Pegaspargase-modified risk-oriented program for adult acute lymphoblastic leukemia: results of the GIMEMA LAL1913 trial.

Pediatric-inspired chemotherapy is the standard of care for younger adults with Philadelphia chromosome-negative acute lymphoblastic leukemia/lymphoma (Ph- ALL/LL). In LAL1913 trial, the Gruppo Italiano Malattie EMatologiche dell'Adulto added pegaspargase 2000 IU/m2 to courses 1, 2, 5, and 6 of an 8-block protocol for patients aged from 18 to 65 years, with dose reductions in patients aged >55 years. Responders were risk stratified for allogeneic hematopoietic cell transplantation (HCT) or maintenance per clinical characteristics and minimal residual disease (MRD). Of 203 study patients (median age, 39.8 years), 91% achieved a complete remission. The 3-year overall survival, event-free, and disease-free survival (DFS) rates were 66.7%, 57.7%, and 63.3%, respectively, fulfilling the primary study end point of a 2-year DFS >55%. Although based on the intention-to-treat, the DFS being 74% and 50% in the chemotherapy (n = 94) and HCT (n = 91) assignment cohorts, respectively, a time-dependent analysis proved the value of HCT in patients who were eligible (DFS HCT 70% vs no HCT 26%; P <.0001). In multivariate analysis, age and MRD were independent factors predicting DFS rates of 86% (age ≤ 40 and MRD-negative), 64%-65% (MRD-positive or age > 40) and 25% (age > 40 and MRD-positive); P < .0001. Grade ≥2 pegaspargase toxicity was mainly observed at course 1, contributing to induction death in 2 patients but was rare thereafter. This program improved outcomes of patients with Ph- ALL/LL aged up to 65 years in a multicenter national setting. This trial was registered at www.clinicaltrials.gov as #NCT02067143.

Molecular remission at the end of treatment is a necessary goal for a good outcome in ELN favorable-risk acute myeloid leukemia: a real-life analysis on 201 patients by the Rete Ematologica Lombarda network.

Favorable acute myeloid leukemia (AML) patients (pts.) demonstrate a relatively good outcome with standard induction; thus, pts. are generally not addressed to allogeneic transplant in first remission. However, it is not clear if also in a real-life setting, the outcome is homogeneous in the different favorable molecular groups and which are the parameters significantly associated to an increased relapse risk, useful to suggest the need of an intensified approach. In order to clarify this point, we collected clinical data on consecutive unselected AML pts. assigned to favorable category (modified ELN 2010 due to the inclusion of double-mutated CEBPA-positive cases), diagnosed and treated in six centers of the Italian network Rete Ematologica Lombarda (REL) from 2007 to 2015. We assessed response (CR, mCR), relapse rate (CIR), and outcome (OS, DFS) after first-line treatment. A total of 201 pts. was studied and the analysis was performed globally and in each molecular group: t(8;21)(q22;q22)/RUNX1-RUNX1T1 (30 pts., 14.9%), inv. (16)(p13q22) or t(16;16)(p13q22)/CBFB-MIH11 (35 pts., 17.4%), normal karyotype and mutated NPM1 and negative FLT3-ITD (116 pts., 57.7%) or double-mutated CEBPA (CEBPAdm) (20 pts., 10%). Complete remission (CR) was obtained in 188 pts. (93.5%), molecular CR (mCR) in 114 (67.5%); After a median follow-up of 2.4 years, cumulative incidence of relapse (CIR) was documented in 78 of 188 responding pts. (41%) after a median time of 11.3 months. CIR was higher in the CBFB-MIH11 group, in pts. achieving only a hematological response without mCR (72.1 vs 28.1%, p < 0.001), in older pts. and it resulted independently associated with a lower median cytarabine cumulative dose (CCD). Median OS was not reached: after 5 years it was 66.3%, and median DFS was 5.3 years, both without difference among groups. Molecular CR reached at any time, during or after the end of first-line treatment, was significantly associated with better DFS, and in particular, mCR assessed at the end of treatment was confirmed in multivariate analysis as an independent prognostic factor both for DFS and OS. In conclusion, the present study confirms in a real-life context the overall good prognosis of favorable-risk AML; the achievement of any molecular negativity during first-line treatment, particularly when assessed at the end of treatment, is associated with lower relapse and better survival. Increasing age at diagnosis has a negative prognostic impact, while CCD higher than 18 g/sqm is associated with better outcome.

Clofarabine-based chemotherapy as a bridge to transplant in the setting of refractory or relapsed acute myeloid leukemia, after at least one previous unsuccessful salvage treatment containing fludarabine: a single institution experience.

For refractory or relapsed acute myeloid leukemia patients, allogeneic hematopoietic stem cell transplantation is the only curative treatment option, but the disease must be in remission before this can be attempted. "Salvage" therapy regimens containing high-dose cytarabine plus fludarabine or cladribine with or without anthracyclines or plus mitoxantrone and etoposide fail in 30-50% of cases. We report the outcome of 14 patients treated with a clofarabine-based treatment administered after at least one failed fludarabine-based "salvage" attempt in a "real life" (outside a clinical trial) context. No death related to the clofarabine-based treatment was observed. Four of the 14 patients (29%) reached complete remission and one (7%) achieved a reduction of marrow blasts to fewer than 10%. Three of these five patients were successfully transplanted and have shown a long-term survival. The small number of this group of patients does not permit the identification of clinical features clearly related to a favorable outcome, but we note that all the three long-term survivals were FLT3 wild type. Clofarabine-based "salvage therapy" in patients with very poor expectancy is feasible even after a fludarabine-based salvage attempt, albeit with success only in a small percentage of cases (3/14 = 21%).

Invasive fungal infections in lymphoproliferative disorders: a monocentric retrospective experience.

Invasive fungal infections (IFIs) seem to be a relevant cause of morbidity and mortality in patients with chronic lymphoproliferative disorders. We studied retrospectively the epidemiology, clinical manifestations and outcome of invasive fungal infections in 42 patients with lymphoproliferative diseases, treated between January 2004 and February 2012 for probable or proven IFI. In our entire population (1355 patients) of chronic lymphoproliferative malignancies, the incidence of probable/proven IFI was 3% (molds 2.3%, yeasts 0.5%, mixed infections 0.2%). Eight patients developed a yeast infection documented by blood cultures in seven cases and by the microscopic observation of Candida spp. in the vitreum after vitrectomy in one case. Among molds we diagnosed three proven infections by histologic evidence of Aspergillus spp. (n = 2) and Mucor (n = 1) in the lung and 28 probable mycoses. Three mixed infections from both molds and yeasts were also observed. Twenty-two cases showed positivity of galactomannan antigen in the serum (n = 16), in bronchoalveolar lavage (BAL) fluid (n = 4) or in both (n = 2). Cultures were positive in 11 cases. The overall rate of response to therapy was 64%. Fungal-attributable mortality rate was 17%, with a significant difference between molds and yeasts (16% vs. 25%, p = 0.03). At univariate analysis, the only risk factors related to mortality were severe and prolonged neutropenia (p = 0.003) and age (p = 0.03). Among molds, the rapid start of antifungals was probably partially responsible, together with new drugs, for the reduction of mortality, despite the severe immunosuppression of these patients.

Verifying Hellström-Lindberg score as predictive tool for response to erythropoietin therapy according to the "International Working Group" criteria, in anemic patients affected by myelodysplastic syndrome: a monocentric experience.

The Hellström-Lindberg score (HLS) (1997) is designed to predict erythroid response to erythropoietin treatment in myelodysplastic patients. In order to test the validity of this scoring system, 58 patients affected by myelodysplastic syndrome, treated with a "standard dose" approach between 2001 and 2010, were analyzed. The response to erythropoietin treatment was evaluated in accordance with the "international working group" (IWG) criteria. Among the patients only two were scored "poor," 12 "intermediate," and 44 "good" (15 of whom were scored "3" and 29 "4"). Although the system was verified as a predictive tool for response to erythropoietin therapy, we noted that of patients scored as "good," those with a numerical score of "4" responded more frequently than did those scored "3", as evaluated under both the 2006- and 2000-IWG ("major response") criteria. The modest response rate in patients scoring "3" did not show a difference in response rate in comparison to the "intermediate" group. The present data suggest that only patients scoring "4" on the scale may show an adequate response to the standard dose erythropoietin therapy, while frontline high-dose therapy should be offered to other patients. A further analysis considering endogenous erythropoietin as a possible determinant of response revealed the optimal cut-off value of 80 mIU/mL, instead of the value of 100 mIU/mL utilized by the HLS.

Twice daily fludarabine/Ara-C associated to idarubicin, G-CSF and ATRA is an effective salvage regimen in non-promyelocytic acute myeloid leukemia.

Preclinical data suggest that all-trans retinoic acid (ATRA) synergizing with granulocyte colony stimulating factor (G-CSF), can improve the effectiveness of chemotherapy in acute myeloid leukemia (AML). Fludarabine 15 mg/m(2) is the minimum dose able to optimize intensification with fludarabine-arabinosylcytosine regimen. In this study 52 patients with relapsed/refractory AML obtained a complete remission (CR) rate of 69.2% after FLAIRG regimen (Fludarabine and arabinosylcytosine twice daily, idarubicin, G-CSF, ATRA). This schedule resulted effective and tolerable enabling 53% of the responding patients to receive transplant procedure. FLAIRG regimen could be proposed as a "bridge" to transplant treatment in this poor risk setting.

Advanced mast cell disease: an Italian Hematological Multicenter experience.

The aim of the study is to evaluate clinical features, treatments and outcome of patients with systemic mast cell disease (MCD) who arrived to the attention of hematologists. A retrospective study was conducted over 1995-2006 in patients admitted in 18 Italian hematological divisions. Twenty-four cases of advanced MCD were collected: 12 aggressive SM (50%), 8 mast cell leukemia (33%), 4 SM with associated clonal non-mast cell-lineage hematologic disease (17%). Spleen and liver were the principal extramedullary organ involved. The c-kit point mutation D816V was found in 13/18 patients in which molecular biology studies were performed (72%). Treatments were very heterogeneous: on the whole Imatinib was administered in 17 patients, alpha-Interferon in 8, 2-CdA in 3; 2 patients underwent allogeneic hematopoietic stem cell transplantation. The overall response rate to Imatinib, the most frequently employed drugs, was of 29%, registering one complete remission and four partial remission; all responsive patients did not present D816V c-kit mutation. Overall three patients (12%) died for progression of disease. We conclude that MCD is characterized by severe mediator-related symptoms but with a moderate mortality rate. D816V c-kit mutation is frequent and associated with resistance against Imatinib. Because of the rarity of these forms, an effective standard of care is lacking. More data are needed to find new and successful therapeutic strategies.

Prospective monocentric study of non-tunnelled central venous catheter-related complications in hematological patients.

Indwelling central venous catheters (CVCs) are used in the management of hematologic patients. However, insertion and maintenance of CVCs are susceptible to complications. Study design and methods data concerning 388 consecutive catheterisations, performed in oncohematologic patients between April 2003 and December 2004, were prospectively collected. At insertion thrombocytopenia was present in 109 cases (28.1%) and neutropenia in 67 (17.3%). Hemorrhage after CVC insertion occurred in five thrombocytopenic patients (1.3%). The median duration of catheterisation was 18.8 days (range 1-89), longer in the 7-French CVCs utilised in leukemic patients (24.3 days) and shorter in 12-French CVCs (11 days), used for PBSC harvesting. Deep venous thrombosis was diagnosed in 13 cases (3.3%). Ninety-two catheterisations (12.6/1000 days-catheter) were complicated by infections: 19 local infections (4.8%) and 73 (18.8%) bacteraemias of which 45 (11.6%) were catheter-related, mainly due to Gram positive germs (32/45, 71.1%). The frequency of catheter-related bacteraemia was 7.2 events/1000 days-catheter. Thirteen CVCs were removed due to thrombosis, 15 due to infections, 20 due to malfunction, the remaining 333 at patients discharge. At univariate analysis high-dose chemotherapy (p = 0.013), 7-Fr lumen (p = 0.023), acute myeloid leukemia (AML) (p = 0.001), duration of neutropenia >10 days and length of catheterisation were significantly correlated to infection. Multivariate analysis confirmed the duration of catheterisation, AML and high-dose chemotherapy as risk factors. Even though hematological in-patients are at increased risk for bleeding and infections, non-tunnelled CVCs offer a safe venous access also in patients affected by severe thrombocytopenia and prolonged neutropenia.

Outcome of hyperleukocytic adult acute myeloid leukaemia: a single-center retrospective study and review of literature.

Hyperleukocytic acute myeloid leukaemia is considered to have a poor prognosis due to high early death rate secondary to leukostasis. Supportive treatments do not seem to have reduced early exitus in this subset of patients. Prognostic impact of hyperleukocytosis on outcome has been the object of few studies. Clinical characteristics and outcome of 45 consecutive adult patients with newly diagnosed acute myeloid leukaemia presenting to our institution with a white cell count (WBC) above 100 x 10(9)L(-1) were reviewed. The outcome of this subset of patients was compared with 200 patients with a leukocyte count lower than 100 x 10(9)L(-1) similarly treated in the same period. Eight hyperleukocytic patients (17%) died of intracranial haemorrhage or pulmonary failure due to leukostasis within the first 7 days of treatment. A significant association was found between complete response (CR) and absence of hyperleukocytosis, but if early deaths were removed from analysis the difference was no longer significant. Hyperleukocytosis also significantly reduces the overall survival (OS) but does not significantly influence the disease-free survival (DFS). We reviewed in literature studies in which the outcome of series of at least 10 patients with hyperleukocytosis were compared with that of patients with a leukocyte count lower than 100 x 10(9)L(-1). Our data were consistent with those of the literature regarding the rate of early mortality and causes of death. In most of the reviewed series hyperleukocytosis does not seem to influence the outcome of patients. Avoiding early death seems to be an important step in this subset of patients. New data about pathophysiology of leukostasis are needed.

Assessing energy expenditure in cancer patients: a pilot validation of a new wearable device.

BACKGROUND: Nutrition problems are common in cancer patients and are frequently due to metabolic derangements. Thus, accurately assessing energy expenditure (EE) is important in planning adequate nutrition support. Indirect calorimetry (IC) represents the gold standard method but is not always available or applicable to all settings. The purpose of this study was to preliminary compare a new wearable device, the SenseWear armband (SWA), to IC in cancer patients. METHODS: Ten (6 M, 4 F) subjects (mean +/- SD: 56.6 +/- 13.3 years) affected by newly diagnosed acute myelogenous leukemia, undergoing induction chemotherapy, were prospectively enrolled. Resting EE (REE) was measured simultaneously by SWA and IC on admission (day 0) and at discharge (end). Total daily EE (TDEE) was determined by SWA 4 times during the stay (days 0, 7, 14, and end) and predicted values were calculated according to IC REE estimates (TDEE = IC x correction factor 1.2). RESULTS: Mean length of stay was 27.1 +/- 6.2 days. Bland-Altman plots revealed no significant differences between overall REE estimates (day 0 + end) performed by IC and SWA (mean +/- SD; 1645 +/- 282 vs 1705 +/- 278 kcal/d) and the correlation was high (r = 0.84; p < .0001). SWA TDEE showed a progressive reduction during the stay. No bias was detected between overall SWA TDEE (1799 +/- 153 kcal/d) and IC predicted TDEE (1974 +/- 176 kcal/d), but there was a wide 95% confidence interval (-672; +321 kcal/d). Moreover, the correlation between these values was significant (r = 0.68; p = .001). CONCLUSIONS: SWA seems to provide accurate and reliable estimation of REE and useful information on TDEE also in cancer patients. Its use appears promising. Validation studies on larger samples and different cancer types should be considered.

High-dose idarubicin in combination with Ara-C in patients with relapsed or refractory acute lymphoblastic leukemia: a pharmacokinetic and clinical study.

OBJECTIVE: High dose (HD) Ara-C combined with a single HD idarubicin dose (IDA) is an efficient and safe salvage regimen for patients with refractory or relapsed acute lymphoblastic leukemia as indicated by phase II studies. No data are available on the pharmacokinetics of IDA after a rapid HD intravenous infusion. An open phase II pharmacokinetic and clinical study was performed to evaluate antileukemic efficacy, IDA pharmacokinetics and to investigate the presence of IDA and its reduced metabolite idarubicinol (IDAol) in cerebrospinal fluid (CSF) of patients treated with HD-IDA. PATIENTS AND METHODS: Twenty-five patients with refractory or relapsed acute lymphoblastic leukemia received Ara-C 3 g/m2 from days 1-5, idarubicin (HD-IDA) 40 mg/m2 as rapid intravenous (i.v.) infusion on day 3 and subcutaneous G-CSF 5 microg/kg from day 7 until PMN recovery. Pharmacokinetics of IDA was evaluated after HD idarubicin administration in nine of these patients. CSF samples were collected in 15 patients at different times. IDA and IDAol concentrations were quantified by a validated HPLC assay described in detail elsewhere. RESULTS: Eleven patients (44%, 95% CI: 23-65%) achieved complete remission with median disease free survival for 6 months. After administration of HD-IDA i.v. bolus of 40 mg/m2, plasma level profiles of unchanged drug and IDAol were similar to those previously described after standard dose and measured with the same analytical method. The mean terminal half-life measured for IDA in this group of patients (14.9 h) was not significantly different from the mean value observed after standard dose (13.9 h, P=0.72). IDAol t1/2 was also similar after HD-IDA (46.2 h) and standard dose (39.4 h, P=0.79). Pharmacokinetic data reveal that in our series of patients IDA and IDAol clearances are significantly higher than those observed in patients treated with 12 mg/m2 of IDA but, although the administered dose (mg/m2) of the drug is 3.3 times higher, IDA exposure (measured in terms of AUC) is only 2.3 times and IDAol exposition 2.1 times greater. Furthermore, HD infusion resulted in a ratio between the AUC of parent drug and idarubicinol not different from the value observed with the standard-dose. IDA and IDAol were measurable only in 3 of the 15 cerebrospinal fluid samples collected. CONCLUSION: Responses observed in our series are comparable to those reported with other salvage regimens. The IDA exposure lower than expected may explain the safety of the single i.v. administration of 40 mg/m2 of IDA, combined with HD Ara-C, with a degree of myelosuppression equivalent to that reported with this agent administered in standard doses. Our data do not allow us to clearly attribute this behavior to a pharmacokinetic non-linearity since the baseline creatinine clearance, even within normal values, and patient age are significantly different in the two groups. Cerebrospinal fluid penetration was poor, reaching levels not considered as cytotoxic.

Aggressive systemic mastocytosis mimicking sclerosing cholangitis.

A 43 year-old woman presented with fever, abdominal pain, epato-splenomegaly, ascites, cholestasis, anemia, thrombocytopenia and previous diagnosis of sclerosing cholangitis based on liver biopsy and endoscopic retrograde cholangiopancreatography(ERCP). The bone marrow biopsy and the revision of liver biopsy using antitryptase stain diagnosed systemic mastocytosis. Because of the aggressive course of the disease the patient was treated with an acute myeloid leukaemia chemotherapy regimen without success.

Bone marrow hypoplasia complicating tacrolimus (FK506) therapy.

Tacrolimus (FK506)-induced hematological toxicity, which has rarely been reported in transplant recipients, may result in anemia episodes, reported mainly in kidney and heart transplant recipients, sporadic cases of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, red cell aplasia (4 reported cases), and generalized bone marrow suppression (only 1 reported case). We describe a case of a liver transplant recipient with pancytopenia that appeared during immunosuppressive therapy with tacrolimus. This patient suffered from progressive anemia, leukopenia with severe neutropenia, and mild thrombocytopenia; bone marrow biopsy showed hypoplasia (20% of cellularity) without dysplasia. Bone marrow recovery was made possible by suspending tacrolimus and changing to immunosuppression with cyclosporine A, despite the two drugs being very similar in their mechanism of immunosuppression. Contrary to previously reported cases (pure red cell aplasia and bone marrow hypoplasia), the recovery of hemoglobin and neutrophil values was slow after tacrolimus suspension, even though in the first month transfusions were no longer necessary.

Utility of percutaneous lung biopsy for diagnosing filamentous fungal infections in hematologic malignancies.

BACKGROUND AND OBJECTIVES: The incidence of invasive filamentous fungal infections in hematologic patients is increasing as a consequence of high dose chemotherapy and bone marrow transplant procedures. Mortality is usually very high. The diagnosis is often difficult and yet a fast, accurate diagnosis is of fundamental importance for treating the infection and planning subsequent management of the hematologic disease. We evaluated the sensitivity of computed tomography (CT)-guided percutaneous biopsy in diagnosing pulmonary fungal infections. DESIGN AND METHODS: Between 1997 and 2002 we performed 17 CT-guided percutaneous transthoracic lung biopsies in 17 hematologic patients with suspected filamentous fungi infection with negative BAL, to obtain a certain diagnosis and to know what species of fungi was responsible for infection. In all cases suspected mycosis began during the post-chemotherapy aplastic period. Patients were receiving antifungal therapy at the time of all biopsies. When the platelet count rose above 50 x 10(9)/L, CT-guided percutaneous lung biopsy with fine-needle aspiration for cytology was performed. RESULTS: Twelve of 17 patients had histologic confirmation of the fungal infection (70.5%), 8 with Aspergillus spp. 4 with Mucorales spp. Biopsies provided non-specific results in 4 cases; in 2 of these cases, clinical course and response to therapy confirmed the diagnosis of mycosis; in the last case bronchoalveolar carcinoma was found as a new diagnosis. Cultures were positive in only 6 cases, all for Aspergillus spp. The sensitivity of CT-guided percutaneous lung biopsy was 70.6% and its positive predictive value (PPV) was 100%. This procedure provided an immediate diagnosis and only one side-effect (1 pneumothorax, without complications). INTERPRETATION AND CONCLUSIONS: Histologic discrimination between aspergillosis and mucormycosis is very important for deciding secondary prophylaxis during transplant procedures, because Mucor is usually resistant to azoles.