254 Letters and Correspondence

TABLE 1. List of Ph’-Negative, BCR-ABL-Negative Patients Submitted for Screenlng Because of Suspected MPD*

I MPD involving one lineage PV 20 ET 34 MPD involving more than one lineage OMF 20 unclassified 25

111 Myeloic reaction 15 IV AML (de novo) 35

Total count 149

I1

*MPD = myeloproliferative disease; PV = polycythemia Vera; ET = essential thrombocythemia; OMF = osteomyelofibrosis; AML = acute myeloid leukemia.

vPh’ in the population from Central Europe [2], indicated 7 years ago, is still true for the population of patients with myeloproliferative diseases (MPD) submitted to our hospital.

As reports of single BCR-ABL positive but Ph’neg cases had questioned the reliability of cytogenetics in CML, RIC banding by the so-called tri- stain technique [3], which is well known for its efficiency in identifying complex marker chromosomes, proved to be the method of choice.

To date 305 cases of clinically suspected MPD have been investigated with both cytogenetic and molecular methods (Southern hybridization and PCR) in our institute. Among 156 BCR-ABL positive CMLs (all with typical rearrangements involving the so-called Mbcr region) there were 152 classical Ph+ cases and only four vPh+ cases [one t(6;9;22), one t(14;22), one t(1;9;22), and one t(9;12;22)]. No Ph’neg CML cases were observed in our institute, which also correlated to the clinical observations.

Another group of 149 patients who were both Ph’ negative and BCR- ABL negative is shown in Table 1. Thus the diagnostic value obtained with karyotyping of R/C banded chromosomes is equal to BCR-ABL determina- tion. The risk of a false diagnosis is negligible with either of these methods

ACKNOWLEDGMENTS

Thanks are due to Barbara Stogermayer for expert technical assistance. This work was supported by the Jubilaumsfonds der Osterreichischen Na- tionalbank (Projects no. 3291 and 4082).

HEIDI KARLIC ERNST E. SCHLOGL HADWIGA NOWOTNY

HELGA GRUNER ALEXANDER VALENT

HERBERT AUER RENATE HEINZ

L. Boltzmann Institute for Leukemia Research and Hematology and 3rd Medical Department, Hanusch Hospital; Institute of Biochemistry, University of Vienna, Austria

REFERENCES I . van der Plas DC, Grosveld G, Hagemeijer A: Review of clinical, cytogenetic and

molecular aspects of Ph-negative CML. Cancer Genet Cytogenet 52: 143-156, 1991.

2. De Braekeleer M: Variant Philadelphia translocations in CML: Is there an uneven geographic distribution? Cancer Genet Cytogenet 20: 185-1 86, 1986.

3. Schweizer D: Counterstain enhanced chromosome banding. Hum Genet 57:1, 1981.

Hemolytic-Uremic Syndrome in a Patient With Chronic Myelogenous Leukemia Treated With Interferon Alpha

To the Editor: A clinical disorder resembling the hemolytic-uremic syn- drome (HUS) or thrombotic thrombocytopenic purpura (TTP) has been observed in patients with disseminated cancer [ 1-51, We report here a case of HUS in a patient who was receiving therapy with interferon alpha for chronic myelogenous leukemia (CML) in its chronic phase. To our knowl- edge, this is the first case of HUS described in association with either CML or interferon alpha therapy.

A 34-year-old man presented with CML, 100% of the leukemic cells bearing the (9;22)(q34;qlI) translocation. His blood urea nitrogen (BUN) and urinalysis were normal. For 1 month he was treated with hydroxyurea (HU), but thereafter 6-mercaptopurine (6-MP) was added because of the lack of a hematologic response. Following 3 months of combined HU/ 6-MP therapy, the patient’s platelet count had risen to more than 800 X 109/L; at this point treatment was changed to interferon alpha-2h (1NF-alpha), 5 X lo6 U/day as a subcutaneous injection, each dose of INF-alpha being preceded by 1 to 2 g of acetaminophen taken by mouth. Hematologic improvement was observed during therapy with INF-alpha, but after 16 months of this treatment the patient suddently developed heacache and hypertension. The patient was found to have a BUN of 21 mg/dL and a serum creatinine of 304 p.mol/L. Urinalysis demonstrated microscopic hematuria and proteinuria (1.8 g/24 h). The patient was ane- mic (7.5 g/dL) and thrombocytopenic (150 X 109/L), and review of the peripheral blood film showed schistocytosis (48/1,000). A Coomb’s test was negative, as were serologic studies for human immunodeficiency virus and antinuclear antibodies. A renal biopsy was performed, which demon- strated extensive microvascular thrombi and glomerular necrosis. The pa- tient was treated with antihypertensive drugs and with plasmapheresis, which resulted in resolution of the patient’s symptoms, schistocytosis, and thrombocytopenia. His renal insufficiency improved hut did not resolve entirely, the BUN and serum creatinine stabilizing at 16 mg/dL and 230 pmol/L, respectively. INF-alpha therapy was discontinued and the patient was treated with HU alone for 20 months. The patient’s disease then progressed to the accelerated phase, and within another 5 months the disease was overtly blastic, with a bone marrow aspirate showing 40% of the cells to be myeloperoxidase positive myeloblasts (FAB-M2). Therapy was initiated with 6-thioguanine, cytosine arabinoside, and mitoguazone. On day 12 of chemotherapy the patient abruptly developed convulsions and distal necrosis of one finger. The patient has found to be hypertensive (220/120 mmHg), his urinalysis demonstrated microscopic hematuria and proteinuria, his renal function had deteriorated (BUN 43 mg/dL, serum creatinine 334 pmol/L), and schistocytes reappeared in the peripheral blood (5011 ,OOO). Plasmapheresis, intravenous prostacyclin, prednisone, and antihypertensive agents were used with a good clinical and biological response. He was discharged from hospital on day 32 of therapy with a normal blood pressure and improved, stable renal function (BUN 33 mg/ dL, serum creatinine 282 p.mol/L). Bone marrow aspiration showed a complete hematologic remission. Two months later, at a time when bone marrow aspiration revealed a relapse in the patient’s disease (5% myelo- blast), the patient’s HUS relapsed and was refractory to intensive therapy with plasmapheresis and antihypertensive drugs, resulting in the patient’s death.

The HUSITTP are rare but well-known complications of cancer chemo- therapy, and have been described in more than 140 cases [3]. The drug most often implicated in the pathogenesis of these microangiopathies is mitomy- cin C, either alone or in combination with doxorubicin or 5-fluorouracil [3,41. We have here reported the first case of HUS occurring in a patient with the chronic phase of CML, undergoing therapy with INF-alpha.

HUS has not been described previously as a complication of INF-alpha

Letters and Correspondence 255

was 50 mm'hr. Serum chemistry revealed normal liver function tests, creatinine and urinalysis were normal. Serology for hepatitis B, C, and HIV was negative. Bone marrow biopsy and cytogenetic analysis showed Phila- delphia chromosome positive (Ph+) chronic myeloid leukemia. The patient received 3 X lo6 U of interferon alpha-2b (Intron A, Shering Plough) given subcutaneously three times a week. After 4 weeks, she developed severe thrombocytopenia (PLT: 7 X 109/1), cutaneous and mucosal petechiae. Antiplatelet antibodies were detected using an ELISA technique.

Interferon was stopped and the patient was treated with prednisone 2 mg/kg body weight/day, hydroxyurea 1 g/day and platelet supplements. After 3 weeks the platelet count was 5 X 109/1, and the patient received high-dose immunoglobulins (400 mg/kg body weight per day for 5 consec- utive days) without increase of platelet count. The patient was then submit- ted to plasma exchange (PE) treatment. Seven PE sessions were performed in 10 days, but the platelet count did not rise (PLT: 9 X 109/1) and hemor- rhagic diathesis persisted. The patient was treated with cyclosporine 15 mg/kg/day in two divide doses for 14 days, plus prednisone 25 mg/day. One week after cessation of cyclosporine, PLT count was 48 X 109/1, and 3 weeks after it was 104 X 109/l. No significant change in blood pressure, blood urea, and creatinine has been detected; liver tests persisted normal. Three months after, the PLT count was 161 X 109/1 and no platelet antibod- ies could be detected; steroid dosage has now been reduced to 12.5 mg on alternate days. The patient showed blastic phase 18 months later and she died in February 1992 without signs of immune thrombocytopenia.

The use of alpha-interferon has been advocated on the basis of anecdotal reports of its success in the treatment of immune thrombocytopenic purpura [2], and of thrombocytopenia associated with HIV infection and hepatitis [4]. However, as an immunomodulator, alpha-interferon could exacerbate diseases that occur as a result of autoimmunity such as autoimmune he- molytic anemia, thrombocytopenic purpura, hypothyroidism, and thyro- toxicosis [ 5 ] , and there have been reports of exacerbations of autoimmune diseases associated with interferon therapy [ 5 ] . Our case illustrates that there was a clear relation between institution of alpha-interferon treatment and exacerbation of immune thrombocytopenia that has been without clini- cal symptoms for 17 years, since the patient was splenectomized.

Matthey et al. [3] reported a patient with ITP, treated with alpha-inter- feron, who subsequently showed severe purpura and bleeding. The patient proved resistant to steroid, intravenous immunoglobulins, vincristine, and cyclophosphamide and died for an intracerebral hemorrhage. In this case cyclosporine therapy was not attempted. Thrombocytopenia, in our case, was refractory to steroids, high-dose immunoglobulins, and plasma ex- change, but showed a good and durable response to a short treatment with cyclosporine.

In view of our experience we suggest caution in the use of interferon- treatment in ITP and we conclude that in severe refractory ITP, cyclospo- rine may offer a useful alternative to other treatment, and its side effects compare favourably with those of other drugs that are commonly used in this disease.

therapy. However, immune-mediated hemolysis, acute tubular necrosis, and immune-mediated nephrotic syndrome have all been associated with INF-alpha. In the case reported here, despite the withdrawal of INF-alpha the patient's HUS recurred coincident with the progression of his CML to the blastic phase. It is therefore possible that the progression of CML to acute myeloblastic leukemia may have some role in the pathogenesis of HUS in our case, for example via damaging the vascular endothelium.

DANIEL SCHLAIFER PHILIPPE DUMAZER

NATHALIE SPENAITO MADELEINE MIGNON-COME

PIERRE BROUSSET CATHERINE LUMBROSO

MIKE COOPER CATHERINE MULLER FRANCOISE HUGUET

MICHEL ATTAL GUY LAURENT JACOUES PRIS

Departments of Hematology, Hemodialysis, lNSERM U 326, Pathology, and Nephrology, H6pital de Purpan, Toulouse, France, and University of Virginia Health Sciences Center, Charlottes ville, Virginia

REFERENCES

1. Ruggenenti P, Remuzzi G: Thrombotic microangiopathies. Cr Rev Oncol Hematol 11:243, 1991.

2. Antman KH, Skarin AT, Mayer RJ, Hargreaves HK, Canellos GP: Microangio- pathic hemolytic anemia and cancer: A review. Medicine 58:377, 1979.

3. Murgo AJ: Thrombotic microangiopathy in the cancer patient including those induced by chemotherapeutic agents. Semin Hematol24:161, 1987.

4. Lesesne JB, Rothschild N, Erickson B, Korec S, Sick R, Keller J, Arbus M, Woolley PV, Chiazze L, Schein PS, Neefe JR: Cancer-associated hemolytic- uremic syndrome: Analysis of 85 cases from a national registry. J Clin Oncol 7:781, 1989.

5. Jackson AM, Rose BD, Graff LG, Jacobs JB, Schwartz JH, Strauss GM, Yang JPS, Rudnick MR, Elfenbein B, Narins RG: Thrombotic microangiopathy and renal failure associated with antineoplastic chemotherapy. Ann Intern Med 101 :41, 1984.

Severe Immune Thrombocytopenic Purpura Relapse After Alpha-Interferon in Chronic Myeloid Leukemia, Successfully Treated With Cyclosporine

To the Editor: The ability of alpha-interferon to induce hematologic and karyotypic remissions in patients with chronic myeloid leukemia (CML) has been well demonstrated [l]. Though alpha-interferon has been used also in the treatment of chronic immune thrombocytopenic purpura (ITP) [ 21, severe bleeding in ITP after alpha-interferon has been reported [3]. We report a patient with CML splenectomized 17 years earlier for ITP that showed severe refractory immune thrombocytopenia relapse after recombi- nant alpha-interferon therapy. This patient was successfully treated with cyclosporine.

A 63-year-old woman presented in November 1989 with fever and fa- tigue. ITP had been diagnosed 17 years earlier and had responded to splenectomy. She had needed no further treatment. On admission, physical examination was unremarkable, laboratory workup revealed: Hb 13g/dl, hematocrit 41%, WBC 219.3 X 109/1, (44% neutrophils, 7% promielo- cytes, 17% myelocytes, 10% metamyelocytes, 7% basophils, 5% blasts, 6% lymphocytes, 4% monocytes) and platelet count of 90 X 109/l. ESR

LUIGI CAVANNA DANIELE VALLISA

RAFFAELLA BERTE ELISABE~A BUSCARINI

FABIO FORNARI MICHELE DI STASI GIUSEPPE CIVARDI

LUIGI BUSCARINI First Department of Internal Medicine, Hematology Section, Hospital of Piacenza, Piacenza, ltaly

REFERENCES

1 . Talpaz M, Kantarjian H, McCredie K et al.: Hematologic remission and cytoge- netic improvement induced by recombinant human interferon alpha in chronic myelogenous leukemia. N Engl J Med 314:106-1069, 1986.

2. Proctor SJ, Jackson G, Carey P, et al.: Improvement of platelet counts in steroid-