Maria Cantonetti

Early Autologous Stem-Cell Transplantation Versus Conventional Chemotherapy as Front-Line Therapy in High-Risk, Aggressive Non-Hodgkin’s Lymphoma: An Italian Multicenter Randomized Trial

PURPOSE To evaluate the role of early intensification with high-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) as front-line chemotherapy for patients with high-risk, histologically aggressive non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS We planned a multicenter, randomized trial to compare a conventional chemotherapy regimen of methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B; arm A) with an abbreviated regimen of MACOP-B (8 weeks) followed by HDT and ASCT (arm B) for intermediate-high-risk/high-risk patients (according to the age-adjusted International Prognostic Index). From September 1994 to April 1998, 150 patients with aggressive lymphoma were enrolled onto the trial. Seventy-five patients were randomly assigned to arm A and 75 patients were randomly assigned to arm B. In both arms, involved-field radiation therapy (36 Gy) was delivered to the site of bulky disease. RESULTS The rate of complete response was 68% in arm A and 76% in arm B (P = not significant [NS]). Three toxic deaths (4%) occurred in arm B and one (1%) occurred in arm A (P = NS). In arm B, 30 patients (40%) did not undergo HDT and ASCT. According to the intention-to-treat analysis at a median follow-up of 24 months, 5-year overall survival probability in arms A and B was 65% and 64% (P =.95), 5-year progression-free survival was 49% and 61% (P =.21), and 5-year relapse-free survival was 65% and 77% (P =.22), respectively. CONCLUSION Abbreviated chemotherapy followed by intensification with HDT-ASCT is not superior to conventional chemotherapy in patients with high-risk, aggressive NHL. Additional randomized trials will clarify whether HDT-ASCT as front-line therapy after a complete course of conventional chemotherapy improves survival in this group of patients.

Multiple myeloma: VMCP/VBAP alternating combination chemotherapy is not superior to melphalan and prednisone even in high-risk patients.

The efficacy of alternating vincristine, melphalan (M), cyclophosphamide, prednisone/vincristine, carmustine, doxorubicin, and prednisone (VMCP/VBAP) polychemotherapy was compared with the M and prednisone (MP) regimen as induction treatment in multiple myeloma (MM). Three hundred four MM patients entered this study between March 1983 and July 1986; the analysis was performed in December 1989. The treatment groups did not show significant differences with respect to major prognostic factors. Median overall survival was 33.8 months. In the VMCP/VBAP and MP arms, after 12 induction chemotherapy cycles, 59.0% and 47.3% (P less than .068) of the patients achieved an M component reduction greater than 50%. No significant difference was observed in the two treatment arms in terms of remission duration (21.3 v 19.6 months, P less than .66) and survival (31.6 v 37.0 months, P less than .28). Patients younger than 65 years did not show any advantage from the alternating polychemotherapy. At diagnosis, the plasma cell labeling index (LI) and serum beta-2 microglobulin (beta 2-m) were evaluated in 173 and 183 patients, respectively. A significantly reduced survival was observed for patients with LI greater than or equal to 2% (16.4 months) or beta 2-m greater than or equal to 6 mg/L (20.4 months). Even in these poor-risk subgroups, VMCP/VBAP was not superior to MP.

Early chemotherapy intensification with BEACOPP in advanced-stage Hodgkin lymphoma patients with a interim-PET positive after two ABVD courses

Interim 2‐[18F]Fluoro‐2‐deoxy‐D‐glucose Positron Emission Tomography performed after two chemotherapy cycles (PET‐2) is the most reliable predictor of treatment outcome in ABVD‐treated Hodgkin Lymphoma (HL) patients. We retrospectively analysed the treatment outcome of a therapeutic strategy based on PET‐2 results: positive patients switched to BEACOPP, while negative patients continued with ABVD. Between January 2006 and December 2007, 219 newly diagnosed HL patients admitted to nine centres were enrolled; 54 patients, unfit to receive this treatment were excluded from the analysis. PET‐2 scans were reviewed by a central panel of nuclear medicine experts, according to the Deauville score ( Meignan, 2009 ). After a median follow up of 34 months (12–52) the 2‐year failure free survival (FFS) and overall survival for the entire cohort of 165 patients were 88% and 98%; the FFS was 65% for PET‐2 positive and 92% for PET‐2 negative patients. For 154 patients in which treatment was correctly given according to PET‐2 review, the 2‐year FFS was 91%: 62% for PET‐2 positive and 95% for PET‐2 negative patients. Conclusions: this strategy, with BEACOPP intensification only in PET‐2 positive patients, showed better results than ABVD‐treated historic controls, sparing BEACOPP toxicity to the majority of patients (Clinical Trials.gov Identifier NCT00877747).

Final results of a multicenter trial addressing role of CSF flow cytometric analysis in NHL patients at high risk for CNS dissemination

This prospective study compared diagnostic and prognostic value of conventional cytologic (CC) examination and flow cytometry (FCM) of baseline samples of cerebrospinal fluid (CSF) in 174 patients with newly diagnosed aggressive non-Hodgkin lymphoma (NHL). FCM detected a neoplastic population in the CSF of 18 of 174 patients (10%), CC only in 7 (4%; P < .001); 11 patients (14%) were discordant (FCM(+)/CC(-)). At a median follow-up of 46 months, there were 64 systemic progressions and 10 CNS relapses, including 2 patients with both systemic and CNS relapses. Two-year progression-free and overall survival were significantly higher in patients with FCM(-) CSF (62% and 72%) compared with those FCM(+) CSF (39% and 50%, respectively), with a 2-year CNS relapse cumulative incidence of 3% (95% confidence interval [CI], 0-7) versus 17% (95% CI, 0-34; P = .004), respectively. The risk of CNS progression was significantly higher in FMC(+)/CC(-) versus FCM(-)/CC(-) patients (hazard ratio = 8.16, 95% CI, 1.45-46). In conclusion, FCM positivity in the CSF of patients with high-risk NHL is associated with a significantly higher CNS relapse risk and poorer outcome. The combination of IV drugs with a higher CNS bioavailability and intrathecal chemotherapy is advisable to prevent CNS relapses in FCM(+) patients.

The addition of rituximab to fludarabine improves clinical outcome in untreated patients with ZAP-70-negative chronic lymphocytic leukemia†

Clinical trials of monoclonal antibodies in combination with chemotherapy have reported previously unattained response rates in patients with B‐cell chronic lymphocytic leukemia (B‐CLL); however, the analysis of ZAP‐70 protein and/or CD38 may explain better the discordant outcomes independent of treatment.

Clinical implications of cytokine and soluble receptor measurements in patients with newly-diagnosed aggressive non-Hodgkin's lymphoma

Abstract:  Serum levels of 13 different cytokines and receptors were measured serially in 78 patients with aggressive non‐Hodgkins lymphoma (NHL) treated by 4 cycles of an intensive multi‐agent chemotherapy regimen. Recombinant human granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) was administered subcutaneously in 36 of these patients from day + 5 to day + 18 after each chemotherapy. Statistically significantly higher pretreatment levels of interleukin‐2 (IL‐2), interleukin‐6 (IL‐6), interleukin‐8 (IL‐8), interleukin‐10 (IL‐10), the soluble IL‐2 receptor (sIL‐2r), the soluble transferrin receptor (sTf‐r), and neopterin, were observed in NHL patients as compared to controls (p< 0.001 for all molecules). sIL‐2r and sTf‐r levels correlated with tumor burden (p< 0.001 and p = 0.003, respectively) whereas IL‐6 was higher in patients presenting B symptoms (p< 0.001). Cytokine levels progressively declined to normal ranges in responding patients, while they remained elevated in non‐responders. Relapsed patients also presented increased concentrations of several molecules. During the administration of GM‐CSF, we observed the drastic increase of sIL‐2r, while lower elevations were recorded for a number of cytokines, including IL‐8, tumor necrosis factor‐α, interleukin‐1β, IL‐6, and IL‐2. However, upon completion of the induction treatment, cytokine/receptor levels were comparable among individuals with the same type of response, whether or not they had received GM‐CSF. No single parameter was found to be of prognostic significance, but the combination of elevated IL‐10 and of sIL‐2r greater than 3000 U/ml selected a subgroup of 7 patients who failed induction treatment (p = 0.002). These results demonstrate that cytokine and soluble receptor measurements can provide valuable informations for a better management of NHL, in terms both of markers to monitor disease activity and of prognostic indicators.

FISH analysis for CML monitoring

Abstract Conventional cytogenetics is considered the gold standard for evaluating CML during interferon (IFN) treatment. Drawbacks to this approach are the small number of metaphases available during IFN therapy and the impossibility of scoring interphase cells. We applied, besides cytogenetics, double-color FISH (dc-FISH) detection of BCR-ABL gene fusion to monitor 20 CML patients on IFN. dc-FISH easily detected 200 cells per specimen, while with cytogenetic examination a mean of 16.1 mitoses per sample were scored. Though the correlation of dc-FISH and cytogenetic data was good (r=0.77, p<0.001), the discrepancy between the two methods as regards the proportion of leukemic cells in the marrow was often important. dc-FISH detected a relevant proportion of BCR-ABL+ cells in three patients classified as complete cytogenetic responders and showed that, after 9–12 months of IFN treatment, a significant reduction of BCR-ABL+ cells was present in all the 20 patients tested. This might suggest that all CML patients are potentially responsive to IFN. Though more data are required, we think that dc-FISH is more informative than cytogenetic analysis for CML monitoring. Notably because of the simplicity of the procedure, this method could be easily standardized among different laboratories, thus permitting cross-comparison in therapeutic trials.

Comprehensive analysis of PTEN status in Sezary syndrome.

Sézary syndrome (SS) is an incurable leukemic variant of cutaneous T-cell lymphoma characterized by recurrent chromosomal alterations, among which, chromosome 10q deletion is very frequent. In this study, we investigated the PTEN status, on locus 10q23, in 44 SS patients; our findings show that PTEN is deleted in 36% of SS cases, whereas PTEN downregulation is observed in almost all of the samples evaluated by quantitative reverse-transcriptase polymerase chain reaction and Western blotting analysis. Neither DNA sequence mutation nor promoter hypermethylation were found at the PTEN locus, but we demonstrate that PTEN level can be also reduced by a group of miRs previously found upregulated and of prognostic relevance in SS; particularly, miR-21, miR-106b, and miR-486 were able to control PTEN abundance either in vitro or in vivo. Finally, because reduced PTEN activates the PI3/AKT-mediated pathway of cell growth and survival, we demonstrate that PTEN deficiency is associated with activated AKT in skin resident but not circulating SS cells, suggesting that the cutaneous milieu may strongly contribute to the SS cell growth. To our knowledge, this is the first study fully exploring the PTEN status in a large cohort of SS patients, unveiling potential elements of clinical utility in this malignancy.

PERCUTANEOUS KYPHOPLASTY: INDICATIONS AND TECHNIQUE IN THE TREATMENT OF VERTEBRAL FRACTURES FROM MYELOMA

Aims and background The purpose of our research was to assess the effectiveness and safety of percutaneous kyphoplasty, the new method of treatment for pain deriving from vertebral compression fractures due to myeloma. Methods We treated 3 patients with pain refractory to conventional medical therapy (analgesics, bed-rest, bracing with orthopedic devices for more than 4 weeks), localized in the lumbar area, painful to the touch and in the absence of neurological signs. Results The method demonstrated a swift pain relief associated with an evident augmentation in the resistance and restoration of the vertebral bodys physiological shape. Polymethylmethacrylate leaks were not observed in the epidural or foraminal area, nor were complications such as pulmonary embolism for involvement of the venous plexus or related to phenomenon of infections due to the procedure, or toxicity due to the polymethylmethacrylate. Conclusions Kyphoplasty was found to be an effective alternative, simple and safe in the treatment of vertebral collapse consequent to multiple myeloma. The same injection of polymethylmethacrylate can be done before the radiotherapy treatment, thereby synergizing its delayed analgesic action to pain, or after the failure or in the case of local recurrence.

Cytogenetic analysis is non-informative for assessing the remission rate in chronic myeloid leukemia (CML) patients on interferon-α (IFN-α) therapy

Abstract Cytogenetic analysis is considered pivotal for assessing the remission rate in CML patients on IFN therapy. On the basis of general agreement, at least 25 metaphases should be analyzed in each case. The main limitations to this approach are: 1) the small number of analyzable metaphases generally found in cytogenetic preparations from IFN-α-treated patients; and 2) the inability of this technique for scoring interphase cells. We compared the results of cytogenetic analysis and double-color FISH detection of bcr/abl genes fusion in 13 CML patients on IFN-α therapy (marrow sampling for cytogenetic and FISH analysis was carried out after 12 months in all patients and repeated after 18 months of IFN therapy in patients 4, 6, and 8). In five specimens, 20 to 25 cells were evaluable for cytogenetic examination, in another five no analyzable metaphases were scored, and in the remaining six samples two to 14 cells could be analyzed. With FISH detection at least 100 cells were easily scored in each specimen (mean number, 175). Comparing the results carried out with the two methods in different samples it emerged that cytogenetic analysis led to improper conclusions as regards the rate of Ph positivity, even in those patients where 20–25 metaphases were analyzed. Although many more cases have to be studied to establish the role of FISH analysis in Ph-positive patients, we are of the opinion that cytogenetic analysis is unfit for easily and accurately assessing the actual quality of remission in IFN-treated subjects.