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Thrombotic Microangiopathy Associated with
Interferon Therapy for Patients with Chronic
Myelogenous Leukemia
Coincidence or True Side Effect?
Farhad Ravandi-Kashani, M.B.,
Jorge Cortes, M.D.1
Moshe Talpaz, M.D.2
Hagop M. Kantarjian, M.D.1
Department of Leukemia, M. D. Anderson Cancer
Center, Houston, Texas.
Department of Bioimmunotherapy, M. D. Anderson Cancer Center, Houston, Texas.
BACKGROUND. Interferon-a (rIFN-a) is an established therapy for patients with
myeloproliferative disorders. Unusual immune-mediated side effects have been
associated with rIFN-a therapy. The association of rIFN-a therapy with hemolytic
uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) has
been reported infrequently.
METHODS. Two patients with chronic myelogenous leukemia (CML) treated with
rIFN-a– based regimens at the University of Texas M. D. Anderson Cancer Center
developed thrombotic microangiopathy (HUS/TTP). The course of their disease is
described. A third patient who developed renal failure while receiving rIFN-a
therapy and had no other causative factor for his renal failure is also described.
RESULTS. The patients were ages 24, 49, and 36 years, and they had received rIFN-a
therapy for 37, 67, and 92 months, respectively, prior to the development of the
disorder. One patient had discontinued rIFN-a 1 month before the event because
of presumed rIFN-a–related cardiomyopathy. Two patients received hydroxyurea
and cytarabine as part of their therapy. No patient was receiving any medication
known to be associated with HUS/TTP. None had a history of diarrheal illness, but
Escherichia coli OH157.H7 was grown from the stool of one patient. Two patients
responded to plasmapheresis with normalization of counts and other indices, but
both developed renal failure and became dependent on dialysis. One patient had
evidence of disease progression and died of multiorgan failure. The third patient
required dialysis for 18 months but is currently off dialysis; this patient has some
residual renal impairment.
CONCLUSIONS. Although no definitive association between rIFN-a therapy and
thrombotic microangiopathies can be concluded from these data, these and other
previously reported cases suggest that HUS/TTP is a rare side effect of rIFN-a
therapy that should be managed in the standard fashion. Hypotheses regarding the
mechanism underlying this association are discussed in this article. Cancer 1999;
85:2583– 8. © 1999 American Cancer Society.
KEYWORDS: chronic myelogenous leukemia, interferon-a, thrombotic microangiopathy, renal failure.
Published in abstract form in Proceedings of ASH,
San Diego, California, 1998, and in Blood 1988,
Volume 92, Number 10, Supplement 1.
Address for reprints: Hagop M. Kantarjian, M.D.,
Department of Leukemia, Box 61, M. D. Anderson
Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.
© 1999 American Cancer Society
ollowing the initial studies in the 1980s that demonstrated the
efficacy of interferon-alpha (rIFN-a) therapy in inducing hematologic and cytogenetic responses in patients with chronic myelogenous
leukemia (CML),1– 4 recent trials have established this agent as the
current standard in the treatment of patients with this disorder who
are not eligible for allogeneic bone marrow transplantation.5 The
efficacy of rIFN-a in achieving hematologic and cytogenetic re-
CANCER June 15, 1999 / Volume 85 / Number 12
sponses is improved when combined with other
agents, such as cytosine arabinoside (ara-C) or homoharringtonine.6 – 8
Interferon therapy has been associated with several well-documented toxicities.5,9 These include a flulike illness with fever, malaise, and myalgia, the severity of which may be associated with higher initial
white blood cell count (WBC) and therefore can be
partly alleviated by the initial use of hydroxyurea to
reduce the WBC count.9 Other reported side effects
include neuropsychiatric symptoms with fatigue, depression, and insomnia.5 Uncommon and immunemediated complications of interferon therapy have
been described.10 These include cutaneous vasculitis,
immune hemolytic anemia, hypothyroidism, immune-mediated thrombocytopenia, nephrotoxicity,
pemphigus foliaceous, rheumatoid arthritis, systemic
lupus erythematosus, and other connective tissue disorders, including polymyositis and Raynaud syndrome.11–20 Rare cases of retinopathy and cardiac toxicity have been reported and may be immunemediated.21,22
Occasional reports have described hemolytic uremic syndrome (HUS) developing in patients receiving
rIFN-a therapy for CML.23–26 Shammas et al. also reported a case of thrombotic microangiopathy in a
patient with CML on hydroxyurea therapy.27 HUS has
also been reported in a patient with hairy cell leukemia who received rIFN-a therapy.28 Therefore, it remains unclear whether this association is a true side
effect of rIFN-a therapy or a mere coincidence.
Thrombotic microangiopathy is a term that encompasses HUS as well as thrombotic thrombocytopenic purpura (TTP). Its association with malignant
disorders has been well established.29,30 The association of HUS/TTP with chemotherapeutic agents for
cancer patients was first reported by Liu et al.31 They
described mitomycin C–induced renal toxicity associated with microangiopathic hemolytic anemia and
thrombocytopenia. Other agents reported to cause
HUS/TTP include methyl-carmustine, bleomycin,
daunomycin, gemcitabine, and deoxycoformycin.32–34
We describe two cases of thrombotic microangiopathic disorders and a third case of renal failure that
was probably secondary to undiscovered HUS/TTP, in
patients who received rIFN-a therapy for CML, and
consider the possible underlying mechanisms.
Case 1
A male age 49 years was diagnosed with Philadelphiachromosome (Ph) negative, BCR-ABL positive CML in
August 1991, when he presented with fatigue, weight
loss, and a WBC count of 226 3 109/L. He was initially
treated with hydroxyurea 3 g/day and rIFN-a 10 MU/
day. Following a hematologic response, he was maintained on rIFN-a at the same dose and hydroxyurea at
0.5 g/day, which resulted in a fall in the BCR-ABL
positive cells to 3% after 32 months of therapy. Five
years after the initial diagnosis, he developed thrombocytosis with a platelet (PLT) count of 636 3 109/L.
Ara-C 10 mg/day was added to the regimen and a
search for a bone marrow transplantation (BMT) donor was initiated. He was found to be 96% Ph-positive
by fluorescent in situ hybridization (FISH) analysis.
Sixty-seven months after initiation of rIFN-a therapy,
in April 1997, he developed severe, refractory anemia
with a hemoglobin level of 6.0 g/dL and was commenced on steroids for a presumptive diagnosis of
IFN-induced immune hemolysis. He had the following
results: PLT 32 3 109/L, total bilirubin 2.1 with indirect
bilirubin 2.0 mg/dL, lactate dehydrogenase (LDH)
6957 IU/L, normal liver enzymes, blood urea nitrogen
(BUN) 35 mg/dL, and creatinine 1.6 mg/dL. The following tests were negative or normal: rapid plasma
reagent (RPR), antinuclear antibody (ANA), hepatitis B
surface antigen (HBsAg), hepatitis B core antibody
(HBcAb), human immunodeficiency virus antibody
(HIV), human T-lymphotrophic virus antibody
(HTLV)-1/2, cytomegalovirus antibodies (CMV), prothrombin time (PT), partial thromboplastin time
(PTT), serum fibrinogen, fibrin split products (FSP),
and serum haptoglobin. A peripheral blood smear revealed moderate schistocytosis. Bone marrow examination was negative for increased number of blast
cells. Stool cultures was positive for Escherichia coli
OH157.H7, but all other cultures were negative. A diagnosis of HUS was made, and the patient was started
on daily plasmapheresis with cryo-poor plasma. He
was not taking any other medications associated with
HUS development. On April 26, 1997, he developed
vertigo and slurred speech, and a CT scan of brain
revealed a small area of hypodensity in the pons and
midbrain suggestive of infarction/hemorrhage. Lumbar puncture was performed and cerebrospinal fluid
(CSF) was negative for an inflammatory process with 1
WBC/high power field (hpf), 27 RBC/hpf, normal protein and glucose, and negative bacterial, fungal, and
mycobacterial cultures. Four days later, he developed
respiratory distress that required artificial ventilation
with bronchoscopic findings, and imaging studies
were suggestive of bronchoalveolar hemorrhage. The
patient continued to receive plasmapheresis and later
developed nonoliguric renal failure, with rise of BUN
and creatinine to 106 mg/dL and 3.7 mg/dL, respectively. He was started on daily hemodialysis. On April
26, 1997, after 6 episodes of plasmapheresis, his blood
counts normalized, but in May 1997 he had evidence
Thrombotic Microangiopathy with rIFN-a/Ravandi-Kashani et al.
of CML acceleration, with rising WBC to 48 3 109/L,
7% peripheral blasts, and 18% bone marrow blasts.
Despite supportive measures, the patient developed
multiorgan failure and died of the complications. A
request for an autopsy was declined by the patient’s
109/L, disappearance of schistocytes, and normalization of other indices, such as LDH (519 mg/dL) and
bilirubin (0.8 mg/dL), in June 1998. However, she
has continued to remain hemodialysis dependent
with end-stage renal disease after over 3 months of
Case 2
Case 3
A white female age 24 years with Ph-positive CML
diagnosed in November 1994 was initially treated with
hydroxyurea at doses of 1.5– 4.0 g/day for 1 month.
Her therapy was changed to a combination of rIFN-a
9 MU/day and ara-C 10 mg/day, and hydroxyurea was
discontinued following achievement of complete hematologic response (CHR). After 2 years of therapy,
she did not achieve a cytogenetic response; Ph chromosome remained at 100% on bone marrow cytogenetics, and a search for a BMT donor was initiated. In
February 1998, 36 months after initiation of therapy
with rIFN-a, she developed exertional dyspnea with
radiographic evidence of cardiomegaly. Echocardiography demonstrated reduced left ventricular ejection
fraction of 35%. Interferon-related cardiomyopathy
was suspected and the patient was commenced on
steroids, digoxin, and furosemide; she had a good
response, and her cardiac status improved. rIFN-a
therapy was discontinued and hydroxyurea was increased to maintain normal blood cell counts. One
month after discontinuation of rIFN-a, in March 1998,
she presented with severe hypertension (BP 230/150)
and was noted to have the following laboratory results:
PLT 20 3 109/L, hemoglobin 11.9 g/dL, WBC 10 3
109/L, BUN 48 mg/dL, creatinine 1.8 mg/dL, fibrinogen 266 mg/dL, FSP 80 mg/dL, D-Dimer 0.25– 0.5, PT
12s, PTT 25s, LDH 4300, total bilirubin 1.9 mg/dL,
direct and indirect Coomb test negative, peripheral
blood smear positive for schistocytes, and haptoglobin
,6 (N30 –226). The following tests were negative or
normal: HBsAg, HBcAb, HIV-1 and -2, HTLV-1 and -2,
smooth muscle antibody (SMA), ANA, c- and p-antineutrophil cytoplasmic antibody (ANCA), complement C4 and C3, and stool for E. coli OH157.H7. Urinalysis showed 50 –100 RBCS with no casts. Urinary
collection every 24 hours revealed 4.5 g/day urinary
protein loss. Renal ultrasound revealed normal echogenicity of the kidneys without hydronephrosis. The
diagnosis of renal failure secondary to HUS with malignant hypertension was made, leading to the initiation of antihypertensive therapy, daily plasmapheresis, and later, in April 1998, with worsening renal
function, (BUN 114 mg/dL, creatinine 3.9 mg/dL) hemodialysis. The patient was not taking any other medications at the time of presentation. She responded to
therapy with normalization of PLT count to 376 3
A male age 36 years was diagnosed with Ph-positive
CML in September 1985 and treated with hydroxyurea. In August 1986, he was started on therapy with
rIFN-a combined with IFN-gamma (rIFN-g) at doses
of 2 MU/m2/day and 0.01 MU/m2/day, respectively.
He was maintained on rIFN-a 5MU/m2/day and
IFN-g 0.025 MU/m2/day and achieved a CHR. In October 1989, rIFN-g was held due to excess toxicity with
fatigue and neuropsychiatric symptoms. By October
1992 he had achieved a major cytogenetic response
with 5% Ph-positive cells on bone marrow analysis.
rIFN-g was reintroduced due to improvement in
symptoms. In April 1994 he presented to his local
hospital with increased fatigue and hypertension,
where he was noted to have renal failure (BUN 83
mg/dL, creatinine 6.2 mg/dL), marked anemia with
hematocrit of 20, and congestive heart failure with a
left ventricular ejection fraction of 35% on echocardiography. Results of other investigations were as follows: WBC 10.9 3 109/L; PLT 282 3 109/L; red blood
cell poikilocytosis and anisocytosis; LDH 259 U/L
(N90 –200); haptoglobin 144 mg/dL; PT 14S; PTT 23s;
urinalysis positive for protein and occasional hyaline
and granular casts; 24-hour urinary protein 1.8 g; normal renal ultrasound results; renal biopsy-hyperplastic arteriolosclerosis with negative immunofluorescent
studies, consistent with malignant hypertension; myocardial biopsy–focal individual hypertrophy with no
appreciable inflammatory cell infiltrate; coronary arteries normal on angiogram with severe, diffuse left
ventricular dysfunction; renal arteriogram negative for
renal artery stenosis; and esophagogastroduodenoscopy negative for any bleeding source. The patient was
not taking any other medications. IFN therapy was
discontinued and the patient was started on hemodialysis and antihypertensive therapy. He received peritoneal dialysis for approximately 18 months with stabilization of his renal function (BUN 31 mg/dL,
creatinine 2.5 mg/dL), allowing discontinuation of dialysis. He continued to have a major cytogenetic response, with 15% Ph-positive cells on bone marrow
examination in January 1996 and 30% Ph-positive cells
in July 1996. He began to receive ara-C 10 mg/day in
October 1997 when his bone marrow analysis revealed
80% Ph-positive cells, with FISH analysis showing 60%
Ph-positive cells. In January 1998 he achieved a com-
CANCER June 15, 1999 / Volume 85 / Number 12
Characteristics of Patients with CML Developing HUS/TTP While on Therapy with rIFN-aa
Patients (Reference no.)
Case 1
Case 2
Case 3
Case 4 (32)
Case 5 (33)
Case 6 (34)
Age (yrs)
CML phase
Time on rIFN-a
Other CML
HU, ara-C
HU, ara-C
HU, ara-C
HU, 6-MP
Infectious agent
E. coli
HU, BMT(busulfan,
CML: chronic myelogenous leukemia; HUS: hemolytic uremic syndrome; TTP: thrombotic thrombocytopenic purpura; rIFN-a: interferon-a; CP: chronic phase; AP: accelerated phase; BP: blastic phase; HU:
hydroxyurea; BMT: bone marrow transplantation; RF: renal failure; HD: hemodialysis; CRF: chronic renal failure.
All patients had Ph-chromosome positive CML.
plete cytogenetic response, with 0% Ph-positive cells
on karyotyping and FISH analysis. He was still in complete cytogenetic remission and off dialysis in April
The association of malignant disorders and cancer
chemotherapeutic agents with HUS and TTP has been
previously described. Most cases occur in patients
with adenocarcinomas, gastric adenocarcinoma being
the most common,29,32 but also with small cell lung
carcinoma, squamous carcinomas, and Hodgkin disease.32 The relative contributions of chemotherapeutic agents or the malignancy are difficult to assess.
CML has been uncommonly associated with microangiopathic disorders.23–27 The possible role of rIFN-a in
inducing this toxic effect is increasingly suspected as
more case reports are described. The clinical features
of our patients and those described in the literature
are summarized in Table 1.
The underlying mechanisms initiating the injury
causing HUS and TTP have been studied in detail. TTP
develops from release into the circulation of plateletaggregating agents, including the von Willebrand factor multimers (vWF). vWF multimers are normally
produced by platelets and endothelial cells and stored
within the alpha granules of platelets and the Weibel–
Palade bodies of the endothelial cells (peroxidase positive protein aggregates identified by electron microscope).35 Unusually large vWF multimers (ULvWF) are
also released from the damaged endothelial cells and
are more effective in binding the platelet membrane
glycoproteins in conditions of elevated fluid shear
stress (relative parallel motion between fluid planes
during flow).36 This results in platelet aggregation,
producing the characteristic intraluminar platelet
thrombi seen in virtually all organs in patients with
In HUS, renal endothelial cell injury, with endothelial cell swelling and the resulting narrowing of the
glomerular capillary lumen, is believed to be the initiating event. HUS is commonly preceded by bloody
diarrhea caused by infectious organisms, such as Shigella dysenteriae or E. coli.37 The toxins elaborated by
these organisms, including the Shiga toxin and the
Shiga-like toxins, are capable of binding the predominant membrane glycophospholipid receptor for the
Shiga toxins, globotriosyl ceramide (Gb3).38,39 Gb3 is
expressed on the membrane of renal endothelial cells
and other endothelial cells, and Shiga toxins have
been demonstrated in vitro to be directly cytotoxic to
endothelial cells.39 Other agents can up-regulate Gb3
expression on the endothelial cells and therefore potentiate the effects of the toxins.40 These include the
cytokines interleukin-1(IL-1)-a or -b and tumor necrosis factor (TNF)-a or -b.39,40
The interval between exposure to the chemotherapeutic agent and the development of HUS/TTP varies, ranging from 1 day to 7 months.32 The mechanism
of endothelial cell injury is poorly understood; it may
involve drug metabolites (free oxygen radicals) or formation of antiendothelial antibodies, similar to quinine-induced HUS. In patients with HUS associated
with quinine intake, antibodies to platelet membrane
glycoproteins may interact with endothelial cell receptors directly or may induce neutrophils to interact
with endothelial cells and damage them, possibly via
release of free radicals.41 Circulating cytotoxic antiendothelial antibodies have been demonstrated in patients with HUS.42
Thrombotic Microangiopathy with rIFN-a/Ravandi-Kashani et al.
The mechanisms by which rIFN-a therapy may
initiate HUS/TTP are not known, but several mechanisms are possible. Perez et al. reported detectable
interferon (IFN) levels in the initial 10-day period from
the diagnosis of HUS in 16 of 35 children with typical
HUS, as compared with none of 10 controls.43 Three of
17 patients had detectable IFN levels after Day 10.
They suggested that activated leukocytes and/or their
products, such as TNF, IFN, IL-1, and free radicals, can
participate in tissue injury and endothelial cell damage with the resulting deleterious effects. Indeed, in an
experimental model of HUS, a central role for leukocytes or leukocyte products had been suggested, and
in vivo neutralization of TNF or IFN with a specific
antiserum protected mice from an HUS-like reaction.44 Therefore, IFN-induced free radical production
by activated phagocytes may result in the pathogenesis of HUS. In another report, IFN production in two
patients with HUS associated with adenovirus infection was also demonstrated, and a possible nephrotoxic role from elevated IFN levels was speculated.45
Possible nephrotoxic effects of IFN have been previously reported.46,47 Exogenous interferons could cause
similar effects.
IFNs, together with other interacting cytokines,
are known to exert complex immunomodulatory effects on endothelial cells with differential modulatory
effects on various endothelial cell surface markers,
including the MHC antigens and intracellular adhesion molecules (ICAM).48 Exogenous IFN may up-regulate endothelial cell Gb3 levels and potentiate the
deleterious effects of bacterial toxins in receptive individuals. rIFN-g has also been shown to modulate the
fibrinolytic response in cultured human endothelial
cells, suggesting another mechanism by which these
agents may turn the fibrinolytic potential of the endothelium in a prothrombotic way.49 rIFN-a has been
shown to increase leukocyte adherence to vascular
endothelium, and this, by way of the mechanisms
described above, may initiate endothelial cell damage
and subsequent release of ULvWF multimers, causing
endothelial cell swelling, platelet aggregation, and intraluminal microthrombi formation.
In summary, HUS/TTP is a rare side effect of IFN
therapy in patients with CML. The mechanisms contributing to its pathogenesis are poorly understood,
but IFNs can, through modulatory effects on endothelial receptors, make these cells more susceptible to the
effects of bacterial toxins. They may also mediate free
radical production by activating phagocytic cells, and
as a result cause endothelial cell injury. The release of
platelet-aggregating agents from the damaged endothelial cells is probably the final event, resulting in
intraluminal thrombus formation and organ damage,
as seen in HUS/TTP. This rare but definite complication of rIFN-a therapy should be recognized early
when clinical and laboratory findings are suggestive,
so that rIFN-a therapy can be discontinued immediately and appropriate therapeutic measures can be
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