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Correspondence
308
Hyperleukocytosis complicating lonafarnib treatment in patients with chronic
myelomonocytic leukemia
TO THE EDITOR
The leukemia differentiation syndrome is a potentially life
threatening complication of all-trans-retinoic acid (ATRA) treatment for acute promyelocytic leukemia (APL) characterized by
fever, leukocytosis, hypoxemia with interstitial pulmonary infiltrates, weight gain, serosal effusions, and prompt response to
treatment with corticosteroids.1 Although the pathogenesis of the
syndrome is unclear, laboratory investigations indicate that ATRA
promotes inflammatory cytokine generation by APL cells and
activates homotypic and heterotypic adhesion, thereby enhancing
endovascular permeability and promoting leukemia cell adhesion
and transmembrane migration.2,3 Initially termed the retinoic acid
syndrome, subsequent studies revealed that the analogous
syndrome may occur in APL patients treated with arsenic
trioxide,4 and rarely in patients with non-promyelocytic subtypes
of acute myeloid leukemia treated with ATRA.5
Lonafarnib (SCH66336 or Sarasart; Schering-Plough Research Institute, Kenilworth, NJ, USA) is a member of a novel
class of therapeutics under investigation in hematologic
malignancies, termed the farnesyl transferase inhibitors (FTIs).6
Like other agents in this class, lonafarnib is a potent inhibitor of
Ras activation and other prenylation-dependent molecules. The
RAS gene superfamily encodes guanosine triphosphate hydrolases (GTPase) that serve as critical regulatory elements in signal
transduction, cellular proliferation, and maintenance of the
malignant phenotype. Farnesylation represents the first posttranslational modification of Ras-GTPases that is necessary for
plasma membrane association and transforming activity.6 We
describe the first report of FTI-associated hyperleukocytosis and
pulmonary sequestration syndrome developing in patients with
chronic myelomonocytic leukemia (CMML).
Case 1: Patient UPN-005 is a 64-year-old male who presented
in June 1998 with complaints of skin rash and increased
bruisability. Physical examination revealed obesity, isolated
ecchymoses, and lower extremity petechiae, without appreciable splenic enlargement. Laboratory studies revealed leukocytosis and monocytosis (28 800/ml with 38% monocytes),
associated with thrombocytopenia (27 000/ml). The bone marrow (BM) was hypercellular accompanied by intense myeloid
hyperplasia with less than 5% blasts and a maturation arrest at
the myelocyte stage; megaloblastoid erythropoiesis and megakaryocytic dysplasia were apparent consistent with a diagnosis
of CMML. Cytogenetic analysis revealed a normal male
karyotype. Mutations of N-, H-, or K-RAS were not detected
by single-strand conformational polymorphism (SSCP) and
heteroduplex analysis. The patient received treatments with
oral etoposide, and subsequently thalidomide without hematologic improvement.
Correspondence: Dr A List, Hematologic Malignancy Program,
Department of Interdisciplinary Oncology, H Lee Moffitt Cancer
Center and Research Institute at the University of South Florida, 12902
Magnolia Drive, Rm 24038, SRB 4, Tampa, FL 33612, USA; Fax: þ 1
813 975 3727; E-mail: [email protected]
Received 5 March 2004; accepted 10 September 2004; Published
online 11 November 2004
Leukemia
On 28 November 2001, the patient initiated treatment with
oral lonafarnib 300 mg b.i.d. in a phase I/II clinical trial (ScheringPlough #P00701). Eligible patients had CMML, refractory anemia
with excess blasts (RAEB), or RAEB in transformation with
symptomatic cytopenias. Pretreatment white blood count was
24 200/ml with 44% monocytes, hemoglobin 13.4 g/dl, and
platelet count 10 000/ml (Figure 1); BM examination was
unchanged compared to the diagnostic study.
The patient experienced a progressive rise in leukocyte count,
reaching 61 000/ml by day 12. Diarrhea ensued associated with
profound hypokalemia (potassium 1.5 meq/l), necessitating temporary withdrawal of study drug treatment by day 16. Gastrointestinal
symptoms promptly resolved with a corresponding decline in the
leukocyte count to baseline values. After a 6-day treatment hiatus,
lonafarnib was resumed at a dose of 200 mg b.i.d. By day 3 of
treatment at the attenuated dose, the patient experienced rapid onset
of dyspnea and orthopnea, accompanied by a 10-pound weight
gain. On physical examination, the patient was in respiratory distress
with physical findings of tachypnea, generalized inspiratory rales,
peripheral edema, and an oxygen saturation of 84% on 6 l of
supplemental oxygen administered by nasal cannulae. An arterial
blood gas obtained without supplemental oxygen revealed a pH of
7.48, pO2 42 mmHg (79% saturation), and pCO2 26 mmHg. Chest
radiograph (Figure 2a) revealed bilateral alveolar infiltrates, whereas
high-resolution spiral computerized tomography (CT) of the chest
confirmed diffuse interstitial infiltrates manifested as bilateral ground
glass consolidation. Laboratory studies revealed a leukocyte count of
80 000/ml, with 38% monocytes and 50% segmented neutrophils,
without significant change in cytologic appearance on the
peripheral smear. An echocardiogram revealed tachycardia with
normal wall motion and left ventricular ejection fraction of 63%.
The patient was aggressively diuresed and was hospitalized in the
intensive care unit where he required 50% supplemental oxygen
administered by venti-mask. Bronchoscopy demonstrated normal
appearing airway mucosa; however, lavage fluid cytospins yielded a
monocytic infiltrate (Figure 2c). Stains and cultures for bacterial,
fungal, and viral pathogens were unremarkable. Intravenous
dexamethasone was administered and lonafarnib was discontinued.
The patient experienced rapid resolution of hypoxemia and
Pulmonary
infiltrates
90,000
80,000
Lonafarnib
70,000
(WBC/µL)
Leukemia (2005) 19, 308–310. doi:10.1038/sj.leu.2403569
Published online 11 November 2004
WBC
ANC
AMC
60,000
50,000
40,000
30,000
20,000
10,000
0
-14
-7
0
7
14
21
28
Study Day
Figure 1
Change in total white blood cell count (WBC), absolute
neutrophil (ANC), and monocyte count (AMC) during treatment with
lonafarnib. The arrow indicates onset of respiratory distress and
development of pulmonary infiltrates.
Correspondence
309
Figure 2
(a) Chest radiograph (anterior posterior) obtained on day
2 of treatment of lonafarnib 200 mg b.i.d. The chest X-ray reveals
bilateral nodular, alveolar filling infiltrates confirmed by chest CT
scan. (b) Near-complete resolution of the diffuse interstitial infiltrates
48 h after initiation of treatment with dexamethasone. (c) Cytospin
preparation from bronchoalveolar levage fluid demonstrating increased number of mature appearing monocytes (arrows). Papanicolaou stain, 1000.
pulmonary infiltrates (Figure 2b) permitting discharge on oral
corticosteroids by hospital day 3.
Cases 2 and 3. Two additional CMML patients treated on the
same trial at the Arizona Cancer Center experienced a prompt
and sustained leukocytosis response (45000/ml/week) to lonafarnib (Table 1). Each of the patients described had stable
leukocyte counts prior to study treatment, and none received
cytotoxic therapy within 3 months of study entry. Patient UPN1109 experienced an immediate rise in white blood cell (WBC)
count averaging 7128/ml per week after initiation of the study
drug. By day 21, the WBC count exceeded 41 000/ml and the
patient reported low-grade fever, dyspnea, and lower extremity
edema. Clinical evaluation revealed hypoxemia with diffuse
interstitial infiltrates on chest radiographs that resolved following drug withdrawal. Patient UPN-1112 experienced a rapid
elevation in WBC count from 57 100/ml at baseline to 150 000/ml
by day 8 of study treatment without accompanying pulmonary
symptoms. Lonafarnib was continued and hydroxyurea was
added and the WBC count returned to the baseline level within
2 weeks of combined treatment.
Overall, 35 patients with CMML were enrolled on the lonafarnib
clinical trial at all centers. Among these, 15 (43%) experienced a
rise in total leukocyte count that exceeded 5000/ml/week (Figure 3).
Using these parameters, 14 of 26 patients (54%) with proliferative
CMML (WBC412 000/ml) at study entry experienced a leukemoid
response to lonafarnib, compared to one of nine patients (11%)
with the nonproliferative variant (P ¼ 0.025; two-tailed Students’ ttest). Prestudy WBC counts in patients with proliferative CMML
ranged from 12 220 to 79 370/ml (median, 26 920/ml).
The patients described herein developed rapid and progressive
elevations in WBC count with lonafarnib treatment, associated in
two cases with respiratory distress that resolved promptly
following treatment with dexamethasone or study drug withdrawal. An infectious etiology was excluded in both patients
presenting with pulmonary infiltrates, whereas cytological examination of the bronchioalveolar lavage fluid in patient UPN-005
confirmed alveolar infiltration by mature monocytes. Despite
associated neutrophilia, expansion of a comparatively mature
monocytic clone distinguishes these cases from the leukemia
differentiation syndrome described with ATRA treatment of APL.
These cases represent the first description of leukemia differentiation-like syndrome occurring in patients treated with an FTI.
Patients with proliferative CMML (WBC412 000/ml) in particular
appear to be at significant risk for this complication. An excessive
leukemoid response (45000/ml/week) was observed in 54% of
patients with proliferative CMML compared to 11% of patients
with the nonproliferative subtype (P ¼ 0.025).
Constitutive Ras/mitogen-activated protein kinase (MAPK)
activation is demonstrable in 40–60% of CMML cases, resulting
either from mutations within RAS alleles or from reciprocal
translocations deregulating receptor tyrosine kinases.6 Leukemic
cells from two of the patients evaluated lacked activating point
mutations of RAS proto-oncogenes and none harbored chromosome translocations, indicating that screening for RAS mutations
per se is insufficient to identify those patients at risk. Like the
retinoic acid syndrome in APL, leukocytosis response to
lonafarnib may occur in the absence of pulmonary signs or
symptoms. Nevertheless, investigators participating in current
FTI trials should be aware of the potential for this complication
and consider close monitoring of patients experiencing a rapid
rise in leukocyte count and/or pulmonary symptoms.
Lonafarnib and tipifarnib (R115777 or Zarnestrat; Janssen
Pharmaceuticals, Beerse, Belgium and Spring House, PA, USA)
are the leading nonpeptidic, orally bioavailable FTIs that are
currently completing phase II clinical investigations in hematologic malignancies.6 No similar cases have been reported to
date in preliminary testing of tipifarnib in patients with either
myelodysplastic or myeloproliferative syndromes, raising consideration that pharmacologic features unique to lonafarnib may
Leukemia
Correspondence
310
Table 1
Clinical and laboratory features of patients experiencing lonafarnib-induced hyperleukocytosis
Patient no. WHO type Age Sex Karyotype Mu-ras
UPN-005 CMML-1
UPN-1112 CMML-1
UPN-1109 CMML-2b
a
64
72
81
M
F
F
46, XY
Negative
47, XX, +8 Unknown
46, XX
Negative
Pretreatment WBC/ml (AMC)a Post-lonafarnib WBC/ml (AMC) Respiratory distress
24 200 (10 648)
57 100 (13 704)
19 600 (4508)
80 000 (30 400)
150 000 (48 000)
41 200 (6180)
Yes
No
Yes
AMC denotes absolute monocyte count/ml.
Total percentage of BM myeloblasts, monoblasts, and promonocytes, 11%.
b
160,000
3
Hematologic Malignancy Program, Department
of Interdisciplinary Oncology, H Lee Moffitt
Cancer Center and Research Institute at the
University of South Florida, Tampa, FL, USA; and
4
Schering-Plough Research Institute,
Schering-Plough Corporation, Kenilworth,
NJ, USA
140,000
Leukocytes/µl
120,000
100,000
80,000
60,000
40,000
References
20,000
0
Day 1
Day 15
Figure 3
Leukemoid response to lonafarnib in 15 patients with
CMML. Complete blood counts were monitored on days 1, 15, and 22
of each 28-day cycle. Represented patients experienced a rise in WNC
count that exceeded 5000/ml/week.
be responsible for this potential biologic effect.7 Nonetheless, in
selected cell line models, suppression of Ras signaling or the
farnesylated Rho-B proteins promotes heterotypic adhesion
through activation of beta-1 and/or beta-2 integrin binding
avidity or increased sensitivity to the inhibitory effects of TGFb,
suggesting that promotion of heterotypic adhesion may arise as a
class effect of Ras protein signal inhibition.8 Additional
investigations are necessary to discern the relevant cellular
target(s) of lonafarnib and possibly other FTIs that may promote
transient expansion of leukemia mass and possibly predispose to
endovascular complications.
A Buresh1
J Perentesis2
L Rimsza1
S Kurtin1
R Heaton1,3
M Sugrue4
A List1,3
1
Departments of Medicine and Pathology,
The Arizona Cancer Center,
University of Arizona College of Medicine,
Tucson, AZ, USA;
2
University of Cincinnati and Children’s
Hospital, Cincinnati, OH,
USA;
1 De Botton S, Dombret H, Sanz M, San Miguel J, Caillot D, Zittoun
R, et al., The European APL Group. Incidence, clinical feature, and
outcome of the all-trans retinoic acid syndrome in 413 cases of
newly diagnosed acute promyelocytic leukemia. Blood 1998; 92:
2712–2718.
2 Larson RS, Brown DC, Sklar LA. Retinoic acid induces aggregation
pf the acute promyelocytic leukemia cell line NB-4 by utilization of
LFA-1 and ICAM-2. Blood 1997; 90: 2747–2756.
3 Maloisel F, Petit T, Kessler R, Oberling F. Cytologic examination of
broncho-alveolar lavage fluid in all-trans retinoic acid syndrome.
Eur J Haematol 1996; 56: 319–320.
4 Camacho LH, Soignet SL, Chanel S, Ho R, Heller G, Scheinberg DA
et al. Leukocytosis and the retinoic acid syndrome in patients with
acute promyelocytic leukemia treated with arsenic trioxide.
J Clin Oncol 2000; 18: 2620–2625.
5 Nagafuji K, Eto T, Tokunaga Y, Hayashi S, Niho Y. Retinoic acid
syndrome during treatment of acute myelomonocytic leukemia with
all-trans retinoic acid and low dose ARA-C. Br J Haematol 1998;
100: 610–611.
6 Reuter CWM, Morgan MA, Bergmann L. Targeting the Ras signaling
pathway: a rational, mechanism-based treatment for hematologic
malignancies? Blood 2000; 96: 1655–1669.
7 Cortes J, Albitar M, Thomas D, Giles F, Kurzrock R, Thibault A et al.
Efficacy of the farnesyl transferase inhibitor R115777 in chronic
myeloid leukemia and other hematologic malignancies. Blood
2003; 101: 1692–11977.
8 Hughes PE, Renshaw RW, Pfaff M, Forsyth J, Keivens VM,
Schwartz MA et al. Suppression of integrin activation: a novel
function of a Ras/Raf-initiated MAP kinase pathway. Cell 1997; 88:
521–530.
Mutations in the BRAF and N-ras genes in childhood acute lymphoblastic leukaemia
Leukemia (2005) 19, 310–312. doi:10.1038/sj.leu.2403589
Published online 11 November 2004
Correspondence: Dr R Kumar, Division of Molecular Genetic
Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Fax: þ 49 6221
421810; E-mail: [email protected]
Received 5 August 2004; accepted 28 September 2004; Published
online 11 November 2004
Leukemia
TO THE EDITOR
Although cure rates in childhood acute lymphoblastic leukaemia (ALL) have improved with a current long-term event-free
5-year survival of 80%, the role of molecular aberrations on
the prognosis of leukaemia remains to be understood. Cytogenetic abnormalities in leukaemic cells can be detected in
90% of all cases, and aberrations such as hyperploidy and