Adoptive immunotherapy and/or immunostimulation may be effective in treating early phases of leukemia relapsing after allogeneic transplant. Donor lymphocyte infusion (DLI) is an established treatment for cytogenetic relapse of chronic myeloid leukemia (CML) after unmanipulated or T-cell–depleted bone marrow transplant (BMT)1; favorable results have also been reported in a few cases of initial posttransplant relapse of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).2 A graft-versus-leukemia (GVL) effect as part of a manifest or occult DLI-elicited graft-versus-host disease (GVHD) is thought to be the reason for these favorable results. For patients who had received autologous transplant, attempts to elicit an antineoplastic effect by immunostimulation have been made using in vitro interleukin-2 (IL-2)–activated autologous lymphocytes and/or IL-2 in vivo administration.34 We report on the successful use of subcutaneous (sc) low-dose IL-2 in a patient suffering from AML with recurrence of cytogenetic abnormalities after autografting

De Rosa G

Luciano L

Pezzullo L

Picardi M

Raiola AM

Rotoli B

Selleri C

Rotoli B.

PICARDI, MARCO

Archivio della ricerca - Università degli studi di Napoli Federico II

1998 92: 4484-4485    G. De Rosa, L. Pezzullo, C. Selleri, A.M. Raiola, L. Luciano, M. Picardi and B. Rotoli With HyperdiploidyCytogenetic Abnormality Recurrency in a Case of Acute Myeloid Leukemia Low-Dose Interleukin-2 for Treating Postautologous Transplant http://bloodjournal.hematologylibrary.org/content/92/11/4484.full.htmlUpdated information and services can be found at: http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub_requestsInformation about reproducing this article in parts or in its entirety may be found online at: http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprintsInformation about ordering reprints may be found online at: http://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtmlInformation about subscriptions and ASH membership may be found online at: Copyright 2011 by The American Society of Hematology; all rights reserved.20036.the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by     For personal use only. by guest on September 28, 2012. bloodjournal.hematologylibrary.orgFrom by cytokines and activation of monocytes by the ligand CD40. J ExpMed 178:669, 19937. Caux C, Massacrier C, Vanbervliet B, Dubois B, Van Kooten C,Durand I, Banchereau J: Activation of human dendritic cells throughCD40 cross-linking. J Exp Med 180:1263, 19948. Aloe L, Bracci-Laudiero L, Bonini S, Manni L: The expandingrole of nerve growth factor: From neurotrophic activity to immunologicdiseases. Allergy 52:883, 19979. Torcia M, Bracci-Laudiero L, Lucibello M, Nencioni L, LabardiD, Rubartelli A, Cozzolino F, Aloe G, Garaci E: Nerve growth factor isan autocrine survival factor for memory B lymphocytes. Cell 85:345,199610. Otten U, Ehrhard P, Peck R: Nerve growth factor induces growthand differentiation of human B lymphocytes. Proc Natl Acad Sci USA86:10059, 198911. Ehrhard PB, Erb P, Graumann U, Otten U: Expression of nervegrowth factor and nerve growth factor receptor tyrosine kinase Trk inactivated CD4-positive T-cell clones. Proc Natl Acad Sci USA 90:10984, 199312. Lambiase A, Bracci-Laudiero L, Bonini S, Bonini S, Starace G,D’Elios MM, De Carli M, Aloe L: Human CD41 T cell clones produceand release nerve growth factor and express high-affinity nerve growthfactor receptors. J Allergy Clin Immunol 100:408, 199713. Kindler V, Zubler RH: Memory, but not naive, peripheral bloodB lymphocytes differentiate into Ig-secreting cells after CD40 ligationand costimulation with IL-4 and the differentiation factors IL-2, IL-10,and IL-3. J Immunol 159:2085, 199714. Pantazis NJ, Blanchard MH, Arnason BG, Young M: Molecularproperties of the nerve growth factor secreted by L cells. Proc Natl AcadSci USA 74:1492, 197715. Brodie C, Gelfand EW: Functional nerve growth factor receptorson human B lymphocytes: Interaction with IL-2. J Immunol 148:3492,199216. Levi-Montalcini R: The nerve growth factor: Thirty-five yearslater. EMBO J 6:1145, 198717. Burton LE, Schmelzer CH, Szonyi E, Yedinak C, Gorrell A:Activity and biospecificity of proteolyzed forms and dimeric combina-tions of recombinant human and murine nerve growth factor. JNeurochem 59:1937, 199218. Ehrhard PB, Ganter U, Bauer J, Otten U: Expression of funcionaltrk protooncogene in human monocytes. Proc Natl Acad Sci USA90:5423, 199319. Samuelsson A, Yari F, Hinkula J, Ersoy O, Norrby E, PerssonMAA: Human antibodies from phage libraries: Neutralizing activityagainst human immunodeficiency virus type 1 equally improved afterexpression as Fab and IgG in mammalian cells. Eur J Immunol 26:3029,1996Low-Dose Interleukin-2 for Treating Postautologous Transplant Cytogenetic AbnormalityRecurrency in a Case of Acute Myeloid Leukemia With HyperdiploidyTo the Editor:Adoptive immunotherapy and/or immunostimulation may be effec-tive in treating early phases of leukemia relapsing after allogeneictransplant. Donor lymphocyte infusion (DLI) is an established treat-ment for cytogenetic relapse of chronic myeloid leukemia (CML) afterunmanipulated or T-cell–depleted bone marrow transplant (BMT)1;favorable results have also been reported in a few cases of initialposttransplant relapse of acute lymphoblastic leukemia (ALL) and acutemyeloid leukemia (AML).2 A graft-versus-leukemia (GVL) effect aspart of a manifest or occult DLI-elicited graft-versus-host disease(GVHD) is thought to be the reason for these favorable results. Forpatients who had received autologous transplant, attempts to elicit anantineoplastic effect by immunostimulation have been made using invitro interleukin-2 (IL-2)–activated autologous lymphocytes and/orIL-2 in vivo administration.3,4 We report on the successful use ofsubcutaneous (sc) low-dose IL-2 in a patient suffering from AML withrecurrence of cytogenetic abnormalities after autografting.A 56-year-old woman received diagnosis of AML French-American-British (FAB) M1 in October 1995. Hemoglobin (Hb) level was 6.7g/dL, platelet count 52 3 109/L, white blood cell count 4.3 3 109/L,with 46% blast cells. A bone marrow (BM) aspirate showed 90%medium-large sized leukemic blasts with immunophenotype CD131,CD331, CD341, HLA-DR1. Cytogenetic analysis on 24-hour culturedBM cells showed a hyperdiploid karyotype in 10 of 10 metaphases, with8 near-triploid clones (chromosome count: 71,71,71,72,72,73,75,75),having a common core XXX 11,12,13,14,15,16,17,17, 18,19,110,111,112,113,114,115,115,116,120,121,122. The patientwas induced into complete remission (CR) with the EORTC-GIMEMAAML-10 protocol, and received the scheduled consolidation coursewith some delay for a pulmonary infection. In March 1996 stem cellswere mobilized by glycosylated recombinant human granulocyte colony-stimulating factor (rhG-CSF) 10 µg/kg/d for 5 days and 2.2 3 106/kgCD341 cells were collected from peripheral blood by four aphereses.Autograft was performed in May 1996, after conditioning with BAVC(carmustine 800 mg/m2 day 26, VP-16 150 mg/m2 days 25 to 23,cytarabine 300 mg/m2 days 25 to 23, amsacrine 150 mg/m2 days 25 to23). Hematological recovery was excellent and the patient wasdischarged on day 120. Complete immunological reconstitution (nor-mal natural killer [NK] cells and CD4/CD8 ratio) was documented 8months after transplant. The patient remained in hematological andcytogenetic (46 XX) CR until May 1997, when macrocytosis (meancorpuscular volume [MCV] 105 fL) and moderate thrombocytopenia(70 3 109/L) appeared. BM showed moderate trilinear dysplasia with-out blast excess by morphology and flow cytometry; at that time NKcells and CD4/CD8 ratio were decreased. Cytogenetic analysis revealeda hyperdiploid karyotype (66-72 XXX) in 6 of 12 metaphases with thesame chromosomal abnormalities as at diagnosis. Because there wereno other signs of leukemia relapse, in July 1997 we started anoutpatient-based treatment with low-dose recombinant IL-2 (Proleukin;Chiron, Emeryville, CA), 0.9 MU/m2 sc 4 days a week. Three monthslater, the hyperdiploid clone was no longer detectable in BM (46 XX in12 of 12 metaphases). In October 1998 she was still leukemia free, witha normal karyotype (46 XX in 15 of 15 metaphases) and persistence ofdysplasia (MCV 108 fL, platelet count 69 3 109/L). Tolerance to IL-2was excellent, with a normal quality of life; no eosinophilia wasobserved. NK cells (especially the subset CD1221) increased, andCD4/CD8 ratio rapidly returned to normal. Thus, even a prolongedadministration of low-dose IL-2 seems sufficient to produce a measur-able immunostimulation. IL-2 treatment was stopped after 1 year.IL-2 has been used in recent years as maintenance treatment of AMLpatients, with discordant results5,6; the drug was usually ineffective inrelapsed or refractory AML patients, when the blast cell burden was high;whereas encouraging results were observed in a few patients with low tumorburden. High intravenous doses by continuous infusion were generally used,causing severe side effects and poor compliance to the treatment. In acontrolled trial with short infusion of high-dose IL-2 for 2 months in AMLpatients autotransplanted in first CR, no advantage was found on theprobability of relapse.7 We have used low doses of IL-2 for a prolongedperiod of time without any side effects; this treatment was followed byreversion of the recurrent cytogenetic abnormalities.4484 CORRESPONDENCE For personal use only. by guest on September 28, 2012. bloodjournal.hematologylibrary.orgFrom Hyperdiploidy is reported in 10% to 20% of childhood ALLand seems to be associated with good prognosis; it is a rare findingin AML.8 No report on the association between hyperdiploidy anddysplasia is present in the literature; in our patient, hyperdiploidyand dysplasia were probably expressions of different phenomena.Dysplasia was probably a late effect of the previous chemotherapy:it was absent at diagnosis, and persisted at relapse even after dis-appearance of hyperdiploidy. The absence of BM blastosis atcytogenetic relapse is puzzling. We may surmise that in our patientthe hyperdiploid clone was not the actual leukemic clone, butrather a preleukemic expansion of an (n-1) population from whichleukemia emerged. Even if this is the case, the immunological controlof the (n-1) clone may be of paramount importance in preventingleukemia relapse. Finally, it is possible that different forms ofleukemia may have different sensitivity to an immunologicaltreatment, depending essentially on cell-surface alterations thatcan be recognized by activated lymphocyte subsets. In this setting,a hyperdiploid clone might be a better target for an immunologicalattack, because cells may have an increased number of surfacemolecules. Thus, it may well be that immunologic treatment of alow-burden acute leukemia has selected indications, which are still to bedefined.G. De RosaL. PezzulloC. SelleriA.M. RaiolaL. LucianoM. PicardiB. RotoliDivision of HematologyFederico II UniversityNaples, ItalyREFERENCES1. Kolb HJ, Holler E: Adoptive immunotherapy with donor lympho-cyte transfusions. Curr Opin Oncol 9:139, 19972. Mehta J, Powles R, Kulkarni S, Treleaven J, Singhal S: Inductionof graft-versus-host disease as immunotherapy of leukemia relapsingafter allogeneic transplantation: single-center experience of 32 adultpatients. Bone Marrow Transplant 20:129, 19973. Benyunes MC, Higuchi C, York A, Lindgren C, Thompson JA,Buckner CD, Fefer A: Immunotherapy with interleukin-2 with orwithout lymphokine-activated killer cells after autologous bone marrowtransplantation for malignant lymphoma: a feasibility trial. BoneMarrow Transplant 16:283, 19954. Massumoto C, Benyunes MC, Sale G, Beauchamp M, York A,Thompson JA, Buckner CD, Fefer A: Close simulation of acutegraft-versus-host disease by interleukin-2 administered after autologousbone marrow transplantation for hematologic malignancy. Bone Mar-row Transplant 17:351, 19965. Meloni G, Foa R, Vignetti M, Guarini A, Fenu S, Tosti S, GillioTos A, Mandelli F: Interleukin-2 may induce prolonged remissions inadvanced acute myelogenous leukemia. Blood 84:2158, 19946. Soiffer RJ, Murray C, Gonin R, Ritz J: Effect of low-doseinterleukin-2 on disease relapse after T-cell–depleted allogeneic bonemarrow transplantation. Blood 84:964, 19947. Blaise D, Attal M, Pico JL, Reiffers J, Stoppa AM, Bellanger C,Molina L, Nedellec G, Vernant JP, Legros M, Gabus R, Huguet F,Brandely M, Hercend T, Olive D, Maraninchi D: The use of a sequentialhigh dose recombinant interleukin-2 regimen after autologous bonemarrow transplantation does not improve the disease free survival ofpatients with acute leukemia transplanted in first complete remission.Blood 87:2419, 19968. Clarke MR, Lynch EF, Cantis LC, Sherer ME, Shekhter-Levin S:Near-tetraploidy in adult acute myelogenous leukemia. Cancer GenetCytogenet 86:107, 1996Expression of AC133, a Novel Stem Cell Marker, on Human Leukemic Blasts Lacking CD342 Antigenand on a Human CD341 Leukemic Cell Line: MUTZ-2To the Editor:A novel hematopoietic stem and progenitor cell marker, monoclonalantibody (MoAb) AC133, was recently published by Miraglia et al1 andYin et al2 in the December 15, 1997 issue of Blood. AC133 recognizesonly CD34 bright and CD382 subsets of human progenitor cellsincluding colony-forming unit granulocyte macrophage (CFU-GM)needed for short-term engraftment and probably the severe combinedimmunodeficient (SCID) mouse repopulating cell.3 Investigators coulddetect AC133 in a majority of CD341 cases of acute leukemia,suggesting that it may be an early marker for human progenitor cells. Incontrast, they could not detect AC133 in the CD342 leukemic blasts of 1patient with acute myelogenous leukemia (AML) or in any of 5 humanAML cell lines, although expression was found in 3 nonhematopoieticcell lines of human origin.We investigated several human cell lines by multiparameter immuno-phenotyping using AC133-PE (Miltenyi, Bergisch Gladbach, Germany)and CD34-Cy5, CD90-FITC (Immunotech, Marseille, France). Wefound that a majority of cells of MUTZ-2 coexpressed CD34 andAC133 (Fig 1). Mutz-2 is a cell line derived from AML and displays anFAB:M2 morphology.4 This is the first known human hematopoieticcell line expressing AC133, representing a possible additional tool forexperiments concerning the function of the AC133 receptor.We also characterized expression of CD34 and AC133 in bone marrowblasts from 10 patients withAML. None of the six patients with a pure CD34negative blast population had detectable levels of AC1331 blasts. On theother hand, we saw a 53-year-old male AML patient with blasts of FAB:M4morphology and a high percentage of bone marrow infiltration (.90%leukemic blasts) who had a mixed population of CD341 and CD342 blasts(Fig 2). As expected, we found coexpression of CD34 and AC133 in 44% ofthe blast population. Only a very small population of leukemic blasts wasAC1332 and CD341. Interestingly, we could find a significant blastpopulation (18%) in which expression of AC133 was not accompanied byexpression of CD34 or CD90 (Thy-1). This first report of aCD342CD902AC1331 leukemic blast population could represent clonaldiversity of the blast population. On the other hand, it may suggest a possibledifferentiation pathway, wherein CD342CD902AC1331 cells give rise toCD341AC1331 cells. Alternatively, the CD341AC1331 blasts could beprogenitors of the CD342AC1331 cells seen in this patient. Therefore, ourfinding of a CD342AC1331 blast population raises questions about thesignificance of AC133 expression in AML. A more detailed investigation ofthe role of AC133 in AML differentiation pathways needs to be done.Karsten Kratz-AlbersMichael Zu¨hlsdorfRegine LeoWolfgang E. BerdelThomas Bu¨chnerHubert ServeDepartment of Internal MedicineDivision of Hematology and OncologyUniversity of Mu¨nsterMu¨nster, GermanyCORRESPONDENCE 4485 For personal use only. by guest on September 28, 2012. bloodjournal.hematologylibrary.orgFrom 

Low-dose interleukin-2 for treating postautologous transplant cytogenetic abnormality recurrency in a case of acute myeloid leukemia with hyperdiploidy.

Low-dose interleukin-2 for treating postautologous transplant cytogenetic abnormality recurrency in a case of acute myeloid leukemia with hyperdiploidy.

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