Shinshu M ed J, 62⑶ :167〜172, 2014

Azacitidine Treatment Following Intensive Chemotherapy withDaunorubicin and Cytarabin for Acute Transformation inMyelodysplastic/Myeloproliferative Neoplasms
Toru KAWAKAMI ＊, Kaoko SAKAI , Sayaka NISHINA , Yuto MIMURA
Takaaki MIYAHIRA , Yasushi SENOO , Hideyuki NAKAZAWA and Kiyoshi KITANO
1) Department of Hematology, NHO Matsumoto Medical Center
2) Division of Hematology, Department of Internal Medicine, Shinshu University School of Medicine

We report here a case of a 70‑year‑old male with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) having hepatosplenomegaly, mild monocytosis, and normal karyotypes without JAK2 mutation. The
patient developed an acute transformation and during the intensive therapy with daunorubicin and cytarabin,
diﬀuse alveolar hemorrhage appeared due to disseminated intravascular coagulopathy.After induction,bonemarrow blasts reduced to 5.1%, and the patient received two courses of azacitidine therapy. During thesecourses, blasts in the peripheral blood were not observed.Intensive chemotherapy consisting of daunorubicinand cytarabin followed by azacitidine therapy might be eﬀective for acute transformation in M DS/MPN.
Shinshu Med J 62 : 167 ―172, 2014
(Received for publication December 16, 2013;accepted in revised form January 30, 2014)
Key words:myelodysplastic‑myeloproliferative diseases, azacitidine, acute transformation

Introduction
M DS/M PN include clonal myeloid neoplasms

well established that the blast percentage is correlated signiﬁcantly with the outcome in a patientwith clonal myeloid disease .

that at the time of initial presentation have some

For those ineligible for stem cell transplantation,clinical, laboratory or morphologic ﬁndings thatpromising therapeutic options with long‑term sur-

support myelodysplastic syndrome (M DS), andvival seem to be limited.Azacitidine (AZA)demon-other ﬁndings more consistent with myeloprolifer-strated signiﬁcantly prolonged overall survival in

ative neoplasms (M PN) according to the WHOpatients with MDS . AZA is also used for patientsclassiﬁcation 2008. This diagnostic category

who suﬀer from CMM L and MPN

includes chronic myelomonocytic leukemia

usefulness of AZA in MDS/MPN has not been well(CM ML), atypical chronic myeloid leukemiadetermined. Here, we report a case of MDS/MPN(aCM L), juvenile myelomonocytic leukemiatransformed into acute myelomonocytic leukemia(JMM L) and myelodysplastic/myeloproliferative(AM ML) who underwent AZA treatment after

neoplasm,unclassiﬁable(M DS/M PN,U).The WHO

reduction of increased blasts by intensive chemo-classiﬁcation deﬁned CM M L I and CMML II accord-

therapy with a combination of daunorubicin (DNR)

ing to medullary and peripheral blast count. It isand cytarabin (Ara‑C).

Correspondence author:Toru Kawakami
Department of Hematology, NHO M atsumoto M edical
Center, 2‑20 ‑30 Muraimachi ‑minami, M atsumoto,.However,theCase Report
A 70‑year‑old male was referred to our hospital

Nagano 399 ‑8701, Japanbecause of left ﬂank pain in June 2011. Hepatos-

E‑mail:yfa74377＠nifty.com

plenomegaly was found on physical examination

No. 3, 2014167

Kawakami.Sakai.Nishina et al.

Fig. 1 Bone marrow examinations
A Bone marrow biopsy(hematoxylin‑eosin, ×400)and B smear (Wright‑Giemsa, ×400)in June 2011.Trilineage
dysplastic features including multiple, widely‑separated megakaryocytes (arrow head)were revealed.
C, D Bone marrow aspiration (C hematoxylin‑eosin, ×1,000 and D double staining of naphthol AS‑D chloroacetate esterase and α‑naphtyl butyrate esterase,×1,000)in January 2012.M yeloblasts and monoblasts(arrow)are both seen.

and the laboratory data showed a white blood cell

monocytes, 36.6 %(WBC)count of 43.16×10 /l(blasts 8%,myelocytes

lymphocytes, 0.2% plasma cells, and 0.6% mega-12%, metamyelocytes 16%, neutrophils 53%,

karyocytes.Karyotyping performed on the marrow

lymphocytes 6%, atypical lymphocytes 2%,

aspirate revealed 46, XY (20/20). Fluorescence inmonocytes 3% (1.29 ×10 /l),nucleated erythrocytes

situ hybridization using the BCR/ABL1 probe

49 /100 WBC), hemoglobin concentration 8.0 g/dl,

detected no fusion signals and JAK2 V617F muta-

and platelet count 476×10 /l. Neutrophil alkaline

tion was negative. Monocytosis in the patient was

phosphatase score was decreased.The bone marrowﬂuctuating around 1.0×10 /l and did not persist for

examination revealed myeloid‑ and megakar-

3 months. Therefore, the patient was given a diag-yocytic ‑lineage hyperplasia

slightnosis of aCM L according to the WHO classiﬁcation

myeloﬁbrosis and trilineage dysplastic features

2008. However, the diﬀerential diagnosis between(Fig. 1A, B). The diﬀerential cell count on bone

aCM L and CM ML seemed to be diﬃcult.

marrow showed 3.0 %witherythroblasts,0.8 %myeloblasts, 6.4 %Although the patient was given oral hydroxyurea

promyelocytes, 14.6% myelocytes, 17.4% neutro-for two months, the number of WBC began tophils, 0.0% eosinophils, 0.3% basophils, 2.0%

increase in the middle of December 2011 and rea-168

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Azacitidine treatment for M DS/M PN

Fig. 2 Clinical course of this patientBlack portions of the circle graphs mean fractions of blasts in bone marrow. (HU ;hydroxyurea, DNR ;daunorubicin hydrochloride, Ara‑C ;cytarabine, ACR ;aclarubicin hydrochloride, AZA ; azacitidine, Plt ;platelet, RCC ;red cell concentrates, PC ;platelet concentrates, M IT ;mitoxantrone)ched 134.74×10 /l (blasts 95%)at the beginning of(0.24×10 /l)), hemoglobin concentration 4.7 g/dl,January 2012,when the diagnosis of acute transfor-and platelet count 618×10 /l. The bone marrow

mation was made by bone marrow examination

aspiration showed reduced blast count (5.1%) and(Fig.1C):blasts were positive for myeloperoxidase,

trilineage dysplastic features. At this point, theeither naphthol AS‑D chloroacetate esterase or α‑

patient experienced upper gastrointestinal bleeding

naphtyl butyrate esterase (Fig. 1D), CD13, CD33,

and received intravenous therapy with a proton

and CD34. Chromosomal analysis using the bonepump inhibitor. Performance status was 4.

marrow aspirate revealed a normal karyotype (20/Subsequently, the patient was treated with AZA20). Induction therapy consisting of DNR at 35 mg/(75 mg/m once dailys.c.for 7 consecutive days)andm once daily i.v.for 5 consecutive days and Ara‑C

the blasts in peripheral blood did not appear during

at 70 mg/m c.i.v. for 7 days (DNR＋Ara‑C) was

the ﬁrst two courses. During the treatment withperformed. It was complicated by disseminated

AZA,the toxicity observed was only hematological,

intravascular coagulopathy (DIC)and diﬀuse alveo-

and the patientʼs general condition improved.How-

lar hemorrhage, and the patient temporarily

ever, a skin rash on the whole body appeared after

required intensive care. A month after induction

the two courses of AZA. The skin biopsy revealed

therapy, the laboratory data showed a WBC countinﬁltration of leukemic cells. The WBC increasedof 4.01×10 /l (blasts 1%, metamyelocytes 1%,with blasts again in May 2012 (Fig. 2). Neither theneutrophils 86%, lymphocytes 6%, monocytes 6%

combinations of chemotherapies, such as DNR＋

No. 3, 2014169

Kawakami.Sakai.Nishina et al.

Ara‑C, aclarubicin hydrochloride＋Ara‑C, nor sin-evolution in CMM LII was higher than that ingle‑agent administration of mitoxantrone hydroch-CMML I . A retrospective analysis of 213 CMML

loride were eﬀective. The patient developed DIC

patients revealed that a hemoglobin level below 12

and central nervous system inﬁltration and died in

g/dL,the presence of circulating immature cells,anSeptember 2012.

absolute lymphocyte count above 2.5 x 10 /L, andDiscussion

marrow blasts of 10% or more were independently
associated with shorter survival by multivariate

According to the WHO Classiﬁcation 2008,

analysis, and high risk patients who had four risk

mature myeloid neoplasms are stratiﬁed in line withfactors were estimated to have a median survival of

their biological features (myeloproliferative, with5 months .In summary,the prognosis of the present

eﬀective hematopoiesis, versus myelodysplastic,

case was estimated to be less than 1 year.

with ineﬀective hematopoiesis,as well as bygenetic

AZA is a hypomethylating agent and the main-features). In the present case of M DS/M PN, how-stay of therapy for patients with M DS , and it has

ever, the diﬀerential diagnosis between aCML andreceived Food and Drug Administration (FDA)

CMML seemed to be diﬃcult.When the patient wasapproval for the treatment of not onlyMDS and but

referred to our hospital, monocytosis was mild andalso CMML. A retrospective analysis on CMML

did not persist for 3 months,leading to the diagnosis

treated with AZA revealed that there was a statisti-of aCML. On the other hand, the fact that thecally signiﬁcant OS advantage in responders

immature monocytes graduallyincreased during thecompared with nonresponders:15.5 versus 9 months

clinical course suggests a diagnosis of CM ML. Inand treatment was found to be generally well toler-

this case,it might be categorized into CM ML II due

ated . The eﬃcacy of azacitidine were also report-

to the percentage of peripheral blasts.

ed among patients with Philadelphia (Ph)‑negative

Both aCM L and CMM L have a poor prognosis

MPN who had progressed to MDS or AML .

because of the high probability of acute transforma-According to the report, the overall response ratetion. It has been reported that the median survival

was 52%, median response duration was 9 months,

was 24 months and blastic transformation preceded

and the median OS was 11 months. A standard

death in 31% of patients with bcr /abl negative

treatment for CMM L with acute transformation isCML . In this report, a prognostic scoring system

yet to be clariﬁed. The optimal therapy for elderly

which stratiﬁed patients into two groups based on

aCM L patients ineligible for hematopoietic stem

age,hemoglobin level,and WBC count was suggest-cell transplantation is also unknown. JAK or SRC

ed and the patients in the high risk group were said

kinase inhibitors, which may have the potential toto have a median survival of only 9 months. Withbe eﬀective in association with CSF3R mutations

regard to prognostic factors in aCM L,a case series

for aCM L

studyindicated that the risk of leukemic evolution isbedside. Hence, without a deﬁnitive diagnosis ofassociated with palpable hepato‑ or splenomegaly,

CMML or aCML, the optimal therapeutic strategy

monocytosis,bone marrow blastosis,marked dyser-for a patient with MDS/MPN,like the present case,ythropoiesis, and the need for transfusion . In thisremains unclear.AZA might be eﬀective because ofcase, the prognosis was predicted to be poor

the pathophysiological similarity of CMML andbecause the patient had several risk factors for

aCM L to M DS and accepted tolerance in elderly

leukemic evolution : palpable hepatosplenomegaly,

patients.

, cannot currently be used at themarked dyserythropoiesis,and the need for transfu-

Our patient started to receive AZA after induc-sion. It has been reported that the median survival

tion therapy for acute transformation. This was

was 20 months for CM M L I and 15 months forbecause the bone marrow examination after induc-

CMML II, and that the cumulative risk of AM L

tion therapy revealed an MDS‑like state, and his170

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Azacitidine treatment for M DS/M PN

compromised physical condition precluded such

AZA,no previous treatment such as low‑dose Ara‑

options as intensive chemotherapies or cytotoxic

C is associated with a better response to AZA .Inagents. Subsequently, blasts in the peripheral blooda phase III randomized trial, AZA signiﬁcantly

disappeared and did not increase for about 2

prolonged overall survival and improved several

months.After he experienced a relapse of leukemic

patient morbidity measures in elderly patients withevolution, he became increasingly ill and died 15

low bone marrow blast count AML . We consider

months after the ﬁrst visit. As only two cycles ofthat AZA might possibly improve the prognosis in

AZA treatment were done in the present case, it ispatients with a diagnosis of MDS/M PN but in adiﬃcult to attribute the anti‑leukemic eﬀect solely

gray zone between CMML and aCML, if it is ad-to AZA treatment. There is also a possibility that

ministered before acute transformation.

the eﬀect maybe due to the induction chemotherapy

Conﬂict of Interest

consisting of DNR and Ara‑C.However,the disease
was expected to relapse earlier without any treatment because blasts remained even after intensive

The authors declare that they have no conﬂict ofinterest.

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