Case 28-2009: A 68-Year-Old Man with Fatigue, Cough, and Peripheral-Blood Monocytosis

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case records of the massachusetts general hospital
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Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor
Jo-Anne O. Shepard, m.d., Associate Editor
Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor
Christine C. Peters, Assistant Editor
Case 28-2009: A 68-Year-Old Man with Fatigue,
Cough, and Peripheral-Blood Monocytosis
Bimalangshu R. Dey, M.D., Ph.D., Thomas R. Spitzer, M.D.,
and Robert P. Hasserjian, M.D.
Pr e sen tat ion of C a se
Dr. Alfred Ian Lee (Oncology): A 68-year-old man was seen in the cancer center of this
hospital because of fatigue, cough, and peripheral-blood monocytosis.
The patient had been well until approximately 7 weeks earlier, when fatigue and
cough developed, followed by burning on urination and suprapubic discomfort.
Approximately 3 weeks before evaluation at this hospital, he saw his primary care
provider. Laboratory-test results are shown in Table 1. Trimethoprim–sulfamethoxa­
zole was prescribed for a presumptive diagnosis of prostatitis. Culture of a urine
specimen reportedly grew Escherichia coli.
Six days later (17 days before evaluation at this hospital), the patient returned to
his primary care provider for follow-up; his urinary symptoms had resolved, and
the fatigue had lessened. The physical examination was normal. A monospot test
for Epstein–Barr virus mononucleosis was negative, and results of dipstick screening
of the urine were normal; other test results are shown in Table 1. He was referred
to a hematologist, whom he saw 10 days before the current evaluation; results of
additional tests are shown in Table 1. Ten days later (on the day of the current
evaluation), results of flow cytometry performed on a specimen of peripheral blood
obtained at the earlier visit to the hematologist were reported and revealed 58%
myeloid blasts, which expressed CD33, CD14, CD15, CD34, HLA-DR, and CD64.
Neither the V617F mutation of the Janus kinase 2 (JAK2) gene nor the BCR-ABL
translocation was detected. The patient was referred urgently to the cancer center
of this hospital, where he was seen later the same day.
He felt well and reported no chills, chest pain, shortness of breath, night sweats,
or weight loss. He was married and semiretired. He had worked in an office in a
navy yard and also had worked on antique cars, and he may have had exposure to
paints and thinners. He had smoked a pipe in the past, and he drank one to two
alcoholic beverages per day. His only medication was acetylsalicylic acid (81 mg
daily). He had no allergies. He was of western European ancestry. Two siblings had
diabetes mellitus, his children and grandchildren were healthy, and there was no
family history of leukemia, lymphoma, or blood disorders. The physical examination was normal. Levels of serum electrolytes, total protein, albumin, globulin,
total and direct bilirubin, calcium, and uric acid and tests of renal and liver
From the Hematology–Oncology Unit
(B.R.D., T.R.S.) and the Department of
Pathology (R.P.H.), Massachusetts General Hospital; and the Departments of
Medicine (B.R.D., T.R.S.) and Pathology
(R.P.H.), Harvard Medical School.
N Engl J Med 2009;361:1099-106.
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Table 1. Laboratory Data.*
Reference Range,
23 Days Earlier
Hematocrit (%)
41.0–53.0 (men)
Hemoglobin (g/dl)
13.5–17.5 (men)
White-cell count (per mm3)
17 Days Earlier
10 Days Earlier
Evaluation at This
Differential count (%)
Band forms
Atypical lymphocytes
26, some immature
Platelet count (per mm3)
Mean corpuscular volume (μm3)
Prostate-specific antigen (ng/ml)
Urea nitrogen (mg/dl)
Leukocyte alkaline phosphatase (IU/liter)
3.98 (ref <4.0)
Creatinine (mg/dl)
Fibrinogen (mg/dl)
28 (ref 6–26)
24 (ref 6–26)
1.6 (ref 0.5–1.3) 1.5 (ref 0.5–1.3)
Activated partial-thromboplastin time (sec)
Prothrombin time (sec)
International normalized ratio
Lactate dehydrogenase (U/liter)
*Ref denotes reference range; these ranges are those used by the patient’s primary care provider. To convert the values for urea nitrogen to
millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4.
†Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at
Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They
may therefore not be appropriate for all patients.
function were normal; other results are shown in
Table 1.
A diagnostic test was performed, and a management decision was made.
Pathol o gic a l Discussion
Dr. Robert P. Hasserjian: The diagnostic test consisted of a bone marrow biopsy and aspiration. Examination of the biopsy specimen showed that
the bone marrow was replaced by sheets of large
cells with folded and often lobulated nuclei, prominent nucleoli, and abundant pink cytoplasm
(Fig. 1A). On the smear of the aspirate (Fig. 1B),
73% of the cells were promonocytes and 11%
were monoblasts. On cytochemical staining, the
blasts and promonocytes were positive for alphanaphthyl butyrate (nonspecific) esterase (Fig. 1C)
and negative for myeloperoxidase, confirming
their monocytic lineage. Bone marrow flow cytometry revealed a predominant population of
CD33+, CD13+, CD117+/−, CD14−, and CD4dim+
cells, a subgroup of which expressed CD34. The
constellation of findings confirms a diagnosis of
acute myeloid leukemia (AML) with monocytic differentiation. This case illustrates one of the pitfalls
in the diagnosis of AML on the basis of the morphologic features of the peripheral blood: manual
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? del(16)
Relative Fluorescence
Base Pairs
Figure 1. Findings in the Bone Marrow at Diagnosis.
The bone marrow–biopsy specimen
A) shows
is markedly
hypercellular and has been
Deythat the bone marrow
replaced by sheets of large cells with
oval-to-irregular nuclei. The bone marrow–aspirate
specimen (Panel B) conREG F FIGURE: 1 of 2
3rd gray or pale basophilic cytosists of a predominant population of promonocytes, which appear as large cells with
plasm and folded nuclei (arrowhead), and fewer monoblasts,Line
which appear
cells with a higher nuclear:cytoplasm
4-C as large
ratio and more prominent nucleoli than the
Cytochemical staining of the bone marrow–aspiH/T
Combo butyrate esterase (Panel C). Cytogenetic analysis
rate specimen revealed blasts that are positive for alpha-naphthyl
(Panel D) reveals an abnormal 47,XY,+8,del(16)(q2?1q2?2)
in 2 of 20 cells in metaphase (additional chromoAUTHOR, PLEASE
type has been
some 8, arrow). (Karyotype provided by
of Cytogenetics,
Brigham and Women’s
Please check carefully.
Hospital and Massachusetts General Hospital.) Polymerase-chain-reaction
analysis of the bone marrow, with primers flanking the site of recurrent internal tandem duplication (ITD) of the FLT3 gene (Panel E), reveals an FLT3-ITD
ISSUE: 09-10-09
mutation (arrow) in addition toJOB:
FLT3 (arrowhead). (Image provided
by A. John Iafrate, M.D., Ph.D., Molecular Diagnostics Laboratory, Massachusetts General Hospital.)
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differential counts performed at other hospitals
included “atypical lymphocytes” (Table 1), which
in retrospect probably represented the promonocytes and monoblasts of this patient’s AML.
To define distinct clinicopathological entities
and to predict the prognosis for patients with
AML, such as this one, the current World Health
Organization (WHO) classification uses immunophenotype, cytogenetics, and molecular genetic
findings, as well as clinical features (e.g., a history of myelodysplastic syndrome or previous
therapy that is known to cause myeloid neoplasia, neither of which was present in this case).1
Thus, additional studies were performed in this
case. An abnormal karyotype — 47,XY,+8,del(16)
(q2?1q2?2) — was identified (Fig. 1D); fluorescence in situ hybridization (FISH) did not reveal
an inversion of chromosome 16 that was affecting the CBFB and MYH11 genes. These findings do
not represent any distinct cytogenetic category of
AML, and thus, the case is classified as AML not
otherwise specified.
In such cases, mutation analysis of the nucleophosmin (NPM1), CCAAT/enhancer binding protein α (CEBPA), and fms-related tyrosine kinase 3
(FLT3) genes is helpful in stratifying patients prognostically.2,3 In particular, point mutations in the
NPM1 gene (in the setting of a normal karyotype
and wild-type FLT3 gene) predict a favorable prognosis.2 Polymerase-chain-reaction analysis of a
bone marrow sample revealed no mutation of
NPM1. However, an internal tandem duplication
of the FLT3 gene (FLT3-ITD) was identified (Fig.
1E). Although FLT3-ITD is not considered to represent a discrete genetic category of AML (since
FLT3 mutations can occur in any type of AML), it
confers an adverse prognosis.4
The final WHO diagnosis in this case is acute
myeloid leukemia not otherwise specified (acute
monocytic leukemia) with FLT3-ITD.
Discussion of M a nagemen t
m e dic i n e
roughly half of all patients with AML. The response to treatment in this group is variable, and
patients are thus further stratified according to
the status of the FLT3 and NPM1 genes.3 This patient had FLT3-ITD, an adverse prognostic factor.
Treatment of AML in the elderly
Even though the patient was healthy, with a good
performance status, we knew that in a retrospective analysis of patients with AML who were older
than 65 years, the mortality at 1 year was 86%,
and only 6% were alive at 2 years.5 Thus, an important initial discussion with this patient must
focus on deciding whether standard AML induction treatment, investigational therapy in the context of a clinical trial, or palliative and supportive
care is the most appropriate strategy. Whereas
standard induction regimens containing an anthracycline and cytarabine result in complete remission in about half of elderly patients with AML,
this patient’s probability of remaining in remission at 3 years is less than 15%,6,7 and the treatment-related mortality rate can be 12 to 50%.8
Furthermore, there is no defined, well-established,
standard postremission or consolidation therapy
for older patients. We discussed enrolling our patient, who had a good performance status and no
concurrent illnesses, in a clinical trial of a new
agent. Clofarabine, which is a nucleoside analogue
(a hybrid molecule derived from fludarabine and
cladribine) that is approved by the Food and Drug
Administration (FDA) for the treatment of acute
lymphoblastic leukemia, has recently been found
to be an effective agent with an acceptable adverseevent rate for investigational use in older patients
with AML.9 Because of his high risk of treatmentrelated death with conventional therapy, this elderly patient was enrolled in a phase 2 clinical
trial ( number, NCT00373529)
that used induction therapy with 5 days of offlabel intravenous clofarabine. He had no clinically
significant side effects and achieved a complete
Dr. Bimalangshu R. Dey: This patient with a new
diagnosis of AML is at the median age at which Stem-Cell Transplantation for AML
patients receive a diagnosis of this disease — 68 in the Elderly
Since AML is rarely cured by a single course of
chemotherapy, treatment typically involves addiPrognostic factors in AML
tional chemotherapy, known as consolidation.
The prognosis is determined principally by age The next challenge in this patient with AML, who
and cytogenetic aberrations. The patient was older was at high risk because of his age and FLT3-ITD–
than 60 years and had trisomy 8, putting him positive leukemia, was to offer a consolidation
into an intermediate-risk group, which constitutes strategy that might improve his chance of cure
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and avoid unacceptable treatment-related side effects or death. The options typically available include additional chemotherapy followed by allogeneic stem-cell transplantation, or consolidative
chemotherapy, with or without autologous stemcell rescue. In patients such as this one, who have
a genetically based adverse risk, a high-intensity,
myeloablative chemotherapy regimen that eradicates all bone marrow elements, followed by allogeneic stem-cell transplantation, offers a 44%
probability of 5-year survival, better than the 15%
or less with additional chemotherapy, with or
without autologous stem-cell rescue.10 However,
in this patient, who is older than 60 years, the risk
of transplantation-related death with myeloablative conditioning is high (27% by 3 months and
43% by 3 years after transplantation).11
The observation that the development of graftversus-host disease (GVHD) is associated with
better relapse-free survival12,13 led to the idea that
a graft-versus-leukemia effect might be occurring, which could be exploited in patients such
as this one, who could not tolerate high-dose
conditioning regimens. Several trials have shown
the feasibility of nonmyeloablative allogeneic
stem-cell transplantation for patients up to the
age of 75 years; with a 2-year overall survival rate
of 40 to 60%.14,15
As consolidation therapy during the patient’s
first remission, he received an HLA-matched allo­
geneic stem-cell transplant from a related donor,
after nonmyeloablative conditioning with off-label
low-dose busulfan and fludarabine and prophylaxis against GVHD with off-label cyclosporine
and mycophenolate mofetil. He recovered well after the transplantation, was discharged, and did
not require rehospitalization for more than 100
days after the transplantation; there was no GVHD
during this time. Mycophenolate mofetil was discontinued before discharge, and low-dose cyclo­
sporine was continued.
Dr. Hasserjian: A bone marrow sample obtained
after induction and before transplantation revealed normal hematopoiesis; neither morphologic assessment nor flow cytometric analysis
revealed evidence of residual acute leukemia, and
FISH revealed no evidence of trisomy 8, factors
consistent with a remission. However, a bone
marrow aspirate obtained on a routine visit 100
days after the bone marrow transplantation showed
60% blasts, representing relapsed AML. A chimerism FISH study on the patient’s bone marrow
(Fig. 2A), with specific probes to the X and Y
chromosomes (this was possible because the patient had a female donor), revealed 48% donor
cells with two X signals and 52% recipient cells
with one X signal and one Y signal.
Treatment of relapsed AML
Dr. Thomas R. Spitzer: Unfortunately, even after stemcell transplantation, relapse of AML remains a
major obstacle, especially after reduced-intensity
stem-cell transplantation. This is the chief cause
of treatment failure, particularly among patients
with AML who are at high risk for relapse, as in
this case. Treatment options for such patients
have been largely unsatisfactory. Palliative chemotherapy, supportive care, and enrollment in a clinical trial evaluating new agents are appropriate
for selected patients unable or unwilling to under­
go more aggressive therapy. Transplantation of
stem cells from the same or an alternative donor
has occasionally been attempted16,17 and has been
successful mostly in younger, otherwise healthy patients who were in remission for at least 6 months
after the initial transplantation.
Recently, infusions of lymphocytes from the
transplant donor have been used for the treatment of hematologic malignant conditions in
patients with relapse after allogeneic stem-cell
transplantation, usually preceded by some type of
chemotherapy to reduce the number of leukemic
cells (cytoreduction).18-20 When the disease relapsed in this patient, the leukemic cells were of
host origin, whereas normal hematopoietic cells
were of donor origin, as shown by FISH analysis
of the X and Y chromosomes. The goal is to induce remission and a return to normal donor
hematopoiesis by means of cytoreductive chemotherapy and to maintain that remission by means
of adoptive cellular immunotherapy (i.e., infusions of donor lymphocytes intended to induce a
stronger graft-versus-leukemia effect). The best
evidence of a graft-versus-leukemia effect has
been observed in patients with chronic myeloid
leukemia, who had a 70 to 80% probability of
achieving a complete and durable molecular genetic remission.18,19 However, GVHD and bone
marrow aplasia have each occurred in up to half
of those patients. Unfortunately, infusions of
donor lymphocytes have been less successful for
the treatment of AML that relapsed after stem-cell
transplantation, with approximately 20% of patients achieving remissions lasting 2 years.20 On
the basis of retrospective rather than prospective
observations of cases of AML, the best results
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Figure 2. Pathologic Changes after Initial Therapy for AML.
A fluorescence in situ hybridization (FISH) study on bone marrow at the time of first relapse, with specific probes to
the X and Y chromosomes (Panel A), reveals 48% donor cells with two red X signals (arrow) and 52% recipient cells
with one red X signal and one greenICM
Y signal
(arrowhead). A skin-biopsy specimen obtained 1 month later shows in2a-d At the dermal–epidermal2nd
terface dermatitis with dyskeratotic REG
cellsF (Panel
B, arrow).
junction (Panel C), lymphocytes
TITLEkeratinocytes (arrowheads), effecting
(arrows), presumably of donor origin, surround
Revised the epithelial damage characterEMail
istic of cutaneous GVHD. FISH analysis of bone marrow chimerism
second remission (Panel D) reveals
H/T red X and one green Y signal, arrow). (Pan96.5% donor cells (two red X signals) and only 3.5% recipient cells (one
els A and D courtesy of Paola dal Cin, Ph.D., Laboratory of Cytogenetics, Brigham and Women’s Hospital and MasAUTHOR,
sachusetts General Hospital.)
Figure has been redrawn and type has been reset.
Please check carefully.
have occurred in young patients, those in posttransplantation remission for more than 5 months,
those with a favorable karyotype, and those in
whom cytoreductive chemotherapy resulted in
remission before the infusion of donor lymphocytes.20 This patient’s risk factors thus do not
predict a durable response to an infusion of donor lymphocytes.
Another strategy that is being explored in patients with AML that is in relapse after stem-cell
transplantation is the off-label or investigational
use of hypomethylating agents such as azacitidine and decitabine, which are approved by the
FDA for use in myelodysplastic syndromes.21,22
These agents are thought to act by decreasing or
reversing hypermethylation of genes, including
tumor-suppressor genes; therefore, they inhibit the
growth of tumor cells (cytoreduction) and potentially cause other epigenetic modifications that
may expose new antigens on tumor cells that
could be targets for a graft-versus-leukemia effect.
Our patient received decitabine to reduce the number of tumor cells, with planned infusions of
donor lymphocytes. He achieved a second complete remission of the AML, but cutaneous and
gastrointestinal GVHD developed, requiring immunosuppressive therapy with increased doses of
cyclosporine, oral prednisone, and oral beclo­
methasone and precluding the use of a donorlymphocyte infusion.
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Dr. Hasserjian: A skin biopsy performed 130
days after the stem-cell transplantation (Fig. 2B
and 2C) showed prominent interface dermatitis
with numerous dyskaryotic cells, vacuolation of
the dermal–epidermal junction, and focal lymphocytic infiltration surrounding basal keratinocytes, all of which are features of GVHD. Five
months later, 9 months after transplantation, a
bone marrow sample revealed bone marrow in
remission, with maturing trilineage hematopoiesis. A FISH study of bone marrow chimerism
(Fig. 2D) revealed 96.5% donor cells (two X signals) and only 3.5% recipient cells (one X signal
and one Y signal). However, 5 months later (14
months after transplantation), leukocytosis again
developed, with 66% circulating blasts, indicating a second relapse of the AML.
Dr. Spitzer: The patient is undergoing additional
chemotherapy with decitabine. His immunosuppression is being tapered to potentiate a graftversus-leukemia effect. The ultimate goal of this
strategy is to take advantage of his persistent
donor immunity and to induce a strong and more
durable graft-versus-leukemia response. The challenge in this case and most others is to separate
the beneficial graft-versus-leukemia effect of the
transplantation from the deleterious manifestations of GVHD.
Dr. Nancy Lee Harris (Pathology): Dr. Attar, can
you tell us how the patient is doing now?
Dr. Eyal Attar (Hematology–Oncology): Because
of his previous excellent response to decitabine,
I elected to treat him with additional decitabine.
He has received two cycles of decitabine chemotherapy and has had complete resolution of his
peripheral-blood blasts. The GVHD in the skin
has resolved, and symptoms related to his upper
gastrointestinal tract are under control with oral
beclomethasone. We hope that this combined
strategy of cytoreduction and a graft-versusleukemia effect will result in complete remission.
He continues to have an excellent performance
Dr. Philip C. Amrein (Hematology–Oncology):
Since relapse is a concern after nonmyeloablative transplantation, would you consider a con-
solidation cycle of chemotherapy before transplantation?
Dr. Dey: Although rates of early death associated with transplantation are reduced in patients
undergoing nonmyeloablative allogeneic stem-cell
transplantation as compared with myeloablative
transplantation, the leukemic relapse rate is high­
er. Therefore, various strategies, including consolidation therapy before nonmyeloablative transplantation, additional cytoreductive therapy, and
infusions of donor lymphocytes after the transplantation, are currently being explored in order to
reduce the post-transplantation leukemic relapse.
Dr. Spitzer: Also, clinical trials are under way
to look at post-transplantation chemotherapy with
hypomethylating agents.
Dr. Harris: It sounds as though you have turned
an acute leukemia into a chronic disease, in
which you are balancing GVHD against graftversus-leukemia and giving the patient chemotherapy that is not terribly toxic, which is resulting in a reasonable quality of life despite persistent
leukemia a year and a half after the diagnosis.
Dr. Spitzer: Unfortunately, most patients with
AML who have a relapse after transplantation
have another relapse, even if we are able to get
them back into remission, and very few are cured
— that is, in remission for 2 years or more. The
precise role of the strategy of nonmyeloablative
stem-cell transplantation in elderly patients with
AML, particularly in regard to survival, cost-effectiveness, and quality of life, remains to be defined in future clinical trials.
A nat omic a l Di agnosis
Acute myeloid leukemia, not otherwise specified
(acute monocytic leukemia), with FLT3-ITD.
This Clinicopathological Conference was presented at the
Massachusetts General Hospital Cancer Center Grand Rounds,
March 26, 2009.
Dr. Dey reports receiving lecture fees from Celgene (which makes
azacitidine); Dr. Spitzer, consulting fees from Genzyme (which
makes clofarabine and fludarabine), Hospira, and Viropharma; and
Dr. Hasserjian, consulting fees from Genzyme. No other potential
conflict of interest relevant to this article was reported.
We thank Drs. Alfred Lee and Eyal Attar for assistance in
preparing the case history and for review of the manuscript.
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shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. This slide set contains all of the
images from the CPC, not only those published in the Journal. Radiographic, neurologic, and cardiac studies, gross specimens,
and photomicrographs, as well as unpublished text slides, tables, and diagrams, are included. Every year 40 sets are produced,
averaging 50-60 slides per set. Each set is supplied on a compact disc and is mailed to coincide with the publication of the
Case Record.
The cost of an annual subscription is $600, or individual sets may be purchased for $50 each. Application forms for the current
subscription year, which began in January, may be obtained from the Lantern Slides Service, Department of Pathology,
Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974) or e-mail [email protected]
n engl j med 361;11 september 10, 2009
The New England Journal of Medicine
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