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Correspondence

Langerhans cell histiocytosis following acute leukemia in an adult To the editor: A 69-year-old man presents with cough and SOB approximately 3.5 years following diagnosis of a poorly differentiated acute lymphocytic leukemia (progenitor cell phenotype). By flow cytometry, the initial leukemia in 1998 was positive for HLA-DR, CD34, and CD45 and negative for lymphoid and myeloid markers including: CD3, CD5, CD7, CD19, CD10, CD20, CD13, CD33, CD11b, and CD14; CD1a and S-100 protein staining were not available on this sample. A pathologic diagnosis of a progenitor cell leukemia most suggestive of acute lymphocytic leukemia was made. The patient received induction therapy in November 1998 and achieved a complete remission. Consolidation therapy was discontinued after one cycle due to severe cytopenias. Maintenance therapy was discontinued after 6 months secondary to methotrexate-induced hepatoxicity. Approximately 3.5 years after the initial diagnosis, the patient presented with back pain and leg weakness and found to have a paraspinal mass with cord compression. He underwent surgical resection followed by consolidative radiation. The lesion (see Fig. 1) was composed of sheets of medium to large sized mitotically active cells with relatively abundant cytoplasm. Occasional multinucleated tumor giant cells were also identified. The cell nuclei were vesicular with irregular contour and occasional grooves. Considering the remote history of a lymphocytic leukemia and the morphologic features which raised the possibility of an epithelioid/dendritic cell neoplasm, a panel of immunohistochemical stains was used to characterize the lesion. The tumor cells were positive for vimentin, CD1a, S-100 protein, CD43 and focally for keratins, CD45, CD68, and lysozyme. Negative immunostains included EMA, Melan-A, CD3, CD20, CD21, CD35, Kappa and Lambda light chains, and MPO. Leder’s histochemical stain was negative. Based on the morphology and the immunohistochemical profile, a diagnosis of a dendritic cell neoplasm most consistent with Langerhans cell sarcoma was rendered. Electron microscopic studies were not performed. Bone marrow biopsy revealed trilineage hematopoiesis with no evidence of leukemic involvement. Approximately 2 months later, he developed a similar soft tissue mass in the right upper chest extending into the right supraclavicular area. Radiation treatment resulted in a complete clinical response in the chest mass and he had no evidence of progression for 1 year. The patient then developed shortness of breath and fevers. A CXR showed a right

Fig. 1. Infiltrate of atypical cells with occasional grooved nuclei and with scattered multinucleated cells. Insert shows that the tumor cells are positive for CD1a. [Color figure can be viewed in the online issue, which is available at www.interscience. wiley.com.]

upper lobe infiltrate. A bronchoscopy was performed and biopsy specimens showed LCH. The patient was treated with a course of Cladribine, but did not respond. The patient died from pulmonary complications of LCH. The morphologic features of the para spinal lesion and the autopsy lesions (in the lungs, thyroid, and multiple intra-abdominal lymph nodes) were similar. Langerhans cell histiocytosis (LCH) is a rare disorder involving the proliferation of the specialized langerhans histiocyte normally found primarily in the skin. LCH affects children in 66–90% of case reports and has an incidence in adults of 1–2 per million population based on case series [1–3]. LCH has been associated with malignancy, including malignant lymphoma and solid tumors in adults and children [3]. While LCH has been associated with acute leukemia, a literature review reveals only 15 cases where LCH occurred after acute leukemia; all but one case were in children [4,5,6,11]. LCH, formerly histiocytosis X, is a clonal proliferative disease, however, the pathogenesis remains unclear [3]. The disease ranges in severity and presentation and can affect virtually any organ system [2]. Diagnosis of LCH depends on the identification of the tumor cells. These cells are antigen presenting and express HLA-DR and CD1a. Langerhans cells have characteristic HX bodies (Birbeck granules) in the cytoplasm [3]. LCH is associated with a variety of neoplasms and chemotherapy. In one study of 47 patients over the age of 15, 17% had an associated hematological or solid tumor [7]. Of the cases currently reviewed in the literature, the relationship between malignancy and LCH remains unclear as LCH may precede, develop concurrently, or as in this case, develop after malignancy. The relationship between LCH and ALL may be explained by several mechanisms including a chance occurrence, treatment induced effect, a common progenitor cell, or a cytokine-mediated phenomenon. A registry of patients in whom LCH was associated with malignancy was established in 1991. LCH was most frequently associated with malignant lymphoma, leukemia, and lung carcinoma. A series looking at LCH in adults included an association with breast cancer as well [7]. The first review of the registry, in 1994, included 91 patients with LCH associated with malignancy. Of those 91 patients, five patients had LCH associated with ALL. In four of the five cases, ALL preceded the diagnosis of LCH by 6–12 months [6]. A later review of the registry included an additional seven cases of LCH preceded by ALL. In each of the seven cases, LCH was diagnosed while the patients were receiving chemotherapy [5]. Only patients less than 18 years of age at the time of diagnosis were included in the report, excluding two patients with LCH associated with malignancy ages 75 and 79. The time course in these cases suggests a chemotherapy-related pathogenesis of LCH either by chemo induced mutagenesis or immunosuppression. Raj et al. describe a case of a 7-year-old male who developed LCH 2 years after the completion of chemotherapy for ALL [8]. This time frame suggests that development of LCH was not related to immunosuppression. In support of this hypothesis, Raj et al. demonstrated that the standard tests for T- and B-cell function in their patient were normal [8]. More recent reports also support an alternative pathogenesis of LCH developing after ALL. Feldman et al. report on two cases of LCH developing after ALL in children. They demonstrate a clonal relationship between the two neoplasms in each patient with identical T-cell receptor rearrangements [9]. A follow-up study by Rodig et al. in these two patients investigating a role for NOTCH1 did not show evidence to suggest that the lineage switch was mediated through NOTCH1 down regulation [12]. However, progenitor cells with lymphoid and dendric cell potential remains a likely mechanism for the observed relationship of these two neoplasms. While NOTCH1 expression is known to influence cell fate, there are other epigenetic factors that play a role including the cytokine environment. Interestingly, Ko et al. describe two cases of LCH and T-lymphoblastic lymphoma in the same lymph node both of which were CD561. The Feldman cases were also CD561, although most LCH are not CD561 [9,10]. CD56 function in hematopoietic cells is unclear. Much of the literature regarding LCH and malignancy relies on pediatric populations. As noted by Tavernier et al., because adult patients with ALL

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correspondence have a poorer prognosis than children and have more comorbidities at the time of diagnosis and treatment, subsequent development of second malignancies is likely underestimated [11]. Tavernier reports on at least one other adult patient with ALL from the LALA-87 and LALA-94 trials who subsequently developed LCH. In our case, the diagnosis of a Langerhans cell tumor was based on morphologic features supported by immunohistochemical staining with CD1a and S-100. The pathological diagnosis rendered in this case was based on the criteria adopted by the International Lymphoma Study Group [1]. Up to now, to the best of our knowledge, there is only one other reported case of LCH developing in an adult after diagnosis of ALL. While these cases may represent a chance occurrence, given that the association of LCH and ALL has been explored in pediatric populations and secondary malignancies in adults with ALL are likely underestimated, further investigation of LCH and ALL in adults seems warranted. Further investigation of future cases with thorough investigation of genetic mutations cell surface receptor expression may help elucidate the pathogenesis of these cancers.

REBECCA HIRSH DILIP GIRI ROGERS GRIFFITH RICHARD STONE NEAL READY Clinical Fellow Hematology Oncology Columbia University Medical Center Conflicts of interest: Nothing to report. Published online 6 July 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ajh.21490

References 1. Pileri SA, Grogan TM, Harris NL, et al. Tumors of histiocytes and accessory dendritic cells: An immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases. Histopathology 2002;41:1–29. 2. Baumgartner I, von Hochstetter A, Baumert B, et al. Langerhan’s cell histiocytosis in adults. Med Pediatr Oncol 1997;28:9–14. 3. Willman CL, Busque L, Griffith BB, et al. Langerhans’ cell histiocytosis (histiocytosis X)—A clonal proliferative disease. N Engl J Med 1994;331:154–160. 4. Egeler RM, Neglia JP, Puccetti DM, et al. Association of Langerhans cell histiocytosis with malignant neoplasms. Cancer 1993;71:865–873. 5. Egeler RM, Neglia JP, Arico M, et al. The relation of Langerhans cell histiocytosis to acute leukemia, lymphomas, and other solid tumors: The LCH Malignancy Study Group of the Histiocyte Society. Hematol Oncol Clin North Am 1998;12:369–378. 6. Egeler RM, Neglia JP, Arico M, et al. Acute Leukemia in association with Langerhans cell histiocytosis. Med Pediatr Oncol 1994;23:81–85. 7. Malpas JS, Norton AJ. Langerhans cell histiocytosis in the adult. Med Paediatr Oncol 1996;27:540–546. 8. Raj A, Bendon R, Moriarty T, et al. Langerhans cell histiocytosis following acute lyphoblastic leukemia. Am J Hematol 2001;68:284–286. 9. Feldman A, Berthold F, Arceci RJ, et al. Clonal relationship between precursor T-lymphoblastic leukaemia/lymphoma and Langerhans-cell histiocytosis. Lancet Oncol 2005;6:435–437. 10. Ko YH, Kim WS, Kim Y. Expression of CD56 antigen in Langerhans cell histiocytosis associated with T-lymphoblastic lymphoma in a same lymph node. Virchows Arch 2006;448:90–94. 11. Tavernier E, Le QH, de Botton S, et al. Secondary or concomitant neoplasms among adults diagnosed with acute lymphoblastic leukemia and treated according to the LALA-87 and LALA-94 trials. Cancer 2007;110: 2747–2755. 12. Rodig SJ, Payne EG, Degar BA, et al. Aggressive Langerhans cell histiocytosis following T-ALL: Clonal related neoplasms with persistent expression of constitutively active NOTCH1. Am J Hematol 2008;83:116–121.

Treatment of multiple myeloma in patients with Gaucher disease

munoglobulin profile and clonality for patients with GD older than 50 years of age and every other year for patients younger than 50 years [4]. If monoclonal protein (M-protein) is found, bone marrow biopsy and aspirate should be performed, alongside with cytogenetic analysis of plasma cells. However, it is not known which, if any, of the standard or investigational protocols for treating myeloma in the general population can lead to reproducibly favorable outcomes in patients with GD. We present a case of myeloma in a patient with N370S/L444P GD, with details of the applied treatment and outcome. A critical review of published results of myeloma therapy in GD is also provided. A Swedish male was splenectomized in 1958, at the age of 32 years, due to massive splenomegaly and thrombocytopenia (platelet count 42 3 109/L). Histopathology of the spleen disclosed GD. In 1986, at the age of 60 years, the patient developed monoclonal gammopathy of undetermined significance (MGUS) of IgG-lambda type. Fifteen years later, in 2001, he was referred to hematologist because of serum M-protein increase to 34 g/L. Laboratory investigations showed Hb 103 g/L, WBC 6.0 3 109/L, platelet count 139 3 109/L, b2-microglobulin 5.2 mg/L, and normal levels of serum albumin, creatinine, and calcium. Bone marrow (BM) examination disclosed 17% plasma cells and 40% Gaucher cells. The cited plasma cell count is expressed as the percentage of hematopoietic cells only; Gaucher cell burden was assessed in the trephine biopsy, as the percentage of all nonfatty cells in the BM. BM cytogenetics revealed t(11;14), and further immunohistochemistry confirmed that approximately 50% of plasma cells expressed cyclin-D1. The patient had no skeletal pain, and skeletal X-ray did not show any lesions typical for myeloma. The patient’s disease was classified as IgGlambda myeloma (stage I A), without indications for treatment. Four years later, in 2005, the patient developed painful peripheral neuropathy in both legs and skin lesions diagnosed as leukocytoclastic vasculitis. M-protein began to rise, reaching 49 g/L in December 2006, followed by the progress of thrombocytopenia (platelet count 54 3 109/L). Possible relationship between patient’s myeloma and worsening of thrombocytopenia and peripheral neuropathy was considered, leading to a cautious initiation of oral MP treatment: melphalan (20 mg/d, days 1–2; reduced 50%) and prednisone (150 mg/d, days 1–4) given every sixth week. After the first MP course, 29% reduction of M-protein to 35 g/L was obtained but no further Mprotein regress was noted despite two more MP courses. The treatment had no impact on the peripheral neuropathy or the skin lesions. Moreover, after the third MP course the platelet count decreased permanently to 10–25 3 109/L and treatment was ceased. One year later, M-protein was stable (32 g/L) but the patient became transfusion-dependent for both platelets and RBC. BM examination in February 2008 revealed dysplastic features in two series (mild dyserythropoiesis and dysmyelopoiesis), which were however not significant, with only 4% plasma cells. Cytogenetic investigation disclosed normal karyotype, but FISH was positive for t(11;14). The patient initially refused the proposed enzyme replacement therapy (ERT) with imiglucerase infusions, so the substrate reduction therapy with oral miglustat (300 mg/d) was administered. Miglustat was well tolerated but did not influence the level of thrombocytopenia or anemia. After 10 weeks, the patient changed his mind and treatment with imiglucerase (60 U/kg/14 d) was initiated. Nevertheless, combination therapy was continued in hope to achieve as rapid reduction in the BM Gaucher cell burden as possible. In June 2008, diagnosis of MDS RAEB-2 (refractory anemia with excess of blasts type 2) was established based on significant dysplastic features in two hematopoietic series, 11–16% blasts in BM and 3% blasts in peripheral blood. At that time, there were 13% plasma cells and 40% Gaucher cells in BM. Cytogenetic analysis of BM did not reveal any new abnormalities. Seven months after the initiation of GD therapy, the patient still remained transfusion-dependent. Shortly afterwards, transformation to acute myeloid leukemia occurred and the patient deceased. We think that melphalan treatment could have probably played a role in the development of MDS in our patient. However, it is difficult to assess if it was the only causative factor. It is known that concentration of glycosphingo-

To the editor: Several studies have reported an increased incidence of multiple myeloma in patients with type 1 Gaucher disease (GD) [1–3]. Available data requires attention of all physicians dealing with GD to the signs of myeloma in patients with GD. Current guidelines for the management of the hematological aspects of GD recommend annual control of im-

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lipids other than glucocerebroside may be increased in GD. Some of these lipids may be able to act as signaling molecules or transcription factors that could conceivably alter early pluripotent hematopoietic stem cells in some patients, which could result in the development of B-cell dyscrasias, MDS, and leukemia.


correspondence TABLE I. Published Reports on Results of Myeloma Therapy in Gaucher Disease Sex/age

GD genotype

Sx

ERT

F/66

n.g.

N

N

F/58

N370S/L444P

Y

F/57

N370S/L444P

N

Myeloma type

Therapy

Response

IgG-kappa

MP

SD

N

IgG-lambda

N

Lambda light chain

MP VAD VAD MEL200 and APSCT

Progress after 4 MP n.g. CR Relapse within 3 months after APSCT Died 3 months after myeloma diagnosis due to heart failure

M/55

n.g.

N

Y

Kappa light chain (progression from MGUS)

M/61

n.g.

Y

Y

IgG-kappa

M/80

N370S/L444P

Y

N

IgG-lambda (progression from MGUS)

DXM

Complications Prolonged pancytopenia

Miller et al. [5] Harder et al. [6] Cheung et al. [7]

Prolonged severe thrombocytopenia; renal failure de Fost et al. [8]

MP (reduced) Thalidomide MP (reduced)

Reference

Favorable SD

Unacceptable pancytopenia

de Fost et al. [8]

Prolonged severe thrombocytopenia; myelodysplasia (?)

Machaczka et al. [this report]

Sx, splenectomy; ERT, enzyme replacement therapy; Y, yes; N, no; n.g., not given; SD, stable disease; CR, complete response; MP, melphalan and prednisone; DXM, dexamethason; VAD, vincristine, adriamycin, DXM; MEL200, conditioning with melphalan 200 mg/m2; APSCT, autologous peripheral stem cell transplantation.

There are virtually no published guidelines on optimal treatment strategies in patients with GD who develop myeloma. We could identify only four published reports [5–8] including important details on the outcome of myeloma therapy in a total of five patients with GD (Table I). A striking observation is the serious and persistent myelotoxicity of melphalan-based regimens (even if dose-reduced), with only moderate and temporary efficacy at the same time. This is a surprising finding given that this alkylating agent is otherwise considered safe and effective in myeloma therapy. We speculate that Gaucher cells in BM may have increased hematopoietic stem cells’ vulnerability to melphalan treatment in some unknown mechanism. Based on the same reports, VAD and Thalidomide were better tolerated and in two described cases produced remission [7,8]. The use of newer myeloma agents (bortezomib, lenalidomide) have never been reported in GD context. Bortezomib is the first agent targeting the proteasome, which results in the disruption of multiple pathways and checkpoints in the cell cycle, ultimately leading to apoptosis. However, ER oxidative stress due to protein misfolding and proteasome overload has been suggested as possible contribuent, the effect of which adds to GD-related changes. Bortezomib might theoretically enhance this pathway and its own toxicities might be increased in patients with GD. The optimal myeloma therapy for advanced disease remains poorly defined. In general population, consolidation with one or two cycles of high-dose chemotherapy and autologous hematopoietic cell transplantation (HCT) has been considered optimal treatment for advanced stage myeloma for patients younger than 65 years of age. Autologous HCT have been previously successfully performed in patients with GD; however, difficulties with engraftment were described in recently published case of autologous HCT for relapsed non-Hodgkin’s lymphoma in 69-year-old male with naı¨ve N370S/N370S GD [9]. Initiation of imiglucerase therapy has effectively circumvented graft failure and the patient became transfusion independent. Long-lasting remissions and possible cures have been reported in myeloma patients who received allogeneic HCT. A graft-versus-myeloma (GVM) effect of donor T-cells, the phenomenon which is absent after autologous HCT, may provide long-term disease control. Encouraging data on nonmyeloablative HLA-identical sibling allogeneic HCT after autologous HCT has been recently reported [10,11]. On the other hand, long-term follow-up results of allogeneic HCT in GD performed in Sweden in the preERT era (before 1991), revealed effective engraftment and durable curative effect of allogeneic HCT on GD [12]. Our currently updated, but not published, data indicates that particularly favorable outcome can be achieved in patients with GD who were transplanted from HLA-identical siblings. The authors believe that, when discussing possible therapeutic options for advanced stage myeloma in patients with GD, allogeneic HCT from HLAidentical sibling donor should be considered in eligible younger patients. Such an approach has a curative potential in both entities: myeloma and GD.


MGUS may emerge even in patients with clinically very mild GD. An intriguing question is whether early institution of ERT would prevent the development of MGUS in patients with GD. Yet, there is no evidence to support this hypothesis. Brautbar et al. found a decrease in immunoglobulin levels during ERT, although only in cases with a polyclonal gammopathy [13]. Results of the same study showed that in five patients with GD with MGUS ERT does not eliminate or even decrease M-protein level once it appears. However, data from the study published by de Fost et al. suggest a beneficial effect of ERT in preventing the occurrence and the progression of gammopathies inclusive MGUS [8]. The question whether early institution of ERT after MGUS detection can decrease the likelihood of transformation to myeloma still remains open. Another important issue relates to the role and the timing of ERT with regard to myeloma outcome in previously naı¨ve patients with GD. Published cases of chemotherapy in patients with GD suffering from different cancers suggest better tolerance of cytotoxic drugs with less side effects when on ERT [8,14–18]. ERT may attribute to a better tolerability of chemotherapy by reducing GD burden in BM and improving function of macrophages (and in consequence of the entire immune system). Therefore, we propose to initiate ERT directly after establishing the diagnosis of myeloma in all naı¨ve patients with GD eligible for myeloma therapy.

MACIEJ MACHACZKA1 RICHARD LERNER1 MONIKA KLIMKOWSKA 2 HANS HA¨GGLUND1 1

Hematology Center, Karolinska University Hospital Huddinge, Stockholm, Sweden Department of Pathology, Karolinska University Hospital Huddinge, Stockholm, Sweden Conflicts of interest: Nothing to report. Published online 6 July 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ajh.21492 2

References 1. Rosenbloom BE, Weinreb NJ, Zimran A, et al. Gaucher disease and cancer incidence: A study from the Gaucher Registry. Blood 2005;105:4569–4572. 2. de Fost M, vom Dahl S, Weverling GJ, et al. Increased incidence of cancer in adult Gaucher disease in Western Europe. Blood Cells Mol Dis 2006;36:53– 58. 3. Taddei TH, Kacena KA, Yang M, et al. The underrecognized progressive nature of N370S Gaucher disease and assessment of cancer risk in 403 patients. Am J Hematol 2009;84:208–214. 4. Hughes D, Cappellini MD, Berger M, et al. Recommendations for the management of the haematological and onco-haematological aspects of Gaucher disease. Br J Haematol 2007;138:676–686.

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correspondence 5. Miller W, Lamon JM, Tavassoli M, et al. Multiple myeloma complicating Gaucher’s disease. West J Med 1982;136:122–128. 6. Harder H, Eucker J, Zang C, et al. Coincidence of Gaucher’s disease due to 1226G/1448C mutation and of an immunoglobulin G lambda multiple myeloma with Bence-Jones proteinuria. Ann Hematol 2000;79:640–643. 7. Cheung WY, Greenberg CR, Bernstein K, et al. Type I Gaucher disease following chemotherapy for light chain multiple myeloma. Intern Med 2007; 46:1255–1258. 8. de Fost M, Out TA, de Wilde FA, et al. Immunoglobulin and free light chain abnormalities in Gaucher disease type I: Data from an adult cohort of 63 patients and review of the literature. Ann Hematol 2008;87:439–449. 9. Carreiro J, Balwani M, Grosskreutz C, et al. A case report of secondary autograft failure due to Gaucher disease. Am J Hematol 2008;83:937. 10. Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Eng J Med 2007;356:1110–1120. 11. Rotta M, Storer BE, Sahebi F, et al. Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting. Blood 2009;113:3383–3391. 12. Ringden O, Groth CG, Erikson A, et al. Ten years’ experience of bone marrow transplantation for Gaucher disease. Transplantation 1995;59:864– 870. 13. Brautbar A, Elstein D, Pines G, et al. Effect of enzyme replacement therapy on gammopathies in Gaucher disease. Blood Cells Mol Dis 2004;32:214– 217. 14. Petrides PE, leCoutre P, Mu¨ller-Ho¨cker J, et al. Coincidence of Gaucher’s disease due to a private mutation and Ph’ positive chronic myeloid leukaemia. Am J Hematol 1998;59:87–90. 15. Bo¨hm P, Kunz W, Horny H-P, Einsele H. Adult Gaucher disease in association with primary malignant bone tumors. Cancer 2001;91:457–462. 16. Manz M, Riessen R, Poll L, et al. High-grade lymphoma mimicking bone crisis in Gaucher’s disease. Br J Haematol 2001;113:191–193. 17. Brody JD, Advani R, Shin LK, et al. Splenic diffuse large B-cell lymphoma in a patient with type 1 Gaucher disease: Diagnostic and therapeutic challenges. Ann Hematol 2006;85:817–820. 18. Leone JP, Dudek AZ. Enzyme replacement therapy for Gaucher’s disease in patient treated for non-small cell lung cancer. Anticancer Res 2008;28:3937– 3939.

Two cases of pegylated asparaginase-associated severe and persistent hyperbilirubinemia

before the administration of second dose of pegaspargase) and reached its highest at 10.2 mg/dL on day 33. Magnetic resonance cholangiopancreatography (MRCP) test on day 32 revealed hepatomegaly with diffuse hepatic steatosis without biliary dilatation or choledocholithiasis. Normalization of bilirubin level occurred on day 64. During the induction therapy, she had well tolerated all six doses of L-asparaginase given as 6,000 IU/ m2/dose subcutaneously other than a local injection site reaction observed with the sixth dose. The second patient was an 81-year-old female with pre-B-cell ALL whose total bilirubin level increased to 0.5–19.5 mg/dL following one dose of pegaspargase therapy. Pegaspargase was administered as 2,500 mg/m2 IV, in combination with multiple chemotherapeutic agents, including vincristine, daunorubicin, and corticosteroid. On day 34, total bilirubin level reached its highest at 19.5 mg/dL. MRCP test on day 21 revealed diffuse hepatic steatosis without hepatomegaly, biliary dilatation, or choledocholithiasis. Complete resolution of hyperbilirubinemia took place on day 77. Although the incidence of mild to moderate hyperbilirubinemia is common with asparaginase therapy, mechanism for the associated hepatotoxicity is not yet clearly understood. To date, at least one case report and a case series have described fatal hepatotoxicities associated with asparaginase therapy [2,3], and L-asparaginase was the associated agent in each of these reported cases, with the exception of one patient who died with a relapsed ALL 6 months after receiving a total of 10 doses of pegaspargase at 6,000 IU/m2, which is more than twice the standard dose; the cause of death in this patient, however, appears to be attributable to the relapsed disease rather than pegaspargase therapy. Aside from the aforementioned case, to my knowledge, this is the first case series that describe potentially fatal hyperbilirubinemia associated with pegaspargase therapy. Although I believe pegaspargase is the causative agent for the severe hyperbilirubinemia in our patients, other concurrently administered agents cannot be completely ruled out for the observed toxicity. Nevertheless, with the increasing use of pegaspargase, clinicians should be aware of the potentially life-threatening hyperbilirubinemia, which can persist for a prolonged period of time (upto 77 days) as we have observed in our patients.

SARA KIM To the editor: Pegaspargase is a PEGylated formulation of asparaginase that was designed to prolong its serum half-life and to lower both the immunogenecity, and the adverse events of asparaginase (i.e. coagulopathy, pancreatitis, hyperglycemia, hepatotoxicity, and hypersensitivity reactions) [1]. Asparaginase can be isolated from Escherichia coli [L-asparaginase (Elspar1); Pegaspargase (Oncaspar1)] or Erwinia chrysanthemia (Erwinia, an investigational agent in U.S). Here we report two patients with acute lymphocytic leukemia (ALL), both of whom developed a prolonged and severe hyperbilirubinemia following pegaspargase therapy (Table I). The first patient was a 42-year-old female with pre-B-cell ALL, who underwent a consolidation therapy and developed a grade 4 hyperbilirubinemia after receiving two doses of pegaspargase therapy as 2,000 mg/m2 IV. Concurrently administered agents included vincristine, daunorubicin, and corticosteroid. Her total bilirubin level was elevated to 0.6–2.6 mg/dL on day 17 (immediately

Department of Pharmacy, The Mount Sinai Medical Center One Gustave L. Levy Place, Box 1211, New York Conflicts of interest: Nothing to report. Published online 6 July 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ajh.21493

References 1. Asselin BL, Whitin JC, Coppola DJ, et al. Comparative pharmacokinetic studies of the asparaginase preparations. J Clin Oncol 1993;11:1780–1786. 2. Sahoo S, Hart J. Histopathological features of L-asparaginase-induced liver disease. Semin Liver Dis 2003;23:295–299. 3. Bodmer M, Sulz M, Stadlmann S, et al. Fatal liver failures in an adult patient with acute lymphoblastic leukemia following treatment with L-asparaginase. Digestion 2006;74:28–32.

TABLE I. Two Cases of Pegylated Asparaginase-Associated Hepatotoxity LFTs (units) Time Case 1 8/6/08 (Day 1): first dose of pegaspargase 8/22/08 (Day 17): second dose of pegaspargase 9/7/08 (Day 33) 10/8/08 (Day 64) Case 2 8/21/08 (Day 1): pegaspargase 9/23/08 (Day 34) 11/5/08 (Day 77)

T.bil/D.bil (mg/dL)

ALT (U/L)

AST (U/L)

GGT (U/L)

ALP (U/L)

LDH (U/L)

0.6/0.1 2.6/1.9 10.2/8 1/0.5

22 201 72 55

18 97 143 53

27 1129 608 54

72 456 274 72

312 545 475 314

0.5/0.2 19.5/18.8 1/0.5

72 363 28

26 268 29

247 1533 n/a

124 1002 204

409 665 408

ALP, alkaline phosphatase; ALT, alannine transaminase; AST, aspartate transaminase; GGT, gamma-glutamyl-transferase; LDH, lactate dehydrogenase; D.bil, direct bilirubin; T.bil, total bilirubin.

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correspondence Monitoring of cytomegalovirus reactivation during induction and nontransplant consolidation of acute leukemia To the editor: Cytomegalovirus (CMV) reactivation in the bloodstream is a relevant issue in hematologic patients who undergo hematopoietic stem cell transplantation (HSCT), where the prevalence of CMV reactivation range is between 30 and 70% [1]. This high prevalence reflects the degree of immunodeficiency associated with transplant procedures. Induction and nontransplant consolidation regimens for acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) carry a high myelosuppressive and immunosuppressive potential. However, the prevalence of CMV reactivation in acute leukemia not undergoing HSCT is currently unknown. This study was based on 44 patients with AML and 13 patients with ALL, who underwent a systematic screening for CMV reactivation by weekly CMV pp65 antigen testing and CMV DNA PCR studies starting from the beginning of induction until the last nontransplant consolidation course. Clinical and molecular characteristics at diagnosis are reported in Table I. Induction regimens for AML were idarubicin, cytarabine, etoposide (ICE) or mitoxantrone, cytarabine, etoposide (MICE) [2,3]. Nontransplant consolidation was based on high dose Ara-C [4]. ALL were treated with a regimen based on high doses of daunorubicin [5]. Overall, 57 patients with acute leukemia were tested for CMV reactivation, with a total of 533 tests performed. Results of CMV monitoring documented that reactivation of CMV was restricted to ALL. Median number of tests for CMV monitoring, median testing interval from the first to the last test, and median interval between single tests did not differ between ALL and AML. Reactivation of CMV occurred in 2/13 (15.3%) ALL. At the time of CMV reactivation and thereafter, none of the patients with ALL with CMV reactivation showed clues of overt CMV disease. No patient with AML developed CMV reactivation. In an attempt to identify the mechanisms predisposing to CMV reactivation, we compared quantitative immunologic defects at diagnosis of ALL and AML and during induction and nontransplant consolidation. Median duration of severe lymphopenia and neutropenia did not differ between ALL and AML. In a different clinical setting, i.e., chronic lymphocytic leukemia, CMV reactivation has been shown to associate with low serum albumin at diagnosis [6]. Based on this, we analyzed serum levels of albumin and g-globulin

at diagnosis. Median serum albumin and g-globulin did not differ between ALL and AML. The results of our screening suggest that CMV monitoring is not routinely required in the AML setting. Conversely, a fraction of patients with ALL may undergo CMV reactivation. The occurrence of CMV reactivation in ALL does not appear to be related to specific defects of immune function detectable at diagnosis of leukemia, or arising during treatment. It is conceivable that differences between ALL and AML treatment regimens, and in particular the inclusion of prednisone during ALL induction regimen, may be relevant for CMV reactivation in a fraction of ALL. The prevalence of CMV reactivation in ALL is similar to that reported in chronic lymphocytic leukemia during treatment with alemtuzumab, a setting in which a regular CMV monitoring is strictly indicated [7]. Based on this, a regular monitoring for CMV reactivation may be potentially useful during induction and nontransplant consolidation of ALL.

MONIA LUNGHI PAOLA RICCOMAGNO LORENZO DE PAOLI CHIARA VENDRAMIN ANNARITA CONCONI GIANLUCA GAIDANO DAVIDE ROSSI Division of Hematology, Amedeo Avogadro University of Eastern Piedmont and Ospedale Maggiore della Carita`, Novara, Italy Conflict of interest: Nothing to report. Contract grant sponsors: Ricerca Sanitaria Finalizzata, Regione Piemonte, Torino, Italy; Progetto Alfieri, Fondazione CRT, Torino, Italy; Novara-AIL Onlus and Associazione Franca Capurro per Novara Onlus, Novara, Italy Published online 6 July 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ajh.21494

References 1. Meijer E, Boland GJ, Verdonck LF. Prevention of cytomegalovirus disease in recipients of allogeneic stem cell transplants. Clin Mcrobiol Rev 2003;16:647– 657. 2. Suciu S, Mandelli F, de Witte T, et al. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years

TABLE I. Clinical and Molecular Characteristics Characteristics at diagnosis Age Male:female WHO classification AML with recurrent cytogenetic abnormalities AML with multilineage dysplasia Therapy-related AML AML, NOS Precursor B-ALL Precursor T-ALL Karyotype Low risk Standard risk High risk Molecular features AML/ETO PML/RARa MLL fusion NPM mutations FLT3 internal tandem duplication BCR/ABL E2A/PBX ALL1/ENL Blasts in peripheral blood (3 109/l) Blasts in bone marrow (%) Hb (g/dl) Platelet count (3 109/l) Grade 4 neutropenia Albumin (g/l) Gamma-globulin (g/l) CMV serology positive

AML

ALL

61 (25th–75th: 46–69) year 28:16

48 (25th–75th: 38–60) year 8:5

9/44 (20.5%) 9/44 (20.5%) 1/44 (2.3%) 25/44 (56.8%) na na

na na na na 12/13 (92.3%) 1/13 (7.7%)

8/44 (18.2%) 27/44 (61.4%) 9/44 (20.5%)

– 6/13 (46.2%) 7/13 (53.8%)

2/44 (4.5%) 6/44 (13.6%) 1/44 (2.3%) 2/10 (20.0%) 5/25 (20.0%) 0/44 na na 45.0 (25th–75th: 6.1–90.0) 80.0 (25th–75th: 43.0–90.0) 8.4 (25th–75th: 6.8–10.2) 56 (25th–75th: 29–93) 39/44 (88.6%) 36.0 (25th–75th: 34.2–40.7) 12.5 (25th–75th: 10.0–14.7) 40/44 (90.9%)

na na na na na 5/13 (38.5%) 1/13 (7.6%) 1/13 (7.6%) 78.0 (25th–75th: 37.5–89.0) 95.0 (25th–75th: 90.0–95.0) 7.7 (25th–75th: 5.8–9.6) 32 (25th–75th: 10–57) 9/13 (69.2%) 40.0 (25th–75th: 36.0–41.5) 11.0 (25th–75th: 8.5–17.0) 10/13 (76.9%)

na, not applicable.


697

correspondence

3.

4.

5.

6.

7.

with acute myeloid leukemia (AML) in first complete remission (CR1): An intention-to-treat analysis of the EORTC/GIMEMA AML-10 trial. Blood 2003;102:1232–1240. Amadori S, Suciu S, Jehn U, et al.;EORTC/GIMEMA Leukemia Group. Use of glycosylated recombinant human G-CSF (lenograstim) during and/or after induction chemotherapy in patients 61 years of age and older with acute myeloid leukemia: Final results of AML-13, a randomized phase-3 study. Blood 2005;106:27–34. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 1994;331:896–903. Cimino G, Elia L, Mancini M, et al. Clinico-biologic features and treatment outcome of adult pro-B-ALL patients enrolled in the GIMEMA 0496 study: Absence of the ALL1/AF4 and of the BCR/ABL fusion genes correlates with a significantly better clinical outcome. Blood 2003;102:2014–2020. Borthakur G, Lin E, Faderl S, et al. Low serum albumin level is associated with cytomegalovirus reactivation in patients with chronic lymphoproliferative diseases treated with alemtuzumab (Campath-1H)-based therapies. Cancer 2007;110:2478–2483. O’Brien SM, Keating MJ, Mocarski ES. Updated guidelines on the management of cytomegalovirus reactivation in patients with chronic lymphocytic leukemia treated with alemtuzumab. Clin Lymphoma Myeloma 2006;7:125–130.

Thalidomide-induced pneumonitis in a patient with plasma cell leukemia: No recurrence with subsequent lenalidomide therapy To the editor: Originally developed as a sleep-aid and antiemetic for pregnant women, thalidomide was prescribed before adequate toxicity testing had taken place. It was pulled from the market in the 1960s once it was recognized as a potent teratogen. However, thalidomide slowly re-entered clinical practice and more recently has been broadly used in the treatment of multiple myeloma [1,2] and plasma cell dyscrasias [3]. Toxicities consistently observed with thalidomide-based therapies include neuropathy, constipation, and psychological disturbances. Without anticoagulant prophylaxis, thromboembolic events are also observed [4–6]. Serious respiratory side effects have been reported with thalidomide use, but these are rare. The most notable pulmonary toxicity reported has been from thromboembolic events resulting in pulmonary embolisms. In one study on thalidomide and dexamethasone treatment for multiple myeloma patients, 4% of participants experienced nonspecific dyspnea at a Grade 3 or 4 toxicity level [7]. Other pulmonary toxicities have been discussed in the literature as case reports, where hypersensitivity pneumonitis has been uncommonly reported [8–11]. Lenalidomide is an immunomodulatory (IMiD) analog of thalidomide. It was designed to have increased potency and fewer nonhematologic side effects compared with thalidomide. Myelosuppression is the most prominent toxicity of lenalidomide [12,13]. Grade 3 or 4 pneumonitis appears to occur in up to 6% of patients, although this may be under-reported [13,14]. To date, there has been one case report of lenalidomide-induced hypersensitivity pneumonitis [15]. A 76-year-old woman presented to our hospital with severe shortness of breath on mild exertion and increasing fatigue. Two months before she was newly diagnosed with lambda-monotypic plasma cell leukemia and began her first cycle of MPT therapy (melphalan 6 mg 3 7 days, prednisone 60 mg 3 7 days, and thalidomide 50 mg at bedtime daily). Aside from moderate myelosuppression, she tolerated her first two cycles relatively well. Ten days before her hospital admission, the patient presented to an outpatient clinic with increasing shortness of breath and fatigue. Her oxygen saturation was 95% on room air, and a CT scan at that time confirmed bilateral pulmonary infiltrates with multiple parenchymal nodules. As there was concern at that point for thalidomide-induced pulmonary toxicity versus an atypical infection, the decision was made to discontinue thalidomide and start empirical antibiotic therapy. Although a formal evaluation was not performed, the patient appeared to have, at least, a partial response (according to both International Myeloma Working Group and European Group for Blood and Bone Marrow Transplant criteria) to therapy at the time of discontinuation of thalidomide. Whereas, a 70% reduction in her serum monoclonal protein and an 82% reduction in her serum free light assay was noted. On admission, the patient continued to have increasing fatigue and severe shortness of breath. She reported a 12 pound weight loss in the past 2 months. At presentation her oxygen saturation was 89%, which recovered to

698

95% on 2 L oxygen. Physical exam revealed decreased breath sounds bibasilarly with crackles and rhonchi throughout the lung fields and 11 pitting lower extremity edema bilaterally. Lower extremity Doppler exams were negative for deep vein thromboses. A CT angiogram was deferred by the patient. A repeat CT scan showed an interval increase in her ground-glass opacities. A bronchoalveolar lavage (BAL) sample contained 0% neutrophils, 38% lymphocytes, 37% monocytes, and 24% eosinophils. The infectious studies on the BAL specimen revealed a negative DFA for Pneumocystis carinii, negative fungal cultures, and negative viral studies for RSV, adenovirus, influenza, parainfluenza, and CMV. A gram stain showed normal flora. The high percentage of eosinophils in the BAL, along with the ground-glass opacity CT findings and the absence of infectious etiology strongly supported the diagnosis of eosinophilic pneumonia, likely induced by the thalidomide. The patient improved greatly during a 2-day hospital stay on steroid therapy (1 mg/kg of prednisone, with a plan to taper to 20 mg of prednisone, on which she would remain for 4–6 weeks). On follow-up a week later, the patient reported feeling very well and had been able to resume her previous exercise tolerance. The patient continued therapy for her plasma cell leukemia with melphalan and prednisone (MP) only. After two cycles of MP, disease progression was noted, evidenced by a rise of her monoclonal IgG lambda. Careful consideration was given to switching her therapy to a combination of lenalidomide and dexamethasone. Given the structural similarity of thalidomide and lenalidomide and the overlap in some toxicity, there was a small but undocumented risk that she could experience an exacerbation of pneumonitis. Lenalidomide plus dexamethasone (lenalidomide 15 mg daily for 3 weeks along with dexamethasone 40 mg weekly) was started. Her second cycle on this regimen utilized a dose-reduced level of lenalidomide of 5 mg due to impaired renal function. During 4 cycles of this therapy, the patient achieved transfusion-independence and had no signs of pulmonary toxicity. Although pulmonary toxicity is a known side effect to thalidomide, there is only one previous episode of documented lenalidomide-induced pneumonitits [15]. To our knowledge, this is the first report of lenalidomide use following the development of thalidomide-induced pneumonitis. Careful consideration is necessary when recommending the use of other IMiDs following thalidomide-induced hypersensitivity.

JENNIFER PRETZ1 BRUNO C. MEDEIROS1,2 1 Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 2 Stanford Comprehensive Cancer Center, Stanford, CA. Published online 16 July 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ajh.21495 Conflicts of interest: Nothing to report

References 1. Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: Randomised controlled trial. Lancet 2006;367:825–831. 2. Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): A randomised trial. Lancet 2007;370:1209–1218. 3. Schwartz RN, Vozniak M. Current and emerging treatments for multiple myeloma. J Manag Care Pharm 2008;14:S12–S18. 4. Palumbo A, Facon T, Sonneveld P, et al. Thalidomide for treatment of multiple myeloma: 10 years later. Blood 2008;111:3968–3977. 5. Ludwig H, Hajek R, Tothova E, et al. Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma. Blood 2009;113:3435–3442. 6. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma.Leukemia 2008;22:414–423. 7. Rajkumar SV, Hayman S, Gertz MA, et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol 2002;20:4319–4323. 8. Carrion Valero F, Bertomeu Gonzalez V. Lung toxicity due to thalidomide. Arch Bronconeumol 2002;38:492–494. 9. Onozawa M, Hashino S, Sogabe S, et al. Side effects and good effects from new chemotherapeutic agents. Case 2. Thalidomide-induced interstitial pneumonitis. J Clin Oncol 2005;23:2425–2426.


correspondence WICO W. LAI2,3 BONNIE M. FONG4 SIDNEY TAM4 YOK-LAM KWONG1

10. Feaver AA, Mccune DE, Mysliwiec AG, Mysliwiec V. Thalidomide-induced organizing pneumonia. South Med J 2006;99:1292–1294. 11. Tilluckdharry L, Dean R, Farver C, Ahmad M. Thalidomide-related eosinophilic pneumonia: A case report and brief literature review. Cases J 2008;1:143–146. 12. Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 2006;108:3458–3464. 13. Hazarika M, Rock E, Williams G, et al. Lenalidomide in combination with dexamethasone for the treatment of multiple myeloma after one prior therapy. Oncologist 2008;13:1120–1127. 14. Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005;106:4050–4053. 15. Thornburg A, Abonour R, Smith P, et al. Hypersensitivity pneumonitis-like syndrome associated with the use of lenalidomide. Chest 2007;131:1572–1574.

1 Department of Medicine, Queen Mary Hospital Department of Ophthalmology, Queen Mary Hospital 3 Eye Institute, University of Hong Kong 4 Department of Clinical Biochemistry, Queen Mary Hospital, Hong Kong, China Charmaine Hon is currently at Hong Kong Ophthalmic Associates Published online 16 July 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ajh.21505 2

References Two cases of monocular visual loss during oral arsenic trioxide therapy of acute promyelocytic leukemia

To the editor: Arsenic trioxide (As2O3) is a standard medication for relapsed acute promyelocytic leukemia (APL). Visual problems have been detected in environmental toxicology studies of arsenic exposure [1]. This may not be surprising as arsenic can cause peripheral neuropathy [2] and also enters the cerebrospinal fluid (CSF) [3]. In 100 APL patients receiving oral-As2O3, two serious visual problems were observed, both in patients in complete remission (CR) with normal platelet counts. However, both cases had other major causative factors to blindness. A 25-year-old man with APL in first CR received oral-As2O3 (10 mg/day) and all-trans retinoic acid (ATRA, 45 mg/m2/day) maintenance (2 weeks every 2 months 3 2 years). After completion of maintenance, he complained deterioration of right eye vision to light perception only, after a basketball injury sustained during the last course of oral treatment. Fundoscopic examination showed a large retinal tear with total rhegmatogenous detachment. He was treated with posterior vitrectomy, lensectomy, retinectomy, endolaser photocoagulation, and silicone oil injection, without visual recovery. With inductively-coupled plasma mass spectroscopy, [2] elemental arsenic in the plasma, aqueous humor, and vitreous humor were found to be 115, 35, and 57 nmol/L, respectively. A 35-year-old man with APL in relapse achieved second CR with oralAs2O3 (10 mg/day 3 30 days) followed by idarubicin consolidation (9 mg/ day 3 5 days). He was a chronic smoker (three packs/day) with a history of right eye amaurosis fugax. Two days after chemotherapy, he developed sudden right eye blindness, due to central retinal artery occlusion. No source of cardiac or carotid embolization was found. He was treated with anterior chamber paracentesis, acetazolamide, and timolol eye drops, but optic atrophy ensued. The patient completed idarubicin consolidation and As2O3 1 ATRA maintenance without complications. Acute visual loss during remission is unusual for patients with acute leukemia. However, both of our patients had clear anatomical causes for blindness. Furthermore, unilateral (rather than bilateral) blindness suggested a limited role for systemic arsenic toxicity. Nevertheless, a weak contribution of ocular arsenic toxicity should not be completely ruled out. Both As2O3 and ATRA can increase intracranial pressure, resulting in pseudotumor cerebri [4,5] and a secondary increase in intraocular pressure, which may augment retinal injury. Also, As2O3 can cause vasoconstriction [6] and worsen retinal artery occlusion. Finally, we documented for the first time that elemental arsenic enters the eye at 30–50% of the plasma level, a ratio comparable to that in CSF. This may have direct retinal toxicity, especially with high peak concentrations associated with intravenous-As2O3. For physicians prescribing long-term or intravenous As2O3, we recommend full ophthalmologic evaluation. The role of electroretinographic studies [7] for detecting subclinical retinal toxicities in patients treated with As2O3 remains to be defined.

Acknowledgments The S.K. Yee Medical Foundation provided oral arsenic trioxide free to the patient.

WING-YAN AU1 CHARMAINE HON2 KIN YAU2,3


1. Kazi TG, Afridi HI, Kazi GH, et al. Evaluation of essential and toxic metals by ultrasound-assisted acid leaching from scalp hair samples of children with macular degeneration patients. Clin Chim Acta 2006;369:52–60. 2. Huang SY, Chang CS, Tang JL, et al. Acute and chronic arsenic poisoning associated with treatment of acute promyelocytic leukaemia. Br J Haematol 1998;103:1092–1095. 3. Au WY, Tam S, Fong BM, Kwong YL. Determinants of cerebrospinal fluid arsenic concentration in patients with acute promyelocytic leukemia on oral arsenic trioxide therapy. Blood 2008;112:3587–3590. 4. de Botton S, Coiteux V, Chevret S, et al. Outcome of childhood acute promyelocytic leukemia with all-trans-retinoic acid and chemotherapy. J Clin Oncol 2004;22:1404–1412. 5. Galm O, Fabry U, Osieka R. Pseudotumor cerebri after treatment of relapsed acute promyelocytic leukemia with arsenic trioxide. Leukemia 2000;14:343– 344. 6. Lagerkvist B, Linderholm H, Nordberg GF. Vasospastic tendency and Raynaud’s phenomenon in smelter workers exposed to arsenic. Environ Res 1986;39:465–474. 7. da Costa GM, dos Anjos LM, Souza GS, et al. Mercury toxicity in Amazon gold miners: Visual dysfunction assessed by retinal and cortical electrophysiology. Environ Res 2008;107:98–107.

Successful discontinuation of anticoagulation following eculizumab administration in paroxysmal nocturnal hemoglobinuria To the editor: Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disease that can present with bone marrow failure, hemolytic anemia, and thrombosis [1,2]. The disease originates from a multipotent hematopoietic stem cell that acquires a PIG-A mutation [3,4]. Expansion and differentiation of the PIG-A mutant stem cell leads to clinical manifestations of the disease. The PIG-A gene product is required for the biosynthesis of glycophosphatidylinositol anchors, a glycolipid moiety that attaches dozens of proteins to the plasma membrane of cells. Consequently, the PNH stem cell and all of its progeny have a deficiency or absence GPIanchored proteins (GPI-AP). Two of these GPI-AP, CD55, and CD59, are complement regulatory proteins that are fundamental to the pathophysiology of the disease [5,6]. CD55 inhibits C3 convertases and CD59 blocks formation of the membrane attack complex. The loss of these complement regulatory proteins renders PNH erythrocytes susceptible to intravascular and extravascular hemolysis, but it is the intravascular hemolysis that contributes to most of the morbidity and mortality of the disease [7]. Thrombosis is the leading cause of death in PNH [8–10]. The etiology of thrombosis in PNH is multifactorial and believed to be related to: (1) Intravascular hemolysis and nitric oxide scavenging causing platelet activation and endothelial injury [7], (2) platelet microvesicle formation leading to accelerated thrombin generation [11], and (3) loss of the GPIanchored urokinase receptor perturbing fibrinolysis [12,13]. Venous thrombosis, with particular proclivity of abdominal and saggital veins, is most common but the risk of arterial thrombosis is also increased in PNH [8–10]. A case of multiple cerebral arterial thromboses, upper extremity vein thrombosis, and Budd-Chiari syndrome with the onset of PNH recently was reported demonstrating that thrombosis in PNH can affect both venous and arterial systems [14]. The risk for thrombosis in PNH patients is highest in those with large PNH granulocyte clones [9,15]. Eculizumab is a humanized monoclonal antibody that blocks the terminal complement assembly [16]. In two phase III clinical trials, eculizumab administration resulted in marked reduction of intravascular hemolysis, a decrease

699

700

20

42 10

32

47 12

in transfusion requirements and improved quality of life [17,18]. There was also 85% (1.07 vs. 7.37 events/100 patient-years) absolute reduction in thrombosis rate while on eculizumab treatment [19]. These results suggest chronic administration of eculizumab can significantly reduce the overall lifetime thromboembolic event rate. Nevertheless, a major unresolved issue in the management of PNH patients on eculizumab is whether or not anticoagulation can be safely discontinued, especially in patients with previous thrombotic events [20]. Here, we report successful discontinuation of anticoagulation after initiation of eculizumab in three young PNH patients with histories of extensive thromboses. Patient characteristics are shown in Table I. The first patient is a 34-yearold male with a 17-year history of classical PNH. For 12 years, his disease

Pulmonary emboli, portal vein, splenic vein (status postsplenic embolization), sagital vein, renal and hepatic failure status postliver transplant CVA (right corona radiata punctate infarct) Severe extensive dermal thromboses, subacute left cerebellum ischemia

manifested with chronic hemolysis and occasional paroxysms of abdominal pain and hemoglobinuria. The patient did not have any suitable donor for allogenic bone marrow transplantation. He was treated with folic acid supplementation and intermittent pulses of prednisone. Five years ago, he developed splenic vein thrombosis with marked splenomegaly, gastric varices, and portal vein occlusion with cavernous transformation. He was started on warfarin, but his clinical condition progressively deteriorated in spite of anticoagulation. He developed a sagittal vein thrombosis, which manifested as severe frontal and

3230/227 1248/326

Not available 12.16/2.36

Zero Zero

retro-orbital headaches. New thrombi were also found in the infrahepatic and retrohepatic inferior vena cava as well as the hepatic veins, which caused

3420 4120 97% 99% 7 9 22/Female 31/Male 2 3

LDH, lactate dehydrogenase; ECOG-PS, Eastern Cooperative Group performance status.

159,000 107,000 10.7 14.9

Zero 29/1.4 430–2300/161 154,000 10.4 3790 100% 17 34/Male

Patient

1

Duration of PNH (years) Age (years)/Gender

TABLE I. Patients Characteristics

PNH granulocyte (FLAER)

WBC 3 10 per liter

6

Hgb (g/dL) (most recent)

Platelets counts 3 106 per liter (most recent)

LDH (U/L) before eculizumab/ most recent

d-Dimer (mg/dL) before eculizumab/most recent

ECOG-PS (current)

Site of thrombosis

Duration on eculizumab (months)

Duration off anticoagulations (months)

correspondence

hepatomegaly, caudate hypertrophy, and worsening ascites. Eventually, he developed renal insufficiency and was placed on dialysis. Eculizumab was initiated 32 months ago, which resulted in an immediate reduction in intravascular hemolysis evidenced by a decrease in lactate dehydrogenase (LDH) to nearly normal levels and a decreased need for blood transfusions. Breakthrough hemolysis occurred 1 week after each eculizumab dose, most likely because of removal of the drug during weekly paracentesis. Three months after initiation of eculizumab, the patient received a liver transplant. He required no dialysis after surgery, with a creatinine level of 1.1 mg/dL by the time of discharge on post-transplant day 9. His liver function also slowly improved, with a total bilirubin level of 0.8 mg/dL, an alanine aminotransferase level of 44 U/L, and an international normalized ratio (INR) of 1.0 at discharge. Treatment with eculizumab was continued during and after surgery and he has had no evidence of overt hemolysis or complement-mediated breakthroughs. He required no postoperative blood transfusions. A routine follow-up abdominal CT scan after surgery revealed an asymptomatic lower extremity deep vein thrombosis that felt to be old; thus, his anticoagulation was continued for 6 months. Because of the difficulty maintaining a therapeutic INR on warfarin and a history of PNH associated thrombosis before eculizumab administration while on warfarin, the patient insisted in discontinuing anticoagulation. He has not experienced any thrombotic event since then and his most recent d-dimer is within normal limit. He continues to work full time and has an Eastern Cooperative Oncology Group (ECOG) performance status of zero. The second patient is a 22-year-old female with a 7-year history of PNH which was complicated by multiple hemolytic episodes and red blood cell transfusion dependence. In December 2003, she had a cerebral vascular accident in the right corona radiate, associated with left-sided motor and sensory deficits. Anticoagulation with warfarin initiated. The patient was treated with eculizumab in August 2005 and has required only one transfusion since starting the drug. Currently, she is transfusion independent with an LDH of 227 U/L compared with 3230 U/L before starting eculizumab. She and her parents were concerned about the risk of bleeding associated with lifelong anticoagulation and elected to discontinue warfarin 5 months after starting eculizumab therapy. She has not developed any new thrombosis since then and continues to work with an ECOG performance status of zero. The third patient is a 31-year-old man with a 9-year history of PNH. Initially, he had a few exacerbations of his disease but gradually the frequency of his flares increased. Approximately 1-year ago, he had an episode of severe dermal thromboses involving his ears as well as extensive skin necrosis in the front and back of his chest and abdominal walls. A punch biopsy showed occlusion of the small superficial vessels consistent with microthrombi. Periodic acid-Schiff stain also highlighted the vascular occlusion, in a fashion consistent with thrombi. The deeper sections also showed more prominent changes of early epidermal necrosis, including


correspondence an influx of neutrophils. Magnetic resonance angiogram of the brain showed a small linear focus of enhancement involving the left cerebellum, consistent with subacute ischemia. He was placed on anticoagulation with low-molecular weight heparin and converted to warfarin therapy. He was started on eculizumab in July 2008 while still taking warfarin. His LDH decreased from 1248 U/L during the flare to 441 U/L within 2 weeks after initiation of eculizumab. Approximately 1 month after starting eculizumab, he inquired about discontinuing his warfarin due to his passion for playing basketball and other sports. Furthermore, he was requiring 15–20 mg of warfarin daily to maintain his INR in therapeutic range. After much discussion with his doctor, he elected to come off of anticoagulation. He has not reported any thrombotic event in the last 10 months. His d-dimer decreased from 12.16 mg/L in June 2008 to 2.36 mg/L in December 2008. His ECOG performance status is zero. Before eculizumab, thrombosis was the leading cause of death from PNH. Accordingly, many investigators recommended prophylactic anticoagulation for PNH patients with platelet counts of 100 3 109/L and no contraindications to anticoagulation [15]. Virtually all PNH patients with documented thrombosis are treated with lifelong anticoagulation. Recent Phase III studies of eculizumab in PNH patients demonstrate that (1) eculizumab markedly reduces the thrombosis risk and (2) that prophylactic anticoagulation in PNH patients does little to reduce the risk for thrombosis in PNH patients not on eculizumab. Specifically, the thromboembolism event rate per 100 patient-years following eculizumab administration was reduced from 7.4 events to 1.1 events, an 85% reduction. In antithrombotic-treated patients, the thromboembolism event rate was also reduced (10.6 events per 100 patient-years to 0.6 events per 100 patient-years) with eculizumab treatment. Interestingly, the use of antithrombotic therapy before eculizumab did not appear to influence the thrombosis risk (7.4 events per 100 patient-years versus 10.6 events per 100 patient-years); furthermore, eculizumab markedly reduced the thrombosis risk regardless of whether or not patients were receiving anticoagulation. Thus, a question of major clinical importance is whether lifelong anticoagulation is necessary for PNH patients who are well controlled on eculizumab therapy. Here, we report withdrawal of anticoagulation in three young PNH patients after eculizumab therapy. All three patients had severe thrombotic events before initiation of eculizumab. All of them have active life styles that make lifelong anticoagulation inconvenient and chose to discontinue warfarin after careful discussion with their treating physician. Currently all three patients are transfusion independent on eculizumab and have remained free of thrombosis from 10 to 42 months after stopping anticoagulation. Ideally, the decision of whether or not it is safe to withdraw anticoagulation in PNH patients on eculizumab should be answered in a randomized controlled clinical trial. Given the rarity of PNH, it is unlikely that such a trial will ever be performed; thus, the best attempts to answer this question may come from registry data. Our data suggest that it may be safe to withdraw anticoagulation in PNH patients on eculizumab; however, more experience and longer follow-up is necessary before recommending withdrawal of anticoagulation in all PNH patients. Until then, careful discussion with the patient concerning the potential risks and benefits of lifelong anticoagulation should occur.

ASHKAN EMADI ROBERT A. BRODSKY Department of Internal Medicine, Division of Hematology, Johns Hopkins University, Baltimore, MD Conflicts of interest: Nothing to report. Published online 25 July 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ajh.21506 Conflict of interest: Dr. Brodsky serves on the international advisory board for Alexion Pharmaceuticals and declares no other competing financial interests.

References 1. Brodsky RA. Paroxysmal nocturnal hemoglobinuria: Stem cells and clonality. Hematology Am Soc Hematol Educ Program 2008;2008:111–115.


2. Inoue N, Izui-Sarumaru T, Murakami Y, et al. Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH). Blood 2006;108:4232–4236. 3. Miyata T, Takeda J, Iida Y, et al. The cloning of Pig-A, a component in the early step of gpi-anchor biosynthesis. Science 1993;259:1318–1321. 4. Miyata T, Yamada N, Iida Y, et al. Abnormalities of PIG-A transcripts in granulocytes from patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 1994;330:249–255. 5. Medof ME, Kinoshita T, Nussenzweig V. Inhibition of complement activation on the surface of cells after incorporation of decay-accelerating factor (DAF) into their membranes. J Exp Med, 1984;160:1558–1578. 6. Rollins SA, Sims PJ. The complement-inhibitory activity of CD59 resides in its capacity to block incorporation of C9 into membrane C5b-9. J Immunol 1990;144:3478–3483. 7. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: A novel mechanism of human disease. JAMA 2005;293:1653–1662. 8. Hillmen P, Lewis SM, Bessler M, et al. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995;333:1253–1258. 9. Moyo VM, Mukhina GL, Garrett ES, Brodsky RA. Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays. Br J Haematol 2004;126:133–138. 10. de Latour RP, Mary JY, Salanoubat C, et al. Paroxysmal nocturnal hemoglobinuria: Natural history of disease subcategories. Blood 2008;112: 3099–3106. 11. Wiedmer T, Hall SE, Ortel TL, et al. Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria. Blood 1993;82:1192–1196. 12. Ploug M, Plesner T, Ronne E, et al. The receptor for urokinase-type plasminogen activator is deficient on peripheral blood leukocytes in patients with paroxysmal nocturnal hemoglobinuria. Blood 1992;79:1447– 1455. 13. Sloand EM, Pfannes L, Scheinberg P, et al. Increased soluble urokinase plasminogen activator receptor (suPAR) is associated with thrombosis and inhibition of plasmin generation in paroxysmal nocturnal hemoglobinuria (PNH) patients. Exp Hematol 2008;36:1616–1624. 14. Abou Antoun S, El-Haddad B, Wehbe E, Schulz T. Lysis and thrombosis: Manifestation of the same disease. Am J Hematol 2008;83:505–507. 15. Hall C, Richards S, Hillmen P. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood 2003;102: 3587–3591. 16. Brodsky RA. Narrative review: Paroxysmal nocturnal hemoglobinuria: The physiology of complement-related hemolytic anemia. Ann Intern Med 2008;148:587–595. 17. Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006;355:1233–1243. 18. Brodsky RA, Young NS, Antonioli E, et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 2008;111:1840–1847. 19. Hillmen P, Muus P, Du¨hrsen U, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 2007;110:4123–4128. 20. Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood 2009; 113:6522–6527.

Complete resolution of leukemia cutis with sorafenib in an acute myeloid leukemia patient with FLT3-ITD mutation

To the editor: Sorafenib, a small molecule tyrosine kinase inhibitor, has shown efficacy in suppressing leukemic cells in mouse myeloid leukemia models with FLT3 gene internal tandem duplication (FLT3-ITD) [1]. Significant activity for sorafenib has also been reported in a phase I clinical trial in patients with relapsed or refractory acute myeloid leukemia (AML) with FLT3-ITD [1]. We present a case of AML with FLT3-ITD in hematologic remission who developed leukemia cutis, which completely resolved after treatment with sorafenib alone. A 73-year old male, known to have mitral valve prolapse with 41 mitral regurgitation, presented to the hospital for evaluation of right upper quadrant pain. He was treated with IV antibiotics for suspected cholecystitis with gallstones and elevated serum levels of liver enzymes. His white blood cell count was 6300/lL, and a peripheral blood smear showed lymphocytosis. His hemoglobin was 13 g/dL, hematocrit 38%, and platelet count 58,000/lL. His serum lactate dehydrogenase was of 11,000 U/L, and the serum alkaline phosphatase level was 437U/L. A bone marrow aspirate and biopsy were performed, and flow cytometric analysis of the aspirate detected abnormal cells comprising 75% of white blood cells. The leukemic cells expressed the immature marker, CD123, but lacked CD34 and CD117. Expression of CD33, CD11b, and HLA-DR by these

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correspondence

Fig. 1.

Leukemia cutis before sorafenib.

blasts confirmed the diagnosis of immature monocytic, CD11bpos AML [2]. The blasts lacked lymphoid antigens as well as the mature monocytic marker, CD14. The bone marrow biopsy was hypercellular (100%) with extensive replacement of hematopoietic tissue by blasts, consistent with AML. Cytogenetic analysis of this bone marrow revealed a karyotype of 47, XY, 18[11]/46, X,-Y, 18[4]/46, XY [5]. Polymerase chain reaction analysis of cDNA detected FLT3-ITD positivity. Therefore, a diagnosis of FLT3-ITDpos AML was made. Due to his cardiac comorbidities, he was treated with azacitidine, 125 mg/m2/day rapid intravenous injection for 5 days. His bone marrow became markedly hypoplastic, and his hospital course was complicated by enterococcus sepsis. His bone marrow recovered 6 weeks after treatment, and the patient was discharged. He returned for follow-up 3 days later with skin eruptions on his trunk, flanks, inguinal area, and upper thighs [Fig. 1]. A bone marrow biopsy was hypercellular (80–90%) with trilineage hematopoiesis, and no morphologic evidence of AML. Cytogenetic analysis of the aspirate revealed 20 normal metaphases, and flow cytometry failed to detect leukemic blasts. However, a skin punch biopsy of one of numerous pale pink, papular lesions revealed leukemia cutis [Fig. 2]. By immunohistochemistry, the skin lesion cells were CD4pos, CD33pos, CD68pos, and CD56pos, negative for lymphoid markers, CD3 and CD20. A myeloperoxidase stain highlighted only scattered granulocytes. This immunohistochemical profile was consistent with monocytic leukemia, reminiscent of the patient’s initial diagnosis. Since his leukemia was FLT3-ITDpos, he was treated with sorafenib, 400 mg orally twice daily. The leukemic skin lesions began to resolve within 3 days after treatment, and complete resolution was observed after 10 days of treatment with sorafenib [Fig. 3]. Patients with AML (20–30%) are found to have FLT3-ITD transcripts where the juxtamembrane domain of the FLT-3 receptor tyrosine kinase is duplicated [3], and patients with this mutation have a high risk of relapse, even after allogeneic stem cell transplantation [1,4–7]. Sorafenib was recently found to inhibit proliferation and induce apoptosis in FLT3-ITDpos AML blasts at concentrations that are easily achievable in vivo [7]. This effect is thought to be mediated by activation of the Bim and bcl-2 mediated intrinsic apoptotic pathway leading to regression of the leukemic clone [8]. This is the first clinical report of successful treatment with sorafenib of leukemia cutis in a patient with FLT3-ITDpos AML.

SUNG HO LEE ELISABETH PAIETTA JANIS RACEVSKIS PETER H. WIERNIK Department of Medical Oncology, New York Medical College, Bronx, New York Published online 25 July 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ajh.21511 Conflict of interest: Nothing to report.

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Fig. 2. Skin punch biopsy: (A) 320 H&E. (B) CD33 Stain. (C) 34 H&E. (D) 3100 H&E.

Fig. 3.

10 days after sorafenib.

References 1. Zhang W, Konopleva M, Shi YX, et al. Mutant FLT3: A direct target of sorafenib in acute myelogenous leukemia. J Natl Cancer Inst 2008;100:184–198. 2. Paietta E, Andersen J, Yunis J, et al. Acute myeloid leukemia expressing the leucocyte integrin CD11b—A new leukemic syndrome with poor prognosis: Result of an ECOG database analysis. Br J Haematol 1998;100:265–272. 3. Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 1996;10:1911–1918. 4. Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: Analysis of 854 patients from the United Kingdom medical research council AML 10 and 12 trials. Blood 2001;98:1752–1759. 5. Safaian NN, Czibere A, Bruns I, et al. Sorafenib (Nexavar1) induces molecular remission and regression of extramedullary disease in a patient with FLT3ITD acute myeloid leukemia. Leuk Res 2009;33:348–350. 6. Metzelder S, Wang Y, Wollmer E, et al. Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: Sustained regression before and after allogenic stem cell transplantation. Blood 2009;113:6567–6571. 7. Hu S, Niu H, Minkin P, et al. Comparison of antitumor effects of multitargeted tyrosine kinase inhibitors in acute myelogenous leukemia. Mol Cancer Ther 2008;7:1110–1120. 8. Zhang W, Konopleva M, Ruvolo VR, et al. Sorafenib induces apoptosis of AML cells via Bim-mediated activation of the intrinsic apoptotic pathway. Leukemia 2008;22:808–818.
