Leukemia & Lymphoma
`
`ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20
`
`Management of Severe Neutropenia With
`Cyclosporin During Initial Treatment of
`Epstein-Barr Virus-Related Hemophagocytic
`Lymphohistiocytosis
`
`Shinsaku Imashuku, Shigeyoshi Hibi, Kikuko Kuriyama, Yasuhiro Tabata,
`Tetsuo Hashida, Asayuki Iwai, Masahiko Kato, Nobuko Yamashita, Megumi
`Oda, Masashi Uchida, Naoko Kinugawa, Machiko Sawada & Mutsuko Konno
`
`To cite this article: Shinsaku Imashuku, Shigeyoshi Hibi, Kikuko Kuriyama, Yasuhiro Tabata,
`Tetsuo Hashida, Asayuki Iwai, Masahiko Kato, Nobuko Yamashita, Megumi Oda, Masashi Uchida,
`Naoko Kinugawa, Machiko Sawada & Mutsuko Konno (2000) Management of Severe Neutropenia
`With Cyclosporin During Initial Treatment of Epstein-Barr Virus-Related Hemophagocytic
`Lymphohistiocytosis, Leukemia & Lymphoma, 36:3-4, 339-346, DOI: 10.3109/10428190009148855
`To link to this article: https://doi.org/10.3109/10428190009148855
`
`Published online: 01 Jul 2009.
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`Leukemia irnd Lvmphomu, ?ooO. Vnl. 36(3-4), pp. 339-346
`Repnnts available directly from the publisher
`Photocopying permitted by license only
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`0 2wO OPA (Overseas Publishers Association) N.V.
`Published by license under
`the Hawood Academic Publishers imprint,
`part of the Gordon and Breach Publishing Group.
`Printed in Malaysia
`
`Management of Severe Neutropenia With Cyclosporin
`During Initial Treatment of Epstein-Barr Virus-Related
`Hemophagocytic Lymphohistiocytosis
`
`SHINSAKU IMASHUKU~*, SHIGEJOSHI HIBI~, KIKUKO KURIYAMA~, Y A S U H ~ O TABATA~,
`TETSUO HASHIDA~, ASAYUKI IWAI , MASAH~KO KATO~, NOBUKO ~AMASHITA , MEGUMI ODA~,
`MASASHI UCHIDAg, NAOKO KINUGAWA , MACHIKO SAWADA’ and MUTSUKO KONNd
`
`aDivision of Pediatrics. Children’s Research Hospital, Kyoto Prefectural Llniversiy of Medicine, bDepartment of Pediatrics, Kyoto Prefec-
`tural University of Medicine, “Division of Pediatrics, Akashi Munici a1 Hospital, Division of Pediatrics, Kagawa Children :F Hospital,
`
`eDepartment of Pediatrics, Gunma University, School of Medicine, f Department of Pediatrics, Okayama University, School of Medicine,
`
`YDivision of Pediatrics, Tokuyama Central Hospital, hDivision of Pediatrics, Chiba Children k Hospital, ‘Department of Pediatrics, Shiga
`Medical Center for Children and ’Department of Pediatrics, Sapporo Kohsei General Hospital, Hirokoji, Kawaramachi, Kamigyo-ku.
`Kyoto, Japan 602-8566
`
`Severe neutropenia (absolute neutrophil count c500/p1) is probably due to the combined
`effects of dysregulated cytokine production and chemotherapeutic agents, and is one of the
`risk factors in the initial treatment of patients with Epstein-Barr virus-related hemophagocytic
`lymphohistiocytosis (EBV-HLH). We report here 9 cases of neutropenic HLH, of which 8
`were treated with cyclosporin (CSA, 2-6 mgikg/day; continuous infusion, or 6mgkglday; per
`os, for periods ranging from 9 days to >8 weeks) in the initial neutropenic phase during
`induction treatment using corticosteroids and etoposide. Five of the 6 cases, in which CSA
`treatment was started early (before the second week of induction), survived the critical period
`with recovery of neutrophil counts within a week. The remaining 3 cases, in which CSA was
`introduced later or not at all, died of infection.
`Based on these results, we recommend a prompt short-term CSA infusion during neutro-
`penic episodes in the most common treatment regimen of etoposide and corticosteroids in
`patients with HLH. Improved neutrophil recovery as a result of CSA treatment makes it pos-
`sible to continue immunochemotherapy safely and obtain improved patient outcomes.
`
`Keywords: hemophagocytic lymphohistiocytosis, Epstein-Ban virus, neutropenia, cyclosporin A
`
`1 lTRODUCTION
`
`IAHS (infection-associated HS) or MA IS (mz ig-
`nancy-associated HS), as well as FHL (familial) or
`non-familial HLH, are used to indicate the origin of
`Development of hemophagocytic lymphohistiocyto-
`disease* For
`deteriorating HLH cases* the
`sis (HLH) ( 1,2) is triggered by viral or bacterial infec-
`most common therapeutic strategy is to administer a
`tion, or associated with ]ymphoma and other
`combination of etoposide and corticosteroids such as
`malignancies, and may occur at any age. The terms
`the
`that described
`Protocol HLH-94
`VAHS (vims-associated hemophagocytic syndrome),
`* Correspondence: Shinsaku Imashuku, M.D. Division of Pediatrics, Children’s Research Hospital, Kyoto Prefectural University of Med-
`icine, Hirokoji, Kawaramachi, Kamigyo-ku, Kyoto, Japan 602-8566, e-mail: shinim95@mbox.kyoto-inet.or.jp
`
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`340
`
`SHINSAKU IMASHUKU et al.
`
`(3). Even with such immunochemotherapy, the
`event-free survival (EFS) rate of patients with FHL
`remains approximately 10% at 4yrs.(4), while that of
`non-familial HLH patients 50-70%
`(5). One reason
`for poor therapeutic results is a delay in the initiation
`of specific management, because differential diagno-
`sis among the different categories of underlying dis-
`ease can be difficult (2). Other risk factors include
`familial cases which require hemopoietic stem cell
`transplantation (4), and fulminant and fatal cases of
`Epstein-Barr virus (EBV)-related HLH (EBV-HLH)
`(6-8), for which more effective control measures
`have recently been reported (9).
`Opportunistic infections acquired during neutrope-
`nia are a major factor contributing to mortality during
`the induction phase of treatment for EBV-HLH. The
`persistent pancytopenia, particularly neutropenia,
`which has been reported in patients with HLH, may
`be caused by disease-related cytokine effects as well
`as the effects of therapy (10-12). Agranulocytosis has
`been reported to be associated with granular lympho-
`cyte proliferative disorders, mostly those which are
`T-cell- related (12-15) as well as with Epstein-Ban
`virus infection (16;-22). We previously confirmed that
`large granular lymphocytosis plays an important role
`in the pathogenesis of HLH, particularly that of
`EBV-HLH (23). In such neutropenic conditions in
`T-cell type granular lymphocyte proliferative disease
`or EBV-associated HLH, concurrent infections are
`predominantly bacterial or fungal in origin (1 1,24,25).
`Understanding
`of
`this
`pathophysiology
`in
`EBV-HLH-related neutropenia may provide new
`life-saving therapeutic measures. Cyclosporin A
`(CSA) has been found to be useful in the treatment of
`macrophage activation syndrome occurring in pri-
`mary and secondary HLH (26-30) and in chronic
`neutropenia or immune neutropenia (3 1,32). We
`report here prompt improvement of neutropenia as a
`result of early introduction of CSA during induction
`treatment for EBV-HLH. This made possible prophy-
`laxis of severe infectious complications with continu-
`ation of
`immunochemotherapy, and resulted in
`eventual disease control in 5 of 6 cases.
`
`PATIENTS AND METHODS
`
`Clinical features at the onset of EBV-HLH in the
`9 cases included in this study are summarized in
`
`TableI. Diagnosis of HLH was made according to
`the criteria described by Henter et al. (1,2), and
`EBV-HLH was diagnosed by serology and by detec-
`tion of the EBV genome in various biological speci-
`mens at the onset of clinical symptoms (9). EBV
`involvement was confirmed in 8 of the 9 cases and
`suspected in the remaining case from clinical features
`including bone marrow findings. None of the cases
`were familial. Assays of serum ferritin and cytokines
`were performed as previously described (5).
`Patient profiles are summarized in Table I; the
`study group consisted of 5 girls and 4 boys with a
`median age of 5yr7mo. All cases showed cytopenias
`of 2-3 lineages, with extremely high serum levels of
`ferritin, LDH, soluble IL-2 receptor and inter-
`feron-gamma. Initial induction treatment and CSA
`introduction are summarized in Table II. Initial treat-
`ment protocols were independent in 5 cases (Cases 1-
`3, while the HLH-94 protocol (3) was employed in
`the remaining 4 cases; a core combination of corticos-
`teroids (prednisolone, methylprednisolone, or dexam-
`ethasone) and VP16 were included in all cases.
`Granulocyte-colony stimulating factor (G-CSF) was
`administered in 3 cases. HLH-94 is an international
`protocol developed by the Histiocyte Society; which
`consists of an 8-week induction using VP16/dexam-
`ethasone (Dexa) followed by maintenance treatment
`using a combination of VP16DexdCSA
`for
`non-resolving cases at the completion of the induction
`period (3). Severe neutropenia was defined as an
`absolute neutrophil count (ANC) lower than 500/p1.
`Treatment response or outcome was evaluated at the
`end of the induction phase, both for neutropenia
`(recovered or not) and for clinical improvement of
`HLH. Improvement of HLH was designated either
`complete response (CR) or partial response (PR). CR
`indicates complete resolution of clinical symptoms
`and signs as well as normalization of laboratory data,
`particularly serum ferritin levels, which are a good
`indicator of disease activity. Patients showing persis-
`tent fever and other symptoms, or persistent high lev-
`els of serum ferritin in spite of the absence of
`symptoms, were considered to have attained PR.
`Intensified or maintenance treatment was continued
`in cases of PR until CR was attained.
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`CSA FOR NEUTROPENIA IN EBV-HLH
`
`34 I
`
`Cases
`
`agehex
`
`disease
`
`fever
`
`cvtnpenia
`
`liver
`dysfunction
`
`D1c
`
`Ferririn"
`( n g W
`
`L D P
`flu4
`
`SlL-2P
`(U/ml)
`
`TABLE I Patient profiles
`
`IFN-y "
`(U/ml)
`
`1.240
`na
`141
`208
`125
`na
`440
`234
`226
`
`lyr6mo/F
`I
`pos
`pos
`pos
`3b
`HLH
`IlyrA4
`2
`pos
`pos
`pos
`3
`EBV-HLH
`I7yrA4
`3
`pos
`pos
`EBV-HLH
`pos
`2
`pos
`pos
`2
`pos
`EBV-HLH
`6yrA4
`4(#1)
`pos
`pos
`3
`pos
`12yr2mo/M EBV-HLH
`5
`pos , pos
`lyr/F
`EBV-HLH
`6
`3
`pos
`pos
`pos
`2
`pos
`lyr3rno/F EBV-HLH
`7
`pos
`neg
`2
`pos
`lyr7moF EBV-HLH
`8
`pos
`pos
`2
`pos
`5yr7mo/F EBV-HLH
`9
`In Case I , involvement of EBV was suspected, but not confirmed.
`a. normal ranges are: femtin (8-78 ng/ml), LCH (234471 IU/l), sIL-2R (<1,090 U/ml) and IFN- y (<1.0 Ulml)
`b. number of lineages involved, pos : positive, neg: negative, na: not available
`
`405,500
`48,960
`120,425
`13,496
`70,000
`78,000
`35,000
`>3,000
`10,222
`
`9,840
`6,775
`8,360
`2,216
`6,000
`13,755
`2,000
`1,623
`6,040
`
`29,200
`na
`26,400
`22,700
`39,900
`na
`43,800
`36,100
`8,180
`
`TABLE 11 Induction treatment for HLH with or without early introduction of CSA
`
`Cases
`
`treatment
`
`CSA beginning
`
`doses
`
`I
`2
`3
`4 ~ 1 )
`
`0
`none
`VP 16/Cs/G-CSF
`5mg/kg/d, drip
`wk 1
`VP16/Cs
`3mg/kg/d, drip
`wk 4
`ETNP16IG-CSF
`3mg/kg/d, drip
`wk 3
`VP16/Cs
`3mg/kg/d, drip
`wk 2
`VP16/Cs
`5
`2mg/kg/d, drip
`wk 1
`VPI 6ICs
`6mg/kg/d, drip
`wk 2
`VPI 6/Cs
`6
`3mg/kg/d, drip
`wk 2
`ETNPl6/Cs
`7
`wk 0
`1.6mg/kg/d, drip
`VP16/Cs
`8
`6mg/kg/d, PO
`wk 2
`VPI 6/Cs/G-CSF
`9
`Cs: corticosteroids, G-CSF recombinant granulocyte-colony-stimulating factor; E T exchange transfusion, PO: per 0s
`
`duration
`none
`2 weeks
`2 weeks
`1.5 weeks
`3 weeks
`>8 weeks
`>4 weeks
`2 weeks
`9 days
`2 weeks
`
`RESULTS
`
`Disease outcomes and changes in ANC are summa-
`rized in Table HI. On admission, 7 of the 9cases
`already had neutropenia (<I ,OOO/pl) (Table 111) and
`all cases received corticosteroids and VPI 6 as an ini-
`tial regimen and 3 received G-CSF as well (Table 11).
`The effect of CSA, which was administered by con-
`tinuous infusion (1.6-6 mg/kg/day) except in one
`case(6mg/kg/day, orally), was evaluated in 9 courses
`in 8 patients (Case 4 was treated twice for neutropenic
`
`episodes with CSA). As shown in Table 11, CSA was
`introduced early (week 0-week 2) in 7 episodes, and
`later (week 3-week 4) in 2 episodes. The duration of
`CSA treatment ranged from 9 days to longer than 8
`weeks. By week 2 of induction treatment, 8 of the 9
`cases displayed severe neutropenia (<500/pl), where-
`upon VP16 was stopped in some, but not in all cases.
`In those cases in which ANCs returned to levels
`above 1 ,OOO/pl following CSA administration, rein-
`stitution of a combination of corticosteroid and VP 16
`therapy became possible and all of these cases subse-
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`342
`
`SHINSAKU IMASHUKU et al.
`
`quently showed favorable responses. Five of the 8
`cases treated with CSA showed recovery; three of
`these cases attained CR and two showed PR. Case 1
`died without CSA rescue. Case 2 displayed extremely
`hypocellular bone marrow, did not respond to CSA
`regardless of very early introduction and died of
`MRSA sepsis. Case 3 was unresponsive to late rescue
`by CSA and died of aspergillosis. Over the period
`during which CSA was administered, no adverse
`reactions were noted. Representative treatment
`courses are illustrated in Fig. 1, and two cases in
`which favorable outcomes were obtained are briefly
`described below.
`
`CASE REPORTS
`
`Case 5
`
`A 12 year-old boy presented with persistent fever,
`cytopenia (ANC 44/pl, platelet count 24,oOO/pl),
`hepatomegaly (7cm), splenomegaly (Scm), jaundice
`(total bilirubin 11.3mg/dl), coagulopathy and cervical
`adenopathy in April 1997. He was initially treated
`with exchange transfusion (ET), followed by VP16
`(100-150mg/day. IV) for 5 days and prednisolone
`(PSL, 60mg/day. per 0s). A week later because of per-
`sistent severe cytopenia (ANC 80/p1, Hb 8.7g/dl,
`PLTS 15, oOO/pl), CSA (2.Omg/kg, continuous infu-
`sion, daily) and dexamethasone (Dexa, lOmg/day,
`continuous infusion) were introduced; this treatment
`completely rescued hemopoiesis in 10 days. Thereaf-
`ter, the patient was treated according to the HLH-94
`protocol (3). Serum ferritin was reduced from
`14,500ng/ml initially to l,OOOng/ml. but remained
`abnormally high at the end of 2 months treatment.
`Thereafter, this patient’s disease has been well con-
`trolled with the maintenance protocol of HLH-94.
`(Fig lc).
`
`Case 7
`
`A 1 year 3 month-old girl presented with fever,
`cytopenia (ANC 6891~1, Hb 8.7g/dl, platelet count
`28,OOO/pl), hepatomegaly (5 cm), no splenomegaly,
`
`coagulopathy, and with generalized edema in January
`1997. Soon after exchange transfusion (ET), treat-
`ment according to the HLH-94 protocol (3) was
`begun. Although the response was rapid, progression
`of neutropenia (nadir 34/p1) necessitated interruption
`of VP16 administration, so that the patient was treated
`with CSA (2mg/kg/day, continuous infusion) alone
`for 2 weeks. At the point of hemopoietic recovery, the
`patient was replaced on the HLH-94 induction regi-
`men and thereafter showed good response to the
`maintenance protocol. (Fig lb)
`
`DISCUSSION
`
`HLH is a disease of uncontrolled, dysregulated cellu-
`lar immune reaction, in which abnormally regulated
`T-cell activation leads to secondary macrophage acti-
`vation (23,33). This abnormal immune response is
`induced by various triggering factors such as viral or
`bacterial infections or specific types of lymphoma.
`The pathophysiology of this condition is associated
`with an increase in the levels of both T-cell-derived
`and macrophage-derived cytokines, particularly
`TNF-a and IFN-y(34,35). It has been shown that pro-
`liferation of granular lymphocytes is closely related to
`the pathogenesis of HLH (23). In addition, the impact
`of hypercytokinemia was previously reported as a
`factor influencing patient prognosis (34-37). In these
`studies, levels of serum IL-1 p and TNF-a, IFN- y,
`and sIL-2 receptor were shown to have a significant
`prognostic correlation.
`these
`Particularly
`in EBV-related diseases,
`cytokines exert myelosuppressive effects causing
`neutropenia (1 1,1622) Recently, Larochelle et al.
`(38) showed that EBV actually penetrates and causes
`apoptosis in neutrophils. We have found a significant
`inverse correlation between serum concentrations of
`IFN-y and white blood cell counts in HLH patients
`(unpublished data). Moreover, at the onset of disease
`in 70 cases of childhood HLH, 22 cases (31.4%) had
`severe (ANC <500/pl) and 18 cases (25.7%) had mild
`(ANC 500-999/@) neutropenia; of these severe cases,
`half were EBV-associated (our unpublished observa-
`tions). Even in these situations, neutropenia often
`escapes a physician’s attention if there are white
`blood cell counts above 1 ,OOO/pl.
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`CSA FOR NEUTROPENIA IN EBV-HLH
`
`343
`
`FIGURE 1 Treatment of EBV-HLH cases. Changes of ANC as well as serum fenitin (FRN) levels are plotted as indicators of disease activ-
`ity. A: Case 3 showed prompt reduction of serum FRN, but neutropenia persisted. Although CSA was introduced at week 4, the patient died
`of fungal infection. B: Case 7 showed prompt reduction of FRN. In response to CSA introduced at week 1 and skipping of VP16 administra-
`tion, good recovery of ANC was obtained. C: Case 5 ; although there was severe neutropenia at the beginning of therapy, VP16PSL therapy
`was initiated. CSA rescue started at week 1 together with switching from PSL to Dexa. The patient attained a good response to therapy with
`no complications
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`

`344
`
`SHINSAKU IMASHUKU et al.
`
`TABLE Ill Absolute neutrophil count (ANC) on admission and during induction, and patient outcomes
`
`wk 1
`
`wk 2
`
`wk 3
`
`~
`
`wk 4
`
`wk 5
`
`wk 6 AhC recovery Outcome at 8 weeks
`
`cause of death
`
`Cases on admission
`
`l a
`
`2
`
`700
`
`1,118
`
`168
`520
`
`3
`4 ~ 1 )
`
`(m -
`
`5
`
`6
`
`7
`
`8
`
`44
`
`2,886
`
`689
`
`120
`
`200
`
`54b
`
`6
`962
`3,344
`
`100
`
`42b
`
`0
`6
`175
`
`100
`
`-
`
`-
`
`-
`
`572b
`400
`36b
`8
`3,120b 573b
`
`-
`-
`572b
`897b
`352
`
`80b
`
`360b 1,330b 1,30Ob 1,207b
`
`490
`
`372
`
`30b
`
`34b
`
`240b
`
`1,630b
`
`na
`
`362b
`
`2,738
`
`12,436
`
`-
`
`-
`-
`7,347
`8
`
`na
`
`na
`
`na
`
`1,91Ib 600
`
`216
`
`400
`
`1,370
`
`999
`
`.
`
`sepsis (S.faecium)
`
`sepsis (MRSA)
`
`aspergillosis
`
`sepsis (unknown)
`
`no
`
`no
`
`Yes
`Yes
`Yes
`
`Yes
`
`yes
`
`Yes
`
`Yes
`
`Yes
`
`died
`
`died
`
`died
`PR
`died'
`
`PR
`
`CR
`
`CR
`
`CR
`
`PR
`
`6,549b 7,O0Ob 6,018 2,640
`980
`0
`384
`9
`na: not available, P R partial response, CR: complete response
`
`Values in Case 1 indicate WBC (not ANC),
`a.
`Values obtained during CSA administration,
`b.
`c. died after 8 weeks
`
`CSA has recently been found to be beneficial for
`EBV-HLH cases as well as for cases of large granular
`lymphocyte leukemia (LGLL) or macrophage activa-
`tion syndrome in juvenile arthritis (26-30). In the
`treatment of neutropenia in patients with HLH, an
`application of G-CSF has also been indicated
`(15,39,40) and was in fact administered to 3 cases in
`our series; however, there are concerns that exoge-
`nous G-CSF may enhance monocytopoiesis through
`endogenous M-CSF (4 1). Additionally, G-CSF may
`exert lung damage similar to that seen in adult respi-
`ratory distress syndrome (ARDS) as a result of cytok-
`ine-induced effects (42,43). Thus in the initial phase
`of EBV-HLH treatment, when high serum levels of
`cytokines are generally recorded, G-CSF may cause
`clinical deterioration. Thomssen et al. (44) reported
`that GM-CSF was not effective in the treatment of
`T-cell LGLL-associated agranulocytosis. For these
`reasons, we
`recommend CSA
`instead of
`G-CSF/GM-CSF for correction of neutropenia during
`the initial treatment of EBV-HLH, to be administered
`if possible within the first two weeks of induction
`therapy. In cases responding poorly to CSA alone, it
`remains to be determined in future trials whether CSA
`
`supported by G-CSF (15,40) may be effective. In fact,
`ANC rescue by CSA was accelerated by G-CSF in
`Case 9 in our series.
`For treatment of EBV-HLH, a combination of
`VP16 and steroids is believed to be the first choice
`regimen; however, to avoid infectious complications
`due to neutropenia, CSA seems to be a key drug. The
`major effect of CSA is to block the production of a
`wide variety of cytokines andor their receptors (45).
`CSA efficiently and rapidly suppresses the cytokine
`storm caused by dysregulated T-cells and activated
`macrophages in HLH. Additionally, a direct benefi-
`cial effect of CSA on EBV-HLH itself, in which gran-
`ular lymphocytes play a role, is expected (46). In
`conclusion, we recommend early introduction of CSA
`during neutropenic episodes in the induction phase of
`EBV-HLH treatment. We assume that once the initial
`neutropenic phase is corrected, remission of the dis-
`ease can be attained with subsequent treatment, prom-
`ising a better prognosis for patients with EBV-HLH.
`
`Acknowledgements
`The authors are grateful for Yasuko Hashimoto for
`her assistance in the preparation of this manuscript.
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`CSA FOR NEUTROPENIA IN EBV-HLH
`
`345
`
`large granular lymphocytosis with cyclosporine A and
`filgrastim. Am J Hemato/ 50: 288-29 I.
`16 Wulff, H.R. (1976) Acute agranulocytosis following infec-
`tious mononucleosis. Report of a case. Scand J Haemato/ 2:
`179-1 82.
`17 Ned, E.U (1976) Infectious mononucleosis. Death due to an
`agranulocytosis and pneumonia. JAMA 236: 1493-1494.
`18 Eriksson, K.F., Hlmberg, L. and Bergstrand, C.G (1979)
`Infectious mononucleosis and agranulocytosis Scand J Infect
`Dis 11: 307-309.
`19 Habib, M.A., Babka, J.C. and Burningham, R.A. (1973) Pro-
`found granulocytopenia associated with infectious mononu-
`cleosis. Am J Med Sci 265: 339-346.
`20 Hammond, W.P., Harlan, J.M. and Steinberg, S.E. (1979)
`Severe neutropenia in infectious mononucleosis. West J Med
`131: 92-97.
`21 Schooley, R.T., Densen, P., Harmon, D., Felsenstein, D., Hir-
`sch, M.S., Henle, W. and Weitzman, S. (1984) Antineutrophil
`antibodies in infectious mononucleosis. Am J Med 76: 85-90.
`22 Streiffer, R.H. (1984) Severe neutropenia and infectious
`mononucleosis. Brief report. J Miss State Med Assoc 25:
`295-297.
`23 Imashuku, S., Hibi, S., Morinaga, S., Takagi, K., Chen, J..
`Mugishima, H., Ishii, T., Sako, M., Arakawa, H. and Kato, M
`(1997) Hemophagocytic lymphohistiocytosis in association
`with granular lymphocyte proliferative disorders in early
`childhood: Characteristic bone marrow morphology. Br J
`Haematol96: 708-714.
`24 Gruber, R., Krauss-Etschmann, S., Jager, G., Belohradsky,
`B.H. and Koletzko, S. (1999) Atypical CD3+ CD4IoW cell
`population in a boy with fatal EBV-infection. Int Arch
`Allergy Immunolll8: 74-78.
`25 Connolly, A.A., Rowe-Jones, J., Leighton, S.E., Ball, S.E.,
`Davies, E.G. and Moore-Gillon, V. (1992) Pseudomonal
`supraglottitis occurring in a patient with profound neutrope-
`nia secondary to virus-associated haemophagocytic syn-
`drome. J Laryngol Otol 106: 739-740.
`26 Abella, E.M., Artrip, J., Schultz, K. and Ravindranath. Y.
`(1997) Treatment of familial erythrophagocytic lymphohisti-
`ocytosis with cyclosporine A. J Pediatr 130: 467470.
`27 Gabor, E.P., Mishalani, S. and Lee, S. (1996) Rapid response
`to cyclosporine therapy and sustained remission in large
`granular lymphocyte leukemia. Blood 87: 1199-1 200.
`28 Bible, K.C and Tefferi, A. (1996) Cyclosporine A alleviates
`severe anaemia associated with refractory large granular
`lymphocytic leukaemia and chronic natural killer cell lym-
`phocytosis. Er J Haemarol93: 406408.
`29 Mouy, R., Stephan, J-L., Pillet, P., Haddad, E., Hubert, P. and
`Prieur, A.M. (1996) Efficacy of cyclosporine A in the treat-
`ment of macrophage activation syndrome in juvenile arthri-
`tis: Report of five cases. J Pediatr 129: 750-754.
`30 Tsuda, H. (1997) The use of cyclosporin-A in the treatment
`of virus-associated hemophagocytic syndrome in adults.
`Leukemia & Lymphoma 28: 73-82.
`31 Schiphorst, P.P. and de Pauw, B.E (1995) Autoimmune neu-
`tropenia successfully treated with cyclosporine. Ann Hemarol
`7 0 223-225.
`32 Janka-Schaub, G.E., Raghavachar, A,, Rister, M. and Belo-
`hradsky, B.M. (1992) Treatment of chronic neutropenia of
`childhood responsive to cyclosporin A in vitro and in vivo.
`Int J Hematol55: 157-163.
`33 Oyarna, Y., Amano, T., Hirakawa, S., Hironaka, K., Suzuki,
`S. and Ota, Z. (1989) Haemophagocytic syndrome treated
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
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`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`References
`I
`Henter, J-I., Elinder, G. and Ost, A. (1991) Diagnostic guide-
`lines for hemophagocytic lymphohistiocytosis. Semin Oncol
`18: 29-33.
`Imashuku, S. ( I 997) Differential diagnosis of hemophago-
`cytic syndrome: underlying disorders and selection of the
`most effective treatment. Int J Hemarol66: 135-151.
`Henter, J-I., Arico. M., Egeler. R.M., Elinder, G., Favara,
`B.E., Filipovich. A.H.. Gadner, H., Imashuku, S., Janka
`Schaub, G., Komp, D., Ladisch, S., Webb, D., for the HLH
`study group of the Histiocyte Society (1997) HLH-94 a treat-
`ment protocol for hemophagocytic lymphohistiocytosis. Med
`Pediatr Oncol28: 342-347.
`Arico, M., Janka, G., Fischer, A,, Henter, J-I., Blanche, S.,
`Elinder, G., Martinetti, M., Rusca, M.P., for the FHL Study
`Group of the Histiocyte Society (1996) Hemophagocytic
`lymphohistiocytosis: Diagnosis, treatment, and prognostic
`factors. Report of 122 children from the international regis-
`try. Leukaemia 10: 197-203.
`Imashuku, S., Hibi. S. and Todo, S. (1997) Hemophagocytic
`lymphohistiocytosis in infancy and childhood. J Pediatr
`130 352-357.
`Mroczek. E.C., Weisenburger, D.D., Grierson, H.L., Markin,
`R. and Purtilo. D.T. (1987) Fatal infectious mononucleosis
`and virus-associated hemophagocytic syndrome. Arch Pathol
`Lnb Med 111: 53CL535.
`Wilson, E.R., Malluh, A., Stagno, S. and Crist, W.M. (1981)
`Fatal Epstein-Barr virus-associated hemophagocytic syn-
`drome. J Pediatr 98: 260-262.
`Kikuta, H., Sakiyama. Y., Matsumoto, S., Oh-Ishi, T.,
`Nakano, T., Nagashima, T.. Oka, T.. Hironaka, T. and Hirai,
`K. (1993) Fatal Epstein-Barr virus-associated hemophago-
`cytic syndrome. Blood 82: 3259-3264.
`Imashuku, S., Hibi, S., Ohara, T., Iwai, A,, Sako. M., Kato,
`M., Arakawa, H., Sotomdtsu. M., Kataoka. S., Asami, K.,
`Hasegawa, D., Kosaka. Y., Sano K., Igarashi, N., Maruhashi,
`K., Ichimi, R., Kawasaki, H., Maeda, N., Tanizdwa, A,, Arai,
`K., Abe, T., Hisakawa, H., Miyashita, H. and Henter, J-I. For
`the Histiocyte Society
`(1999) Effective control of
`Epstein-Barr virus-related hemophagocytic lymphohistiocy-
`tosis with immunochemotherapy. Blood 93: 1869-1 874.
`Tsuda, H.. Maeda. Y., Nakayama, M. and Nishimura, H.
`( 1994) Parvovirus B 19-associated hemophagocytic syn-
`drome with prominent neutropenia. Br J Haematol86: 413-
`414.
`Chen, J-S., Tzeng, C-C., Tsao, C-J., Su, W-C., Chen. T-Y.,
`Jung, Y-C. and Su. I-J. (1997) Clonal karyotype abnormali-
`ties
`in EBV-associated hemophagocytic
`syndrome.
`Haematologica 82: 572-576.
`Sood. R.. Stewart, C.C., Aplan, P.D., Murai, H.. Ward, P.,
`Barcos, M. and Baer, M.R. (1998) Neutropenia associated
`with T-cell large granular lymphocyte leukemia: Long-term
`response to cyclosporine therapy despite persistence of
`abnormal cells. Blood 91: 3372-3378.
`Herrod, H.G., Wang, W.C. and Sullivan, J.L. (1985) Chronic
`T-cell lymphocytosis with neutropenia. Its association with
`Epstein-Barr virus infection. Am JDis Child 139: 405407.
`Garipidou, V., Tsatalas, C. and Sinacos, Z. (1991) Severe
`neutropenia in a patient with large granular lymphocyto '
`prolonged
`successful
`control with
`cyclosporin A.
`Haematologira 76: 424425.
`Jakubowski, A., Winton, E.F., Gencarelli, A. and Gabrilove,
`1. (1995) Treatment of chronic neutropenia associated with
`
`Downloaded by [Keely Southwick] at 10:18 21 November 2017
`
`ALVOGEN, Exh. 1025, p. 0008
`
`

`

`346
`
`SHINSAKU IMASHUKU et al.
`
`with cyclosporin A: T cell disorder? Br J Haemarol73: 276-
`278.
`34 Ishii, E., Ohga, S., Aoki, T., Yamada, S., Sako, M., Tasaka,
`H., Kuwano, A., Sasaki, M., Tsunematsu, Y. and Ueda, K.
`(1991) Prognosis of children with virus-associated hemoph-
`agocytic syndrome and malignant histiocytosis: correlation
`with levels of serum interleukin- 1 and tumor necrosis factor.
`Acra Haematol85: 93-99.
`35 Fujiwara, F., Hibi, S. and Imashuku, S. (1993) Hypercytoki-
`nemia in hemophagocytic syndrome. Am J Pediarr Hemarol
`Oncoll5: 92-98.
`36 Imashuku, S., Hibi, S., Fujiwara, F., Ikushima, S. and Todo,
`lymphobistiocytosis,
`inter-
`S . (1994) Haemophagocytic
`feron-gamma-naemia and Epstein-Barr virus involvement.
`Br J Haemarol88: 656-65 8.
`37 Imashuku, S., Hibi, S., Sako, M., Ishida, Y., Mugishima, H.,
`Chen, J. and Tsunematsu, Y. (1995) Soluble interleukin-2
`receptor: A useful prognostic factor for patients with
`hemophagocytic lymphohistiocytosis. Blood 86: 47064707.
`38 Larochelle, B., Flamand, L., Gourde, P., Beauchamp, D. and
`Gosselin, J. (1998) Epstein-Barr virus infects and induces
`apoptosis in human neutrophils. Blood 92: 291-299.
`39 Azuma, E., Tabata, N., Shibata, T., Komada, Y., Ito, M.,
`Atsumi, S., Kawasaki, Y., Ishii, M. and Sakurai, M. (1990)
`G-CSF enhanced granulocyte production in a child with
`severe neutropenia in the setting of fatal virus associated
`hemophagocytic syndrome. Am J Hematol35: 266-268.
`40 Tsuda, H. and Shirono, K. (1996) Successful treatment of
`virus-associated haemophagocytic syndrome in adults by
`
`cyclosporin A supported by granulocyte colony-stimulating
`factor. Br J Haematol93: 572-575.
`41 Gilmore, G.L., Depasquale, D.K., Fisher, B.C. and Shad-
`duck, R.K. (1995) Enhancement of monocytopoiesis by
`granulocyte colony-stimulating factor: evidence for second-
`ary cytokine effects in vivo. Exp Hematol23: 1319-1323.
`42 Demuynck, H., Zache, P., Verhef, G.E., Schetz, M., van den
`Berghe, G., Lauwers, P. and Boogaerts, M.A. (1995) Risks of
`rhG-CSF treatment in drug induced agranulocytosis. Ann
`Hematol70: 143-147.
`43 Terashima, T., Kanazawa, M., Sayama, K., Ishizaka, A,,
`Urano, T., Sakamaki, F., Nakamura, H., Waki, Y. and Tasaka,
`S. (1994) Granulocyte colony-stimulating factor exacerbates
`acute lung injury induced by intratracheal endotoxin in
`guinea pigs. Am J Respir Crir Care Med 149: 1295-1303.
`44 Thomssen, C., Nissen, C., Gratwohl, A., Tichelli, A. and
`(1989) Agranulocytosis associated with
`Stem, A.
`T-gamma-lymphocytosis: No improvement of peripheral
`blood granulocyte count with human-recombinant granulo-
`cyte-macrophage colony-stimulating factor (GM-C SF). Br J
`Haemarol71: 157-158.
`45 Santori, L., Rastelli, M., Arena, B. and Morleo, M.A. (1997)
`Cyclosporine: update on pharmacology, analytical tech-
`niques and therapeutic monitoring. Boll Chim Farm 136:
`577-588.
`46 Brinkman, K., van Dongen, J.J.. van Lom, K., Groeneveld,
`K., Misere, J.F. and van der Heul, C. (1998) Induction of
`clinical remission in T-large granular lymphocyte leukemia
`with cyclosporin A. monitored by use of immunophenotyp-
`ing with Vbeta antibodies. Leukemia 12: 150-154.
`
`Downloaded by [Keely Southwick] at 10:18 21 November 2017
`
`ALVOGEN, Exh. 1025, p. 0009
`
`