Nicola Orofino

Effects of first- and second-generation tyrosine kinase inhibitor therapy on glucose and lipid metabolism in chronic myeloid leukemia patients: a real clinical problem?

Background Tyrosine kinase inhibitors (TKIs) have dramatically changed the prognosis of patients with chronic myeloid leukemia (CML). They have a distinct toxicity profile that includes glycometabolic alterations: i.e. diabetes mellitus (DM), impaired fasting glucose (IFG), and the metabolic syndrome (MS). The aim of this study was to evaluate the prevalence of these alterations in a cohort of CML-chronic phase patients treated with imatinib, dasatinib or nilotinib. Methods The study involved 168 consecutive CML-chronic phase patients with no history of DM/IFG or MS. Anthropometric and metabolic parameters were assessed, and DM/IFG and MS were diagnosed based on the criteria of the American Diabetes Association and the National Cholesterol Education Program-Adult Treatment Panel III, respectively. Results The nilotinib group had significantly higher levels of fasting plasma glucose, insulin, C-peptide, insulin resistance, and total and LDL cholesterol than the imatinib and dasatinib groups. DM/IFG were identified in 25% of the imatinib- and dasatinib-treated patients, and 33% of those in the nilotinib cohort (p = 0.39 vs imatinib and p = 0.69 vs dasatinib). A diagnosis of MS was made in 42.4% of the imatinib-treated patients, 37.5% of the dasatinib-treated patients, and 36.1% of the nilotinib-treated patients (p = 0.46 vs imatinib and p = 0.34 vs dasatinib). Conclusions Treatment with nilotinib does not seem to induce DM/IFG or the MS to a significantly higher extent than imatinib or dasatinib, though it causes a worse glycometabolic profile. These findings suggest the need for a close monitoring of glucose and lipid metabolism and a multidisciplinary approach in patients treated with nilotinib.

Current and emerging treatment options for patients with relapsed myeloma.

Multiple myeloma (MM) is a neoplastic disorder. It results from proliferation of clonal plasma cells in bone marrow with production of monoclonal proteins, which are detectable in serum or urine. MM is clinically characterized by destructive bone lesions, anemia, hypercalcemia and renal insufficiency. Its prognosis is severe, with a median survival after diagnosis of approximately 3 years due to frequent relapses. Treatments for patients with relapsed/refractory MM include hematopoietic cell transplantation, a rechallenge using a previous chemotherapy regimen or a trial of a new regimen. The introduction of new drugs such as thalidomide, lenalidomide and bortezomib has markedly improved MM outcomes. When relapse occurs, the clinicians challenge is to select the optimal treatment for each patient while balancing efficacy and toxicity. Patients with indolent relapse can be first treated with a 2-drug or a 3-drug combination. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. Autologous stem cell transplantation should be considered as salvage therapy at first relapse for patients who have cryopreserved stem cells early in the disease course. The aim of this review is to provide an overview on the pharmacological and molecular action of treatments used for patients with relapsed/refractory multiple myeloma.

Marked eosinophilia as initial presentation of breast implant-associated anaplastic large cell lymphoma

Nicola Orofino, Francesca Guidotti, Daniele Cattaneo, Mariarita Sciumè, Umberto Gianelli, Agostino Cortelezzi and Alessandra Iurlo Oncohematology Division, IRCCS Ca’ Granda – Maggiore Policlinico Hospital Foundation, University of Milan, Milan, Italy; Hematopathology Service, Division of Pathology, Department of Pathophysiology and Transplantation, University of Milan and IRCCS Ca’ Granda – Maggiore Policlinico Hospital Foundation, Milan, Italy; Oncohematology Unit of the Elderly, IRCCS Ca’ Granda – Maggiore Policlinico Hospital Foundation, Milan, Italy

Clinical and morphologic features in five post-polycythemic myelofibrosis patients treated with ruxolitinib

Dear Editor,Myelofibrosis (MF), either primary (PMF) or secondary topolycythemia vera (post-PV MF), is associated with a dismalprognosis in terms of overall survival (OS) and quality of life(QoL) [1]. Its clinical management is still complicated, and atpresent,theonlycurativetreatmentisrepresentedbyallogenichematopoietic stem cell transplantation. However, the thera-peutic landscape of MF has dramatically changed with theintroduction of JAK1/2 inhibitors as ruxolitinib. The COM-FORT trials showed that ruxolitinib is effective in reducingsplenomegalyandMF-relatedsymptoms,thereforeimprovingQoL[2,3];morerecently,longer-termfollow-upstudiesdem-onstrated also an OS advantage [4, 5].Here, we describe the clinical and morphologic features offivepost-PVMFcasesselectedamong15MFpatientstreatedwith ruxolitinib in our institution. To our knowledge, onlyisolated reports described the morphologic changes occurringin ruxolitinib-treated patients, mostly focusing on modifica-tions in marrow fibrosis degree [6–9].The main clinical and morphologic features of these casespre- and on-treatment are summarized in Table 1. After amedian treatment of 22.1 months, all cases showed improve-mentinIPSS, constitutionalsymptoms, and spleensize, asso-ciated with a slight reduction in the JAK2 allele burden. Inaddition,pre-treatment leukocytosisnormalizedoratleast de-creased in two cases (patients 1 and 5, respectively). Regard-ing ruxolitinib dosage, it varied among the patients, as it waschosen initially according to their platelets counts and thenmodified mainly because of hematological toxicities. Fourpatients are still alive, and one died because of leukemic evo-lution after 22.1 months of treatment.Interestingly, three patients showed complex karyotypes,either before or on-treatment: however, differently fromPMF [10], this did not represent a negative predictive factorof response to therapy.How to evaluate bone marrow (BM) changes duringruxolitinibtherapyiscurrentlydebated.Wecomparedindetailcellularity, hematopoietic lineages, and stromal modificationsin both pre- and on-treatment BM biopsies.Beforetreatment,allcasesshowedmarkedlyincreasedcel-lularity(85–95%)andpolymorphicmegakaryocytes,formingloose and tight clusters; three cases displayed significant in-creasedmyeloid/erythroid(M:E)ratio(>8:1).ThreehadMF-2fibrosis and two MF-3. On-treatment biopsies showed de-creased cellularity in two cases, with reduction of both mye-loid and erythroid lineages. The M:E ratio normalized or atleast decreased in all patients, whereas megakaryocytes’ mor-phology showed only minor changes. In three cases, multifo-cal decrease of marrow fibrosis was documented but only inone the overall fibrosis downgraded from MF-3 to MF-2.In summary, although the small number of cases does notallow definite conclusions, the efficacy of ruxolitinib in post-PV MF is strongly suggested. As in PMF patients, clinicalresponse is quick and sustained in most cases. However,

The myeloproliferative neoplasms, unclassifiable: clinical and pathological considerations

In this study, we investigate in detail the morphological, clinical and molecular features of 71 consecutive patients with a diagnosis of myeloproliferative neoplasms, unclassifiable. We performed a meticulous morphological analysis and found that most of the cases displayed a hypercellular bone marrow (70%) with normal erythropoiesis without left-shifting (59%), increased granulopoiesis with left-shifting (73%) and increased megakaryocytes with loose clustering (96%). Megakaryocytes displayed frequent giant forms with hyperlobulated or bulbous nuclei and/or other maturation defects. Interestingly, more than half of the cases displayed severe bone marrow fibrosis (59%). Median values of hemoglobin level and white blood cells count were all within the normal range; in contrast, median platelets count and lactate dehydrogenase were increased. Little less than half of the patients (44%) showed splenomegaly. JAK2V617F mutation was detected in 72% of all patients. Among the JAK2-negative cases, MPLW515L mutation was found in 17% and CALR mutations in 67% of the investigated cases, respectively. Finally, by multiple correspondence analysis of the morphological profiles, we found that all but four of the cases could be grouped in three morphological clusters with some features similar to those of the classic BCR–ABL1-negative myeloproliferative neoplasms. Analysis of the clinical parameters in these three clusters revealed discrepancies with the morphological profile in about 55% of the patients. In conclusion, we found that the category of myeloproliferative neoplasm, unclassifiable is heterogeneous but identification of different subgroups is possible and should be recommended for a better management of these patients.

Transient elastography spleen stiffness measurements in primary myelofibrosis patients: a pilot study in a single centre.

Keywords: primary myelofibrosis; bone marrow fibrosis; transient elastography; spleen stiffness; ruxolitinib

Choosing treatment options for patients with relapsed/refractory multiple myeloma

Multiple myeloma (MM) is a clonal plasma cell disorder that is still incurable using conventional treatments. Over the last decade, advances in front-line therapy have led to an increase in survival, but there are still some doubts in the case of relapsed/refractory disease. We searched the PubMed database for articles on treatment options for patients with relapsed/refractory MM published between 1996 and 2013. These treatments included hematopoietic cell transplantation (HCT), rechallenges using previous chemotherapy regimens, and trials of new regimens. The introduction of new agents such as the immunomodulatory drugs (IMIDs) thalidomide and lenalidomide, and the first-in-its-class proteasome inhibitor bortezomib, has greatly improved clinical outcomes in patients with relapsed/refractory MM, but not all patients respond and those that do may eventually relapse or become refractory to treatment. The challenge is therefore to select the optimal treatment for each patient by balancing efficacy and toxicity. To do this, it is necessary to consider disease-related factors, such as the quality and duration of responses to previous therapies, and the aggressiveness of the relapse, and patient-related factors such as age, comorbidities, performance status, pre-existing toxicities and cytogenetic patterns. The message from the trials reviewed in this article is that the new agents may be used to re-treat relapsed/refractory disease, and that the sequencing of their administration should be modulated on the basis of the various disease and patient-related factors. Moreover, our understanding of the pharmacology and molecular action of the new drugs will contribute to the possibility of developing tailored treatment.

Erdheim-Chester Disease With Multiorgan Involvement, Following Polycythemia Vera: A Case Report.

Abstract Erdheim–Chester disease is a rare form of non-Langerhans cell histiocytosis characterized by the migration and infiltration of lipid-laden CD68+, CD1a− and S100− histiocytes to various target organs, which leads to the disruption of physiological tissue architecture and reactive fibrosis, and thus impairs organ function. We describe the first case of a patient with Erdheim–Chester disease with multiorgan involvement developed after 6 years from polycythemia vera diagnosis. During the follow-up, an abdominal ultrasound scan revealed the presence of dense, bilateral perinephric infiltration. A computed tomographic guided core biopsy was performed in order to identify the histological nature of this lesion, and a morphological analysis demonstrated the accumulation of foamy histiocytes surrounded by fibrosis. The BRAFV600E mutation was detected, and a diagnosis of Erdheim–Chester disease was made. The extreme rarity of Erdheim–Chester disease strongly suggests the existence of potentially common element(s) that may have contributed to the pathogenesis of both disorders. Obviously, further studies are needed to clarify the mutual roles and effects of JAK2 and BRAF mutations in this patient, as well as their possible therapeutic implications.

Low-dose alemtuzumab in refractory/relapsed chronic lymphocytic leukemia: Genetic profile and long-term outcome from a single center experience

Relapsed/refractory chronic lymphocytic leukemia (CLL) represents a clinical challenge, in particular when high risk gene mutations occur. In this setting, alemtuzumab was recognized to be effective. This retrospective study evaluates long‐term efficacy and tolerability of low‐dose alemtuzumab in relapsed/refractory CLL and correlates clinical outcome with biological feature. Sixty‐two consecutive patients (median age 68 years) were evaluated; alemtuzumab was administered 30 mg weekly for up to 18 weeks. Among the patients included in the analysis, 37% were fludarabine‐refractory, 33.3% carried a TP53 disruption, 14.8% a NOTCH1 mutation and 9% a SF3B1 mutation. Overall response rate (ORR) was 61.3% (complete remission 25.8%). After a median follow‐up of 43 months, overall survival (OS) and progression free survival (PFS) were 43.1 and 15 months, respectively; while ORR was 77.8% for patients carrying TP53 disruptions (OS 33.8 months) and 43.5% for fludarabine‐refractory patients (OS 30 months). Noteworthy, long‐term survivors (OS ≥ 36 months) were 54.8%. None of the biological poor risk factors negatively impacted on ORR, PFS and OS. Grade ≥3 cytopenia occurred in 24.2% patients, 6.5% experienced a grade ≥3 non‐CMV infection and no grade ≥3 CMV‐event occurred. In conclusion, low dose‐alemtuzumab is safe and effective in relapsed/refractory CLL, also in a long‐term follow‐up and high‐risk genetic subgroups. Am. J. Hematol. 90:970–974, 2015.

Multifactorial neutropenia in a patient with acute promyelocytic leukemia and associated large granular lymphocyte expansion: A case report

Neutropenia in the setting of acute hematological malignancies may impact disease prognosis, thus affecting therapy dose intensity. This is often due to chemotherapy-induced aplasia as well as to the disease itself. However, chronic neutropenia deserves further investigation, as the management of reversible concomitant causes may avoid treatment delay. The present study describes a case of an acute promyelocytic leukemia patient with chronic severe neutropenia of multifactorial origin, including acute leukemia itself, chemotherapy, autoimmune activation with anti-platelets and anti-neutrophil antibodies positivity, and the rare association of large granular lymphocyte (LGL) expansion. As neutropenia may challenge the diagnosis and treatment of acute malignancies, clinicians and hematopathologists must discuss the differential diagnosis in order to avoid misdiagnosing and undertreating concomitant diseases. In particular, LGL chronic expansion and autoimmunity should be considered.