/day PO day 1-14

1

95

None

None

3

None

2

   

G-CSF 100 μg SC day 1-14

22

Same as # 21

1

95

3

None

2

2

1

1

41.2

 

23

LDAC day 1-10 with M-CSF day 1-14

2

100

4

3

4

4

3

1

42.0

 

24

LDAC day 1-12 with M-CSF day 1-14

3

100

4

3

4

4

3

1

41.6

 

25

LDAC day 1-12 with G-CSF day 1-12

3

100

4

3

4

4

3

1

42.2

 

ACR 14 mg/m2 IV day 1-4

26

Same as # 25

2

100

3

3

3

3

3

1

41.7

 

Consolidation

27

Same as # 25

1

100

3

None

3

3

2

   

28

Same as # 25

1

100

4

None

3

3

2

2

39.6

 

29

Same as # 25

1

100

4

None

3

4

2

2

39.5

 

30

Same as # 25

1

100

4

None

3

4

2

   

5th relapse to 6th CR

Induction

31

LDAC day 1-12 with G-CSF day 1-12

3

5

4

3

4

4

3

1

40.8

Depression

ACR 14 mg/m2 IV day 1-4

32

MTX 15 mg + Ara-C 40mg + PSL 10mg IT day -1

4

5

4

3

4

4

4

  

Traumatic lumbar compression fracture

LDAC day 1-10 with G-CSF day 1-12

ACR 14 mg/m2 IV day 1-4

Consolidation

33

LDAC day 1-10 with G-CSF day 1-12

3

5

4

3

3

3

3

   

ACR 14 mg/m2 IV day 1-4

34

Same as # 33

1

75

4

None

3

3

3

None

44.0

 

35

Same as # 33

1

90

4

None

3

4

3

None

44.6

 

Maintenance

36

SPAC 300 mg/day PO day 1-7 every 4-6 weeks

1

100

None

None

None

None

2

2

36.0

Sarcopenia

ACR: aclarubicin hydrochloride, Ara-C: cytarabine, BHAC; behenoyl cytarabine, BI: Barthel index, BW: body weight, DNR: daunorubicin hydrochloride, ETP: etoposide, FN: febrile neutropenia, G-CSF: lenograstim 100 μg subcutaneously injected or lenograstim 250 μg intravenously injected, IT: intrathecal injection, IV: intravenous injection, LDAC: cytarabine 10 mg/m2 subcutaneously injected twice a day, M-CSF: mirimostim 8 million units intravenously injected, MIT: mitoxantrone hydrochloride, PO: per oral, PS: performance status, SC: subctaneous injection.

*Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 produced by the National Cancer Institute (http://evs.nci.nih.gov/ftp1/CTCAE/About.html).

Figure 1

Clinical course of the patient. FISH: fluorescence in situ hybridization, (+): positive, (−): negative. *The karyotype was obtained from peripheral blood cells at that time because the patient rejected a bone marrow aspiration procedure.

Discussion

Our patient received lower doses of cytarabine and daunorubicin than the doses that are considered as standard doses for remission induction of AML with inv(16)(p13.1q22) nowadays, and the suboptimal doses of induction chemotherapy may be the cause of her early relapse. However, higher doses of cytarabine and daunorubicin may have put the 72-year-old woman’s life in danger due to associated toxicities. The frail woman eventually went into deep remission after maintenance therapy with a cytarabine prodrug SPAC.

SPAC has been shown to be as effective and tolerable as LDAC in treatment of AML [13-15], though its usefulness of SPAC is not well recognized because it is not available outside Japan. In this case, the AML cells were considered as highly sensitive to cytarabine because of repetitive achievement of CR induced by LDAC. Besides, SPAC was associated with fewer toxicities than LDAC (Table 1). LDAC requires the use of subcutaneous injections twice a day, but elderly patients often have difficulties visiting the hospital frequently. On the other hand, SPAC can be orally administered at home. These advantages enabled our patient to continue the maintenance therapy for two years and contributed to her persistent molecular remission. Thus, SPAC potentially offers a chance of cure for elderly patients with inv(16)(p13.1q22) without life threatening toxicities.

Consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Abbreviations

AML: 

Acute myeloid leukemia

CR: 

Complete remission

LDAC: 

Low-dose cytarabine therapy

SPAC: 

Cytarabine ocfosfate hydrate

Declarations

Authors’ Affiliations

(1)
Department of Internal Medicine, Nanto Municipal Hospital
(2)
Department of Internal Medicine (III), Kanazawa University Graduate School of Medical Science
(3)
Department of Cellular Transplantation Biology, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science

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Copyright

© Arahata et al.; licensee Biomed Central. 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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