Treatment-related acute granulocyte–monocytic leukemia from multiple myeloma: A case report and literature review

Abstract

Rationale:
To investigate the clinical features of treatment-related acute granulocyte-monocytic leukemia (t-AML) from multiple myeloma (MM) thereby improving the understanding of this disease.

Patient concerns:
A 72-year-old woman patient was initially diagnosed as MM. Two years and 7 months after treatment, this patient developed AML M4 as confirmed by the analyses from clinical features, bone marrow morphology, flow cytometry, and cytogenetic examination.

Diagnosis:
Treatment-related acute myeloid leukaemia (t-AML).

Interventions:
Due to lack of the ability to pay the cost, she declined our recommendation to accept therapy as an inpatient and was discharged.

Lessons:
The reported case was a rare t-AML, which is resistant to currently available treatments and has a poor prognosis.

Full text

Treatment-related acute granulocyte–monocytic
leukemia from multiple myeloma
A case report and literature review
Juan Qian, MS, Wenyu Shi, MD, PhD, Li Yang, MD, PhD, Zenghua Lin, MS, Yifeng Cai, MD, PhD,
Hong Liu, MD, PhD
∗
Abstract
Rationale: To investigate the clinical features of treatment-related acute granulocyte–monocytic leukemia (t-AML) from multiple
myeloma (MM) thereby improving the understanding of this disease.
Patient concerns: A 72-year-old woman patient was initially diagnosed as MM. Two years and 7 months after treatment, this
patient developed AML M4 as confirmed by the analyses from clinical features, bone marrow morphology, flow cytometry, and
cytogenetic examination.
Diagnosis: Treatment-related acute myeloid leukaemia (t-AML).
Interventions: Due to lack of the ability to pay the cost, she declined our recommendation to accept therapy as an inpatient and
was discharged.
Lessons: The reported case was a rare t-AML, which is resistant to currently available treatments and has a poor prognosis.
Abbreviations: HB =haemoglobin, MM =multiple myeloma, PLT =platelets, RBC =red blood cells, t-AML =treatment-related
acute myeloid leukemia, WBC =white blood cells.
Keywords: acute granulocyte–monocyte leukemia, multiple myeloma, treatment-associated acute granulocyte–monocyte
leukemia
1. Introduction
Multiple myeloma (MM) is a common hematologic malignancy
derived from pre-B cells and/or plasma cells. The abnormal
proliferation of bone marrow plasma cells leads to osteolytic
bone destruction and serum accumulation of monoclonal
immunoglobulins or light chains (M proteins), resulting in
recurrent infections, anemia and renal dysfunction. With the
application of advanced chemo-radiotherapy and targeted
therapy in cancers, increasing numbers of patients with cancers
can obtain long-term survival. Treatment-related acute myeloid
leukemia (t-AML) refers to the AML in patients after treatment of
tumors or other benign diseases with radiotherapy and
chemotherapy.
[1]
After treatment, the development of MM to
t-AML, especially acute myelomonocytic leukemia, is rarely
reported.
[2]
Herein, we report 1 case of an MM patient who
developed AML (M4) 2 years and 7 months after treatment, and
reviewed the related literature.
2. Case report
The experimental protocol was established, according to the
ethical guidelines of the Helsinki Declaration and was approved
by the Human Ethics Committee of Affiliated Hospital of
Nantong University, China. Written informed consent was
obtained from individual participant.
This patient was a 72-year-old woman who came to our
hospital on April 8, 2014 and claimed dizziness, fatigue, and
cough with expectoration for about a month. The routine blood
examination results were white blood cells (WBC) 3.2 10
9
/L,
RBC 2.65 10
12
/L, hemoglobin (HB) 85 g/L, and platelets (PLT)
12010
9
/L. The biochemistry tests showed normal creatinine
and uric acid with globulin levels of 61.1g/L. The immunoglob-
ulin levels were IgA 42.3 g/L, IgG 3.19 g/L, IgM 0.29 g/L, kappa
light chain 244 mg/dL, lambda light chain 738mg/dL, and C-
reactive protein 111.0 mg/L. The erythrocyte sedimentation rate
was 123 mm/h. Immunofixation electrophoresis showed that the
M component was an IgA-lambda light chain. Bone marrow
cytology analysis demonstrated active proliferation of nucleated
cells, with granule cells:red cell ratio =3.03:1 without apparent
alterations of granulocyte, mononucleocyte, lymphoid and
erythroid proliferation; the PLT displayed clustered distribution.
Moreover, we found 19 megakaryocytes in a slide with a whole
area of 2.2 2.4 cm and myeloma cells accounted for 10%
Editor: Weimin Guo.
JQ and WS have contributed equally to this work.
This work was supported in part by grants from the National Natural Science
Foundation of China (81070400), the Jiangsu Province Innovative Medical Team
and Leading Talent Project (LJ201136), and the Xing Wei, Jiangsu Province Key
Medical Personnel Fund Project (RC2007084).
The authors have no conflicts of interest to disclose.
Department of Hematology, Affiliated Hospital of Nantong University, Nantong,
Jiangsu, China.
∗
Correspondence: Hong Liu, Department of Hematology, Affiliated Hospital of
Nantong University, No. 20, Xishi Road, Nantong, Jiangsu 226001, China
(e-mail: lhong6363@163.com).
Copyright ©2017 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows
others to remix, tweak, and build upon the work non-commercially, as long as
the author is credited and the new creations are licensed under the identical
terms.
Medicine (2017) 96:50(e9293)
Received: 21 January 2017 / Received in final form: 22 November 2017 /
Accepted: 27 November 2017
http://dx.doi.org/10.1097/MD.0000000000009293
Clinical Case Report Medicine®
OPEN
1

(Fig. 1A). Leukemia/lymphoma immunotyping found that R1-
lymphocytes, R2-early bone marrow cells, R3-monocytes, R4-
differentiated myeloid cells, R5-nucleated red blood cells (RBCs),
and R6-CD38++/CD56++/CD138++CD20/CD22MM cells
accounted for 18.80%, 2.81%, 5.14%, 47.04%, 14.69%, and
8.46%, respectively (Fig. 1B). Fluorescence in situ hybridization
analysis found 1q21 gene amplification in 16% cells but normal
D13S319, RB1, and immunoglobulin heavy chain (Fig. 1C). No
apparent bone hyperplasia or signs of destruction in the head,
cervical spine, and thoracic vertebra, or pelvis lumbar degenera-
tion were observed. Based on these tests, the patient was
diagnosed as MM (IgA llight chain type; stage II group A).
From April 14, 2014, the patient was subjected to liposomal
doxorubicin; vindesine; dexamethasome (DVD) chemotherapy
(doxorubicin liposomes: 20 mg 2 d intravenous injection (i.v.);
vindesine: 1 mg 4 d i.v.; dexamethasone: 20 mg4 d i.v.). After
a 4-day interval, the patient was discharged and underwent
continuous oral administration of dexamethasone at 20 mg 4d,
followed by an interval for 4 days, and then oral administration
of dexamethasone at 20 mg 4 d. On May 12, 2014, the patient
underwent routine blood tests. The results showed immunoglob-
ulin levels of IgA 18.70 g/L and lambda light chain levels of 373
mg/dL. This treatment cycle was repeated on May 13, June 13,
July 13, and August 13, 2014. During this treatment period, IgA
and lambda light chain levels decreased, HB level increased, and
erythrocyte sedimentation rate decreased. Examination on
August 22, 2014 showed an IgA level of 5.72 g/L, a lambda
light chain level of 306mg/dL, and trace IgA-lambda light chain
levels by immunostaining electrophoresis. The patient demon-
strated significantly improved condition. Then the patient was
discharged and subjected to thalidomide dexamethasome
chemotherapy (dexamethasone 20 mg qw; thalidomide 100mg
qn).
On October 10, 2016, she had a fever with dizziness, fatigue,
and cough accompanied with some yellow purulent sputum, and
was treated as cold without apparent improvement. On
November 11, 2016, she was admitted to our hospital. The
routine blood examination results were WBC 16.8 10
9
/L, RBC
1.5 10
12
/L, HB 52 g/L, and PLT 17 10
9
/L. The immunoglob-
ulin levels were IgA 5.81 g/L and lambda light chain 708 mg/dL.
Immunofixation electrophoresis showed that the M component
was an IgA-lambda light chain. Bone marrow cytology analysis
demonstrated obviously active proliferation of nucleated cells
with pathological changes of granule cells (I + II accounted for
35.5%), positive for myeloperoxidase staining; mononuclear
cells demonstrated hyperplasia with 48.5% of primary mononu-
clear cells, partly negative for myeloperoxidase staining. There
were no lymphoid abnormalities (Fig. 1D). Leukemia/lymphoma
immunotyping revealed that R1-lymphocytes, R2-early bone
marrow cells, R4-differentiated myeloid cells, and R5-nucleated
RBCs accounted for 8.85%, 84.2%, 1.05%, and 1.43%,
respectively (Fig. 1E). These tests demonstrated a phenotype of
Figure 1. (A) Bone marrow smears showed myeloma cells (Wright staining, 1000). (B) Immunological typing at the time of initial diagnosis. (C) FISH tests at the
time of initial diagnosis. (D) Wright staining showed t-AML (M4), 1000. (E) Immunophenotyping of t-AML (M4). FISH =fluorescence in situ hybridisation.
Qian et al. Medicine (2017) 96:50 Medicine
2

AML-M4. Analysis of chromosomes revealed no karyotype
abnormality. TP53 gene mutation analysis found TP53 was wild
type. Due to lack of the ability to pay the cost, she declined our
recommendation to accept therapy as an inpatient and was
discharged.
3. Discussion and literature review
MM is a common blood system malignancy and accounts for
10% of hematopoietic malignancies and about 1% of all
malignant tumors.
[3]
The treatment of MM has improved greatly
since the 1960s traditional melphalan combined with prednisone
treatment and the 1980s multidrug combination chemotherapy
(such as doxorubicin; vindesine; dexamethasome, DVD, M2
programs) and autologous hematopoietic stem cell transplanta-
tion. Particularly, the advent of molecular targeted drugs has
greatly prolonged the survival time of MM patients. Develop-
ment of MM to t-AML has become a major challenge. Although
MM and AML originate from 2 distinct clones with low
incidences of second tumor, t-AML is an aggressive disease with a
very poor prognosis.
[4]
Recently, there have been several case
reports of t-AML, including plasma cells, acute lymphoblastic
and acute nonlymphotropic subtypes; however, there have been
few reports of AML-M4 with only 1 case reported in China.
[2]
Bergsagel et al conducted that the first prospective clinical
study evaluating the effects of a combination of 3 alkylating
agents in the treatment of MM: melphalan, cyclophosphamide,
and carmustine. They observed higher incidence of all forms of
acute leukemia than expected in all age groups.
[5]
It was reported
that the incidence of acute leukemia in MM patients after
chemotherapy is in the range of 0.2% to 7% with a peak time of
3.5 to 5 years after initiation of treatment.
[6]
Other studies also
demonstrated that conventional chemotherapy before autolo-
gous stem cell transplantation, rather than pretransplant
myeloablative therapy, maintenance therapy, or additional
treatment after transplantation, more likely contributes for
acute leukemia.
[7]
Moreover, patients with MM who undergo
continuous treatment have a higher incidence of acute leukemia
than those who undergo intermittent treatment. The exact
mechanisms of the development of t-AML from MM are largely
unknown. The potential mechanisms may include chemotherapy-
induced recurrent bone marrow suppression and regeneration
results in clonal changes of stem cells; chemotherapy results in
genetic alteration of marrow hematopoietic stem cells, thereby
leading to clone expansion of leukemia stem cells; chemotherapy
triggers an activation of potential leukemia initiating factors;
chemotherapy or radiotherapy impairs the immune surveillance
system leading to loss of the killing and removal of abnormal cells
and leukemia clones; abnormal proliferation of leukemic cells
inhibits MM cell differentiation and proliferation.
[2]
Neverthe-
less, some scholars believe that the history of chemotherapy is not
an essential factor for MM patients to develop AML. Since MM
patients are prone to immune deficiencies often accompanied by
intermittent and recurrent infections, the long-term immune
response may lead to mononuclear cell hyperplasia and finally
AML.
In addition, the evolution of MM to AML may also be
associated with cancer susceptibility of the patient.
[8–10]
Indeed, it
has been estimated that genetic variations can account for up to
95% of variability in drug disposition and effects.
[11]
In addition
to drug disposition and response to treatment, polymorphisms in
genes encoding drug-metabolizing enzymes, DNA repair path-
ways, drug transporters, and drug targets may contribute to a
person’s susceptibility to subsequent malignancies as well.
[12]
Furthermore, the bone marrow microenvironment may be
important in the pathogenesis of AML. MM depends on mutual
interactions between cells and extracellular components of the
bone marrow for survival and growth. Interactions between MM
cells with the bone marrow microenvironment activate a
pleiotropic proliferative and antiapoptotic cascade, including
the nuclear factor-kappa B signaling pathway, resulting in the
growth, survival, drug resistance, and migration of MM cells.
[13]
Moreover, many growth factors secreted by MM and bone
marrow stromal cells stimulate osteoclastogenesis and angiogen-
esis.
[14]
It is thus conceivable that the resultant changes in bone
marrow microenvironment may play a role in the development of
AML after MM.
In this case, the patient did not receive alkylating agents such
as carmustine, cyclophosphamide, melphalan, and busulfan, but
was subjected to 5 cycles of DVD chemotherapy for nearly
3 years. The relatively early development of AML in this MM
patient might be related to her old age, since compared with
young patients, chemotherapy-induced bone marrow suppres-
sion is stronger in old patients, likely leading to difficulty in
short-term recovery, increased clonal changes in stem cells, and
accelerated loss of immune surveillance. In addition, this patient
took thalidomide for nearly 3 years. It has been warned that
thalidomide increases the risk of secondary blood cancers.
[15]
It
is possible the early development of AML in this MM patient
might be related to the usage of thalidomide. However, all
patients with myeloma in our hospital have taken thalidomide.
Except for those patients who cannot tolerate thalidomide-
induced hand and foot numbness, edema and other adverse
reactions and discontinued thalidomide, all the other patients
take thalidomide at the beginning of treatment and continue
long-term oral administration for treatment maintenance with
the maximum dose of 200 mg/d. Only 1 case of secondary M4 in
all MM patients was found in our hospital. Therefore, further
studies are needed to investigate the association of thalidomide
with the development of AML from MM. Furthermore, several
proposed environmental risk factors are shared between MM
and second malignancies. Chronic antigen stimulation from
prior autoimmune, infectious, inflammatory, allergic disorders,
and immune dysregulation may play a role in the pathogenesis
of both MM and AML.
[16–18]
In addition, socioeconomic
status has been shown to influence survival of both MM and
AML, suggesting that lifestyle factors in these disorders are
important.
[19]
Taken together, it seems reasonable to propose that the
development of second malignancies after MM is most likely an
outcome from the multifactorial process. With the extension of
survival time in MM patients, there will be increasing numbers of
reports regarding t-AML derived from MM. However, MM-
derived t-AML progresses rapidly with a very poor prognosis. To
avoid t-AML, it will be critical to better characterize the
molecular features of patients who develop second malignancies
after MM, which would allow us to better define the role of
treatment and nontreatment-related factors and how they
influence each other.
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