Daratumumab plus bortezomib or daratumumab plus lenalidomide as salvage therapy for patients with myeloma: initial follow-up of an Italian multicentre retrospective clinical experience by 'Rete Ematologica Pugliese'.

We report herein a multicentre retrospective analysis of 192 consecutive patients with symptomatic refractory/relapsed multiple myeloma (RRMM) treated with daratumumab in combination with bortezomib or lenalidomide as salvage therapy at 9 haematological centres in Puglia. Choice of both regimens was based on previous treatment and/or physicians' preference. Considering the under-representation of older patients (very old patient ≥ 80 years) in clinical trials and the prognostic and predictive importance and value of frailty status, here, we further characterised the patient cohort by age. The overall response rate (ORR) was generally lower than what was previously reported in the CASTOR (ORR 72.6% vs 85%) and POLLUX (ORR 86.5% vs 93%) trials. The lower ORR in our analysis compared to the CASTOR and POLLUX trials could be related to a less selected population. Similarly, amongst very old patients, the ORR was encouraging: ORR to treatment with DVd (daratumumab + bortezomib + dexamethasone) was 66.7%, and ORR to treatment with DRd (daratumumab + lenalidomide + dexamethasone) was 92.3%. Median TTP (time to progression) was 10.8 months (1-year TTP: 44.7%; 2-year TTP: 25.3%) in the DVd group; median TTP was not reached in the DRd group (1-year TTP: 82.7%; 2-year TTP: 71.4%). Median OS (overall survival) was not reached either in the DRd group (1-year OS: 85.9%; 2-year OS: 73.7%) or the DVd group (1-year OS: 70.2%; 2-year OS: 58.9%).

Combination treatment of flag with non-pegylated liposomal doxorubicin (MYOCET(TM)) in elderly patients with acute myeloid leukemia: a single center experience.

The incidence of acute myeloid leukemia (AML) increases with age, but results of intensive chemotherapy in elderly patients are disappointing. Non-pegylated liposomal formulations of doxorubicin (Myocet™) have been developed with the aim of reducing systemic and cardiac toxicity especially in the elderly. We evaluated the efficacy and toxicity profiles of fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) regimen given in association with Myocet™ in 35 patients with AML, median age 69 years (range 61-83 years). Nineteen (54.3%) had newly-diagnosed AML, twelve (34.3%) patients had secondary AML (ten with Myelodisplastic Syndrome, two with Primary Myelofibrosis) and 4 (11.4%) patients had had a late relapse (>12 months) of AML. Complete remission (CR) and partial remission (PR) were obtained in twenty-two (63%) and 3 (8.5%) patients, respectively. Seven (20%) patients showed a resistant disease. There were 3 early deaths (8.5%). Six patients (17%) experienced severe cardiovascular toxicity. The median overall survival (OS) was 12 months (range 1-52 months) with a median disease-free survival (DFS) of 20 months (range 1-48 months). One-year and two-year DFS were 78.9% and 26.7%, respectively. This study demonstrates that in elderly patients with AML, FLAG-Myocet combination shows promising efficacy response with acceptable toxicity, enabling most patients to receive further treatments, including transplantation procedures.

Successful treatment of Schnitzler's syndrome with anakinra after failure of rituximab trial.

We report a 50-year-old man who presented with a 5-year history of an intermittent widespread pruritic urticarioid rash and fever, fatigue, arthralgia and a monoclonal immunoglobulin-M paraprotein. The patient was initially treated with antihistamines and corticosteroids without the disappearance of symptoms. A skin biopsy from the urticarial rash on the thorax was performed, revealing dermal mononuclear and polymorphonuclear cell infiltrate and normal epidermis. A diagnosis of Schnitzler's syndrome (SS), a rare disorder in which the simultaneous occurrence of monoclonal gammopathy and chronic urticaria is usually observed, was made. After an unsuccessful trial with rituximab at a dosage of 375 mg/sqm weekly for 4 consecutive weeks, the patient was treated with anakinra, an inhibitor of interleukin-1alpha that is thought to be involved in the pathogenesis of the disease, at a dose of 100 mg daily given subcutaneously. He showed a prompt response to the drug and he is still well and symptom-free after 12 months of follow-up. On the basis of both this experience and the review of the literature we conclude that anakinra may be a promising option for the treatment of SS. However, these results need to be confirmed on a larger number of patients.

Chronic lymphocytic leukemia-associated pure red cell aplasia.

Pure red cell aplasia (PRCA) is a well-known marrow failure which may be acquired or constitutional/congenital, as the Diamond-Blackfan syndrome. Acquired PRCA may show as a primary hematological disorder or secondary to an associated disease, infection or drug. PRCA rarely complicates chronic lymphocytic leukemia (CLL), may occur anytime in the course of the disease and, in this context, it is a minority of total PRCA. Anemia due to PRCA in CLL patients must be carefully evaluated and differentiated from other causes (autoimmune hemolytic anemia, neoplastic lymphocyte infiltration of bone marrow, chemotherapy) that require a different therapeutic approach. PRCA is thought to be an immunologically mediated disorder, but there is no uniformity in the setting of the management. Immunosuppressive therapy is frequently given, such as steroids and cyclosporin-A. Recently, anecdotal cases have been published on the effectiveness of monoclonal antibodies rituximab and alemtuzumab.

Verbena officinalis essential oil and its component citral as apoptotic-inducing agent in chronic lymphocytic leukemia.

We evaluated the pro-apoptotic activity of Verbena officinalis essential oil and of its main component citral, on lymphocytes collected from normal blood donors and patients with chronic lymphocytic leukemia (CLL). The number of apoptotic cells was greater in CLL patients than in healthy subjects at all different times of incubation (4, 8 and 24 hours) for samples treated with Verbena officinalis essential oil (A) and citral (B) as well vs controls at different concentrations (0.1% and 0.01%). The greater pro-apoptotic ability was shown by both essential oil of Verbena officinalis and citral at lower concentrations (after 4 h A 0.1%: 17.8% vs 37.1%; A 0.01%: 15.8% vs 52%; B 0.1%: 18.4% vs 46.4%; B 0.01%: 15.8% vs 54.2%; after 8 h A 0.1%: 23% vs 38%; A 0.01%: 22.2% vs 55%; B 0.1%: 32% vs 42.2%; B 0.01%: 22% vs 54.3%; after 24 h A 0.1%: 5% vs 20.7%; A 0.01%: 25.8% vs 47.2%; B 0.1%: 18.4% vs 46.4%; B 0.01%: 15.8% vs 54.2%). Patients carrying deletion 17p13 (p53 mutation) showed a reduced ability to undergo apoptosis with respect to patients with other genomic aberrations or normal karyotype. The proapoptotic activity of Verbena officinalis essential oil and citral is thought to be due to a direct procaspase 3 activation. These data further support evidence that indicate natural compounds as a possible lead structure to develop new therapeutic agents.

Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma.

BACKGROUND: Bortezomib has shown significant activity in myeloma. In this multicenter trial, we assessed for the first time the combination of bortezomib, doxorubicin and low-dose dexamethasone (PAd) in the treatment of relapsed/refractory myeloma. PATIENTS AND METHODS: Sixty-four patients were treated for a median of four 28-day cycles (1-6). Bortezomib was given at 1.3 mg/m(2) (days 1, 4, 8, 11) and dexamethasone at 40 mg (days 1-4); 34 patients receive doxorubicin at 20 mg/m(2) (days 1, 4) while 30 patients pegylated liposomal doxorubicin at 30 mg/m(2) (day 1). RESULTS: Fifty-eight percent of patients had undergone prior autologous transplantation, 70% prior anthracycline and 27% prior bortezomib-based regimens. Forty-three patients (67%) achieved at least a partial response including 16 (25%) with at least a very good partial response. One-year event-free survival was 34% after PAd and 31% after the previous line of therapy (hazard ratio 1.20, 95% confidence interval 0.76-1.90, P = 0.43). One-year overall survival from the start of PAd was 66%. Grade 3-4 toxic effects included thrombocytopenia (48%), neutropenia (36%), infections (15%), anemia (13%), gastrointestinal disturbances (11%) and peripheral neuropathy (10%). Two patients had grade 3-4 cardiac heart failure. CONCLUSIONS: PAd is an active salvage therapy with manageable toxicity in patients with relapsed/refractory myeloma.

Prognostic relevance of serum beta 2-microglobulin in acute myeloid leukemia.

Serum levels of beta 2-microglobulin (S-B2m) were analysed at diagnosis in 69 cases of acute myeloid leukemias (AML) as a possible prognostic indicator. S-B2m was correlated to various clinical and laboratory features and with respect to response to chemotherapy and following clinical outcome. S-B2m was found to be increased (greater than 3 mg/l) in 40.6% of tested patients and, in particular, in the monocytic variants (M4, M5) of AML (4.2 versus 2.3 mg/l, p less than 0.01). S-B-B2m values paralleled white blood cell count, serum lysozyme levels and expression of monocytic membrane markers at presentation, but no correlation was found with age, renal function or immunological myeloid antigens. Increased levels of S-B2m were associated with a lower likelihood of obtaining a complete remission (25 versus 58.5%, p less than 0.01), while in the multivariate analysis S-B2m greater than 3 mg/l and white blood cell count greater than 20 x 10(9)/l were independent variables significantly influencing disease-free survival in responsive patients (five years DFS for S-B2m greater than or less than 3 mg/l: 28 versus 62%, p less than 0.05). In conclusion, the measurement of S-B2m at diagnosis may have prognostic relevance in AML.

Partial deletions of long arm of chromosome 6: biologic and clinical implications in adult acute lymphoblastic leukemia.

Within 285 adult acute lymphoblastic leukemias (ALL) included in the multicenter GIMEMA 0496 trial and prospectively studied by conventional cytogenetics, 18 cases (6%) with long arm deletion of chromosome 6 (6q) were identified. These cases were divided into: (i) del(6q) only (n = 6); (ii) del(6q) plus other numerical and/or structural abnormalities (n = 8); (iii) del(6q) and other 'specific' translocations (n = 4). The biologic and clinical features of the patients carrying this anomaly, as well as their outcome, were compared with those of 267 patients without del(6q). A T cell phenotype was more frequently associated with del(6q) cases in general (P = 0.001) and particularly with cases presenting del(6q) as the isolated abnormality (P = 0.0027). No significant difference with respect to multidrug resistance (MDR)/P glycoprotein expression was observed between the two groups of patients (21% vs 28% of MDR-positive cases, respectively). A BCR-ABL fusion transcript was less frequently detected in cases with del(6q) (11%) compared with those without the anomaly (29%). p15 and p16 deletions were identified by Southern blot analysis in 21% of cases with del(6q) and in 26% of cases without del(6q). In this latter group, a T cell phenotype was less frequently associated with p15 and/or p16 deletion than in the group carrying del(6q) (36% vs 100% of cases, P = 0.011). Overall, patients with ALL and del(6q) had a high complete remission (CR) rate (83%); however, they had a lower 18 month event-free survival (31% vs 41%) and a higher relapse rate (70% vs 37%, P = 0.02) compared with patients without del(6q). To date, this is the largest series of adult ALL cases reported with del(6q) homogeneously treated, which have also been prospectively studied for MDR expression and for the detection of known fusion genes. This anomaly, as an isolated change, identifies a subset of cases with hyperleukocytosis (median WBC count 52 x 10(9)/l) and a strict correlation with a T cell phenotype. Overall, del(6q) seems to be associated with an unfavorable clinical outcome, although this finding will need to be confirmed by extended FISH analysis.

"Real world" outcome of lenalidomide plus dexamethasone in the setting of recurrent and refractory multiple myeloma: extended follow-up of a retrospective multicenter study by the "rete ematologica pugliese".

This current retrospective multicenter analysis represents, to our knowledge, the first Italian study evaluating the efficacy and toxicity profile of "lenalidomide plus dexamethasone" as salvage therapy in patients with recurrent-refractory MM in the real life contest. Our study included patients who are usually excluded from clinical trials because of unfavorable baseline characteristics. Median OS was significantly longer in patients receiving "lenalidomide plus dexamethasone" for more than 12 months compared with those who had received "lenalidomide plus dexamethasone" for a shorter interval (P<0.0001). Median OS was not affected by best response achieved (P 0.4) and age (P 0.3). Quality of response did not correlate with number of previous lines of therapy (P 0.77) and age. Higher ORRs were recorded in the patients group with relapsed MM compared to those with refractory disease, but this difference was not statistically significant (P 0.38).

Effective autologous peripheral blood stem cell transplantation in plasma cell leukemia followed by T-large granular lymphocyte expansion: a case report.

We report a case of de novo plasma cell leukemia, resistant to standard VMD (vincristine, mitoxantrone, dexamethasone) and CVP (cyclophosphamide, vincristine and prednisone) protocols, treated with a chemotherapy intensification regimen (high-dose cyclophosphamide, modified EDAP, Dexa-BEAM) and peripheral blood stem cell transplantation, performed using fractionated total body irradiation and high dose melphalan. The patient is currently alive and well, in very good partial remission 12 months after transplant and 22 months after diagnosis, disclosing a significant proportion of bone marrow and peripheral blood CD3+, CD8+, CD57+, HLA-Dr+ large granular lymphocytes with cytotoxic activity against neoplastic plasma cells.

CD38 expression correlates with adverse biological features and predicts poor clinical outcome in B-cell chronic lymphocytic leukemia.

CD38 identifies a surface molecule with multi-functional activity. Its prognostic importance in B-cell chronic lymphocytic leukemia (B-CLL) is currently under investigation in view of the fact that two different groups have recently indicated that CD38 expression could be an independent prognostic marker in B-CLL. We analyzed the clinico-biological features of 61 immunologically typical (CD5+CD23+) B-CLL patients stratified according to the CD38 expression. Twenty-two (36%) patients expressed CD38 in more than 30% of CD19-positive cells and were considered as CD38-positive B-CLL. Atypical morphology (p 0.02), peripheral blood lymphocytosis (p 0.01) and diffuse histopathologic bone marrow pattern (p 0.003) were findings found to be closely associated with CD38 expression. On the other hand, A and B Binet stages (p 0.02) and interstitial bone marrow involvement (p 0.005) were more represented in the CD38-negative B-CLL group. Trisomy 12 was detected more frequently in the CD38-positive B-CLL group, while 13q14 deletions mainly occurred in CD38-negative group (p 0.005). Finally, median survival of CD38-positive B-CLL patients was 90 months, while it was not reached at 180 months in CD38-negative patients. Taken together, our data strongly suggest that the evaluation of CD38 expression may identify two groups patients with B-CLL greatly differing in their clinico-biological features.

Morphologically typical and atypical B-cell chronic lymphocytic leukemias display a different pattern of surface antigenic density.

Recent evidences suggest that B-cell chronic lymphocytic leukemia (B-CLL) may have heterogeneous biological and clinical features. Immunological phenotype may be useful for distinguishing these different forms of disease. We used a quantitative flow cytometric approach to analyze the expression of several membrane molecules (CD19, CD20, CD22, CD23, CD11c, CD5, CD79b) commonly used to diagnose and characterize B-CLL in a choort of 84 consecutive B-CLL patients diagnosed according to morphological and immunological findings. We found that morphologically so-called "atypical" B-CLL displayed a significantly higher number of CD20 and CD22 molecules than typical forms. On the other hand, CD19 was found to be more expressed in typical B-CLL, although without reaching statistical significance. Finally, no difference was detected with respect to CD23, CD79b, CD11c and CD5 number of molecules/per cell between typical and atypical B-CLL. Other clinico-biological features, such as surface membrane immunoglobulin density, percentage of CD79b and FMC7 expression, peripheral blood lymphocytosis, trisomy 12 and advanced clinical stages were also found to be more frequent in atypical B-CLL. In conclusion, our data confirm the hypothesis that atypical B-CLL is a disease sustained by more mature B-cells, closely related but, at the same time, clearly distincted from neoplastic cells of typical B-CLL.

Treatment of "poor risk" acute myeloid leukemia with fludarabine, cytarabine and G-CSF (flag regimen): a single center study.

We describe a single center experience of 41 consecutive patients with poor prognosis acute myeloid leukemia (AML) who received a single course of FLAG regimen consisting of Fludarabine 30 mg/m2/day plus Cytarabine 2 gr/m2/day (days 1-5) and G-CSF 5 mg/Kg/day (from day 0 to polymorphonuclear recovery) as salvage therapy. Eleven patients were primarily refractory to previous chemotherapy, 10 patients were in first relapse, 2 patients in second relapse and 7 patients in relapse after transplants. Eleven cases were defined as secondary AML (diagnosis of AML made after a preexisting diagnosis of myelodysplastic syndrome). The median age was 52.6 years (range 16-72); 29 patients were males and 12 females. Overall, 23 (56%) patients reached complete remission (CR), 3 patients died of infection (2) or hemorrhage (1) during induction, and 15 (36%) patients had resistant disease. The highest CR rates (80%) were obtained in relapsed cases; de novo and secondary AML registered 60% and 45% of CR rates, respectively. Patients achieving CR received a second FLAG course as consolidation and were submitted to an individualized program post-remission therapy, depending on the age and performance status. Hematological and non hematological toxicities were acceptable. In conclusion, our data confirm that FLAG is a an high effective treatment for poor prognosis AML and in young patients allows intensive post remissional therapy including allogeneic BMT.

Are "early" and "late" T-acute lymphoblastic leukemias different diseases? A single center study of 34 patients.

Clinical and biological parameters were retrospectively reviewed in 34 cases of T-lineage acute lymphoblastic leukemia (T-ALL), classified as "early" (20 cases) or "late" (14 cases) subgroups, according to the degree of blast cell differentiation, assessed by immunophenotyping. In "early" T-ALL, age, co-expression of "immature" (CD34 and HLA-Dr) or myeloid (My+) antigens, proliferative activity (as evaluated by Ki67 monoclonal antibody), and expression of the "multidrug-resistance" (MDR) phenotype (as determined by C-219 monoclonal antibody) were significantly higher, while WBC count and expression of CDl0 were significantly lower, than in "late" T-ALL. Furthermore, although no statistically significant difference was found between the two groups, "late" T-ALL more frequently displayed a greater extramedullary tumor mass ("lymphoma-like" syndrome), LI FAB morphology and a normal karyotype. A single patient, with "late" T-ALL, also showed positivity for TCR gamma/delta chains, specific monoclonal antibodies. On the whole, 30 patients (88.2%) achieved complete remission: 16(80%) were "early" and 14(100%) "late" T-ALL. No statistical difference was found between the two groups with respect to disease free survival (42% vs 54% at six years), whereas median overall survival was significantly shorter in "early" T-ALL (23 months vs median not yet reached at six years for "late" T-ALL, p < 0.05). We conclude that "early" and "late" T-ALL show clinical and biological differences, that could perhaps justify differential therapeutic approaches.

Minimally differentiated acute myeloid leukemia (AML M0): clinico-biological findings of 29 cases.

Twenty-nine cases of minimally differentiated acute myeloid leukemia or AML M0 identified among 441 AML diagnosed in the last 12 years are reported. In all cases, flow cytometric analysis using a large panel of monoclonal antibodies and cytogenetic and molecular studies (IgH, TcRbeta, BCR/ABL, AML1/ETO and CBFB-MYH11 rearrangements) were performed. Of the 29 patients, 27 were treated with intensive chemotherapy based on GIMEMA protocols. We noted a greater incidence of older (over 60 years) and male patients (52% and 65%, respectively). CD33, CD13, CD7 and TdT were expressed in 79.3%, 82.7%, 58.6% and 42.8% of cases, respectively. Antigenic MPO was present in 17 of 22 cases (77.3%). Most cases expressed CD34 (93.1%), HLA-DR (93.1%), CD117 (80%) and CD45RA (87%). CD45RO and CD90 were consistently negative. In all cases, we observed an up-expression of bcl-2 and a down-expression of CD95 with an inverse trend between the two markers (r -5253; p 0.03). Karyotypic abnormalities were demonstrated in 53.6% of cases. Of these, 6 involved chromosomes 5, 7 and 8, t(9;22), confirmed by the BCR/ABL transcript, was detected in one case. Rearrangements of the TcRbeta and IgH chains were observed in 3 and 2 cases, respectively. No AML1/ETO and CBFB-MYH11 transcripts were found. Twelve out of 27 patients (44%) achieved a complete remission (CR) (in 2 cases after rescue therapy). Seven early (range 1-9 months) and one late (32 months) relapses were observed. Five patients are alive, but only the 4 who underwent bone marrow transplantation are in persistent first CR. In conclusion, AML M0 is a subtype of AML antigenically well detectable, endowed with many adverse parameters (older age, TdT and CD34 expression, resistance to apoptosis, unfavorable cytogenetic abnormalities) and poor prognosis. A very aggressive consolidation treatment can be useful to improve the outcome.

Immunophenotype of acute lymphoblastic leukemia cells: the experience of the Italian Cooperative Group (Gimema).

The immunophenotype of 304 adult lymphoblastic leukemias (> 18 years) diagnosed on the basis of the FAB criteria was determined at the time of diagnosis using a panel of monoclonal antibodies. The series comprised cases diagnosed and immunophenotyped in 43 Italian centers (GIMEMA Cooperative Group) between April 1988 and June 1991. The immunophenotypic characterization consisted of two consecutive steps. The initial screening was based on the reactivity for TdT, HLA-Dr, CD7, CD10, CD13, CD19, CD24, CD33 and CD41. According to the results obtained, the second level of investigation assessed the positivity for intra cytoplasmic (Cy) Ig, CD1a, CD2, CD3, CD4, CD5, CD8 and CD20. Based on the hierarchical expression of the different B- and T-cell related antigens, each case was assigned to a given differentiation stage. B-lineage ALL were classified in five subgroups (B0-B4) and T-lineage ALL in four subgroups (T0-T3). Cases in which the blasts were lymphoid according to the FAB criteria, but expressed myeloid antigens in association with B- and T-lymphoid markers were defined as hybrid leukemias. As expected, CD10+ cases (B2-B3) were the most frequent within the B-lineage ALL (83.2% of cases). CyIg+ (B3) accounted for about 20% of CD10+ ALL. Twenty eight cases (13.4%) were at a pre-cALL stage (B0-B1) and of these, 8 (3.8% of the total series) were positive only for TdT and HLA-Dr (B0). Intermediate and mature thymic phenotypes (T2-T3) were predominant within the T-ALL (67.2%) groups. Five cases, were positive only for TdT and CD7 (CD5+), and classified as T0. 9.2% of cases fulfilled the definition of hybrid leukemia, largely in view of the co-expression of B-lymphoid and myeloid markers.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum beta 2-microglobulin in malignant lymphoproliferative disorders.

Beta 2-microglobulin (B2m) was measured on serum samples in 274 patients with acute and chronic lymphoproliferative disorders (85 non-Hodgkin lymphomas-NHL, 30 Hodgkin lymphomas-HL, 34 B-cell chronic lymphocytic leukemias-B-CLL, 8 Waldenström macroglobulinemias-WM, 76 multiple myelomas-MM, 31 acute lymphoblastic leukemias-ALL, 10 hairy cell leukemias-HCL). Two hundred and four patients were studied at the time of diagnosis, and results were correlated to clinical stage, and histologic subtype in NHL, immunoglobulin type in MM, and immunologic phenotype in ALL. Moreover, B2m was tested during and after chemo- and/or radiotherapy, and results were correlated to response, progression or relapse. Elevated pretreatment B2m values were found in widespread forms of NHL and HL, in patients with B symptoms and in the unfavorable histologic subgroups of NHL. Rapid falls in levels followed therapy institution. In B-CLL and in MM a close relationship between B2m and cell mass was found. A significant B2m level reduction followed treatment, whereas its increase could detect a relapse. In ALL, serum B2m was only slightly above the normal range. B2m seems to reflect the total burden of malignant cells mainly in MM and B-CLL; in other lymphoproliferative disorders it provides less prognostic information.

Clinical relevance of immunocytochemical detection of multidrug-resistance-associated P-glycoprotein in hematologic malignancies.

P-glycoprotein (P-170) is the phenotypic marker of tumoral cells that show the phenomenon of multidrug resistance (MDR). Using an immunocytochemical approach, we employed the monoclonal antibody C219 (which recognizes an epitope of such a glycoprotein) to evaluate in cytologic samples the expression of P-170 on neoplastic cells from 52 patients affected by different hematologic malignancies and its eventual correlation to clinical outcome. Longitudinal studies were also performed in 14 patients. Results obtained demonstrated that a) the so-called "MDR phenotype" may be heterogeneously represented (from less than 1 to 100% of positive cells) in hemopoietic tumors at diagnosis (without exposure to pharmacologic agents), as well as during the course of the disease, although a more substantial presence of P-170 occurred in treated patients. There was no correlation between neoplastic kinetic activity (such as expression of Ki 67 recognized nuclear proliferation-associated antigen) and P-170-positive cells. b) Percentage of positive cells as well as intensity of staining seemed to be important in determining MDR; in general, there was a strong correlation between expression of P-170 in more than 20% of neoplastic cells and a lack of response to chemotherapy. However, some false-positive and false-negative cases were observed. c) The detection of scattered P-170-positive cells may predict a pharmacologic selection of intrinsic or mutant-resistant clones.

Bendamustine in combination with ofatumumab in relapsed or refractory chronic lymphocytic leukemia: a GIMEMA Multicenter Phase II Trial.

We conducted a phase II, noncomparative, open-label, multicenter GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) study (CLL0809) to assess the efficacy and safety of bendamustine in combination with ofatumumab (BendOfa) in relapsed/refractory chronic lymphocytic leukemia (CLL). Forty-seven patients from 14 centers were evaluated. Therapy consisted of bendamustine (70 mg/m(2)) for 2 consecutive days every 28 days, and ofatumumab 300 mg on day 1 and 1000 mg on day 8 during the first cycle, and 1000 mg on day 1 subsequently. Treatment was administered up to six cycles. The overall response rate (ORR), as per intention-to-treat analysis, was 72.3% (95% confidence of interval (CI), 57-84%), with 17% complete responses. After a median follow-up of 24.2 months, the overall survival was 83.6% (95% CI, 73.0-95.7%) and the progression-free survival (PFS) was 49.6% (95% CI, 35.9-68.6%). The median PFS was 23.6 months. Univariate and multivariate analyses were used to identify clinical and biological characteristics associated with ORR and PFS. Myelosuppression was the most common toxicity; grade ≥3 neutropenia was observed in 61.7% of patients; however, grade ≥3 infections occurred in 6% of patients. BendOfa is feasible and effective in relapsed/refractory CLL patients, including patients with high-risk clinical and biological features.