Correspondence in reference to the previously published manuscript: Reduction of cycles of bendamustine plus rituximab therapy in the cases with good response for indolent B-cell lymphomas.

Takezaki et al. analyzed the outcome of 57 patients with indolent lymphomas treated with Bendamustine plus Rituximab (BR) according to the number of cycles received, showing that patients who discontinued BR after four cycles had similar outcomes compared to patients who received five or six cycles. Considering the similarities but also the differences between indolent lymphomas and chronic lymphocytic leukemia (CLL), we enriched the results obtained with a cohort of CLL patients treated with BR starting from the experience of the Lazio region group on CLL. Out of 115 patients, 97 (84%) received 4-6 cycles of BR, while 18 (16%) received 1-3 cycles. The outcome of the group of patients who received at least 4 cycles was superior in terms of response rate (ORR 96% vs. ORR 83%, p = 0.041; CR 58% vs. CR 28%, p = 0.052 respectively) and PFS [median PFS 52.6 (40.3-64.9) versus 26.2 (19.3-33.0) months, p < 0.001]. The number of patients undergoing 4 cycles of BR (4-cycles group) and 5-6 cycles (over-4-cycles group) was 9 and 88, respectively. Compared to analysis conducted by the Japanese group in indolent lymphomas, in CLL we did not observe any difference between the outcome of the 4-cycles group and the over-4-cycles group in terms of ORR (89% vs. 97%, p = 0.268) and in survival [median PFS 40.8 (13.7-67.8) versus 52.6 (38.7-66.5) months, p = 0.117]. Moreover, we observed that patients who achieved a clinical CR showed overlapping outcomes with patients who received more than 4 cycles [CR vs. non-CR median PFS not reached vs. 11.0 months; over-4-cycles group median PFS 52.6 months (40.3-64.9); p < 0.001]. Nowadays chemoimmunotherapy with BR is reserved to fit elderly CLL patients, and there are many chemo-free treatment options available; therefore, discontinuation after 4 cycles may be permissible in patients who obtained a CR in order to limit toxicity as much as possible.

Independent prognostic impact of CD15 on complete remission achievement in patients with acute myeloid leukemia.

The prognostic role of CD15 in acute myeloid leukemia (AML) has been tested in different studies with conflicting results. To address this issue, we retrospectively evaluated a cohort of 460 AML patients of all ages with the exclusion of acute promyelocytic leukemia (M/F 243/217, median age 50.6 years [range 0.9-81.2]) intensively treated at our institute between January 1999 and December 2010. CD15 positivity was found in 171 of 406 evaluable patients (42.1%). Complete remission (CR) was achieved by 334 patients (72.6%), while 82 (17.8%) were resistant and 44 (9.6%) died during induction: the median CR duration was 15.5 months (range 0.6-176.0), with 2-year disease-free survival rate of 45.1% (95% confidence interval 39.6-50.6). The median overall survival was 14.4 months (range 0.3-177.0), with 2-year overall survival rate of 42.2% (95% confidence interval 37.5-46.9). At univariate analysis for CR achievement, age < 60 years (P < .001), World Health Organization classification (P = .045), low-risk karyotype (P < .001), no high-risk karyotype (P = .006), positivity for AML-ETO (P = .004)/CBFß-MYH11 (P = .003)/CD15 (P = .006)/CD11b (P = .013), negativity for FLT3-ITD (P = .001), Hb > 8 g/dL (P = .020), and white blood cell < 50 × 109 /L (P = .034) had a favorable impact. At a multivariate logistic regression model, CD15 positivity (P = .002), age < 60 years (P = .008), white blood cell < 50 × 109 /L (P = .017), and low-risk/no high-risk karyotype (P = .026/P = .025) retained an independent prognostic role on CR achievement. The baseline assessment of CD15 positivity appears to have a role in the risk evaluation for CR achievement in AML patients undergoing intensive chemotherapy and should be assessed in prospective studies together with other clinical and biologic features already reported.

Risk of secondary hypogammaglobulinaemia after Rituximab and Fludarabine in indolent non-Hodgkin lymphomas: A retrospective cohort study.

The occurrence of secondary hypogammaglobulinemia (SH) after chemo-immunotherapy represents a potential side effect in patients with indolent non-Hodgkin lymphomas (iNHL). Few data are available on SH occurring after chemotherapy and/or Rituximab (R). We retrospectively investigated the incidence and the risk factors for SH and infectious complications in patients with iNHL after chemo-immunotherapy. Two hundred and sixty six patients treated between 1993 and 2011 were studied. Patients with a basal hypogammaglobulinemia or a monoclonal component were excluded. The incidence of SH was 2.2×1000 person-years (95% CI 1.6-2.9). Exposure to Fludarabine-based schedules (Fbs)±R was associated with a hazard ratio (HR) of 18.1 (95% CI: 4.3-77.0). Conversely, exposure to CHOP±R or CVP±R was not a risk factor (HR 0.3, 95% CI: 0.1-0.8; HR 0.3, 95% CI: 0.08-1.4, respectively). The role of R was studied comparing cohorts differing only for R; no differences were found comparing R-CHOP/R-CVP versus CHOP/CVP (HR 1.07, 95% CI: 0.38-3.05) and R-Fbs versus Fbs (HR 2.07, 95% CI: 0.62-6.99). Autologous stem cell transplantation (ASCT) is also a risk factor (HR: 5.2, 95% CI 2.1-13.0). SH patients presented a high risk for pneumonia development (HR 7.07 95% CI: 2.68-18.44). We recommend monitoring of serum immunoglobulins in an attempt to reduce the probability of infection after Fbs or ASCT.

Negative prognostic value of CD34 antigen also if expressed on a small population of acute promyelocytic leukemia cells.

Potential clinical significance of CD34 expression in acute promyelocitic leukemia (APL) has not been deeply investigated. We hereby analyzed the clinico-biological features and treatment outcome of APL patients in relation to CD34 expression, even when expressed in a small subpopulation: 114 APL patients homogeneously treated with the AIDA schedule were included in the study and prognostic correlation with respect to CD34 expression, both when expressed in association with CD2 and as isolated expression (cutoff ≥2 to <10 % or ≥10 %), were investigated. CD34 was associated to CD2 in 30 patients and was isolated in 19 patients. When compared to the CD34-negative population, CD34/CD2 expression identified a subgroup with characteristic features: M3 variant subtype (26 vs 7 % in the negative group, p = 0.02), bcr3 transcript subtype (73 vs 32 %, p = 0.001), high risk according to the risk of relapse (66 vs 17 %, p = 0.002), high incidence of differentiation syndrome (26 vs 12 %, p = 0.01), lower overall survival (88 vs 95 %), and a significantly higher rate of relapse (22 vs 13.8 %, p = 0.05). We then evaluated the prognostic value of isolated CD34 expression: it was detected in nine patients with a cutoff of expression ≥10 % and in 10 patients with a cutoff ≥2 but <10 %. Isolated CD34 positivity identified a subgroup with a classic morphology (79 %), bcr1 prevalence (53 %), higher rate of relapse (37 vs 13.8 % in the negative group, p = 0.002), higher incidence of differentiation syndrome (55 vs 12 %, p = 0.03), and lower overall survival (60 vs 95 %, p = 0.001). The results of our study confirm that CD34/CD2 expression characterizes a subset of APL with a high WBC count and a variant morphological subtype, associated with an unfavorable clinical course. We also show that the isolated expression of CD34, even at a low cutoff, identifies a group of classic APL with a negative prognosis. Further studies aimed at identifying other molecular signatures in CD34-positive patients are needed in order to optimize the therapeutic strategy for this subset of patients.

Aberrant phenotypic expression of CD15 and CD56 identifies poor prognostic acute promyelocytic leukemia patients.

Limited information is available on the relationship between expression of some additional aberrant phenotypic features and outcome of acute promyelocytic leukemia (APL) patients. Here, we set out to assess the frequency of CD15 and CD56 expression, and their prognostic value in a large series of APL patients. One hundred and fourteen adult patients consecutively diagnosed with PML/RARα-positive APL and homogeneously treated with the AIDA induction schedule at a single institution were included in the study. Twelve (10.5%) and 9 (8%) of the 114 patients expressed CD15 and CD56, respectively. CD15 expression identified a subset of patients with a classic morphologic subtype (92%), a prevalent association with a bcr1 expression (67%) with an unexpectedly higher frequency of relapses (42% vs 20% for the CD15- patients, p=0.03) and a low overall survival (OS) (median OS at 5 years 58% vs 85% for the CD15- patients, p=0.01). CD56 expression was detected only in patients with a classic morphologic subtype, a prevalent bcr3 expression (67%), high incidence of differentiation syndrome (55%), higher frequency of relapse (34% vs 20% for the CD56- population, p=0.04) and a low OS (60% vs 85% for the CD56- population p=0.02). We hereby confirm the negative prognostic value of CD56 and we show that the same applies also to cases expressing CD15. These aberrant markers may be considered for the refinement of risk-adapted therapeutic strategies in APL patients.

Regression of a case of Multiple Myeloma with antiviral treatment in a patient with chronic HCV infection.

We report a case of a 54 year old patient with Multiple Myeloma (MM) and chronic HCV infection. In 2005 MM was diagnosed and a chemotherapy was prescribed. Before starting treatment a chronic HCV infection was found. When she came to our Institution for a second opinion, chemotherapy treatment was not considered immediately necessary so the patient was treated for the HCV chronic infection (Pegilated alpha-Interferon 180 µg/week and Ribavirin 1000 mg p.o./day). After one month of treatment she presented a reduction of Bence Jones protein (BJ) that further decreased in the following three months. The antiviral treatment was suspended after six months and a re-evaluation showed a complete viral response and a regression of MM. Sixty-eight months after the end of antiviral treatment the patient is asymptomatic and presents a condition compatible with an M-GUS. While the association between HCV infection and non-Hodgkin's lymphoma is consolidated and it is clearly demonstrated that antiviral treatment in these patients can induce a high proportion of partial and complete remission, a similar effect was never described in MM. The response obtained in our patient may suggest a possible a role of HCV in the pathogenesis of MM.

Ara-C, Idarubicine and Gentuzumab Ozogamicin (AIM) as Salvage Treatment in Advanced Acute Myeloid Leukemia Patients.

Long-term survival of relapsed/refractory acute myeloid leukemia (AML) remains a major problem, particularly in patients not eligible for transplantation.We hereby evaluated the feasibility and efficacy of adding Gemtuzumab Ozogamicin to salvage chemotherapy (Ara-C, Idarubicine, Peg-Filgrastim) in relapsed/refractory AML. The main endpoints were: the rate of complete remissions (CR) and the proportion of patients capable of undergoing a stem cell transplant.Fourty-two patients were enrolled. The overall CR rate was 76% and no induction deaths were reported. In 56% of patients, a transplant procedure could be performed. The treatment schedule proved feasible and well tolerated, providing a high CR rate and a useful bridge to transplant.

"Real-life" results of front-line treatment with Imatinib in older patients (≥ 65 years) with newly diagnosed chronic myelogenous leukemia.

The age role was evaluated in 117 consecutive patients with newly diagnosed CML at our Institution treated with front-line Imatinib from 9/02 to 3/08. Forty patients (34.1%) aged ≥ 65 years and 77 (65.9%) <65 years. Thirty-four older patients (85%) had at least 1 comorbidity versus 39 younger patients (50.6%) (p<0.001). Complete cytogenetic response (CCyR) was achieved in 34/40 older patients (85%) as compared to 69/77 younger patients (89.6%), without statistically significant differences. Severe (grades 3-4 WHO) hematological and extra-hematological toxicities were more common in older patients (p=0.02 and p=0.017, respectively). Rates of permanent Imatinib discontinuation and dose reduction to 300 mg or less were significantly higher in older patients (p=0.009 and p=0.001, respectively). In conclusion, Imatinib in older patients with newly diagnosed CML seems to have the same efficacy as in younger patients, but tends to be more toxic, leading to higher rates of discontinuation and dose reduction. To overcome this problem, future trials concerning best dosage in this subset of patients could be useful.

Cytogenetic and molecular responses in chronic phase chronic myeloid leukaemia patients receiving low dose of imatinib for intolerance to standard dose.

Imatinib mesylate is the gold standard treatment of chronic myeloid leukaemia (CML) and 400 mg/day is considered the standard dose. Although it is generally well tolerated, some patients require temporary drug discontinuation and permanent dose reduction because of haematological or non-haematological toxicities. Whether or not reduced doses are effective as the standard dose in inducing and/or maintaining complete cytogenetic and molecular response is not clear. We report the outcome of 45 CML patients in early (17) and late (28) chronic phase (CP) in whom, within a series of 250 patients treated with imatinib, reduced the dose of the drug after experiencing adverse events. Median time interval between the start of therapy and dose reduction was 58 days, whereas median administered dose was 300 mg/day. At 6 months from reduction, major cytogenetic responses (MCRs) were observed in 67% of patients, with 58% being complete cytogenetic remission (CCR), and complete molecular response (CMR) were obtained in 18% of patients. At 12 months, all patients who had obtained MCR reached CCR: this was significantly higher in low risk patients (87%) versus non-low risk patients (66 and 46%), and in early phase (82%) versus late phase (53.5%). CMR and major molecular response (MMR) were detected in 20 and 22% of patients, respectively. Low dose imatinib appears effective in patients with intolerance to standard dose, even though long-term effects remain to be established.

Decisional flow with a scoring system to start platelet-lowering treatment in patients with essential thrombocythemia: long-term results.

We prospectively tested, at diagnosis in essential thrombocythemia (ET) patients with no clear indication to platelet (PLT)-lowering treatment, a scoring system based on age, PLT level, cardiovascular diseases, previous thrombotic events, smoking and dysmetabolic diseases. From 04/92 to 03/98, 168 consecutive patients were enrolled. Hydroxyurea (HU) was started at diagnosis in 32 "symptomatic" patients and in 33 patients aged >70 years. The remaining 103 patients ("asymptomatic" and aged <70 years) were classified according to our scoring system. Thirty-two patients with score > or = 4 started HU early after diagnosis. The remaining 71 patients with score <4 at diagnosis received anti-aggregating agents only; of them, 24 (33.8%) started HU during follow-up after a median time from diagnosis of 28 months, while 47 (66.2%) did not start any PLT-lowering treatment. Thrombotic complications occurred in 9/103 patients (8.7%); in particular, they occurred in 4/32 patients (12.5%) with score > or = 4 receiving HU since diagnosis and in 5/71 (7%) with score <4 under anti-aggregating agents only. This scoring system appears effective to discriminate a different risk of thrombotic events, and could be useful to decide when a PLT-lowering therapy needs to be started.

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.

Sequential development of mutant clones in an imatinib resistant chronic myeloid leukaemia patient following sequential treatment with multiple tyrosine kinase inhibitors: an emerging problem?

With the increasing use of new tyrosine kinase inhibitors it has been suggested that the spectrum of kinase domain mutations may change and possible selection of new resistant clones may occur. We describe a Ph + chronic myeloid leukaemia (CML) patient with primary resistance to imatinib who received without success sequential therapy with multiple TKIs, and developed sequential emergence of kinase domain mutations after these treatments.

Isolated molecular relapse in FIP1L1-PDGFRalpha hypereosinophilic syndrome after discontinuation and single weekly dose of imatinib: need of quantitative molecular procedures to modulate imatinib dose.

Imatinib is the treatment of choice for FIP1L1-PDGFRalpha (F/P+) positive myeloproliferative neoplasms, but little is known about optimal dose and duration of treatment to maintain complete molecular remission once achieved. We describe a case of F/P+ patients who started imatinib and reached a molecular remission, but did relapse after 15 months of therapy for poor adherence to therapy, and re-obtained remission only with standard dose of 400 mg/day. We reviewed the literature and highlights the need of quantitative molecular procedures to modulate imatinib dose.

Achievement of complete molecular responses in late chronic phase chronic myeloid leukaemia patients treated with pulsed imatinib while in minimal residual disease.

Chronic myeloid leukaemia (CML) patients in chronic phase (CP) are currently treated with a standard dose of imatinib of 400mg/daily. However, once in complete cytogenetic remission (CCR) it is possible that some patients maintain this status with reduced dose of the drug. Here, we describe five cases of CML in late CP, which were switched to imatinib while in CCR after interferon alpha (IFN alpha) and reached complete and stable molecular remission with intermittent drug administration at 400mg/every 20 days/month.

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.