Marzia Salvucci

Investigating factors associated with adherence behaviour in patients with chronic myeloid leukemia: an observational patient-centered outcome study

Background:Optimal adherence to imatinib therapy is of paramount importance to maximise treatment effectiveness in patients with chronic myeloid leukaemia (CML). The main objective of this study was to investigate patient-reported personal factors associated with adherence behaviour.Methods:Analysis was conducted on 413 CML patients receiving long-term therapy with imatinib. Adherence behaviour was measured with the Morisky Medication Adherence Scale and personal factors investigated included: quality of life, perceived social support, fatigue, symptom burden, psychological wellbeing and desire for additional information. Key socio-demographic and treatment-related factors were also taken into account. Univariate and multivariate logistic regression analyses were used to investigate factors associated with optimal adherence to therapy.Results:In all, 53% of patients reported an optimal adherence behaviour. The final multivariate model retained the following variables as independent predictors of optimal adherence to therapy: desire for more information (ref. no), odds ratio (OR)=0.43 (95% confidence interval (CI), 0.29–0.66; P<0.001), social support (higher score representing greater support), OR=1.29 (95% CI, 1.11–1.49; P<0.001) and concomitant drug burden (ref. no), OR=1.82 (95% CI, 1.18–2.80; P=0.006).Conclusion:This study suggests that a higher level of social support, satisfaction with information received and concomitant drug burden are the main factors associated with greater adherence to long-term imatinib therapy.

Fludarabine treatment in resistant Waldenstrom's macroglobulinemia

Abstract: Fludarabine (FLU) is a fluorinated purine analogue with a promising antineoplastic activity in lymphoproliferative disorders. In this study, we evaluated the efficacy of FLU in 12 previously treated (primary refractory and refractory relapse) patients with Waldenstroms macroglobulinemia. All patients were treated at a dosage of 25 mg/m2 per day for 5 consecutive days for a total of six courses. Of the 12 patients, 5 (41%) achieved partial response (PR), and the remaining 7 showed no benefit from the treatment. An increased response rate was obtained in the 4 primary refractory patients in which 2 PR were documented. Treatment was well‐tolerated and there were no Fludarabine‐related fatalities. With a mean follow‐up of 10 months, only 1 PR patient has relapsed. Fludarabine is an interesting new salvage agent effective against recurrent/resistant Waldenstroms macroglobulinemia and should be evaluated in further studies in untreated patients with Fludarabine in monochemotherapy or in combination with other active modalities.

Is There Any Difference in PBPC Mobilization Between Cyclophosphamide Plus G-CSF and G-CSF Alone in Patients with Non-Hodgkin's Lymphoma?

We attempted to analyze whether the use of high-dose cyclophosphamide (CTX 7g/m2, group A) plus hematopoietic growth factor (G-CSF) or G-CSF alone (10 μmlg/Kg, group B) as a mobilizing regimen, could result in harvesting different numbers of CD34+ cells, committed progenitors and CD34+ cells subsets. The number of CD34+ cells considered as the target for each high-dose chemotherapy was ≥ 2 × 106/Kg/bw. Fifteen leukaphereses procedures were necessary in group A, while 16 procedures were performed in group B. We did not observe any difference between the two groups in terms of CD34+ cells/μmll in the peripheral blood (117 vs 78: p=NS), whereas in the aphereses product we found a significant difference between the two groups of patients in terms of CD34+ cells (6.41 vs 2.89 × 106/Kg/bw: p=.009), CFU-GM(82.5 VS 52.3 × 104/Kg/bw: p=.04). Interestingly, we noted a different distribution of CD34+/33-cells between the 2 groups (mean value 39% vs 65%: p<.05), whereas we did not find any differences regarding CD34+/38-, CD34+/Thy1+, CD34+/HLADR-. The higher number of CFU-GM/Kg/bw collected in the former group did not translate into a superior plating efficiency (27.75 vs 30.29). Furthermore, we observed a strong correlation between CD34+ cells/μml1 in the peripheral blood and the total number of CD34+ cells in the leukaphereses product (r=0.97), whereas this correlation was not found in group B (r=0.15). In both groups of patients the number of CD34+ cell collected correlated well with CFU-GM (r=0.93; r=0.94), but definitely we did not observe any correlation between CD34+ cells/μmls and CFU-GM in patients mobilized with G-CSF alone and this did not allow us to predict the harvest accurately. Finally, we evaluated the engraftment kinetics and we did not observe my statistically significant difference between the two groups of patients.

Primary Mediastinal B-Cell Lymphoma with Sclerosis: Clinical and Therapeutic Evaluation of 22 Patients

In the last decade, there have been several reports on what is now recognized as a new clinical and pathological entity termed primarily mediastinal B-cell lymphoma (PMBCL) with sclerosis. This lymphoma presents unique clinical characteristics with an aggressive outcome and, at present, the best approach seems to be a combination of chemotherapy and radiotherapy. Between June 1989 and September 1994, twenty-two previously untreated patients with PMBCL with sclerosis were treated with a combination of third-generation chemotherapy regimen (MACOP-B or F-MACHOP) and mediastinal irradiation. All the patients presented with bulky mediastinal involvement; the radiologic clinical stage with evaluation of tumor size included computed tomography and Gallium-67-citrate SPECT. Twenty-one patients (95%) achieved a complete response and only one was resistant to treatment. Regarding 67Ga SPECT, 6 patients, including the nonresponder, showed persistent abnormal 67Ga uptake after chemotherapy; however after the mediastinal radiotherapy, all the patients except for the nonresponder were 67Ga-negative. The overall survival was 87%, with a median follow-up of 24 months from the time of diagnosis. Two of the patients who achieved complete response relapsed 7 and 10 months after completion of treatment, respectively. The relapse-free survival rate was 89% at 62 months (median 20 months). In patients presenting with bulky mediastinal PMBCL with sclerosis combined modality treatment using third-generation chemotherapy regimens and radiotherapy induces a good remission rate with greater than 80% chance of surviving disease-free, at 2 years. A longer follow-up before definitive conclusions are drawn is still warranted.

Clinical implications of serum levels of soluble CD23 and tumor necrosis factor alpha in low-grade non-Hodgkin's lymphoma.

Abstract:  In the last few years the research for new biological features in low‐grade non‐Hodgkins lymphoma has provided important results. Several biological parameters are under evaluation and, in particular, cytokines and soluble receptors levels are showing their importance as prognostic parameters. In the present study, serum levels of tumor necrosis factor alpha (TNF‐α) and soluble CD23 (sCD23) were measured at the time of diagnosis and after induction polychemotherapy in 40 patients with newly diagnosed low‐grade non‐Hodgkins lymphoma (LG‐NHL). The treaments were CIOP (cyclophosphamide, idarubicin, vincristine, prednisone) regimen for 28 patients and FMP (fludarabine, mitoxantrone, prednisone) scheme for 12 patients. Pretreatment levels of TNF‐α were highly elevated in patients with LG‐NHL compared with healthy controls (p=0.005) and were significantly correlated with the Ann Arbor stage (p=0.001). sCD23 was detected in 35 patients at diagnosis and were markedly increased in LG‐NHL patients when compared to healthy controls (p=0.005); patients with advanced stage presented higher values than those with early stage disease (p=0.002). All the complete responders (20/40, 50%) showed a decrease of TNF‐α and sCD23 levels. By contrast, the combination of high levels of TNF‐α and sCD23 correspond to a group of non‐responders. Our results suggest that TNF‐α and sCD23 are specific prognostic parameters for LG‐NHL, and that they could be used as tumor markers within a potential biological prognostic index.

Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia

Nilotinib is a second-generation tyrosine kinase inhibitor that has been approved for the first-line treatment of chronic-phase chronic myeloid leukemia, based on the results of a prospective randomized study of nilotinib versus imatinib (ENESTnd). Apart from this registration study, very few data are currently available on first-line nilotinib treatment. We report here the long-term, 6-year results of the first investigator-sponsored, GIMEMA multicenter phase 2, single-arm trial with nilotinib 400 mg twice daily as first-line treatment in 73 patients with chronic-phase chronic myeloid leukemia. Six-year overall survival and progression-free survival rates were 96%, with one death after progression to blast phase. At 6 years, 75% of the patients were still on nilotinib. The cumulative incidence of major molecular response was 98%; only one patient had a confirmed loss of major molecular response. The cumulative incidence of deep molecular response (MR 4.0) was 76%. Deep molecular response was stable (≥2 years) in 34% of these patients. Cardiovascular adverse events, mainly due to arterial thrombosis, occurred in 11/73 patients (15%), after 24 to 76 months of therapy. They were more frequent in elderly patients, and in those with baseline cardiovascular risk factors. None was fatal, although there was a relevant morbidity. This is the study with the longest follow-up of a high dose of nilotinib (400 mg twice daily): it highlights the high efficacy and the cardiovascular toxicity of the drug (CTG.NCT.00481052).

Cryptic translocation of PML/RARA on 17q. A rare event in acute promyelocytic leukemia

Cryptic translocations in acute promyelocytic leukemia are rare. Usually the gene fusion PML/RARA is located on chromosome 15. Combined cytogenetic, fluorescence in situ hybridization (FISH), and molecular (polymerase chain reaction [PCR]) analysis were employed for the diagnosis and precise localization of the fusion gene. Conventional cytogenetics showed a normal karyotype; PCR showed a typical PML/RARA rearrangement in exon 1. FISH analysis revealed that a submicroscopic part of chromosome 15 had been inserted into 17q. This case adds further information on alternative ways of rearrangement of the PML/RARA genes, possibly correlated with all-trans retinoic acid resistance.

Four‐chromosomes complex translocations in acute promyelocytic leukemia: Description of two cases

Abstract:  Two cases of acute promyelocytic leukemia with variant translocations involving 4 chromosomes are described. The karyotypes were 47,XX, + 8,t(13;15;17;20)(q22;q22;q12;q13) and 46,XY,t(5;15;16;17)(q22;q22;p13;q12), respectively. Variant translocations in APL apparently do not follow any preferential routes since no recurrent breakpoint additional to those of chromosomes 15 and 17 has been found in any of the cases reported in the literature and in those described here. Moreover, it seems that the translocation of the RARα gene from chromosome 17 to chromosome 15 is directly involved in the pathogenesis of the disease, while the reciprocal one is not, as demonstrated by variant translocations where 15q migrates to chromosomes other than 17.

Primary Gastric Lymphoma: A Clinical and Therapeutic Evaluation of 82 Patients

Eighty-two patients with primary gastric (IE, II1E, and II2E) non-Hodgkins lymphoma according to the Musshoffs staging system were treated with combined modality including surgery with/without radiotherapy between January 1985 and December 1991. According to the Updated Kiel classification 54 had high-grade histologic subtypes and 28 low-grade. The strategy throughout the study was to resect primary tumor: all patients underwent gastrectomy, 40 subtotal and 42 total gastrectomy. The resection permitted complete surgical staging utilizing three pathologic features: disease confined within or beyond the serosa, negative/positive regional lymph nodes, and negative/positive surgical margins. If there was no evidence of these pathologic factors, the patients who underwent surgery alone received no further radiotherapy. On the other hand, all patients who presented at least one of three pathologic factors were treated with adjuvant radiotherapy after the resection. All except 14 patients presented at least one of the pathologic features and 50 (61%) patients had involvement of the whole gastric wall. Radiotherapy included the gastric bed and para-aortic lymph nodes and, for the patients, who had positive regional lymph nodes in combination with the complete involvement of the gastric wall, the irradiation included the whole abdominal approach. The complete response rate was 97% and the 9-year disease-free survival was 93%. All but one of the 5 relapses occurred within 18 months stressing the need for more specific staging. Gastric resection with/without radiotherapy may still represent the primary therapeutic procedure in early stage gastric non-Hodgkins lymphoma.

Evaluation of residual CD34+Ph+ progenitor cells in chronic myeloid leukemia patients who have complete cytogenetic response during first-line nilotinib therapy

Compared with imatinib, nilotinib is a potent breakpoint cluster region/v‐abl Abelson murine leukemia viral oncogene (bcr‐abl) kinase inhibitor, and it induces higher rate and rapid complete cytogenetic response (CCyR), yet no clinical data are available regarding its efficacy against chronic myeloid leukemia (CML) stem cells. Earlier studies demonstrated that clusters of differentiation 34–positive, Philadelphia chromosome–positive (CD34+Ph+) cells are detectable in about 45% of patients with CML, despite being on long‐term imatinib therapy and having achieved sustained CCyR.