Elisa Cerqui

A randomized comparison of caspofungin versus antifungal prophylaxis according to investigator policy in acute leukaemia patients undergoing induction chemotherapy (PROFIL-C study)

BACKGROUND Invasive fungal infections (IFIs) are considered a major problem among patients undergoing acute leukaemia (AL) induction treatment. PROphylaxis of Fungal invasive Infections in Leukaemia-Caspofungin (PROFIL-C) is a multicentre study aiming to assess the comparative yield of using caspofungin versus standard policy (SP) regimens and the overall impact of IFI in routine clinical care conditions. METHODS All AL patients receiving IFI prophylaxis according to local SP were prospectively included in the study by Northern Italy Leukaemia Group (NILG) centres. To allow the comparison of caspofungin versus SP regimens as prophylaxis strategies, caspofungin treatment was assigned via a centralized randomized procedure. The study was registered at http://www.clinicaltrial.gov (NCT00501098). RESULTS Over a 2 year period, 175 patients were included. The overall incidence of IFI was 32/175 (18.3%) [10/175 (5.7%) probable/proven and 22/175 (12.6%) possible], with no statistically significant differences between caspofungin-based versus SP-based regimens [overall: 15/93 (16.1%) versus 17/82 (20.7%), relative risk (RR) 0.78, 95% confidence interval (CI) 0.42-1.46; probable/proven: 7/93 (7.5%) versus 3/82 (3.7%), RR 2.06, 95% CI 0.55-7.7; possible: 8/93 (8.6%) versus 14/82 (17.1%), RR 0.5, 95% CI 0.22-1.14]. Only one IFI-related death was recorded (10%). CONCLUSIONS The incidence and mortality of IFI were lower than expected in this strictly sequential cohort representative of the routine care in the NILG network. The efficacy and safety of caspofungin were similar to other prophylactic regimens.

Postremission sequential monitoring of minimal residual disease by WT1 Q-PCR and multiparametric flow cytometry assessment predicts relapse and may help to address risk-adapted therapy in acute myeloid leukemia patients

Risk stratification in acute myeloid leukemia (AML) patients using prognostic parameters at diagnosis is effective, but may be significantly improved by the use of on treatment parameters which better define the actual sensitivity to therapy in the single patient. Minimal residual disease (MRD) monitoring has been demonstrated crucial for the identification of AML patients at high risk of relapse, but the best method and timing of MRD detection are still discussed. Thus, we retrospectively analyzed 104 newly diagnosed AML patients, consecutively treated and monitored by quantitative polymerase chain reactions (Q‐PCR) on WT1 and by multiparametric flow cytometry (MFC) on leukemia‐associated immunophenotypes (LAIPs) at baseline, after induction, after 1st consolidation and after 1st intensification. By multivariate analysis, the factors independently associated with adverse relapse‐free survival (RFS) were: bone marrow (BM)‐WT1 ≥ 121/104 ABL copies (P = 0.02) and LAIP ≥ 0.2% (P = 0.0001) (after 1st consolidation) (RFS at the median follow up of 12.5 months: 51% vs. 82% [P < 0.0001] and 57% vs. 81%, respectively [P = 0.0003]) and PB‐WT1 ≥ 16/104 ABL copies (P = 0.0001) (after 1st intensification) (RFS 43% vs. 95% [P < 0.0001]) Our data confirm the benefits of sequential MRD monitoring with both Q‐PCR and MFC. If confirmed by further prospective trials, they may significantly improve the possibility of a risk‐adapted, postinduction therapy of AML.

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.

Lenalidomide in patients with red blood cell transfusion-dependent myelodysplastic syndrome and del(5q): a single-centre “real-world” experience

“Real life” data are needed to complement published trials on the efficacy of lenalidomide in patients with myelodysplastic syndrome (MDS) and del(5q) and on the risk of inducing acute myeloid leukemia (AML) progression. Here, we present results of lenalidomide treatment in a consecutive, population-based series of 21 red blood cell (RBC) transfusion-dependent elderly patients with multiple comorbidities. Of 18 evaluable patients (median follow-up: 22 months), 17 achieved an erythroid hematologic response (HI-E) and 16 an RBC transfusion independence. Cytogenetic response (CyR) rate was 80%, median overall survival was 48 months (range 3–164), and 5-year leukemia-free survival was 84%. Three patients progressed to AML; one, with baseline TP53 mutation, achieved HI-E, partial CyR, and did not progress to AML. Eighteen patients experienced hematological adverse events. Overall, lenalidomide was very effective and well tolerated even in unselected elderly patients with multiple comorbidities and did not appear to increase the risk of AML.

Continuous oral cyclophosphamide and prednisolone as a valuable treatment option for peripheral T cell lymphoma.

Peripheral T cell lymphomas (PTCL) are rare and frequently associated with a poor clinical outcome, with 5-year overall survival (OS) between 20% and 40%, regardless of the therapeutic approach employed (Coiffier et al, 1990; Ascani et al, 1997). Major improvements were expected from Alemtuzumab, an anti-CD52 monoclonal antibody targeting mature T lymphocytes. However, unlike Rituximab in diffuse large B cell lymphoma, no clear advantage has been obtained so far. In a prospective multicentre phase II trial, 24 patients with newly diagnosed PTCL received CHOP (cyclophosphamide, vincristine, doxorubicin, prednisolone) combined with Alemtuzumab. Despite the impressive complete remission (CR) rate (71%), the estimated 2-years OS and failure-free survival rates did not appear better than in historical patients treated with CHOP (53% and 48% respectively) because of the high incidence of major infections (Gallamini et al, 2007). Another study combining CHOP with Alemtuzumab was stopped early, despite an overall response rate (ORR) of 80%, due to significant infectious and haematological toxicities (Moon et al, 2007). Upfront autologous stem cell transplantation (SCT) was recently proposed to improve prognosis in PTCL (Reimer et al, 2009). Promising results were reported by an intent-totreat analysis; unfortunately more than one third of the patients could not be transplanted mostly because of early disease progression. Allogeneic SCT is reserved for selected patients and is mainly used after relapse. In a large retrospective French registry series, 5-years OS and eventfree survival were respectively 57% and 53% with significant long-term transplant-related mortality (TRM) (Le Gouill et al, 2008). Given the lack of effectiveness of most conventional treatments successfully employed in aggressive B cell lymphomas, it may be hypothesized that PTCL has an as yet undetected peculiar pathobiology that may be better managed with alternative treatment modalities. Given that anthracycline-containing regimens have never demonstrated a real benefit (Vose, 2005) and because the major cause of treatment failure was early relapse with frequent recurrence of systemic symptoms, particularly fever, during the intervals between chemotherapy cycles, we explored the efficacy of continuous low-dose cytostatic and corticosteroid therapy, aiming at the achievement of long-term disease control rather than disease eradication. We used an oral combination of prednisolone and cyclophosphamide according to a well-established schedule for systemic vasculitis (Fauci et al, 1979) that provides strong and long-acting immunosuppression of the T cell compartment. We retrospectively analysed 55 patients with unspecified PTCL (PTCL-U) or angioimmunoblastic lymphoma (AILD-T) consecutively seen at our Institute from January 1993 to December 2008, and compared their outcome according to treatment received. All histological diagnoses were reviewed according to the World Health Organization (WHO) classification. Eleven patients were excluded because of early death before the start of any treatment (2), loss to follow up (2), stage I disease treated with radiation only (3) and palliative single agent corticosteroid treatment (4). According to the clinical decision of the attending physician, 20 patients (Group PKT) received polychemotherapy [CHOP or CHOP-like in 14 cases, combined with Alemtuzumab in 4 and consolidated with autologous SCT in one, intensified-CHOP in 5 cases and OxaliDHAP (dexamethasone, cytarabine, cisplatin) in one case] and 24 (Group oralCyP) received low-dose oral cyclophosphamide and prednisolone (Fig 1A). Statistical analyses were performed using Graph Pad Prism software. The characteristics of the subgroups of patients subdivided according to the type of treatment received were compared using Fisher’s exact test or Student’s t test, as appropriate (Table I). Log-rank analysis was used to compare actuarial survival curves. No significant differences in stage, B symptoms, and International Prognosis Index score were found between the two groups. Patients treated with oralCyP were significantly older (P = 0Æ038) and had a significantly worse Prognostic Index for PTCL score (P = 0Æ039) (Gallamini et al, 2004). The ORR was 60% versus 54% (P = 0Æ71) and the CR rate 40% versus 21%, in the PKT and oralCyP group, respectively. Fiveyear relapse-free survival (RFS), calculated from the date of remission, and 5-year OS, from the day of diagnosis, were 13% (95%CI ± 12%) and 29% (95%CI ± 13%) in Group PKT versus 26% (95%CI ± 15%) and 31% (95%CI ± 11%) in Group oralCyP respectively, with no differences between the two groups (P = 0Æ73 and P = 0Æ9) (Fig 1B,C). Toxicity of any grade was observed in 73% and 80% of patients, respectively. Grade ‡ IV WHO toxicity occurred in four patients in each group and included infections in five cases [bacterial pneumonia (2), cytomegalovirus (CMV) colitis (1), CMV pneumonia (1), peritonitis (1)], posterior reversible encephalopathy syndrome, pulmonary embolism and oral mucositis in one case each, with no differences between the two groups. Eleven and 14 patients died in the PKT and oralCyP group, respectively. The cause of death was lymphoma in all patients Correspondence