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`Correspondence
`
`4 McskcwitzC. Dutcher JP. Wiernik PH. Association of thyroid disease
`with acute leukemia. Am] Hematol 1992; 39: £02407.
`5 De Ross C. Della S. Corselto S’vt Cecchini L Calla C. Autoimmune
`polyglandular syndrome. primary empty sells. and acute iymphocytic
`leukaemia. Cfin Endocrlnci19t37; 27:535—543.
`
`6 Ergas D, TsimanlsA Shtalrld M. Duskin C. BerrebiA. T-v large ranular
`lymphocyte leukemia associated with amegakazyocytic throrn oeytor
`panic purpura. Sjogren’s syndrome, and poiyglanduiar autoimmune
`syndrome type II, with subsequent development (f pure red ceEt
`aplasia. Am} Hematol' 2002,- 69: 132—134.
`
`55/7
`
`Thalidomide therapy induces response in relapsed mantle cell lymphoma
`
`Leukemia (2003) 17. 1914—1915. dol:10.1DBBIsJ.leu.24E}3058
`
`Mantle cell lymphoma (MOL) 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 propertiesthat has proven effective in relapsed
`multiple myeloma and, to a lesser extent.
`in other hematological
`diseases, such as myelcdysplastlc syndromes and myeloprcliterattve
`disorders, We
`report
`two cases of
`relapsed refractory MCL
`successfully treated with thalidomide.
`The first patient is a 70-year-old man. who presented in 1995
`with stage lV MCL. Hewas treated according to the current protocol
`at our institution, as reported elsewhere.’ He received CHOP x four
`cycles with only a partial
`response (PR),
`followed by high
`dose cytarabtne—based chemotherapy (DHAP), and consolidation
`with an autoiogous stem cell transplant utilizing total body irradiation
`WEI). meiphalan, and cytarabine as the preparative regimen, A
`complete response (CR) was obtained. The patient relapsed 40
`months later. presenting with diffuse peripheral and abdominal
`lymphadencpathy, splenomegaiy. bone marrow and peripheral blood
`involvement, and a lactate dehydrogenase {LDH} level twice the
`normat. As salvage chemotherapy.
`the patient received concurrent
`cytarabine (2g/m2f12 h. days 1—3) and etoposide (2OUrng/m2/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 (3Dmg/m2lday. days 1—6) and cyclcpho-
`spharnide {BODmme/day, days 1—3), and obtained PR. Treatment
`was
`complicated
`by persistent grade 4
`pancytopenia
`(ANC
`(0.1 x tog/I) and infection. As a consequence. the patient declined
`further chemotherapy After 4 months. when the patient‘s peripheral
`lymphadenopathy increased, he received a 4wweek course of
`rituximab (375 rrIg/‘rr‘l2 per week) without any response.
`In June
`2001. the patient developed worsening pancytopenia and compresm
`sive itiac lymphadenopathy and started thalidomide at 200 nag/day,
`increasing by 100 mg/day every 2 weeks. up to 500 mg/day.
`Hematcpoiesls 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 1231c“ and 175x 109:1, respectively. with
`a complete disappearance of peripheral blood atypical
`tymphocytes
`and a 50% reduction in the size of the lymphadenopathy. Over the
`next year, the patient maintained his response on 300mg/day of
`thatidomide. Although the patient was tolerating the thalidomide, the
`dose was decreased to 200 mg/day for 2 weeks each month,
`to
`decrease the risk of chronic thatidornide side effects. After 4 months
`(September 2002), the patient's disease progressed, with reappear-
`ance of the panoytopenia and increased lymphadenopathy. A bone
`marrow examination was not performed. Thalidomide was increased
`to 200 mg each day in combination wtth three courses of monthty
`dexamethascne (40rnflday X 4 days), reachieving a partial response.
`At 19 months since first starting thalidomide, the patient remains elite
`and with a good partial response.
`The second patient
`is a 567yearwold man, who presented with
`stage IV MCL. and initially achieved a CR after receiving three
`cycles of CHOP. followed by three cycles of DHAP in combination
`with rituximab. and an autologous stem cell transplant utilizing TBl.
`melphalan. and cytarabine as consolidation. After 2 years (May
`
`relapsed with bone marrow involvement.
`the patient
`2002),
`splenomegaly. an elevated LDH (800 iUiL), and a poor performance
`status iKPS=3). He was started on thalidomide 100mg/day plus
`dexamethasone (40rng/dayx4 days). After
`1 month,
`the patient
`demonstrated a significant decrease in splenomegaly and the LDH
`levei. but remained pancytopenic. The dose of thalidomide was not
`increased becausa of
`side effects
`(constipation.
`fatigue.
`and
`paresthesla) 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 ct his neutrophil and
`platelet counts (1,0 and 86 x 109.”. respectively). At last foilowuup
`(March 2003). the patient maintains his response.
`taking thalido-
`mide 100mg/day without any severe toxicity.
`Since the first and subsequent reports of its efficacy in multiple
`rnyeit'.lma,2"1 there has been a growing interest in thalidomide as
`an anticancer therapy, The precise mechanisms responsible for
`thalidomide's antitumor effect remain unknown. Thalidomide ma
`act directly on tumor cells to induce apoptcsts or cell cycle arrest,
`or indirectly, by acting to inhibit angiobgenesisf atter immune cell
`oytokine secretion.’
`enhance T cell,
`natural killer cell.‘
`and
`dendrltic Call activity."
`and inhibit NF-KB activity." These two
`cases represent the first two reports of the therapeutic potential of
`thalidomide
`in
`refractory MCL. Based on these encouraging
`preliminary results. and the immediate need for improvad therapy
`for the treatment of MCL. prospective phase II trials invoiving larger
`groups cf patients are warranted,
`to vitro studies are underway to
`delineate the mechanism of action of thalidomide in MCL.
`
`Department of Hematology, Hdpltai
`Necker Enfants-Mafades, Paris1 France;
`Department of Hematology. Mount Sinai
`Schoolchedicine, NY. USA
`
`G Dama'i'3
`F Lefrére
`R Delarue'
`B Varet'
`R Furman2
`O Hermine1
`
`References
`
`1 Lefrere F, Delmer A, Suzan F. Levy V, Belanger C. Djabarr‘: M
`et at. Sequential chemotherapy by CHOP and DHAP regimens
`followed by highdcse therapy with stem cell transplantation induces
`a high rate {f complete response and improves event-free survival in
`mantle cell
`lymphoma: a prospective study. Leukemia 2002;
`16:
`587—593.
`2 Singhal S Mehtal, Desikan R Ayers D, Roberson P. Eddiemon P at al.
`Antiturnor activity of thalidomide in refractory multiple myeloma.
`N Englj Med 1999; 341: 1565—1571.
`3 RajkumarSV, Gertz MA, Lacy MQ. Dlspenzieri A Fonseca R, Ceyer
`SVl et at. Thalidomide as
`initial
`therapy for salty-stage myelcrnai
`Leukemia 2003; 17: 775—779.
`4 Rajkumar 5V. DispenZEeri A Forceps R, Lacy MCI. CeyerS LustlA
`at al. Thalidomide for previously untreated indolent or smoldering
`multiple myeloma. Leukemia 2001; 15: 12T4—1276.
`5 Raje N, Anderson K. Thalidomidaa revtval story. N Engl/ Med1999;
`341:
`lBOEFTBOQ.
`
`3Current address: lnstitut Paoli, Calmettes. 232 Blvd saints Marguerite.
`13273 codex Q. Marseille, France
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`Correspondence
`t9l5
`
`6 D’Amato El. Loughnan MS, Flynn E Folkman }. Thalidomide is an
`inhibitor of angiogenesis. Proc Natl Acad Sci 1994; 91: 40524065.
`7 Corral LG. Haslett PA. Muller CW. Chen R Wong LM. Ocampo Cl
`et at. Differential cytokihe modulation and T cell activation by two
`distinct classes cf thalidomide analogues that are potent inhibitors of
`TNF-alpha.] immunol 1999; 1G3:300—386.
`8 Haslett PA], Corral LG. Albert M, Kapian G. Thalidomidecostimulates
`primary human T lymphocytes. preferentially inducing proliferation.
`cytokine production. and cytotoxic responses in the CDEH- subset} Exp
`Med 1998; 187‘. 18854892,
`
`9 Davies FE. Raje N. Hideshima T, Lentisch a Young G. Tai YT
`et at. Thalidomide and irnmunomodulatory derivatives augment
`natural killer cell cytotoxicity in multiple myeloma. Blood 200']; 98:
`210-216.
`isnardon D. Gastaut JA. Oiive D
`10 MOhty M. Steppe AM. Blaise D,
`et at. Differential
`regulation of dendritic cell
`function by the
`immunomoduiatory drug thalidomide. I Leukocute Bio! 2002: 72:
`939—945.
`inhibition of
`’11 KeiferlA, Cartridge DC, Ashburner BP. Baldwin jr. as.
`NF—ch Activity by Thalidomide through Suppression of INS Kinase
`Activity. 1 Biol Chem 2001: 276: 22382—22387.
`
`AML with t(8;21) and trisomy 4: possible involvement of C—kit?
`institute of
`‘Leukaemi'a Research Fund Centre.
`Cancer Research, London, UK;
`2Department of Biology and Genetics. Medical
`Faculty. University of Milan. Milan. Italy
`
`Leukemia (2003)17, 1915.d0|210.1038fsi.|eu.2403066
`TO THE EDITOR
`
`SE Langabeer'
`A Beghini2
`L Larizza2
`
`Nishii et a.” have recentiy described a minor subset of acute myeloid
`ieukemia (AML) patients with tt8;21) and trisomy 4. Who had a
`relatively poor prognosis when compared to ti8;21) AML patients
`with or without other cytogenetic abnormalities. A review 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 tt8;2't)lq22;q22) 0r
`invt16)(pl3q22l
`abnormality. has postulated the cooperativity of core—binding factor
`(CBF) gene rearrangements [AML 1-6TOand CBFB-MYHl 1, respec—
`tively) with mutations in those genes encoding receptor tyrosine
`kinases (cg FLT3. KIT)!
`In particular. mutations of the orkit gene.
`located at chromosome 4q1 i—qi 2, have been detected in a
`significant proportion of patients with lilifiF-Ai’ytLa and also in two
`patients with t(3;21l and trisomy 4.4 in one of these latter patients,
`the trisomy 4 lead to duplication and thus increased dosage of the
`mutated oakit allele,E suggesting an additional mechanism of
`leukemogenesis. This observation is supported by evidence of
`amplification of a eukit mutation in the t(8;21) and trisomy four-
`positlve cell
`ilne Kasumi—i ,6 Further
`investigation is
`therefore
`warranted to determine the presence of c—ltit mutations in the three
`ll8;21lAML patients with trisomy 4 described by Nishii etal.’ as the
`most common activating mutation of c-kit has been show to confer
`drug resistance,7 which couid be partly responsible for the relatively
`poor prognosis.
`If mutations are present,
`these patients may be
`eligibie for additional treatment with noveitherapies that inhibit KIT
`tyrosine kihase activity.’
`
`References
`
`1 Nishii K UsuiE, Katayama N. Lorenzo F, NakaseK. KobayashiT etal.
`Characteristics of t(B;2 t) acute myeloid leukemiatAML) with additional
`chromosomal abnormality: concomitant trisomy 4 may constitute a
`distinctive subtype of item) AML. Leukemia 2003; 17: 731437.
`2 Speck NA, Gilliland DC. Core~binding factors in haematopoiesis and
`leukaemia. Nat Rev Cancer 2002; 2: 502—5l3.
`3 Carl M, Coodeve A Wilson C, Winship P, Langabeera Linch D etat.
`Cukit proto-oncogeneexun B iniframe deletion plus insertion mutations
`in acute myeloid leukaemia. Br} Haematol 1999‘. 105: 894—900.
`4 Beghini A Peterlongo F! Ripamomi CB. Larizza L, Calroll R. Morra E
`et al. C-kit mutationsin core binding factor leukemias. 1310on000; 95:
`72 6—727.
`5 BeghinlA RipamonthB. Cesiorina P. Pezzetti L Doneda L. Cairoli it
`at at. Trisomy 4 leadingto a duplication ofa mutated KIT aiiele in acute
`myeloid leukemiawith mast cell involvement. Cancer Genet Cytogenet
`2000; 119:25—31.
`l, Ripamonti CB. Larizza L, Amplification of
`6 Beghini A. Magnani
`a novel c-kit activating mutationAsn522»Lys in the Kasumisi cell line:
`a tiB;21)-kit mutant model for acute myeloid leukemia, Hematology
`J2002: 3: 15?-163.
`7 Ning ZQ. Li J. Arcecl RJ. Activating mutations of c~kit at oodon 8'18
`confer drug resistance in human leukemia cells. Leukemia Lymphoma
`2001; 41: 5137522.
`8 Heinrich MC. Blanke CD. Druker BJ. Corless CL, Inhibtion of KtT
`tyrosine kinase activity: a novel molecular approach to the treatment of
`KITipositive malignancies} Ciin Oncolzooz; 7.0: 1692—1703.
`
`Reply to SE Langabeer et a!
`
`Leukemia (2003)17, 1915—1916. doi:10.1038/sj.|eu.2403067
`TO THE EDiTOR
`
`Dr, Langabeer and his colleagues made several interesting sugges—
`tions in discussing our recent paper.’ Our Work showad that t(6.-2‘l)
`acute myeloid 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;21i AML plus trisomy 4 having a poor prognosis. Dr.
`Langabeer et at, speculate that the presence of c~kit mutation in the
`tt8;21i AML patients with trisomy 4 may have caused these events.
`It
`had been reported that cskit mutations were more frequently
`observed in core binding factor
`leukemia?J Among these c-kit
`
`Correspondence: Dr K Nishii. Fax: +81 59 231 5200
`
`mutations. mutation of ccdon 8‘1 6 (most commonly Asth 6Val) of
`the c—kit caused constitutive activation of the KIT itinr:I.se“"5 and had
`been shown to confer drug resistance.” Therefore, we examined
`for c—kit mutation in a t(8;21) AML with trisomy 4 sample among
`those reported by Nishii et at,1 oniy one sample was avaiiable for
`analysis. Mutation screening was targeted on exon 17 at codon 816
`(amino acid 2468) cf c—kit. cDNA was amplified using reverse
`transcriptionrpolymerase chain reaction (RT—FOR) method and
`aminowacld sequence was investigated as described pl’eVlOUSlY.B'9
`As shown in Figure 1. the presence of the AspSifiVat mutation was
`detected in leukemic cells from this sample. Beghini et aim“ also
`reported the mutation of codon 816 of c~i<it gene in two cases of
`t(8;21) AML with trisomy 4. These observations led us to speculate
`that an activating mutation of o—Kit may be associated with H.821)
`AML with trisomy 4, perhaps this additional aberration could have
`caused the poor prognosis, To confirm the relationship between
`
`Lcrdsemii!
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