cough, diffuse myalgias and hypoesthesia of the left heel. transplantation after conditioning with cytoxan and. His body temperature fluctuated between 37°5C ...
Bone Marrow Transplantation, (1997) 19, 741–743 1997 Stockton Press All rights reserved 0268–3369/97 $12.00
Case report Allogeneic bone marrow transplantation for hypereosinophilic syndrome with advanced myelofibrosis A Sadoun1, L Lacotte1, V Delwail1, E Randriamalala 1, S Patri2, P Babin3, A Brizard4 and F Guilhot1 1
De´partement d’He´matologie et Oncologie Me´dicale; 2Laboratoire de Ge´ne´tique Cellulaire et Mole´culaire; 3Service d’Anatomie et Cytologie Pathologique; and 4Laboratoire d’He´matologie, CHU La Mile´trie, Poitiers, France
Summary:
Case report
A 33-year-old man with an atypical course of hypereosinophilic syndrome including malignant hypercalcemia, osteolytic lesions and evolution into severe myelofibrosis was treated by allogeneic bone marrow transplantation after conditioning with cytoxan and total body irradiation. As the transplant was sex-mismatched, chimerism was studied by means of cytogenetic analysis and Y chromosomal DNA amplification by PCR assay. Long-term complete remission has been assessed by normalization of blood cell counts, magnetic resonance imaging and karyotypic analysis. A relapse was observed 40 months after transplantation. The patient remains alive 44 months post-BMT. This case report is compared with those reported in the literature. Keywords: hypereosinophilic syndrome; allogeneic bone marrow transplantation; hypercalcemia; myelofibrosis
Clinical history
The hypereosinophilic syndrome (HES) is a heterogenous group of disorders whose common denominator is a persistent eosinophilia without detectable causes, generally associated with visceral involvement thought to be related to tissue eosinophil infiltration. While some cases are regarded as nonmalignant, others must be considered as a myeloproliferative disorder and may evolve into leukemia.1 We report a young man with an atypic course of HES including absence of multiorgan dysfunction, severe hypercalcemia with osteolytic lesions and transformation into marked myelofibrosis, who underwent allogeneic bone marrow transplantation (BMT).
Correspondence: Dr A Sadoun, De´partement d’He´matologie et Oncologie Me´dicale, CHU La Mile´trie, 86021 Poitiers, France Received 15 July 1996; accepted 8 November 1996
The diagnosis of HES was made in December 1989, in a 30-year-old man complaining of abdominal pain, diarrhea, cough, diffuse myalgias and hypoesthesia of the left heel. His body temperature fluctuated between 37°5C and 39°C. Physical examination revealed splenomegaly with the spleen 6 cm below the costal margin. Echocardiogram detected no cardiac damage. Broncho-alveolar lavage showed no eosinophilic pulmonary infiltrate. White blood cells (WBC) were 54 × 109/l with 65% eosinophils, 20% neutrophils, 1% basophils, 13% lymphocytes and 1% monocytes. The hemoglobin (Hb) was 13.7 g/dl and platelet count, 280 3 109/l. Leukocyte alkaline phosphatase score was normal. Vitamin B12 and serum alkaline phosphatase levels were respectively .1 400 pmol/l (normal: 120–680) and 274 UI/l (normal: ,220). IgE level was 553 UI/l (normal: ,100). A search for allergic, neoplastic or connective tissue diseases and tissue invasive helminths was negative. Bone marrow aspirate was hypercellular with a marked increase of eosinophils without excess of immature cells. Karyotypic analysis of bone marrow cells was 46,XY (12 mitoses). A Southern blot analysis found no BCR-ABL gene rearrangement. For 30 months, the WBC and eosinophil counts were controlled with difficulty with corticosteroids, hydroxyurea (HU), interferon alpha or courses of low-dose cytosine arabinoside. In July 1992, the patient was admitted with severe hypercalcemia (3.7 mmol/l) with osteolytic and osteosclerosing lesions revealed on pelvic and chest X-rays. The echocardiogram showed mild mitral regurgitation without damage to the atrio-ventricular valves and without cardiac failure. Electromyogram showed no peripheral neuropathy. The WBC count was 22.8 3 109/l with 64% eosinophils, Hb was 8.8 g/dl and platelet count 116 3 109/l. The serum parathyroı¨d hormone (PHT) level was 72.5 pg/ml (N: 15–60). Bone marrow biopsy was hypercellular and showed advanced myelofibrosis. Cytogenetic analysis remained normal. Since an HLA-identical sibling was available, an allogeneic BMT was performed on October 1992 after splen-
Allogeneic BMT for hypereosinophilic syndrome A Sadoun et al
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ectomy. Histologic analysis of the spleen revealed eosinophilic myeloid metaplasia. The donor was sex-mismatched, ABO matched and aged 46 years. Conditioning consisted of total body irradiation (12 Gy in 6 fractions) and cyclophosphamide (120 mg/kg over 2 days). Graft-versus-host (GVHD) and veno-occlusive disease (VOD) prophylaxes were with cyclosporin A + short methotrexate and alprostadil, respectively. Hematologic recovery was prompt with a polymorphonuclear count greater than 500/mm 3 on day 16 and stable platelet engraftment on day 15. The patient did not develop acute GVHD but limited chronic GVHD characterized by persistent lichenoid oral changes, was observed. BMT was first complicated on day 90 by a cerebral abscess of unknown etiology which resolved after treatment with broad-spectrum antibiotics including antitoxoplasmic agents, and on day 210, by a cytomegalovirus pneumonitis which resolved with a course of ganciclovir. Twenty-seven months after BMT, disseminated multiple vesicular skin lesions related to VZV infection appeared and resolved within 10 days on high-dose acyclovir. In January 1996, 40 months after transplantation, the WBC count rose to 15.6 3 109/l with 28% eosinophils and the platelet count decreased to 110 3 109/l. The patient remained asymptomatic. Cytogenetic analysis showed abnormalities including t(2;8) (q22;p23) and t(1;9) (q31;q11). HU therapy has been started again and the patient is alive and well 44 months post-BMT. Evaluation of the response In order to evaluate the residual disease, markers of HES and chimerism were studied at different times after BMT. Eosinophil counts and serum vitamin B12 levels decreased dramatically from high to normal and stable levels in 2–6 months after BMT. These two parameters and the serum alkaline phophatase levels remained completely normal until relapse. The pelvic X-ray revealed resolution of osteolytic and osteosclerosing lesions. Magnetic resonance imaging showed the disappearence of bone lesions 12 months after BMT. Bone marrow examination showed persistent hypocellularity without resolution of myelofibrosis. Surprisingly, bone marrow scintigraphy revealed axial hematopoiesis localized to the skull and backbone. Chimerism was assessed by means of cytogenetic analysis and Y chromosomal DNA-specific repeat sequence amplification by PCR assay.2 Repeated karyotypes on BM cells were performed 1, 7, 15, 20 and 34 months post-BMT and showed only 46,XX mitoses. PCR analysis was carried out from peripheral blood mononuclear cells and showed a decreasing signal until 19 months post-BMT followed by the reappearance of a high signal 34 months after transplantation (Figure 1). Discussion Allogeneic BMT has been used in very few patients with HES.3–5 The characteristics of these transplants are presented in Table 1. No cases of transplantation with advanced myelofibrosis have been reported. In all of these
A
B
C
D
E
F
M
154 Bp
Figure 1 Y chromosomal DNA amplification by PCR assay. Two hundred nanograms of DNA from buccal mucous membrane (A) or blood cells of the patient were analyzed (B: 5 months, C: 7 months, D: 19 months, E: 24 months, F: 34 months, after BMT). The size marker (lane M) is fX174-RF DNA HaeIII digest. The products were electrophoresed on a 8% polyacrylamide gel for 1 h at 160 V.
cases, HES was uncontrolled with corticosteroids and hydroxyurea. These two treatments and an attempt with interferon therapy led to partial remission in our patient but did not prevent transformation into myelofibrosis. Although repeated examination of a sufficient number of mitoses never detected any male cells, Y DNA chromosomal amplification has shown an increasing signal since the 24th month post-BMT. Since this PCR analysis was performed on a blood sample, contamination by recipient non-hematopoietic cells is unlikely. To the best of our knowledge, no other case of relapse after BMT has been reported in HES patients. As PCR assay of Y chromosomal DNA was highly positive 6 months before the relapse, the predictive value of this analysis has to be considered.6 The hypothesis that clonal expansion of a lymphocyte subset could ‘drive’ some HES has been suggested.7 Although our patient has not been examined for an underlying proliferation of clonal T cells, the cytogenetic analysis obtained from early spontaneous marrow mitoses suggests an eosinophil lineage origin. HES is very uncommonly associated with hypercalcemia. The serum PTH level was elevated in this patient but the pathogenic mechanism has not been precisely investigated. However, in other malignancies such as chronic myelogenous leukemia (CML), ectopic production of PTH and secretion of osteoclast activating factors have been implicated in the pathogenesis of hypercalcemia.8 The course of HES is very heterogeneous. Patients with a poor prognosis, for example with cardiac and neurologic manifestations or with bone marrow fibrosis with or without excess of blast cells, should be considered for allogeneic BMT. However, as occurred in this case, relapse may occur in long-term survivors after transplant. As in CML patients9 donor lymphocyte transfusions may eradicate clonal cells when minimal residual disease is detected by cytogenetic or PCR analyses. We did not undertake this cellular therapy
Allogeneic BMT for hypereosinophilic syndrome A Sadoun et al
Table 1
743
Characteristics of reported cases of allogeneic BMT for HES References Archimbaud Am J Hematol 1988
Fukushima Br J Haematol 1995
Sigmund Bone Marrow Tranplant 1995
Our case
Age at BMT (years)
26
21
29
33
Sex
Male
Male
Female
Male
Eosinophilic organ infiltration
Advanced
Non-advanced
Non-advanced
Non-advanced
BM fibrosis
Moderate
Moderate
Moderate
Advanced
Time from diagnosis to BMT
3 months
Not available
6 years
34 months
Type of BMT
Sibling
Sibling sex-mismatched
Sibling sex-mismatched
Conditioning regimen
TBI 12 Gy + CY 120 mg/kg CR
BU 16 mg/kg + CY 120 mg/kg CR
Sibling T depleted sex-mismatched TBI 12 Gy + CY 120 mg/kg CR
CR
ND
100% at d 21
100% 5 years post-BMT
100% 34 months post-BMT
ND
ND
ND
High signal 34 months post-BMT
Died on d 83 of cytomegalovirus pneumonitis
Alive and DF 1 year post-BMT
Alive and DF 5 years post-BMT
Relapsed 40 months post-BMT Alive 44 months post-BMT
Response post-BMT Chimerism Cytogenetic (percentage of donor mitoses) Y chromosomal DNA amplification by PCR assay Outcome
TBI 12 Gy + CY 120 mg/kg
CR = complete remission; ND = not done; DF = disease free; BM = bone marrow.
because the relapse was probably too advanced for this type of treatment. 4
Acknowledgements The careful manuscript preparation from Chantal Delafond is appreciated. This work was supported by grants from Association pour la Recherche sur le Cancer, Ligue Nationale Franc¸aise Contre le Cancer and Fondation Contre la Leuce´mie.
References 1 Fauci AS, Harley JB, Roberts WC et al. The idiopathic hypereosinophilic syndrome: clinical, pathophysiologic and therapeutic considerations. Ann Intern Med 1982; 97: 78–92. 2 Nakahori Y, Mitani K, Yamada M, Nakagome Y. A human Y-chromosome specific repeated DNA family (DYZ1) consists of tandem array of pentanucleotide. Nucleic Acids Res 1986; 14: 7569–7580. 3 Archimbaud E, Guyotat D, Guillaume C et al. Hypereosino-
5 6
7 8
9
philic syndrome with multiple organ dysfunction treated by allogeneic bone marrow transplantation. Am J Hematol 1988; 27: 302–303. Fukushima T, Kuriyama K, Ito H et al. Successful bone marrow transplantation for idiopathic hypereosinophilic syndrome. Br J Haematol 1995; 90: 213–215. Sigmund DA, and Flessa HC. Hypereosinophilic syndrome: successful allogeneic bone marrow transplantation. Bone Marrow Transplant 1995; 15; 647–648. Patri S, Dascalescu C, Chomel JC et al. Monitoring and prognostic evaluation of sex-mismatched bone marrow transplantation by competitive PCR on Y chromosome sequences. Bone Marrow Transplant 1996; 17: 625–632. Cogan E, Schandene´ L, Crusiaux A et al. Brief report: clonal proliferation of type 2 helper T cells in a man with the hypereosinophilic syndrome. New Engl J Med 1994; 330: 535–538. Molho P, Grange MJ, Gue´ris J et al. Hypercalcemia in chronic myelogenous leukemia: evidence for excessive paraythyroid hormone secretion. Nouv Rev Fran d’He´matol 1985; 27: 189–192. Kolb HJ, Schattenberg A, Goldman JM et al. Graft-versusleukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1990; 86: 2041–2050.
