Haematologica 2000; 85:212-224 scientific correspondence mal cells having a better capacity to protect themselves.2 In CML patients developing severe BM aplasia the normal progenitor cells compartment loses the ability to adapt and the BM reservoir is severely compromised. In our case the patient received hydroxyurea for only 4 weeks and developed severe aplasia ten months later. Therefore in our case IFN- played a pivotal role in the development of BM aplasia. Interestingly in our patient bcr/abl was still present despite no sign of BM function. Blastic crisis could never be documented and fibrosis by itself was not responsible for BM suppression. BM aplasia did not revert following discontinuation of the IFN-, was unresponsive to G-CSF and finally proceded to complete BM failure and death. In CML patients lacking a normal stem cell reservoir IFN- may induce hematologic response but irreversible severe aplasia can be expected. Follow-up should be rigorous also when a stable HR is achieved since patients developing BM aplasia are at high risk of treatment-related death.
Fatal bone marrow aplasia during interferon- treatment in chronic myelogenous leukemia
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Patrizia Chiusolo, Simona Sica, Luca Laurenti, Nicola Piccirillo, Giulio Giordano, Giuseppe Leone Divisione di Ematologia, Istituto di Semeiotica Medica, Università Cattolica Sacro Cuore, Rome, Italy
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Key words CML, IFN- treatment, aplasia. Correspondence Patrizia Chiusolo, M.D., Istituto di Semeiotica Medica, Policlinico Gemelli, largo Gemelli 8, 00168 Roma, Italy. Phone: international +39-06-35503953 – Fax: international +39-06-3017319 - E-mail:
[email protected]
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Sir, We describe the occurrence of fatal bone marrow (BM) aplasia in a 49-year old male with CML (Ph1p210; b3a2) during IFN- treatment. At diagnosis the patient’s leukocyte count was 233109/L (N 77, L 15, B 1, Mo 2, Eo 3, myelo- and metamyelocytes 2), hemoglobin 10.9 g/dL and platelet count 462109/L. No HLA identical donor was available. He was treated with hydroxyurea for one month followed by 9106 U of IFN- daily.1 A stable hematologic response (HR) was obtained after 4 months of IFN-. At six months 100% Ph+ metaphases were present in the BM. After 10 months of therapy, pancytopenia developed, with a leukocyte count of 2.4109/L (N 70%), platelet count of 2109/L and hemoglobin of 9.4 g/dL. IFN- was promptly discontinued. BM biopsy showed a rich cellularity, granulocytic hyperplasia constituted by metamyelocytes and granulocytes. Blasts and megakaryocytes were absent. Erythroid precursors were disorganized with a left shift. Some aspects of dyserythropoiesis and an increased amount of reticulin fibers were present. The autoantibody pattern and serology for hepatitis B, C, EBV and CMV were negative. Abdominal ultrasound showed marked hepatosplenomegaly. Karyotype analysis was impossible because of the absence of metaphases, but molecular analysis showed the persistence of bcr/abl. Despite discontinuation of IFN-, the peripheral blood count progressively worsened. A further BM biopsy showed complete disappearance of hemopoietic precursors, the presence of isolated plasma cells and lymphoid aggregates. No blasts were observed. G-CSF did not improve the polymorphonuclear cell count. The patient soon became febrile. Despite broad spectrum antibiotics and antifungal treatment he remained aplastic and died from disseminated aspergillus infection. IFN- induces HR in a large portion of patients with Ph1 CML in chronic phase; 20-40% of patients may achieve disappearance or major reduction in Ph1 metaphases in BM. Severe cytopenias associated with IFN- in CML were described by Talpaz and Shepherd3 in eight patients who sequentially received busulphan or hydroxyurea and IFN-. Three patients died from severe BM aplasia and related infection. Talpaz suggested that IFN- has a myelosuppressive effect on both normal and Ph1 progenitor cells but that these have different recovery capacities, the nor-
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Interferon- (IFN-) has been successfully employed in the treatment of several hematologic malignancies. IFN- therapy can cause a variety of long-term side effects such as thyroid dysfunction, development of other autoimmune diseases and the isolated appearance of autoantibodies. In this paper we describe the occurence of fatal bone marrow aplasia in a patient with chronic myelogenous leukemia (CML) during IFN- treatment.
Haematologica vol. 85(2):February 2000
References 1. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Long-term follow-up of the Italian trial of interferon-alpha versus conventional chemotherapy in chronic myeloid leukemia. Blood 1998; 92:1541-8. 2. Talpaz M, Kantarjian H, Kurzrock R, Gutterman JU. Bone marrow hypoplasia and aplasia complicating interferon therapy for chronic myelogenous leukemia. Cancer 1992; 62:410-2. 3. Shepherd PCA, Richards S, Allan N.C. Severe cytopenias associated with the sequential use of busulphan and interpheron-alpha in chronic myeloid leukemia. Br J Haematol 1994; 86:92-6.
Does interferon- exert an anti-leukemic effect by enhancing cell mediated immunity in chronic myeloid leukemia? Three patients with chronic myeloid leukemia (CML) in complete cytogenetic remission under interferon- (IFN-) therapy displayed a relevant lymphocytosis (20-25%) on their bone marrow biopsy. The immunohistochemistry characterization revealed a polyclonal B and T-cell component with moderate increase of CD8+ lymphocytes. These findings support the hypothesis that IFN- elicits an autologous cellular mediated immunity against CML cells.
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components with a moderate increase in CD8 cells. These findings may further support the hypothesis that IFN- elicits an autologous cell-mediated immunity against CML cells. Pietro Muretto, Silvia Tomassoni, Maria Pia Staccioli, Laura Tabellini,* Francesca D’Adamo,* Costante Delfini* Servizio di Anatomia Patologica; *Divisione di Ematologia, Ospedale S. Salvatore, Pesaro, Italy
Key words CML, IFN-, cell mediated immunity. Acknowledgments Work supported by AIL, Pesaro, Italy.
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Correspondence Costante Delfini, M.D., Divisione di Ematologia, Azienda Ospedaliera San Salvatore, 61100 Pesaro, Italy. Phone: international +39-0721-364074 – Fax: international +390721-364057 – E-mail:
[email protected]
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1. Stiehm ER, Kronenberg LH, Rosenblatt HM, Brison Y, Merigan TC. UCLA conference. Interferon: immunobiology and clinical significance. Ann Intern Med 1982; 96:80-93. 2. Einhorn S, Blomgren H, Strander H. Interferon and spontaneous cytotoxicity in man: I. Enhancement of the spontaneous cytotoxicity of peripheral lymphocytes by human leukocyte interferon. Int J Cancer 1978; 22:405-12. 3. Carella AM, Frassoni F, Melo J, et al. New insights in biology and current therapeutic options for patients with chronic myelogenous leukemia. Haematologica1997; 82:478-95. 4. The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Long-term follow-up of the Italian trial of interferon-alpha versus conventional chemotherapy in chronic myeloid leukemia. Blood 1998; 92: 1541-8. 5. Gordon MY, Dowding CR, Riley GP, Goldman JM, Greaves MF. Altered adhesive interaction with marrow stroma of hematopoietic progenitor cells in chronic myeloid leukemia. Nature 1987; 328:342-4. 6. Bathia R, McCarthy JB, Verfaille CM. Interferon- restores normal 1 integrin-mediated inhibition of hematopoietic progenitor proliferation by the marrow microenvironment in chronic myelogenous leukemia. Blood 1996; 87:3883-91. 7. Teichmann JV, Ludwig WD, Thiel E. Cytotoxicity of IL2 induced lymphokine activated killer (LAK) cells against human leukemia and augmentation of killing by interferon and tumor necrosis factor. Leukemia Res 1992; 16:287-98. 8. Cervantes F, Pierson BA, McGlave PB, Verfaillie CM, Miller JS. Autologous activated natural killer cells suppress primitive chronic myelogenous leukemia progenitors in long-term culture. Blood 1996; 87:2476-85. 9. Luft T, Pang KC, Thomas E, et al. Type I IFNs enhance the terminal differentiation of dendritic cells. J Immunol 1998; 161:1947-53. 10. Choudhury A, Gajewski JL, Liang JC, et al. Use of leukemic dendritic cells for the generation of antileukemic cellular cytotoxicity against Philadelphia chromosome-positive chronic myelogenous leukemia. Blood 1997; 89:1133-42.
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Sir, Interferons have several effects on cell mediated immunity, including inhibition of lymphocyte proliferation and DNA synthesis after activation by lectins, antigens and allogenic cells.1 On the other hand, interferons enhance target-specific T-cell cytotoxicity and spontaneous and natural killer activity both in vitro and in vivo, in murine and in human systems.2 Interferon- (IFN-) induces cytogenetic remissions in patients with chronic myeloid leukemia (CML)3 and prolongs survival.4 One of the mechanisms by which IFN- restores, at least in part, normal hemopoietic function relates to the adhesion defect of CML cells.5 IFN-, by restoring normal 1-integrin ihibitory effect on CML hematopoietic progenitors induces the adhesion of malignant hemopoietic progenitors, to the marrow microenviroment and also causes microenviromental inhibition of CML progenitor proliferation.6 However, the mechanisms underlying the defect in 1integrin and how this latter’s effect is restored after IFN- treatment remain elusive and it is conceivable that other unrecognized mechanisms may also be relevant in the recovery of normal hematopoiesis in CML. IFN- treatment restores lymphokine activated killer (LAK) cytotoxicity against CML cells.7 It was recently found that autologous IL-2 activated natural killer (ANK) cells suppress malignant hematopoiesis in CML.8 Interestingly, IFN- enhances the terminal differentiation of dendritic cells9 which appear to be efficient antigen presenting cells capable of inducing a Tcell-mediated cytotoxicity against the leukemic cells.10 Taken together these studies indicate that IFN- may directly or indirectly cause cell-mediated cytotoxicity against CML cells. We found that three patients, aged 43, 46, 53 years, with CML in continuous complete cytogenetic response (100% Ph1 negativity) who had been receiving IFN- therapy (3 to 9 MIU daily) for 1 to 5 years, displayed unexpected lymphocytosis (2025%) in their bone marrow biopsy (Figure 1). Reexamination of the initial marrow biopsy before starting IFN- treatment did not reveal any lymphoid nodules. The immunohistochemical characterization of the lymphocytes revealed polyclonal B- and T-cell
Figure 1. Bone marrow biopsy of a patient with CML in complete cytogenetic remisssion after treatment with IFN-. A normal hemopoietic cell component is apparent with lymphocytosis, sometimes assembled in nodular clusters (Hematoxylin-eosin, 200).
Haematologica vol. 85(2):February 2000
