Carmela Arrigo

Alemtuzumab therapy for refractory idiopathic hypereosinophilic syndrome with abnormal T cells: a case report.

A diagnosis of idiopathic hypereosinophilic syndrome was made in a 68-year-old woman in 2002. She was treated with hydroxycarbamide, interferon-a and imatinib (400 mg/d) without evidence of response. In November 2003 she was admitted to our department with anaemia, fever and several painful pruritic skin lesions (top). Immunophenotypic analysis of circulating lymphocytes showed an abnormal CD4 subset characterized by absent surface expression of the CD3 antigen (abnormal T cells have a CD3CD4 CD8 phenotype). Serum interleukin-5 (IL-5) concentration was 280 pg/mol (normal 10 pg/mol). Twodimensional Doppler echocardiography showed endocardial thickening; the left ventricular ejection fraction (LVEF) was 48%. A skin biopsy demonstrated a dermal infiltrate consisting primarily of eosinophils (bottom left). A diagnostic work-up including radiological evaluation failed to reveal an overt lymphoproliferative disorder. As a consequence of the previous demonstration that CD52 is expressed on human eosinophils, the patient was administered subcutaneous alemtuzumab in increasing doses of up to 30 mg weekly. Once commenced on alemtuzumab, her pyrexia settled and the cutaneous lesions started to resolve (bottom right), the LVEF improved to 61% and serum IL-5 concentration fell to 9 pg/mol. Currently, 6 months after the revised diagnosis, the patient is well with an eosinophil count of 0.3 · 10/l on alemtuzumab (30 mg) every 3 weeks.

Response to dasatinib in a patient with SQCC of the lung harboring a discoid-receptor-2 and synchronous chronic myelogenous leukemia

We report a patient with squamous cell carcinoma (SQCC) of the lung and a discoid-receptor-2 (DDR2) kinase domain mutation that responded to dasatinib treatment. Our case report is consistent with previous publications suggesting that DDR2 mutation may confer sensitivity to dasatinib.

Erlotinib in a Patient With Acute Myelogenous Leukemia and Concomitant Non–Small-Cell Lung Cancer

In August 2007, a 64-year-old male smoker presented with a 1-month history of progressively worsening dyspnea; peripheral blood leukocyte count was 4.1 10/L with 7% neutrophils, 2% band, 39% lymphocytes and 52% myeloblasts (Fig 1); hemoglobin of 8.9g/ dL; and a platelet count of 61 10/L. Bone marrow biopsy revealed 81% myeloperoxidase-positive blasts, while the immunophenotype was 81% CD34, 75% HLA-DR, 21% CD13, 8% CD33, 0% CD10, 6% CD19, 2% CD3% and 3% CD25 by flow cytometry, consistent with acute myelogenous leukemia (AML) -M1; the cytogenetics were normal. A body computed tomography scan showed a 3 3.7 cm mass in the left lower lobe of the lung (Fig 2). A core-needle biopsy obtained from the lung was consistent with a moderately differentiated adenocarcinoma. Positron emission tomography scanning revealed an uptake in the lung mass and mediastinum confirming the diagnosis of stage IIIA of non–small-cell lung cancer (NSCLC). To assess the epidermal growth factor receptor’s (EGFR) mutational status, a complementary DNA sequencing from core-needle biopsy of the lung was performed, and a leucine-to-arginine substitution at amino acid 858 (L858R) was identified. Given the patient’s poor performance status, no AML therapy was initiated, and he was prescribed oral erlotinib 150 mg daily. After two weeks of erlotinib therapy, routine blood examinations revealed a significant reduction of circulating blasts (10%), while leukocyte count was 3.7 10/L. A repeat bone marrow biopsy revealed manifested biochemical hallmarks of apoptosis as determined by terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate-biotin nick-end labeling assay, which has been shown to be a sensitive and specific method for detecting apoptosis in histologic sections (Fig 3). EGFR was undetectable on myeloblasts. After 3 months of erlotinib therapy, the patient had normal complete blood counts and no circulating blasts. A new chest computed tomography scan showed that the mass in the left lung had nearly completely resolved itself (Fig 4). Seven months after starting the treatment, he remains clinically well on erlotinib without any chest related symptons except for a grade 1 skin rash. A repeat bone marrow biopsy was mildly hypocellular with maturing trilineage hematopoiesis, less than 2% myeloblasts and normal cytogenetics. EGFR is a receptor tyrosine kinase of the ErbB receptor family that is abnormally activated in many epithelial tumors. The aberrant activation leads to enhanced proliferation which provides a strong rationale to target this receptor family. Somatic mutations in the EGFR have been detected in patients with NSCLC and are associated with sensitivity to treatment with gefitinib or erlotinib which are adenosine triphosphate–competitive inhibitors of the receptor’s tyrosine kinase. EGFR mutations occur mainly in the first four exons of the gene encoding tyrosine kinase domain (18-21) and are clustered around the ATP-binding pocket of the enzyme. Approximately 90% of EGFR mutations are missense mutations resulting in leucine to arginine substitution at codon 858 (L858R) in exon 21 and small exon 19 in-frame deletions. Other mutations occur at lower frequency at codon 719, resulting in the substitution of glycine to cysteine, alanine, or serine (G7 19X), and in exon 20 as in-frame insertion mutations. Unfortunately, despite the presence of activating EGFR mutations in their tumors, patients can fail to respond to tyrosine kinase, and also those with an initial dramatic response develop acquired drug resistance after variable periods of time due to additional genetic lesions. A recent study revealed the capacity of gefitinib to induce differentiation in 3 AML cell lines (U937, HL60, and Kasumi-1), all of which lack expression of the EGFR, thus unraveling an interesting off-target effect of a compound that was believed to specifically act on EGFRexpressing cells. On the basis of this report Boehrer et al studied the effects of the EGFR inhibitor erlotinib on EGFR-negative AML and myelodysplastic syndrome (MDS) cells in vitro and ex vivo. This study pointed out that erlotinib has an antineoplastic activity on MDS and AML cells that includes a strong proapoptotic effect in the erlotinibsensitive AML cell line KG-1, as in vivo observed by us in this case report. Furthermore, one patient with both MDS and NSCLC manifested hematologic improvement after treatment with erlotinib. Finally, noteworthy, a recently published case report provides further clinical evidence for the therapeutic efficacy of erlotinib in EGFR– negative myeloid malignancies. The case of our patient points out the importance of the presence of L858R mutation within the kinase domain of EGFR as a predictive factor in determining the response to erlotinib, even if the most relevant aspect of our case is the unexpected antineoplastic activity of erlotinib on AML cells. This off-target effect Fig 1. Fig 2. Diagnosis in Oncology

Erlotinib therapy in a patient with non-small-cell lung cancer and brain metastases

Brain metastases are a common occurrence and a major cause of mortality in non-small-cell lung cancer, with few systemic treatment options. Although targeting epidermal growth factor receptor-associated tyrosine kinase with erlotinib and gefitinib results in durable responses in some patients, the activity of these drugs against brain metastases has been poorly documented. In particular, few reports have so far reported the activity of erlotinib in this setting. Here we report the case of a male Italian smoker with an adeno-carcinoma of the lung whose lung cancer and brain metastases have both responded to erlotinib.

HCV genotype 2 as a risk factor for reactivation in patients with B-cell lymphoma undergoing rituximab combination chemotherapy

Arons, E., Suntum, T., Stetler-Stevenson, M. & Kreitman, R.J. (2009) VH4-34+ hairy cell leukemia, a new variant with poor prognosis despite standard therapy. Blood, 114, 4687–4695. Callet-Bauchu, E., Baseggio, L., Felman, P., Traverse-Glehen, A., Berger, F., Morel, D., Gazzo, S., Poncet, C., Thieblemont, C., Coiffier, B., Magaud, J.P. & Salles, G. (2005) Cytogenetic analysis delineates a spectrum of chromosomal changes that can distinguish non-MALT marginal zone B-cell lymphomas among mature B-cell entities: a description of 103 cases. Leukemia, 19, 1818– 1823. Hockley, S.L., Giannouli, S., Morilla, A., Wotherspoon, A., Morgan, G.J., Matutes, E. & Gonzalez, D. (2010) Insight into the molecular pathogenesis of hairy cell leukaemia, hairy cell leukaemia variant and splenic marginal zone lymphoma, provided by the analysis of their IGH rearrangements and somatic hypermutation patterns. British Journal of Haematology, 148, 666–669. Matutes, E., Wotherspoon, A. & Catovsky, D. (2003) The variant form of hairy-cell leukaemia. Best Practice & Research. Clinical Haematology, 16, 41–56. Matutes, E., Oscier, D., Montalban, C., Berger, F., Callet-Bauchu, E., Dogan, A., Felman, P., Franco, V., Iannitto, E., Mollejo, M., Papadaki, T., Remstein, E.D., Salar, A., Sole, F., Stamatopoulos, K., Thieblemont, C., Traverse-Glehen, A., Wotherspoon, A., Coiffier, B. & Piris, M.A. (2008) Splenic marginal zone lymphoma proposals for a revision of diagnostic, staging and therapeutic criteria. Leukemia, 22, 487–495. Swerdlow, S.H. (2008) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer, Lyon. Traverse-Glehen, A., Baseggio, L., Bauchu, E.C., Morel, D., Gazzo, S., Ffrench, M., Verney, A., Rolland, D., Thieblemont, C., Magaud, J.P., Salles, G., Coiffier, B., Berger, F. & Felman, P. (2008) Splenic red pulp lymphoma with numerous basophilic villous lymphocytes: a distinct clinicopathologic and molecular entity? Blood, 111, 2253–2260.

Myelodysplastic syndrome appearing during imatinib mesylate therapy in a patient with GIST.

The introduction of imatinib has been a major advance in the treatment of gastrointestinal stromal tumor (GIST). However, despite its remarkable efficacy and toxicity profile little is known about the potential for long-term toxicity. This may be an important issue because some patients (pts) with chronic myelogenous leukemia (CML) develop, during imatinib treatment, chromosomal abnormalities in philadelphia chromosome (Ph) negative cells with evolution to myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML), furthermore a nonrandom association between GIST and myeloid leukemia has been recently reported. We report here a case of refractory cytopenia with mutilineage dysplasia (RAEB-1) with monosomy 7 which rapidly transformed into AML in a patient with GIST during imatinib treatment.

Visceral leishmaniasis after alemtuzumab in a patient with chronic lymphocytic leukaemia

A 64-year-old, human immunodeficiency virus-negative, man was diagnosed in 2009 as Rai stage IV chronic lymphocytic leukaemia with unmutated IGHV genes and del 17p13.1. He was treated with six courses of intravenous fludarabine, cyclophosphamide and rituximab, attaining a partial remission that lasted only 28 weeks. Overt progression was then managed with subcutaneous alemtuzumab at 30 mg three times a week for 12 weeks. After this treatment, the enlarged lymph nodes disappeared, while the CD4-positive T-lymphocyte count decreased, from 0Æ09 · 10/l to 0Æ003 · 10/l (normal range: 0Æ5–1Æ0 · 10/l). Four weeks after completion of alemtuzumab therapy, the patient developed fever (39 C) and was readmitted to our hospital. The blood count showed pancytopenia (haemoglobin concentration 70 g/l, white cell count 1Æ8 · 10/l and platelet count 22 · 10/l). Computed tomography of the chest, abdomen and pelvis showed massive splenomegaly. Bone marrow films showed no signs of a lymphoproliferative disease but, to our surprise, numerous amastigotes of leishmania species were seen (top, right and left); furthermore, leishmania parasites were also demonstrated in May-Grünwald-Giemsa stained peripheral blood films (bottom, right and left). The patient was treated with liposomal amphotericin B and no leishmania amastigotes were detectable in bone marrow films at the end of treatment. Severe immunodeficiency characterized by a marked lymphopenia is a well-known risk factor for opportunistic parasitic infections. Clinicians should be alert to the possibility of leishmaniasis not only in endemic areas but also when there is the possibility of a latent infection that may become clinically apparent when a patient becomes profoundly immunosuppressed.

Dasatinib induces a response in chronic lymphocytic leukemia

To the editor: Dasatinib is a novel oral multitargeted kinase inhibitor of Bcr-Abl and Src family widely used for the treatment of imatinib-resistant chronic myelogenous leukemia. Furthermore, preclinical studies by Shah et al[1][1] indicate that dasatinib may also inhibit gastrointestinal stromal

Extramedullary plasmacytoma presented as a non-functional invasive pituitary macro-adenoma.

Pituitary adenomas are the most common etiology of sellar masses. Intra-sellar plasmacytomas are rare causes of sellar tumors of non-pituitary origin and may mimic non-functional pituitary adenomas clinically and radiologically. We report an uncommon case of an intrasellar plasmacytoma presenting as the only manifestation of multiple myeloma.

Disseminated molluscum contagiosum in a patient with chronic lymphocytic leukaemia after alemtuzumab

A 62-year-old man was diagnosed as Rai stage IV B-cell chronic lymphocytic leukaemia (CLL) in 2001. He did not achieve any response to four courses of oral chlorambucil, so he received treatment with intravenous fludarabine attaining partial remission. This, however, lasted only 4 weeks. Intravenous alemtuzumab was administered intravenously at a dose of 30 mg three times a week for 12 weeks (after an initial dose of 3 mg). After treatment, a partial nodular response in the bone marrow was achieved, the splenomegaly was reduced by > 50%, the enlarged lymph nodes disappeared, and the CD4-positive T-lymphocyte count decreased from 30 cells to 3 cells ⁄mm. One week after completion of therapy with alemtuzumab, the patient developed a fever again with multiple flesh-coloured umbilicated papules, located everywhere (top). Skin biopsy confirmed the clinical diagnosis of molluscum contagiosum (bottom). Molluscum contagiosum frequently occurs as an opportunistic infection in immunocompromised patients, and there seems to be a correlation between the extent and severity of molluscum contagiosum and lower CD4-positive T-lymphocyte counts. Alemtuzumab also has a significant activity in fludarabine-treated CLL patients, even if severe immunosuppression frequently occurs.