Ambra Di Veroli

Infections increase the risk of central venous catheter-related thrombosis in adult acute myeloid leukemia

INTRODUCTION Central venous catheters (CVC) related thrombosis (CRT) represents a well known complication in patients with acute myeloid leukemia (AML) receiving intensive chemotherapy but the efficacy of antithrombotic prophylaxis still remains controversial. PATIENTS AND METHODS We analyzed 71 consecutive AML patients whose CVC was inserted before each chemotherapy cycle for an overall number of 106 CVC placements. In 47/106 insertions, a prophylaxis with 100 IU/kg/day low molecular weight heparin (LMWH) was administered for 7 days after CVC insertion and additional 7 after CVC removal. This unconventional dose of LMWH, although higher than usual, appeared adequate for a short-course approach. LMWH was delivered regardless of the platelet (PLT) count once provided that it should have been maintained above 20 x 10(9)/L by transfusions. RESULTS Of 106 insertions, we observed 19 (18%) episodes of CRT, 58 (54%) of sepsis and 50 (47%) infections of CVC-exit site with no difference between LMWH and no-LMWH group. Occurrence of CRT was significantly associated with CVC-exit site infections (14/19, p=0.01) and sepsis (16/19, p=0.005) with no difference between LMWH and no-LMWH group. In multivariate analysis, both CVC-exit site infections and sepsis were confirmed to be independent risk factors for CRT development. CONCLUSION Our retrospective study, although based on a small sample size, suggests that the occurrence of CVC-exit site infections and neutropenic sepsis following chemotherapy significantly increases the risk of CRT in AML, independently from the use of LMWH prophylaxis.

Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia in the ATRA and ATO era

The role of allogeneic stem cell transplant in advanced acute promyelocytic leukemia patients who received standard first- and second-line therapy is still unknown. We report the outcome of 31 acute promyelocytic leukemia patients (median age 39 years) who underwent allogeneic transplant in second remission (n=15) or beyond (n=16). Sixteen patients were real-time polymerase chain reaction positive and 15 negative for PML/RARA pre-transplant. The 4-year overall survival was 62% and 31% for patients transplanted in second remission and beyond, respectively (P=0.05), and 64% and 27% for patients with pre-transplant negative and positive real-time polymerase chain reaction, respectively (P=0.03). The 4-year cumulative incidence of relapse was 32% and 44% for patients transplanted in second remission and beyond, respectively (P=0.37), and 30% and 47% for patients transplanted with negative and positive real-time polymerase chain reaction, respectively (P=0.30). Transplant-related mortality was 19.6%. In conclusion, allogeneic transplant is effective in advanced acute promyelocytic leukemia in the all-trans-retinoic acid and arsenic trioxide era, and should be considered once relapse is diagnosed.

Phase II Study of Bortezomib as a Single Agent in Patients with Previously Untreated or Relapsed/Refractory Acute Myeloid Leukemia Ineligible for Intensive Therapy.

We explored the safety and efficacy of bortezomib given as single agent in patients with untreated or relapsed/refractory acute myeloid leukemia (AML), unfit for conventional chemotherapy. Fourteen patients were treated with bortezomib 1.5 mg/m2 administered twice weekly for two weeks, every 3 weeks. Median age was 70 years (range 60–81) and the median number of cycles delivered was 2 (range 1–4). Of 13 evaluable patients, in 8 (61%), the administration of bortezomib resulted in an antileukemic effect as demonstrated by peripheral blood and/or bone marrow blast reduction. In 4 (50%) of these 8, a decrease by 37% of transfusion requirement was also observed (P = 0.009). Overall median survival was 4 months (range 0.25–10). Neurotoxicity was the most frequent adverse event with 7 of 13 (54%) patients experiencing grades 3-4 peripheral neuropathy. Neurotoxicity led to treatment discontinuation in 4 (57%) of 7. In conclusion, the observed anti-leukemic activity of bortezomib indicates that there is room for designing additional studies in which combination with other chemotherapeutic agents should be considered. Clinical registration no.: EUDRACT 2006-006923-38.

Platelet gel for treatment of mucocutaneous lesions related to graft-versus-host disease after allogeneic hematopoietic stem cell transplant.

BACKGROUND: Platelet (PLT) gel has been successfully used in tissue regeneration of diabetic/surgical wounds through the releasing of growth factors such as basic fibroblast growth factor and PLT‐derived growth factor. Therefore, the PLT gel could represent a therapeutic tool in treating the deep and painful wounds sometimes occurring during graft‐versus‐host disease (GVHD).

Molecular remission in advanced acute promyelocytic leukaemia after treatment with the oral synthetic retinoid Tamibarotene.

Chan, W.C., Foucar, K., Morice, W.G. & Catovsky, D. (2008) T-cell large granular lymphocytic leukaemia. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (ed. by S.H. Swerdlow, E. Campo, N.L. Harris, E.S. Jaffe, S.A. Pileri, H. Stein, J. Thiele & J.W. Vardiman), pp. 272–273. IARC Press, Lyon. Chen, W., Karandikar, N.J., McKenna, R.W. & Kroft, S.H. (2007) Stability of leukemia-associated immunophenotypes in precursor B-lymphoblastic leukemia/lymphoma: a single institution experience. American Journal of Clinical Pathology, 127, 39–46. Jamal, S., Picker, L.J., Aquino, D.B., McKenna, R.W., Dawson, D.B. & Kroft, S.H. (2001) Immunophenotypic analysis of peripheral T-cell neoplasms. A multiparameter flow cytometric approach. American Journal of Clinical Pathology, 116, 512–526. Kroft, S.H. (2004) Monoclones, monotypes, and neoplasia pitfalls in lymphoma diagnosis. American Journal of Clinical Pathology, 121, 457–459. Lamy, T. & Loughran, Jr, T.P. (2003) Clinical features of large granular lymphocyte leukemia. Seminars in Hematology, 40, 185–195. Lundell, R., Hartung, L., Hill, S., Perkins, S.L. & Bahler, D.W. (2005) T-cell large granular lymphocyte leukemias have multiple phenotypic abnormalities involving pan-T-cell antigens and receptors for MHC molecules. American Journal of Clinical Pathology, 124, 937–946. Mohan, S.R., Clemente, M.J., Afable, M., Cazzolli, H.N., Bejanyan, N., Wlodarski, M.W., Lichtin, A.E. & Maciejewski, J.P. (2009) Therapeutic implications of variable expression of CD52 on clonal cytotoxic T cells in CD8+ large granular lymphocyte leukemia. Haematologica, 94, 1407–1414. Morice, W.G., Kurtin, P.J., Leibson, P.J., Tefferi, A. & Hanson, C.A. (2003) Demonstration of aberrant T-cell and natural killer-cell antigen expression in all cases of granular lymphocytic leukaemia. British Journal of Haematology, 120, 1026–1036. Morice, W.G., Kimlinger, T., Katzmann, J.A., Lust, J.A., Heimgartner, P.J., Halling, K.C. & Hanson, C.A. (2004) Flow cytometric assessment of TCR-Vbeta expression in the evaluation of peripheral blood involvement by T-cell lymphoproliferative disorders: a comparison with conventional T-cell immunophenotyping and molecular genetic techniques. American Journal of Clinical Pathology, 121, 373–383. Olteanu, H., Karandikar, N.J., Eshoa, C. & Kroft, S.H. (2010) Laboratory findings in CD4(+) large granular lymphocytoses. International Journal of Laboratory Hematology, 32, e9–e16.

Chelation efficacy and erythroid response during deferasirox treatment in patients with myeloproliferative neoplasms in fibrotic phase.

At present, very few data are available on deferasirox (DFX) in the treatment of patients with Philadelphia‐negative myeloproliferative neoplasms in fibrotic phase (FP‐MPN) and transfusion dependence. To address this issue, a retrospective analysis of 28 patients (22 male and 6 female) with FP‐MPN and iron overload secondary to transfusion dependence was performed, based on patients enrolled in the database of our regional cooperative group who received treatment with DFX. DFX was started after a median interval from diagnosis of 12.8 months (IR 7.1–43.1) with median ferritin values of 1415 ng/mL (IR 1168–1768). Extra‐hematological toxicity was reported in 16 of 28 patients (57.1%), but only two patients discontinued treatment due to toxicity. Among 26 patients evaluable for response (≥6 months of treatment), after a median treatment period of 15.4 months (IR 8.1–22.3), 11 patients (42.3%) achieved a stable and consistent reduction in ferritin levels <1000 ng/mL. As for hematological improvement, 6 of 26 patients (23%) showed a persistent (>3 months) rise of Hb levels >1.5 g/dL, with disappearance of transfusion dependence in four cases. Treatment with DFX is feasible and effective in FP‐MPN with iron overload. Moreover, in this setting, an erythroid response can occur in a significant proportion of patients.

Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis

In patients with Myelofibrosis (MF) treated with ruxolitinib (RUX), the response is unpredictable at therapy start. We retrospectively evaluated the impact of clinical/laboratory factors on responses in 408 patients treated with RUX according to prescribing obligations in 18 Italian Hematology Centers. At 6 months, 114 out of 327 (34.9%) evaluable patients achieved a spleen response. By multivariable Cox proportional hazard regression model, pre-treatment factors negatively correlating with spleen response were: high/intermediate-2 IPSS risk (p=0.024), large splenomegaly (p=0.017), transfusion dependency (p=0.022), platelet count <200×109/l (p=0.028), and a time-interval between MF diagnosis and RUX start >2 years (p=0.048). Also, patients treated with higher (≥10 mg BID) average RUX doses in the first 12 weeks achieved higher response rates (p=0.019). After adjustment for IPSS risk, patients in spleen response at 6 months showed only a trend for better survival compared to non-responders. At 6 months, symptoms response was achieved by 85.5% of 344 evaluable patients; only a higher (>20) Total Symptom Score significantly correlated with lower probability of response (p<0.001). Increased disease severity, a delay in RUX start and titrated doses <10 mg BID were associated with patients achievinglower response rates. An early treatment and higher RUX doses may achieve better therapeutic results.In patients with Myelofibrosis (MF) treated with ruxolitinib (RUX), the response is unpredictable at therapy start. We retrospectively evaluated the impact of clinical/laboratory factors on responses in 408 patients treated with RUX according to prescribing obligations in 18 Italian Hematology Centers. At 6 months, 114 out of 327 (34.9%) evaluable patients achieved a spleen response. By multivariable Cox proportional hazard regression model, pre-treatment factors negatively correlating with spleen response were: high/intermediate-2 IPSS risk (p=0.024), large splenomegaly (p=0.017), transfusion dependency (p=0.022), platelet count <200x109/l (p=0.028), and a time-interval between MF diagnosis and RUX start >2 years (p=0.048). Also, patients treated with higher (≥10 mg BID) average RUX doses in the first 12 weeks achieved higher response rates (p=0.019). After adjustment for IPSS risk, patients in spleen response at 6 months showed only a trend for better survival compared to non-responders. At 6 months, symptoms response was achieved by 85.5% of 344 evaluable patients; only a higher (>20) Total Symptom Score significantly correlated with lower probability of response (p<0.001). Increased disease severity, a delay in RUX start and titrated doses <10 mg BID were associated with patients achievinglower response rates. An early treatment and higher RUX doses may achieve better therapeutic results.

Spleen enlargement is a risk factor for thrombosis in essential thrombocythemia: Evaluation on 1,297 patients

Spleen enlargement, present in 10–20% of Essential Thrombocythemia (ET) patients at diagnosis, is a feature clinically easy to assess, confirmable by echography with a very low chance of misinterpretation. Nonetheless, the clinical and prognostic role of splenomegaly has been seldom evaluated. From 1979 to 2013, 1297 ET patients retrospectively collected in the database of the Lazio Cooperative Group and Bologna University Hospital were evaluable for spleen enlargement at diagnosis and included in the analysis. On the whole, spleen was enlarged in 172/1297 (13.0%) patients; in most cases (94.8%) splenomegaly was mild (≤5 cm). Patients with splenomegaly were younger, predominantly male, presented higher platelet count and JAK2V617F allele burden and had a lower incidence of concomitant cardiovascular risk factors. At least one thrombotic event during follow‐up occurred in 97/1,125 (8.6%) patients without spleen enlargement compared to 27/172 (15.7%) patients with spleen enlargement (P = 0.003). Despite comparable use of cytoreductive/antiplatelet therapies in the two groups, the cumulative risk of thrombosis at 5 years was significantly higher in patients with baseline splenomegaly (9.8% versus 4.4% in patients without splenomegaly, P = 0.012). In multivariate analysis exploring risk factors for thrombosis, splenomegaly retained its negative prognostic role, together with previous thrombosis, leucocyte count and male gender. Baseline splenomegaly seems to be an independent additional risk factor for thrombosis in nonstrictly WHO‐defined ET patients. This data could be useful in the real‐life clinical management of these patients. Am. J. Hematol. 91:318–321, 2016.

Minimal residual disease as biomarker for optimal biologic dosing of ARA-C in patients with acute myeloid leukemia

We assessed by flow cytometry minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) given standard‐dose (SDAC) and high‐dose ARA‐C (HDAC) regimens. Of 163 patients enrolled, 130 (median age, 45 years; range, 18–59 years) qualified for analysis, all achieving complete remission after treatment with SDAC (n = 78) or HDAC (n = 52) plus etoposide and daunorubicin. Consolidation consisted of intermediate‐dose ARA‐C and daunorubicin. MRD negativity was significantly more frequent in the SDAC vs. HDAC arm after both induction (37% vs. 15%, P = 0.007) and consolidation (44% vs. 18%, P = 0.002). Respective median residual leukemic cell counts with SDAC and HDAC use were 1.5 × 10−3 and 4 × 10−3 (P = 0.033) after induction and 5.7 × 10−4 and 2.9 × 10−3 (P = 0.008) after consolidation. Based on ARA‐C schedule and post‐consolidation MRD status, the four patient groups (SDAC‐MRD−, HDAC‐MRD−, SDAC‐MRD+, and HDAC‐MRD+) displayed 5‐year overall survival rates of 60%, 33%, 24%, and 42% (P = 0.007), respectively, with 24%, 35%, 74%, and 48% (P < 0.0001) respective cumulative incidence of relapse estimates. MRD may serve as a biomarker for optimal biologic dosing of ARA‐C, and SDAC regimen appears to yield more frequent MRD negativity. Am. J. Hematol. 90:125–131, 2015.

Recurrence of a t(8;21)-Positive Acute Myeloid Leukemia in the Form of a Granulocytic Sarcoma Involving Cranial Bones: A Diagnostic and Therapeutic Challenge

Granulocytic sarcoma (GS) is a rare extramedullary solid tumor defined as an accumulation of myeloblasts or immature myeloid cells. It can cooccur with or precede the acute myeloid leukemia (AML) as well as following treated AML. The incidence of GS in AML patients is 3–8% but it significantly rises in M2 FAB subtype AML. This variety of AML harbors t(8;21) in up to 20–25% of cases (especially in children and black ones of African origin) and, at a molecular level, it is characterized by the generation of a fusion gene known as RUNX1-RUNX1T1. Approximately 10% of M2 AML patients will develop GS, as a consequence, the t(8;21) and the relative transcript represent the most common cytogenetic and molecular abnormalities in GS. FLT3-ITD mutation was rarely described in AML patients presenting with GS. FLT3 ITD is generally strongly associated with poor prognosis in AML, and is rarely reported in patients with t(8;21). GS presentation is extremely variable depending on organs involved; in general, cranial bones and sinus are very rarely affected sites. We report a rare case of GS occurring as a recurrence of a previously treated t(8;21), FLT3-ITD positive AML, involving mastoid bones and paravertebral tissues.