Stefano Fratoni

Bortezomib-related colon mucositis in a multiple myeloma patient

To the editor, Diarrhoea is a common side effect of bortezomib [1, 2]. It is generally mild and usually does not cause the patient’s hospital admission. The pathogenesis of this unpredictable complication associated with bortezomib remains substantially unclear, although it seems related to a peripheral autonomic neuropathy [2]. Although other pathogenetic mechanisms are involved in the bortezomib-related intestinal toxicity, it is believed that this agent does not induce direct mucosal damage [3]. We report a case of a patient affected by multiple myeloma (MM), presented with severe renal failure, who developed a colon mucositis following bortezomib. On February 2007, a 50-year-old man was admitted for a severe renal failure (serum creatinine 12, 2 mg/dl and creatinine clearance, <15 ml/min) requiring dialysis support. Laboratory tests showed the following: anemia (8, 1 g/dl), serum M protein IgA-k (0, 47 g/dl), Bence Jones proteinuria (10, 5 g/24), bone marrow monoclonal plasma cells (60%) and chromosome 13 deletion. A radiological evaluation revealed multiple litic skeletal lesions. A diagnosis of MM IgA kappa stage III B, according to Durie and Salmon classification, was made; the disease renal involvement was confirmed by biopsy that revealed a light chain tubular damage (myeloma kidney). In view of reported experience on the management of MM complicated by renal failure [4, 5], as induction treatment, the patient was offered a regimen combining bortezomib (1.3 mg/m on days 1, 4, 8 and 11) and dexamethasone (20 mg on days 1–4) given intravenously every 3 weeks for three cycles. He was properly informed and gave his consent. At day +14 of the third cycle of the treatment plan, the patient presented uncontrollable diarrhoea (grade 4 WHO), massive rectorrhage, bloating and severe abdominal pain for which he was admitted. Physical exam showed normal vital signs, diffuse abdominal discomfort with mild tenderness and increased of bowel movements. Oral mucosa was normal, and he did not refer dysphagia. There were no significant changes in blood counts and biochemistry. Coproculture, Clostridium difficilis toxina determination Support Care Cancer (2009) 17:325–327 DOI 10.1007/s00520-008-0573-3

Evaluation of the prognostic role of tumour-associated macrophages in newly diagnosed classical Hodgkin lymphoma and correlation with early FDG-PET assessment

In Hodgkin Lymphoma (HL), about 20% of patients still have relapsed/refractory disease and late toxic effects rate continue to rise with time. ‘Early FDG‐PET’ and tissue macrophage infiltration (TAM) emerged as powerful prognostic predictors. The primary endpoint was to investigate the prognostic role of both early FDG‐PET and TAM; the secondary endpoint was to test if early FDG‐PET positivity could correlate with high TAM score.

Gingival myeloid sarcoma in myelodysplastic syndrome

To the Editor, Myeloid sarcoma (MS) of the gingiva is an extremely rare observation in the context of different myeloproliferative disorders [1–3], including chronic myelomonocytic leukemia (CMML) [1, 4] and acute myeloid leukemia (AML). In CMML patients, gingival hypertrophy is often associated with tumor progression and a more aggressive disease [4]. Although the evolution of myelodysplastic syndrome (MDS) in overt AML is a common occurrence, isolated gingival MS in patients with stable MDS without AML progression has been only exceptionally observed [3]. Herein, we report on a case of gingival MS occurred as isolated AML progression in a previously diagnosed MDS. The patient was a 63year-old Caucasian male who was diagnosed as having MDS, subtype refractory cytopenia with multilineage dysplasia; he presented with trilinear cytopenia (transfusion-dependent severe anemia, thrombocytopenia, and neutropenia), bone marrow (BM) hypocellularity with 3 % of blasts and a cytogenetic abnormality consistent with trisomy 8. According to the IPSS [5] and WPSS [6], the MDS risk was classified as Int-1 and intermediate categories, respectively. The patient had always been healthy and had no significant comorbidities; in particular, no oral and/or gastrointestinal diseases were reported. Given the immune-mediated pathogenesis likely involved in most forms of hypoplastic MDS [7], the patient was managed by cyclosporine. This treatment effort resulted in a substantially maintained stable disease without any significant toxicity. Six months after the diagnosis, the patient complained a well-circumscribed little enlargement of the right upper gingiva surrounded by a painful ulcer. An excision biopsy of the intraoral mass was performed. Histological analysis showed submucosal infiltration by aggregates of myeloperoxidase and CD68 positive myeloid blast cells. A comprehensive hematological revaluation, including BM aspirate and trephine biopsy and a karyotype analysis, revealed a stable MDS without any evidence of AML progression in the BM; in particular, the percentage of blast cells was the same of that found at the MDS diagnosis. Cytogenetic analysis confirmed the presence of trisomy 8. Two courses of fludarabine and high dose of cytosine arabinoside regimen were given resulting in the disappearance of the gingival swelling and the BM blast cells. A suitable donor was not available, for which autologous stem cell transplantation (ASCT) with busulfan and cyclophosfamide conditioning regimen was given as consolidation treatment. However, 3 months after ASCT, he presented a relapse of AML, without any extramedullary localization. AML rapidly progressed until the patient’s death. The unusual intraoral localization of MS and the presence of the trisomy 8 in our case, may suggest a possible link between these findings. Indeed, recurrent oral ulcers and the excess of chromosome The authors have no affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. The authors declare that they have full control of all primary data and they agree to allow the journal to review their data if requested. A. Tendas : L. Scaramucci :M. Giovannini : L. Cupelli : A. Perrotti : P. de Fabritiis Hematology Unit, S. Eugenio Hospital, Rome, Italy

Management of immune thrombocytopoenia in a patient with newly-diagnosed smouldering myeloma and colorectal cancer

Immune thrombocytopoenia (ITP) is one of the most common autoimmune manifestations of B cell lymphoproliferative diseases. The association with multiple myeloma (MM) and solid tumours is rare. Here, a case of ITP associated with asymptomatic multiple myeloma and colon carcinoma, refractory to standard therapy and responsive to rituximab, is described. ITP should be considered in the differential diagnosis of thrombocytopoenia in MM and colon cancer. Understanding of the potential risk and reversibility of ITP should aid in the management of these patients.

Cutaneous involvement in multiple myeloma and bortezomib

Dear Editor, Cutaneous involvement in multiple myeloma (MM) is uncommon. Generally, it occurs in the late stage of the disease and is considered a sign of poor prognosis. Its pathogenesis is not entirely clear. Changes in adhesion molecule expression, especially with regard to CD138 and CD56 antigens, could contribute to different plasma cell migration and homing [1]; therefore, a possible association between the malignant plasma cell immunophenotype and skin infiltration is debated. We report a case of skin lesions from an IgA MM patient who was successfully treated with bortezomib and dexamethasone. On October 2004, a 69-year-old woman was admitted to our centre for a recent and fortuitous finding of a serum monoclonal protein. Laboratory and radiological tests showed the following data:

Hodgkin disease subsequent to follicular lymphoma on maintenance rituximab.

In the course of follicular lymphomas (FL), although a disease transformation in clinically more aggressive lymphoproliferative disorders, mostly diffuse large Bcells non-Hodgkin lymphomas (NHL), may develop in a consistent proportion of cases [1], the occurrence of Hodgkin disease (HD) in a FL patient represents a rare event [2]. A 67-year-old male patient was seen in August 2005 because of right cervical lymphadenopathy. The lymph node was removed. The resected tissue revealed closely packed and uniform follicles consisting of a mixture of small size centrocytes and no more than 15 medium-sized or large centroblasts for high power field. Immunoistochemical staining revealed that neoplastic follicles expressed CD20, CD10, bcl-2 and bcl-6; a proliferation index of 25 – 40% as showed by expression of Ki67 was also detected [Figures 1(A) – 1(L)]. Thus, a diagnosis of grade 2 FL was made. A comprehensive work-up revealed intra-abdominal limphadenopathies; bone marrow was not involved. The patient was diagnosed as having a stage IIIA FL and was enrolled in a clinical trial, receiving four cycles of FND (fludarabine, mitoxantrone and dexametazone) regimen by which he achieved a complete response (CR). Therefore, 4 weekly rituximab (375 mg/m) were given as consolidation treatment and then he received the same dose every 2 months as maintenance therapy. In October 2006, the patient, having received the last rituximab dose 2 months before, presented with general malaise, sweating and weight loss. The physical and radiological evaluations showed cervical and para-aortic enlarged lymph nodes. A comprehensive laboratory work-up revealed mild normochromic anaemia and elevated levels of lactic acid dehydrogenase and erythrocyte sedimentation rate. A left cervical lymph node biopsy was performed. The pathological examination of the removed lymph node revealed classic Reed-Sternberg and mononuclear Hodgkin’s cells (HC), which were surrounded by a rosettes of T CD3 positive lymphocytes [Figures 1(M) – 1(R)]. These features were consistent with a diagnosis of lymphocyte – depletion subtype Hodgkin disease. On immunoistochemical staining, HC were CD15 and CD30 positive and showed a weak bcl-2 expression. In the light of the reported high aggressiveness and the poor prognosis portrayed by HD when occurring in the course of lymphoproliferative disorders [3,4], the patient was treated with two cycles of IEV (ifosfamide, epirubicin and etoposide) regimen. Therefore, the achieved CR was then consolidated by an autologous stem cells transplantation (ASCT), which provided clinical and survival benefits have been reported in this setting [5]. To date, 6 months after the ASCT,

Necrotizing fasciitis in myelodysplastic syndrome: an exceptionally rare occurrence.

To the Editor, Necrotizing fasciitis (NF) is a rapidly progressive, lifethreatening soft tissue infection, caused by group A streptococcus or mixed aerobic/anaerobic bacteria [1]. Although rare, cases of NF have been reported in patients with acute leukemias [2], interpreted as paraneoplastic phenomena; however, NF in patients with myelodysplastic syndrome (MDS) has not been reported so far. We describe the case of a 58-year-old man with MDS subtype refractory anemia with excess blasts who developed NF during the course of the disease. Cytogenetic analysis revealed an unfavorable clonal alteration, t(6;9)(p22;q34), resulting in the DEKCAN gene fusion [3]; therefore, the patient was classified as Int-2, which is considered a very high risk category, according to the IPSS and WPSS. No previous diseases or significant comorbidities were reported, and he was eligible to receive stem cell transplantation from an HLA identical sister. Because of the high risk of progression to AML, a bridge therapy with azacitidine (75 mg/m, schedule 5+2+ 2, each cycle every 4 weeks) [4] was given, in the time interval required for donor screening. The treatment with azacitidine was well tolerated, and only mild toxicities were detected. After four courses of therapy, a complete remission (CR) was achieved, according to the International Working Group 2006 criteria [5]. Shortly after the completion of the fifth treatment course, the patient complained of elevated fever associated with typical signs of soft tissue infection, such as tense edema, severe pain, blisters/bullae, crepitus, and subcutaneous gas, in the right hand. He reported a minor trauma on the right hand as a possible origin of the infectious complication. A diagnosis of NF was made, followed by broad spectrum antibiotic therapy and early and complete surgical debridement. Peripheral blood, wound, and skin blister cultures revealed several bacterial species, such as Enterococcus faecium, Staphylococcus haemolyticus, and Acinetobacter lwoffii; Candida albicans was also isolated. The antimicrobial therapy was adjusted according to microbiological findings. Despite these measures, including the application of hyperbaric therapy, the local lesion progressed rapidly to the whole arm, and the patient deteriorated until death due to septic shock. In conclusion, this case represents the first description of NF in the MDS setting. In our experience, this infectious complication has led to a fatal outcome although it occurred while the patient was apparently well and in CR after an uncomplicated and well-tolerated treatment with azacitidine. Hematologists should be aware of this infectious complication with a severe prognosis and a rapidly progressive clinical course, although this is rarely reported in the preleukemic setting [2].

Evolution of chronic myelomonocytic leukemia from refractory anemia: the unusual course of a myelodysplastic syndrome.

TO THE EDITOR: Transformation from myelodysplastic syndrome (MDS) to chronic myelomonocytic leukemia (CMML) is rarely observed. However, this has been reported in cases of refractory anemia with ring sideroblasts or excess of blasts [1-4]. Moreover, MDS patients may present with monocytosis that does not meet the diagnostic criteria of CMML, which makes diagnosis and classification of these atypical mixed disorders a challenge [5, 6]. These difficulties in diagnostic classification and prognostic stratification may be concerning with regard to decision-making, particularly in this new era of effective disease-modifying therapies, such as hypomethylating agents [6, 7]. Recently, we faced such concerns during the management of a patient who developed CMML 7 years after having been diagnosed with refractory anemia (RA). The full clinical onset of CMML was preceded by progressive loss of response to ongoing treatment with an erythropoiesis-stimulating agent (ESA), worsening anemia, thrombocytopenia, leukocytosis, and increasing monocytosis. A morphological study of the peripheral blood (PB) and bone marrow (BM) revealed the coexistence of myelodysplastic and myeloproliferative syndromes. A cytogenetic alteration (45, X0,-Y), which was not present at diagnosis of RA 7 years earlier, was also detected during the CMML phase. The patient received azacitidine and showed a good response. Here, we describe this rare case and its implications in disease classification and management. On January 2005, a 74-year-old man presented with moderately macrocytic slight thrombocytopenia. Five years earlier (in 2000), he had received postoperative radiotherapy after radical prostatectomy for prostate cancer. Apart from this prostatic neoplasm, for which a regular oncological follow-up had confirmed a persistent complete remission until then, he mentioned one previously cured gastric ulcer and well-controlled hypertension. He complained of fatigue and general unease for the past few weeks. A complete blood count prescribed by his general practitioner had revealed macrocytic anemia with a low reticulocyte count, mild thrombocytopenia, and slight neutropenia. On admission, he appeared pale and fatigued. A comprehensive laboratory evaluation did not reveal any remarkable abnormalities. His coagulative profile and renal and hepatic function were normal. Suspicions of hemolytic disorders, virus infections, and iron and vitamin deficiencies were also dismissed. Morphological examination of PB smears showed isolated erythrocyte macrocytosis but did not provide any other diagnostic findings. BM aspiration and trephine biopsy were performed. BM examination revealed hypercellular BM with evident erythrodysplasia and 6% of blasts without fibrosis. Conventional karyotyping and fluorescence in situ hybridization analyses did not show abnormalities. Therefore, the patient was diagnosed with MDS, RA, according to the French-American-British classification. The patient had an International Prognostic Scoring System score of 1 (intermediate-1 risk). On admission and during the diagnostic phase, he received 4 units of red blood cell (RBC) concentrates. Thus, the patient was scheduled to receive ESA at a weekly dose of 40,000 units by subcutaneous injection (in January 2005). Since then, the patient was regularly followed-up at our clinic and continued to receive erythropoietin treatment. Normal PB values were maintained without the requirement for transfusion, clinical complications, or side effects until June 2012, when his hematologic status slowly began to deteriorate. Worsening anemia (requiring RBC transfusions), thrombocytopenia, and leukocytosis with absolute monocytosis became prominent. A comprehensive medical examination was performed. The examination of PB smears showed absolute monocitosis with 2% of circulating blasts. BM examination showed marked erythroid dysplasia and monocytosis with 15% blasts. A karyotype abnormality, such as 45, X0,-Y, which was not detected at initial diagnosis of RA 7 years earlier, was also found; however, the JAK2 V617F mutation was absent. Therefore, the patient was diagnosed with RA, coexisting with type II CMML. The patient had a MD Anderson Prognostic Score of 3 (intermediate-2 risk) [8]. After a brief course of hydroxycarbamide, administered in order to reduce leukocytosis, the patient received 6 cycles of azacitidine (75 mg/m2, schedule 5+2+2, each cycle every 4 weeks), according to approved indications [9]. After the second course, transfusion independence was achieved and the PB counts significantly improved with disappearance of monocytosis. Complete remission of CMML was achieved after 6 courses of hypomethylating therapy, without any adverse events. In conclusion, this case represents an atypical presentation of CMML secondary to MDS. In addition to its rarity and anecdotal interest, we believe that this report should be discussed with regard to several topics, such as the possible evolution of low-risk MDS in CMML, the existence of secondary CMML as a distinct disease, its absence in the current classification systems, and, finally, the efficacy of hypomethylating therapy [4, 10].

Acute lymphoblastic leukemia subsequent to autoimmune hemolytic anemia: a case report

Dear Editor, Autoimmune hemolytic anemia (AIHA) is a serious complication of lymphoid malignancies, mostly chronic lymphocytic leukemia and B cell non-Hodgkin lymphomas [1, 2]. Very few descriptions of AIHA developed in patients affected by B cells acute lymphoblastic leukemia (ALL) [3, 4] have been reported. We recently observed and hereby report the case of a patient who developed an early pre-B ALL, massively infiltrating the ileum, 9 months after the diagnosis of AIHA, while the latter was in complete remission. In June 2006, a 56-year-old man came to visit referring severe malaise, fatigue, and the emission of hyperchromyc urine. On physical examination, he presented pallor, jaundice, and tachycardia; liver and spleen were palpable 2 cm below the costal margin. A comprehensive laboratory workup revealed a severe anemia associated with a typical Coombs-positive (warm antibodies) hemolytic pattern. A total-body computed tomography (CT) scan showed no pathologic findings. In particular, no signs of infiltration of the ileum were detected. Before starting steroids, a bone marrow (BM) aspirate and a trephine biopsy were done; an erytroyd hyperplasia and a small amount of mature lymphocytes were observed. A high dose of prednisone was allowed for a rapid hematologic recovery, and he was discharged and regularly followed as an outpatient. Basing on hematologic findings, prednisone was progressively reduced and then definitively withdrawn 4 months later. In March 2007, he came to visit referring malaise and fatigue. A severe pancytopenia was found. A BM aspirate allowed the diagnosis of B ALL, L2 according to the French–American–British classification. The lymphoid blasts resulted as pre-B cells (CD10 and TdT positive) on immunophenotyping. The trephine biopsy taken at the time of the diagnosis of AIHA was retrospectively evaluated. No lymphoid cells expressing CD10 and/or TdT were present. The patient was enrolled in a clinical protocol and received a regimen including vincristine, daunorubicine, prednisone, and Lasparaginase as induction therapy. During aplasia, a septic shock because of Escherichia coli occurred and was then resolved by standard measures and broad-spectrum antibiotic therapy. The patient fully recovered, but 15 days later, a sudden bowel perforation complicated his clinical course; he underwent a laparotomy; a long tract of ileum, appearing necrotic, was removed. The patient’s clinical conditions progressively deteriorated until his death supervened for a septic shock refractory to all intensive care and resuscitating measures. On histological examination, the removed bowel tract showed a massive infiltration of Peyer’s plaques by immature lymphoid B cells and an extensive intestinal necrosis, involving all parietal structures. This case presents some peculiar features, such an AHIA followed by a pre-B cells ALL, which, at the best of our knowledge, has not been reported so far. A bidirectional association between autoimmune diseases and lymphoproliferative disorders has been recently Ann Hematol (2008) 87:237–238 DOI 10.1007/s00277-007-0370-y

Gelatinous Degeneration of the Bone Marrow: Two Case Reports Showing Different Hematological Features and Clinical Outcomes

patient did not present either spleen or liver enlargement. Full blood count on admission showed normochromicnormocytic anemia with reticulocytopenia and normal white blood cell and platelet counts. Total and unconjugated bilirubin and serum haptoglobin levels were normal. Direct and indirect Coombs tests were negative. Serological tests for human immunodeficiency virus, cytomegalovirus, Epstein-Barr virus, parvovirus B19 and B and C hepatitis viruses were negative. In addition, the serum levels of triiodothyronine were normal. Moreover, no clinical or laboratory features of autoimmune diseases were revealed. Examination of peripheral blood smears revealed normal red blood cells, whereas erythrocyte fragments were not detectable. The radiological results, which included a whole-body CT, revealed no abnormalities. An occult blood loss was ruled out by fecal and urine analyses. A BM aspirate performed on admission resulted in a dry tap. Therefore, a BM trephine biopsy was taken. Histological examination of the BM sample revealed GMT ( fig. 1 ). The patient did not respond to treatment, which included erythropoietin, prednisone and cyclosporine. Currently, she is maintained with supportive therapy only, consisting of two units of packed red blood cells every 2 weeks. For the past 22 months, her hematological status has remained stable. Gelatinous bone marrow transformation (GMT) is a rare histological disorder of unknown pathogenesis. It is characterized by fat cell atrophy, focal loss of hematopoietic cells and deposition of extracellular gelatinous substances, which are histochemically mucopolysaccharides, rich in hyaluronic acid [1] . GMT has been reported to occur in association with chronic debilitating diseases such as anorexia nervosa, malnutrition and HIV infection, and following treatment-induced cytotoxicity of the bone marrow (BM) [2, 3] . However, very few cases of GMT have been reported outside the setting of malnutrition and the cancer anorexia-cachexia syndrome. This complication has been described in association with several hematological malignancies, such as myelodysplastic syndrome and acute myeloblastic leukemia [4] with monosomy 7, and with other neoplastic disorders [5] . In this report, we describe 2 cases of GMT that were not associated with any of the previously reported medical conditions and were characterized by different hematological features and clinical outcomes. The first patient was a 64-year-old Caribbean woman who had been living in Rome for more than 30 years. She was referred to our clinic in December 2005 because of anemia. Her past medical history was unremarkable. In particular, she did not use alcohol, drugs or tobacco. Her nutritional status was very good. The physical examination was unremarkable, with the exception of pallor; the Received: April 30, 2007 Accepted after revision: July 12, 2007 Published online: September 21, 2007