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`Correspondence
`
`23177
`
`4 Moskowitz C, Dutcher JP, Wierik PH, Association of thyroid disease
`with acute leukemia, Am { Hematol 1992; 39; 102-107.
`5 De Resa C, Delia 8, Corselo SV Cecchini L, Calla €. Autoimmune
`polyglandular syndrome, primary emply sella, and acute lymphocytic
`leukaemia. Clin Endocrinol 1987; 2'7;535-543,
`
`6 Ergas D, Tsimanis A, Shtalrid M, Duskin C, Berrebi A, T-y large granular
`lymphocyte leukemia associated with amegakaryocytic thrombocyto-
`penic purpura, Sjogren’s syndrome, and polyglandular autoimmune
`syndrome type Il, with subsequent development cd pure rad cal
`aplasia. Am { Hematol! 2002; 69: 132-134.
`
`Thalidomide therapy induces response in relapsed mantle cell lymphoma
`Leukemia (2003) 17, 1944-1915. dol:10.1038/s}.leu.2403058
`
`relapsed with bene marrow invelvement,
`the patient
`2002),
`splenomegaly, an elevated LDH (6001U/L), and a poor performance
`status (KPS=3). He was started on thalidomide 100me/day plus
`dexamethasone (40me/day x 4 days). After
`4 month,
`the patient
`demonstrated a significant decrease in splenomegaly and the LDH
`level, but remained pancytopenic, The dose of thalidomide was not
`increased because of
`side effects
`(constipation,
`fatigue,
`and
`paresthesia) and the dexamethasone was stopped. Over the next
`5 months, while taking only thalidomide 100 mg/day, the patient
`demonstrated progressive improvement of his disease, with resolu-
`tion of the splenomegaly, normalization of the LDH and hemoglo-
`bin levels, and significant
`improvement of his neutrophil and
`platelet counts (1.0 and 86 x 10°/l, respectively). At last follow-up
`(March 2003), the patient maintains his response,
`taking thalido-
`mide 100me/day without any severe toxicity.
`Since the first and subsequent reports of its aficacy in multiple
`myeloma," there has been a growing interest in thalidomide as
`an anticancer therapy, The pracise mechanisms responsible for
`thalidomide’s antitumor effect remain unknown. Thalidomide ma
`act directly on tumor cells to induce apoptosis or call cycle arrest,
`or indirectly, by acting to inhibit angiogenes|s,° alter immune cell
`cytokine secretion,’
`enhance T cell,”
`natural killer cell’
`and
`dendritic cell activity,”
`and inhibit NF-«B activity.” These two
`casas representthe first two reports of the therapautic potential of
`thatidomide
`In
`refractory MCL. Based on these encouraging
`preliminary results, and the immediate need for improved therapy
`for the treatment ef MCL, prospective phaseII trials involving larger
`groups d patienis are warranted,
`in vitro studies are underway to
`delineate the mechanism of action of thalidomide in MCL.
`
`Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma that
`cannot be cured despite aggressive therapy,
`including autologous
`stem cell transplantation, Thalidomide is an immunomodulatory
`drug with numerous properties tat has proven effective in relapsed
`multipfe myelorna and, to a lesser extent,
`in other hematological
`diseases, such as myelodysplastic syndromes and myeloproliferative
`disorders, We
`report
`two cases of
`relapsec refractory MCL
`successfully treated with thalidomide,
`The first patient is a 70-year-old man, who presented in 1995
`with stage IV MCL. He was treated according to the current protocol
`at cur institution, 28 reported elsawhers.’ He received CHOP x four
`cycles with only a partial
`response (PR),
`followad by high-
`dose cytarabine-based chemotherapy (DHAP), and consolidation
`with an auiglogous stem cell transplant utilizing total body irradiation
`(FB, melphalan, and cytarabine as the preparative regimen, A
`complete response (CR) was obtained. The patient relapsed 40
`months later, presenting with diffuse peripheral and abdominal
`lymphadenopathy, splenomagaly, bone marrow and peripheral blood
`involvement, and 4 lactate dehydrogenasa {LDH} level twice the
`normal. As salvage chemotherapy,
`the patient received concurrent
`cytarabine (2g/m7/12 h, days 1-3) and etoposide (200 mg/m?/day,
`days 1-3). After a transient response, the patient progressed 3 weeks
`after the third cycle. The patient next received two cycles of
`concurrent fludarabine (3O0mg/m*/day, days 1-3) and cyclopho-
`sphamide (800mg/m@/day, days 1-3), and obtained PR. Treatment
`was
`complicated
`by persistent grade 4
`pancytopenia
`(ANC
`<0,1 x 70°) and infection. As a consequenca, the patient declined
`further chemotherapy. Affer 4 months, when the patient's peripheral
`lymphadencpathy increased, he received a 4-week course of
`rituximab (375 mg/m* per week) without any response.
`In June
`2001, the patient devaloped worsening pancytopenia and compras~
`sive iilac lymphadenopathy and started thalidomide at 200 mp/day,
`increasing by 700mg/day every 2 weeks, up to 500me/day.
`Hematopoiesis and lymphadenopathy progressively improved, with
`the patient becoming transfusion independent within 2 months of
`beginning thalidomide, By the 4th month,
`the hemoglobin and
`platelet levels had reached 12 g/dl and 176x 10/1, respectively, with
`a complete disappearanca of peripheral blood atypical
`lymphocytes
`1 Lefrere F, Delmer A Suzan F, Levy V, Belanger G Djabarri M
`and a 50% reduction in the size of the lymphadenopathy. Over the
`et af. Sequential chemotherapy by CHOP and OHAP regimens
`next year, the patient maintained his response on 300 mg/day of
`followed by high-dose therapy with stem ceil transplantation induces
`thalidomide, Although the patient was tolerating the thalidomide, the
`a high rate d complete response and improves event-free survival in
`dose was Cecreased to 200me/day for 2 weeks each month,
`to
`mantle cell
`lymphoma: a prospective study. Leukemia 2002;
`14:
`587-593.
`decrease the risk of chronic thajidornice side effects, After 4 months
`ho
`Singhal § Mehta], Desikan R. Ayers D, Robersen P, EddlemionPet al.
`(September 2002), the patient's disease progressed, with reappear-
`Antitumor activity of thalidomide in refractory multipie myeloma,
`ance of the pancytopenia and increased tymphadenopathy. A bone
`N Engl } Med 1999: 344: 1565-1571.
`marrow examination was not performed, Thalidomide was increased
`3 Rajkumar §V, Gertz MA, Lacy MQ, Dispenzieri A. Fonseca R, Ceyer
`to 200 mg each day in combination with three courses of monthly
`& et al. Thalidomide as
`initial
`therapy for early-stage myeloma,
`Leukemia 2003; 17: 775-779.
`dexamethasone (40me@/day x 4 days), reachieving a partial response.
`At 179 months since first starting thalidomide, the patient remains allve
`Rajkumar SV, Dispenzier| A. Forseca R. Lacy MQ, Ceyer § LustJA
`and with a good partial response.
`et af, Thalidomide for previously untreated indolent or smoldering
`muitple myeloma. Lewkern/a 2001; 15: 1274-1276,
`The second patient
`is a 66-year-old man, who presented with
`5 Raje N, Anderson K, Thalidomidea revival story. N Eng! { Med 1999;
`stage IV MCL, and initially achieved a CR after receiving three
`341: 1606-1609.
`cycles of CHOP, followed by three cycles of DHAP in combination
`with rituximab, and an autologous stam cell transplant utilizing TBI,
`melphalan, and cytarabine as consolidation, After 2 years (May
`
`‘Department of Hamatology, Hapital
`Nacker Enfanis-Malades, Paris, France;
`‘Department of Hematology, Mount Sinai
`School of Medicine, NY, USA
`
`G Damaj'?
`F Lefrére
`R Delarue'
`B Varet’
`R Furman?
`O Hermine’
`
`References
`
`hb
`
`3 Current address:institut Paoli, Calmettes, 232 Blvd sainte Marguerite,
`13273 cedex 9, Marseilla, France
`
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`Celgene Ex. 2009, Page 2
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`

`

`
`Cotrespondence
`1915
`
`Folkman !. Thalidomide is an
`6 D'Amato Ri Loughnan MS, Flynn €
`inhibitor of angiogenesis. Proc Nat! Acad Sci 1994; 91: 40582-4085.
`7 Corral .G, Haslett PA, Muller CW, Ghen R Wong LM, Ocampo C]
`et af. Differential cytokine modulation and T cell activation by two
`distinct classes cf thalidomide analogues that are potent inhibitors of
`TNF-alpha. / immune! 1999; 163:380-386,
`Haslett PAJ, Corral LG, Aibert M, Kaplan G. Thalidomidca costimulates
`primary human T lymphocytes, preferentially inducing proliferation,
`cytokine production, and cytotoxic responses in the CD8+ subset. { xp
`Mecf 1998; 187: 1885-1892,
`
`9 Davies FE, Raje N, Hideshima T, Lantesch §& Young G, Tai YT
`et af, Thalidomide and immunomodulatory derivatives augment
`natural killer cell cytotoxicity in multiple myeioma. Blood 2001: 98:
`210-216,
`10 Monty M, Stoppa AM, Blaise D, Isnardon D, Gastaut JA, Olive D
`et al Differential
`regulation of dendritic call
`function by the
`immunomodulatory drug thalidomide. { Leukocute Biof 2002; 72:
`939-945.
`inhibition of
`11 Keifer JA, Cuttridge DC, Ashburner BP, Baldwin jr. AS.
`NF-«B Activity by Thalidomide through Suppression of IxB Kinase
`Activity. f Biol Chem 2001; 276: 22382-22387.
`
`AML with t(8;21) and trisomy 4: possible involvement of c-kit?
`
`SE Langabear'
`A Beghini*
`L Larizza?
`
`References
`
`institute of
`‘leukaernia ResearchF und Centre,
`Cancer Research, London, LK;
`* Department of Siology and Genatics, Medical
`Faculty, University of Milan, Mitan,
`italy
`
`wooN
`
`Nishii K Usui Katayama N, Lorenzo F, Nakase K, KobayashiT et al,
`Characteristics of t(8;2 1) acute myeloid laukemia(AML) with additional
`chromosomal abnormality: concomitant tisomy 4 may constitute a
`distinctive subtype of 48:21) AML. Leukemia 2003: 17; 731-737.
`Speck NA, Gilliland OC, Core-binding factors in haematopciesis and
`leukaemia. Nat Rev Cancer 2002; 2: 502-513,
`Cari M, Coodeve A Wilson C, Winship P, Langabeer§, Linch D etal,
`C-kit proto-oncogeneexon 8 in-frarne deletion plus insertion mutations
`in acute myeloid leukaemia. Gr / Haematol 1999; 105; 694-900.
`Baghini A PeterlongoR Ripamont! C8, Larizza |, Calroll R, Morra E
`etal. C-kit mutationsin core binding factor laukemias. Blood 2000; 95:
`726-727.
`BeghiniA Ripamortl C8, Castorina P, Pezzettil, Doneda i, Cairoli R
`et al, Trisomy 4 leadingto a duplication of a mutated KIT allele in acute
`myeloid leukemiawith mast cell involvament. Cancer Genet Cytogenet
`2000; 119: 26-34.
`|, Ripamonti CS. Larizza L. Amplification of
`6 Baghini A’ Magnani
`2 noval c-kit activating mutation Asn®??-Lys In the Kasumi-1 cell line:
`a (8;21)-kit mutant model for acute myeloid leukemia, Haematology
`J 2002; 3: 187-163.
`7 Ning 27Q, LiJ, Arceci RJ, Activating mutations of c-kit at codon 816
`confer drug resistance in human leukemia cells, Leukemia Lymphoma
`2001; 41; 513-522,
`8 Heinrich MC, Blanke CD, Druker BJ, Coness CL. Inhibition of KIT
`tyrosine Kinaseactivity: a novel molecular approachto the treatmentof
`KIT-pesitive malignancies. { Clin Oncol 2002; 20: 1692—1703.
`
`a o
`
`r
`
`Leukemia (2003)17, 1915. dol:10.1038/sj.leu.2403066
`TO THE EDITOR
`
`Nishiiet af have recently described a minor subset of acute myeloid
`faukemia (AML) patients with 8;21) and trisomy 4, who had a
`relatively poor prognosis when compared to (8:27) AML patients
`with or without other cytogenetic abnormalities, A raview of the
`literature suggests a possible mechanism for this poor prognosis.
`Current theory regarding the pathogenesis of AML, especially in
`those patients with either a (8:27)(q22;q22) or
`inv(T6)(pt3q22)
`abnormality, has postulated the ccoperativity of core-binding factor
`(CBF) gene rearrangements (AML 7-€7Oand CBFB-MYH? 1, respec-
`tively) with mutations in thosa ganes ancading receptor tyrosine
`kinases (eg FLTS, KIT)’
`In particular, mutations cf the s-kit gene,
`located at chromosome 4q11-q12, have been detected in a
`significant proportion of patients with CBF-AML?® and also in two
`patients with (8;21) and trisomy 4.4 In one of these latter patients,
`the trisomy 4 lead to duplication and thus increased dosage of the
`mutated c-kit alleie® suggesting an additional mechanism of
`leukemogenesis. This observation is supported by evidence of
`amplitication of a c-kit mutation in the (821) and trisomy four-
`positive cell
`tine Kasumi-1.° Further
`investigation js
`therefore
`warranted to determine the presence of ¢-kit mutations in the three
`(8:21) AML patients with trisomy 4 describad by Nishii etal,’ as the
`most commen activating mutation of c-kit has been show to confer
`drug resistance,’ which could be partly rasponsitle for the relatively
`poor prognosis.
`If mutations are present,
`these patients may be
`eligible for additional treatment with novel therapies that inhibit KIT
`tyrosine kinase activity.’
`
`Reply to SE Langabeer et al
`
`Leukemia (2003)17, 1915-1916. dof:10. 1088/sj.leu.2403067
`TO THE EDITOR
`
`Dr. Langabeer and his colleagues made several interesting sugges-
`tions in discussing our recent paper.” Qur work showed that t(8;217}
`acute myslold leukemia (AML) with trisomy 4 had different
`morphology, phenotype, and clinical outcome when compared to
`(8:21) AML with or without other chromosomal abnormalities,
`especially t(8;21} AML plus trisomy 4 having a poor prognosis. Dr.
`Langabeer et a/, speculate that the presence of c-kit mutation in the
`{8;21} AML patients with trisomy 4 may have caused these events. It
`had been reported that c-kit mutations were more frequently
`observed in core binding factor
`leukemia.2 Among thase c-kit
`
`Correspondence: Dr K Nishii, Fax: +81 59 234 6200
`
`mutations, mutation of codon 816 (most commonly Asp816Val) of
`the c-kit caused constitutive activation of the KIT kinase*? and had
`been shown to confer drug résistance. *” Therefore, we examined
`for c-kit mutation in a t(8:21) AML with trisomy 4 sample among
`those reported by Nishii et ai! only one sample was available for
`analysis, Mutation screening was targeted on exon 17 at codon 816
`{amine acid 2468) of c-kit. CDNA was amolified using reverse
`transcription-polymerase chain reactlon {RT-PCR) method and
`amino-acid sequence Was investigated as described previously."
`As shown in Figure 1, the presence of the Asp816Val mutation was
`detacted in leukemic cells from this sample. Beghini at a/1®"! also
`reported the mutation of codon 816 of c-kit gene in two cases of
`4(8;21) AML with trisomy 4. These observations led us to speculate
`that an activating mutation of c-kit may be associated with 1(8;21)
`AML with trisomy 4, perhaps this additional aberration could have
`caused the poor prognosis. To confirm the relationship between
`
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