Anna Maria Frustaci

Posaconazole prophylaxis during front-line chemotherapy of acute myeloid leukemia: a single-center, real-life experience

Background Posaconazole is effective as primary antifungal prophylaxis of invasive fungal diseases in patients with acute myeloid leukemia. Design and Methods The impact of primary antifungal prophylaxis administered during front-line chemotherapy for acute myeloid leukemia was evaluated by comparing 58 patients who received oral amphotericin B (control group) to 99 patients who received oral posaconazole (posaconazole group). The primary endpoint was the incidence of proven/probable invasive fungal diseases. Secondary endpoints included incidence of invasive aspergillosis, survival at 4 and 12 months after the diagnosis of acute myeloid leukemia and costs. Results Proven/probable invasive fungal diseases were documented in 51.7% of patients in the control group and in 23.2% in the posaconazole group (P=0.0002). Invasive aspergillosis was documented in 43% of patients in the control group and in 15% in the posaconazole group (P=0.002). No survival difference was observed in patients aged over 60 years. In patients aged 60 years or less, a statistically significant survival advantage was observed at 4 months, but no longer at 12 months, in the posaconazole group (P=0.03). It was calculated that in the posaconazole group there was a mean 50% cost reduction for the antifungal drugs. Conclusions Primary antifungal prophylaxis with posaconazole during front-line chemotherapy was effective in preventing invasive fungal diseases in a “real-life” scenario of patients with acute myeloid leukemia, resulted in an early but transitory survival advantage in younger patients and was economically advantageous.

Comorbidities and FLT3‐ITD abnormalities as independent prognostic indicators of survival in Elderly acute myeloid leukaemia patients

Elderly acute myeloid leukaemia (AML) patients have a dismal prognosis due to biological features of disease in itself and to presence of comorbidities. Aim of this study was to evaluate the prognostic impact of comorbidity prognostic score systems applied in our population of patients. as well as other clinical‐biological features. We retrospectively considered the outcome of 120 patients aged >65 years diagnosed as having AML between January 2001 and December 2005. Comorbidities were evaluated by using Charlson comorbidity index (CCI), Hematopoietic cell transplantation comorbidity index (HCTCI) and a score proposed by Dombret et al. in 2007. Median patient age was 67 years. Forty‐six patients were treated with intensive chemotherapy and 23 reached a complete remission. Seventy‐four patients received only supportive therapies or low‐dose chemotherapy. Multivariate analysis showed the effects of leukocytosis (p = 0.0013), antecedent Myelodysplastic syndrome (MDS) (p = 0.011), FLT3 abnormalities (p = 0.032), CCI (p = 0.0037) and Dombret et al. score (p = 0.045) as independent prognostic parameters for survival. Based on these variables we were able to stratify patients in low and high risk, with different median overall survival: patients were considered as low risk if they had none or only one of the above mentioned adverse factors for survival, with a median overall survival of 447 days. Patients with two or more adverse factors were categorized as high risk: this subgroup had a median overall survival of 227 days (p = 0.001). Comorbidities are independent factors that influence survival. Application of CCI and Dombret score may help to better identify patients at diagnosis who can benefit from intensive chemotherapy. Copyright

Bendamustine and rituximab combination is safe and effective as salvage regimen in Waldenström macroglobulinemia

According to the European Society for Medical Oncology and National Comprehensive Cancer Network guidelines on Waldenström macroglobulinemia, bendamustine (B) may be considered a suitable therapeutic option. To address the role of B in combination with rituximab (BR), we analyzed the outcome of 71 patients with relapsed/refractory disease, median age 72 years, treated with R 375 mg/m2 day 1 and B days 1 and 2 (dosage ranging from 50 to 90 mg/m2). Patients had previously received a median number of 2 lines of treatment (range 1–5). Overall and major response rates were 80.2% and 74.6%. Major toxicity was grade 3/4 neutropenia occurring in 13% of courses. There was no significant association between baseline features or patients’ characteristics and response achievement. Median progression-free survival was not reached after a median follow-up of 19 months (range 3–54). None of the patients developed aggressive lymphoma or secondary myelodysplastic syndrome/acute myeloid leukemia. BR was found to be an active and well-tolerated salvage regimen leading to rapid disease control.

Fludarabine, Cyclophosphamide, and Rituximab in Salvage Therapy of Waldenström's Macroglobulinemia

The combination FCR (fludarabine, cyclophosphamide, and rituximab) proved to be active in Waldenströms macroglobulinemia in a mixed population of untreated and previously treated patients. Prolonged myelosuppression and concerns about purine analogue treatment led to the conclusion that this regimen should be avoided in younger patients in first-line treatment. In this retrospective study on 40 patients we observed a response rate of 80% (32) after FCR salvage treatment with 32.5% (13) of patients reaching at least a very good partial remission. None of the prognostic variables had a significant effect on response or good quality of response achievement. Median event-free survival was reached at 77 months; median progression-free survival was not reached after a median follow-up of 51 months with any difference when categorizing patients according to quality of response. The results of this study suggest that the FCR regimen might overcome poor prognostic features and should be taken into account as salvage treatment. Tardive immunosuppression and myelosuppression warrant accurate patient follow-up.

Differences in hematological and non-hematological toxicity during treatment with imatinib in patients with early and late chronic phase chronic myeloid leukemia

Imatinib is a relatively specific inhibitor of the BCR/ABL tyrosine kinase, effective in chronic myeloid leukemia (CML). The aim of our study was to analyse the frequency and type of hematological and non-hematological adverse events in our series of late and early chronic phase patients with CML treated with imatinib and correlate the grade of hematological toxicity with the response obtained. Hematological events were seen in 59 out of 150 (39%) late chronic phase (CP) patients: of these, 24% experienced toxicity Grade 3–4. Of the 100 early CP patients, 26 (26%) had hematological adverse event: 7% experienced toxicity Grade 3–4 (p = 0.0001). We found that only in early CP patients, the occurrence of hematological side effects of any grade within 6 months of therapy had a negative influence on cytogenetic response. We compared the incidence of non-hematological adverse events occurring in late and in early CP patients and found that in these latter, some side effects were more frequent, such as weight gain, periorbital edema, muscle cramps, skin rashes, diarrhea, weeping. On the contrary, we found that bone pain and hemorrhagic events were more common in late CP patients. Grade 3–4 adverse events were recorded at rates below 4% and decreased over time: in late CP patients hemorrhages and muscle cramps were the most common side effects of Grade 3–4, whereas in early CP patients, the most frequent events were nausea, weight gain and cutaneous rash. We have observed that hematological and non-hematological side effects during imatinib therapy are different among late and early CP patients and that severe hematological toxicity may influence cytogenetic response only in early CP patients.

A phase II multi-center trial of pentostatin plus cyclophosphamide with ofatumumab in older previously untreated chronic lymphocytic leukemia patients

There is a significant need to develop an efficient treatment, without sacrificing efficacy, for older fit patients with chronic lymphocytic leukemia (CLL) as fludarabine, cyclophosphamide and rituximab (FCR) have very often led to treatment-related toxicities, causing delay or therapy

Is HBV prophylaxis required during CLL treatment with ibrutinib

The management of viral hepatitis B (HBV) reactivation in patients with hematological malignancy depends on the stage of HBV infection and the type of regimen administered. Virological and serological status clearly influence the risk of HBV reactivation as patients with HBV DNA detectable and/or HBsAg positive are up to eight times more likely to experience HBV reactivation than HBsAg negative/antiHBc positive patients [1]. Furthermore, HBV reactivation strictly depends on the level of immunosuppression related to the type of treatment administered. The guidelines of the American Gastroenterology Association (AGA) on the prevention of HBV reactivation provided recommendations on antiviral prophylaxis according to the risk gradient of immunosuppressive drugs as well as serological host status. On these basis the risk of reactivation has been divided into high risk (if the rate of HBV reactivation is 10%), moderate risk (if risk of reactivation is between 1-10%), and low risk (if risk of reactivation is <1%) [2]. Considering the potent and durable immunosuppressive effect exerted by the B-cell depleting agents, the population treated with anti CD20 monoclonal antibodies is considered at high risk. There is a strong evidence indeed, to routinely administer antiviral prophylaxis with nucleoside/nucleotide analogs even in HbsAg negative/ anti Hbc positive patients [2]. The European Conference on Infection in Leukemia (ECIL-5), in the recently reported recommendations, strongly supports this indication [3]. Tyrosine kinase inhibitors such as imatinib nilotinib and ruxolitinib are now widely used in the treatment of different hematological malignancies. These agents are considered moderately immunosuppressive and in literature there are no systematic studies focusing on the risk of HBV reactivation, nevertheless a series of case reports recently identified a potential association between tyrosine kinase inhibitors and HBV reactivation [4–7]. Although the mechanism of HBV reactivation during imatinib, nilotinib and ruxolitinib is still unclear, both in vitro and in vivo studies have demonstrated an impairment of T-cell activation, proliferation and function that may lead to a viral expansion [4,5,8,9]. Imatinib clearly proved to inhibit T-cell receptor (TCR)-mediated T cells proliferation and activation in a dose-dependent manner and its effect on c-kit induces profound changes in B-and T-cell development in mice possibly contributing to an immunosuppressive effect [8,10]. Similarly, Nilotinib showed the ability to inhibit the Src-family kinase LCK and T-cell function and to hamper the proliferation and function of CD8þ T lymphocytes [5]. Ruxolitinib also proved to be able to suppress the immune system through the inhibition of the actions of interferon c and interferon a/b [8]. Furthermore, ruxolitinib blocks the function of dendritic cells (DC) and impairs the T-cell mediated immunity [11]. Giving the well-established role of both DC and T-cells in the defense against HBV infection [12], all these findings could indirectly explain the relation between TK inhibitors treatment and HBV reactivation. Based on this evidence the AGA included patients treated with imatinib and nilotinib as having a moderate risk for experiencing HBV reactivation and routinely viral prophylaxis is only weakly recommended in this setting [2]. The more recent ECIL-5 guidelines instead, do not provide any suggestion about the possible management of patients treated with TKIs [3]. Ibrutinib is an oral Bruton’s Tyrosine Kinase (BTK) inhibitor approved by the Food and Drug Administration and the European Medical Agency for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia (CLL), and Waldenstrom’s macroglobulinemia. Compared to chemoimmunotherapy ibrutinib is associated with a lower risk of infections [13]. To our knowledge, published studies do not reveal the possible role of ibrutinib as a trigger of HBV reactivation and there is only one case reporting an occult HBV flare during BTK inhibitor treatment [14]. Furthermore, in ibrutinib clinical trials HbsAg positivity was considered as an exclusion criteria and no

Bing Neel Syndrome in a Previously Untreated Patient With Waldenström's Macroglobulinemia: Contribution of MYD88 L265P Mutation on Cerebrospinal Fluid

Bing Neel Syndrome (BNS) is defined as direct central nervous system involvement of Waldenstrom’s macroglobulinemia. BNS is usually a late event, although an incidence of 30% to 36% has been described in large series of previously untreated patients. A wide variety of clinical manifestations and radiologic findings for BNS have been reported in published data, depending on the site and type of infiltration. In addition to the radiologic findings, the diagnostic approach includes lymphoplasmacytic cell quantitation and flow cytometric analysis of the cerebrospinal fluid (CSF). Recently, the evaluation of MYD88 L265P mutation in the CSF has been proposed as a possible diagnostic biomarker for BNS. We describe the case of a 58-year-old patient with BNS. The detection of MYD88 L265P mutation in the CSF contributed to the diagnosis and to the sequential monitoring of minimal residual disease. In the future, the use of CSF sequential molecular monitoring could play an important role in treatment decisions.

Bendamustine and subcutaneous Alemtuzumab combination is an effective treatment in relapsed/refractory chronic lymphocytic leukemia patients

Alemtuzumab has been extensively used in the salvage setting of chronic lymphocytic leukemia (CLL) resulting less effective on bulky lymphadenopathy.[1][1] Higher response rates have been achieved when combined with fludarabine and cyclophosphamide (FC), but this regimen has led to some safety

Factors predicting survival in chronic lymphocytic leukemia patients developing Richter syndrome transformation into Hodgkin lymphoma

We hereby report the clinical and biologic features of 33 of 4680 (0.7%) patients with chronic lymphocytic leukemia (CLL), managed at 10 Italian centers, who developed Hodgkin lymphoma (HL), a rare variant of Richter syndrome. The median age at CLL and at HL diagnosis were 61 years (range 41‐80) and 70 years (range 46‐82), respectively, with a median interval from CLL to the diagnosis of HL of 90 months (range 0‐258). In 3 cases, CLL and HL were diagnosed simultaneously. Hl was characterized by advanced stage in 79% of cases, International Prognostic Score (IPS) ≥4 in 50%, extranodal involvement in 39%, B symptoms in 70%. Prior treatment for CLL had been received by 82% of patients and included fludarabine in 67%. Coexistence of CLL and HL was detected in the same bioptic tissue in 87% of cases. The most common administered treatment was the ABVD regimen given to 22 patients (66.6%). The complete response (CR) rate after ABVD was 68%, and was influenced by the IPS (P = .03) and interval from the last CLL treatment (P = .057). Survival from HL was also influenced by the IPS (P = .006) and time from the last CLL treatment (P = .047). The achievement of CR with ABVD was the only significant and independent factor predicting survival (P = .037). Taken together, our results show that the IPS and the interval from the prior CLL treatment influence the likelihood of achieving CR after ABVD, which is the most important factor predicting survival of patients with CLL developing HL.