ALBERT

Description: Abstract 3890 Introduction: Early stage classical Hodgkin lymphoma (cHL) is highly curable with a combination of chemotherapy and radiotherapy. Nevertheless a small proportion of patients with localized stage do not respond to therapy and progressed. We want to explore the predictive value on therapy outcome of an early evaluation of treatment response by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan performed after two corses of ABVD in pts with localized Hodgkin's disease. Patients and methods: From 2002, 246 new localized stage cHL pts were consecutively admitted to twelve Italian hematological centers on behalf of Intergruppo Italiano Linfomi. Pts with stage I-IIA according to Ann Arbor stage, independent of presence of bulky disease, were considered for the study. FDG-PET was mandatory at baseline, after two cycles and at the end of therapy. International Harmonization Project (IHP) interpretation criteria were recommended to define PET positivity. We evaluated the progression free survival of pts starting from the time of diagnosis to relapse or progression of disease or last follow-up. No treatment variation based only on PET-2 results was allowed. All bulky-disease pts reports were centrally reviewed. Results: The median age was 33 years (13-78), 133 pts were female, 225 pts were stage II, bulky was reported in 76 pts, 231pts were treated with combined modality and 15 pts were treated with chemotherapy alone. The FDG-PET performed after two cycles (PET2) was positive in 32 pts (13%). Seventeen non-bulky pts were PET2 positive: 10 (59%) progressed or relapsed and 7 remained in CR. By contrast 152/153 (99%) non-bulky pts with a negative PET2 remained in CR. Thus the PPV value of a PET2 in non-bulky pts was 59% and the NPV was 99%, moreover the sensitivity and specificity of PET2 were 91% and 96%, respectively. In bulky disease pts we performed a revision of all reports according to Deauville criteria and 3 cases were converted from PET2 positive to PET2 negative. In revised bulky disease pts 15 were PET2 positive: 6 (40%) progressed or relapsed and 9 remained in CR. In this group of pts the PPV was 40%, the NPV 93% and sensitivity and specificity were 60% and 90% respectively. In univariate analysis negative FDG-PET performed after two cycles (p .0000), absence of bulky disease at diagnosis (.005) were statistically correlated with a better progression free survival. In multivariate analysis only PET2 was independently predictive of relapse/progression probability (p .000). With a median follow-up of 35 months (range 4–87), the 2-yr FFS probability for PET2 negative and for PET2 positive non-bulky patients were 98% and 29% respectively (p: .000) for patients with bulky-disease were 99% and 45% respectively (p: .002). Conclusion: This multicentric study confirms that FDG-PET scan performed after two courses of conventional standard dose chemotherapy was able to predict treatment outcome in early stage non-bulky cHL. In bulky disease we suggest new interpretation criteria to define interim PET results. Disclosures: Vitolo: Roche: Membership on an entity's Board of Directors or advisory committees.

Description: Background: Hodgkin’s lymphoma is one of the maligant diseases with the highest rate of cure particularly if diagnosed in early stage. Nevertheless a small proportion of patients with localized stage do not respond to therapy and become chemorefractory. FDG-PET clearly showed the high predictive value in identifing patients with bad prognosis in advanced stages. The aim of this prospective study was to evaluate the prognostic value of FDG-PET in patients with localized Hodgkin’s disease. Patients: From 2002, 122 new localized stage Hodgkin’s lymphoma patients were consecutively admitted to seven Italian hematological centers on behalf of Intergruppo Italiano Linfomi. Patients with stage I-IIA according to Ann Arbor stage, independent of presence of bulky disease, were considered for the study. FDG-PET was mandatory at baseline, after two cycles (immediately before the start of the third cycle) and at the end of therapy. We evaluated the progression free survival of patients starting from the time of diagnosis to relapse or progression of disease or last follow-up. Patients were candidate to receive 3 or 4 course of ABVD followed by involved field radiotherapy at 30 Gy, except in the cases in which physician decided to omit radiotherapy due to excess of toxicity. All patients were given the planned therapy except in case of overt progression. All patients were treated with ABVD Results: The median age was 31 years (16–75), 63 patients were female and 59 male, 10 patients presented stage I and 112 stage II, bulky was reported in 29 patients. One-hundred and ten patients were treated with combined modality (CT+RT) and 12 patients were treated with chemotherapy alone (all with 6 cycles). One hundred and eleven patients attained CR while 11 were chemoresistent: 6 showed disease progression during CT and 5 showed an early relapse. The FDG-PET performed after two cycles (PET2) was positive in 18 patients (15%) and the FDG-PET performed at the end of therapy was positive in 12 patients. Fourteen patients showed disease progression during therapy or within 6 months after having reached CR, three patients died due to the disease. In univariate analysis negative FDG-PET performed after two cycles (p .0000), absence of bulky disease at diagnosis (.003) and the use of radiotherapy (.0006) were statistically correlated with a better progression free survival. In multivariate analysis only PET2 was independently predictive of relapse/progression probability (p .007). With a median follow-up of 29 months (range 6–79) 119 patients are alive and 108 (88%) are free from progression. The 2-yr FFS probability for PET2 negative and for PET2 positive patients were 95% and 46% respectively Conclusion: This prospective and multicentric study confirms that FDG-PET scan performed after two courses of conventional standard dose chemotherapy was able to predict treatment outcome in early stage Hodgkin disease.

Description: INTRODUCTION. Continously improving results have been obtained during the last two decades in the control of Philadelphia chromosome (Ph’) positive chronic myeloid leukemia (CML). However, the final goal of molecular remission remains difficult to be obtained, even in the imatinib era. AIMS: Evaluation of the rate of long lasting molecular remission (undetectable p210 transcript at RQ-PCR confirmed by NESTED/RT-PCR in at least two subsequent tests performed over a period of 12 months or more) in response to imatinib or to imatinib-IFNa combination employed as first, second or subsequent line of therapy. PATIENTS. Imatinib alone or in combination with IFNa was given as first, second or subsequent line of therapy to a total of 47 patients. In particular, twenty-one patients were treated at the time of diagnosis with imatinib alone (18,G1) or imatinib-pegilated IFN combination (3,G2). Twenty-three additional patients (G3) received imatinib as second line therapy. Finally, 11 patients were treated with the imatinib-IFNa combination as second (5,G4) or third (6,G5) line therapy. In details, G4 consisted of three patients in cytogenetic relapse (3) or no response (2) after first line imatinib (1)or IFNa-ARA-C(1)therapy. All six patients included in G5 were complete kariotypic, but not molecular responder to imatinib given as second line treatment. METHODS. Molecular response was evaluated by NESTED/real-time-PCR (Guo JQ et al.; Leukemia : 2002; 15:2447–53) and real-time quantitative-PCR (Gabert J et al. Leukemia : 2003; 17: 2318–57) time intervals of 3–6 months from the beginning of therapy. RESULTS. A complete molecular remission lasting 12 months or more was obtained in 11 of 42 evaluable patients(therapy duration ≥ 18 mths).The response rate was higher in patients receiving the imatinib-IFNa combination(6/14) than in those given imatinib in monotherapy (5/36).In details, 4/14 and 1/3 patients respectively receiving early imatinib or imatinib-IFNa combination achieved a stable molecular remission. Two to four consecutive negative tests were documented in all five cases over a period ranging from 12 to 19 mths with 4 patients still in continous remission. Furthermore, 1/22 and 5/11 patients obtained a complete molecular response to imatinib given as second line therapy or imatinib-IFNa combination employed as second (4) or third (1) line therapy. Five negative tests were documented over a period of 12 mths in the patient responsive to imatinib monotherapy. Three to 7 negative consecutive tests were obtained during a period of 12 to 36 mths in the remaining five cases while receiving the imatinib-IFN-a combination. At the present time, 5 of these 6 patients are in continous molecular remission. In all molecularly responsive patients, stable molecular remission was usually preceded by a period of fluctuating negative-positive results of NESTED-PCR tests. CONCLUSIONS. It is not possible to achieve any firm conclusion regarding the effect of the imatinib-INFa combination on molecular response because of the small sample size of treated patients. However, our findings suggest an additive effect of imatinib and IFNa in Ph’ clone control as indicated by the improvement of the quality of remission in long lasting kariotypically, but not molecularly responsive patients when this combination therapy was utilized.

Description: Background: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of aggressive diseases characterized by poor prognosis. At 5 years, only 25 to 45% of patients treated with standard-dose chemotherapy are still alive. Retrospective studies show that patients with disease responsive to conventional-dose chemotherapy obtain durable remission after myeloablative treatment with autologous peripheral blood stem-cell (PBSC) support. This treatment strategy seems more effective when employed in untreated rather than relapsing patients. We present a series of 13 PTCL pts treated upfront (10 pts) or at the time of relapse-progression (3pts) with a 3 phase sequential therapeutic program including induction, intensification and consolidation treatment. The latter consisted of a myeloablative drug combination with PBSC support. Patients and methods: The median age of the 13 patients was 51 years (25–69). Histology was: PTCL-unspecified in 6 (46%) pts, anaplastic large cell lymphoma in 5 (38%), angioimmunoblastic and enteropathy-type T-cell lymphoma in 1 (8%) and 1 (8%) pt. Nine cases presented with advanced (III–IV) Ann Arbor stage and 2 had bulky disease. Nine cases complained B symptoms and 10 had high LDH levels. Six pts presented an intermediate-high IPI score (≥3 risk factors). Induction therapy consisting of dose-dense, dose-intense megaCEOP (1200mg/sqm cyclophosphamide, 110mg/sqm epirubicin, 1,4mg/sqm vincristine and 100mg prednisone) regimen was employed in 9 pts. Conventional dose CHOP or MACOP-B or P-VEBEC scheme was given in 2, 1 and 1 patient, respectively. Intensification treatment consisted of MAD (8mg/sqm mithoxantrone, 4g/sqm ARA-C, 40mg/die desamethasone) in 9 cases, 7g/sqm of cyclophosphamide in 1 patient and DHAP (100mg/sqm cisplatin, 4g/sqm ARA-C, 40mg/die desamethasone) in 3 cases. Three hundred mg/sqm carmustine, 100mg/sqm etoposide, 200mg/sqm cytosine arabinoside, and 140mg/sqm melphalan (BEAM) was used as myeloablative chemotherapy in all patients except for one who received mithoxantrone (60mg/sqm) and melphalan (180mg/sqm) as conditioning. Results: All patients completed the first 2 phases of the therapeutic program. Post-intensification disease status was complete remission (CR) in 4 (31%) pts, CRu in 2 (15%), partial remission (PR) in 5 (38%), stable disease (SD) in 1 (8%) or progressive disease (PD) in the last 1 (8%). Ten (77%) pts completed the whole treatment program, while 3 pts did not receive transplant because of insufficient stem cell harvest (1), progressive disease (1) or unacceptable peripheral and autonomic neuropathy due to MAD in 1 CR pt. After autologous PBSC transplantation, PR-to-CR conversion was observed in 3 cases and a total 7 of 10 (70%) transplanted pts achieved a CR. The median duration of overall objective response (8 CR, 2 PR) was 19 months (3–65) in the whole patient group, while it was 20 months (6–65) in transplanted pts. With a median follow-up of 26 months (9–83) from diagnosis 5 of the 13 pts (39%) are alive. These ones are the 5 pts in CCR after transplantation. No transplant-related mortality was observed. Eight (61%) pts died as a result of disease progression (6), infectious complications (1 in PR), or secondary acute myeloid leukemia (1). Median survival was 27 (9–82), 33,5 (18–82) and 40,5 (23–82) months for the overall cohort, the 10 transplanted pts and the 8 CR cases (7 transplanted and 1 not transplanted), respectively. Conclusion: disease status at transplant appeared to be the major factor that impacted outcome in our series. Although in a small number of patients, our data suggest that frontline autologous PBSC transplantation consolidation is feasible and may improve treatment outcome for chemosensitive PTCL patients.

Description: Fifty-two kariotypic abnormalities additional to Philadelphia chromosome (Ph’) were documented at the time of diagnosis or during the course of the disease in 114 CML patients. Five were evaluated only once at the time of diagnosis, while 109 were repeatedly studied overtime during a median period of 138 (1–275)months. A clonal evolution was already present at diagnosis (early clonal evolution) in 12, while in 23 patients, it was documented in the course of the disease (late clonal evolution). Simultaneous appearence of multiple chromosome abnormalities (4/12 and 4/23) and a tendency to acquire further alterations (5/12 and 2/23, respectively) were associate with both early and late secondary clones. Partial or complete chromosome losses (-1, -6, 6q-, 7p-, 11q-, 12p-, -14, -16, -17,-18, -21) other than -Y (11 events), + 8 (9) and loss of Y chromosome (8) were the most commonly cytogenetic abnormalities, irrespective of the time of their occurrence. Translocations other than Ph’ (5 events), complex Ph’ translocations (5), duplication of Ph’ (5), single iso(Ph’) (4), duplication of iso(Ph’) (1) or iso17q (2) were found with a decreasing frequency. The type of kariotypic alteration varied with the time of onset. In fact, partial or complete chromosome monosomies and duplication of iso(Ph’) never represented early, but only late events. Duplication of Ph’ was a late (4/5) rather than an early event (1/5). Similarly, the presence of the iso(Ph’) was documented either in early or late clonal evolution in 1 and 3 instances respectively. Furthermore, +8 developed several months after diagnosis in all, but 2 cases. Complex Ph’ translocations or loss of Y chromosome do not correlate with any specific phase of the leukemic course. Cytogenetic abnormalities neither correlated with Sokal risk nor with the type of break-points (b3a2,b2a2) documented at diagnosis. However all 3 clones bearing p230 chimeric protein showed early cytogenetic evolution. Secondary clones seem to have different impact on disease history. The occurrence of partial or complete deletions, the iso17q and the late, but not early, loss of Y chromosome were all predictive of a rapid disease progression. Early secondary clones with additional translocations had no effect on the chronic behaviour of the disease, while such clones were associated with a rapid progression (2/3) to blastic phase when they occurred during the course of disease. The presence of +8 as the sole cytogenetic abnormality and complex translocations, irrespective of the time of their onset, did not correlate with leukemia evolution. Finally,simple Ph’ duplication of or single and double iso(Ph’), when not associated with other cytogenetic abnormalities, did not correlate with an aggressive course, even if it can be assumed that these cytogenetic events are responsible for an increased concentration of the p210 oncoprotein. In conclusion, regardless of whether bcr/abl has a direct or an indirect role in promoting genomic instability, in our cohort of CML patients additional non random chromosomal abnormalities frequently characterize both early and late phase of the disease and some of them may represent crucial steps in development and progression of leukemia.

Description: Background: There are evidences supporting the existence of a synergism between the proteasome inhibitor bortezomib and anthracyclines. In addition, in vivo data show enhancement of the antitumor activity of pegylated liposomal doxorubicine (Peg LD) when used in combination with bortezomib. Patients and therapy. Based on these findings we are using this combination as salvage therapy in active multiple myeloma in an ongoing study. So far, 18 patients MM patients (7 F and 11 M, median age 62 years, range 45–71) with resistant or relapsing disease after high or conventional dose chemotherapy have been enrolled. Patient distribution according to disease status and previous therapy is as follow: 3 and 7 patients with disease resistant to (including PR cases) or relapsing after high dose chemotherapy with PBSC support, respectively; 4 and 4 patients with disease resistant to or relapsing disease after conventional dose chemotherapy, respectively. Bortezomib 1,3mg/m2 is given as a bolus IV injection on days 1,4,8 and 11 for eight three-week cycles (induction therapy), then administered on days 1,8,15 and 22 for three five-week cycles as maintainance therapy. PegLD is given at a dose of 40mg/m2 every 3 weeks. In the first cohort, including four patients, Peg LD is employed after the completion of the 8th cycle of bortezomib, during the maintenance phase therapy. In the remaining fourtheen cases, Peg LD is combined with bortezomib starting from the 4th induction cycle. Sequential drug administration was chosen in order to evaluate if the antitumor activity exerted by combination therapy is superior to that achieved with bortezomib employed as single agent. Results. In the first cohort, including 4 patients (3 with resistant disease to high dose chemotherapy and 1 with relapsing disease after two different combinations of conventional dose chemotherapy), bortezomib resulted in three objective responses (2 nCR, 1 PR) and one disease stabilization. However, the addition of PegLD did not induce in any significant improvement of response in 3/4 cases who have completed the planned treatment. In the second cohort, including 6 patients with resistant to high (2 pts) or conventional (4 pts) dose therapy and 8 with relapsing disease, myeloma progression has been documented in two istances after the second cycle of bortezomib. One patient died of uncontrolled disease, while another, responding to VP-16 salvage therapy, is at present time alive and in good PR. Of the remaining 12 patients, 9 have reached a PR and 3 a nCR after the first 3 cycles of bortezomib. In the 7 patients who at present time have received at least three cycle of bortezomib-PegLD combination, a conversion of 2 PRs in CRs and a further reduction of serum concentration of paraprotein in a third patient were documented. Overall, bortezomib or PegLD-bortezomib combination, has been well tolerated. Grade 1–2 thrombocytopenia was the most common hematological toxicity. All patients have complained mild to moderate asthenia and grade 1–2 paresthesias. Conclusion. It is not possible to achieve any firm conclusion regarding the effect of bortezomib-PegLD combination on the control of resistant-relapsing MM, mainly because of the small sample size of treated patients. However, our findings suggest that this combination therapy may exert in some cases a significant antitumor activity.

Description: The rate of complete karyotypic remission (CKR) and complete molecular remission (undetectable BCR/ABL specific transcript by real-time quantitative-PCR (Gabert J et al. Leukemia: 2003; 17: 2318–57) and NESTED/real-time-PCR (Guo JQ et al.; Leukemia: 2002; 15:2447–53)) to various therapies was analysed in 35, of the 114 CML patients observed in our institution, who showed cytogenetic clonal evolution. Overall, 52 karyotypic abnormalities additional to Ph’ were documented at the time of diagnosis (early clonal evolution) or late in the course of the disease (late clonal evolution). Seven of 12 patients with early clonal evolution achieved one (5 pts) or more (2 pts) CKRs, for a total number of 9, in response to IFNα (2 CKRs), IFNα plus ARA-C (1 CKR), imatinib (5 CKRs) or imatinib-IFNα combination (1 CKRs). Six of the 23 patients with late clonal evolution achieved one or more CKRs during the course of their disease after treatment with IFNα (2), IFNa plus ARA-C (1) or imatinib (5). In addition, 7 of the 13 CK responders reached a complete molecular remission in response to IFNa (1), IFNa plus ARA-C (1) imatinib (1), or imatinib plus IFNa (4). The 5 complete molecular remissions documented in patients with early clonal evolution, were observed following treatment with IFNα plus ARA-C (1), imatinib (1), or imatinib plus IFNα (3). Two patients with late clonal evolution obtained complete molecular remission in response to IFNα and imatinib plus IFN therapy, respectively. Cytogenetic and molecular response rates were higher in patients with early (58%, 57%) than in patients with late secondary clones (26%, 33%), while there were no significant differences in time to achieve cytogenetic (2–20 months vs 1–25 months) or molecular (3–26 months vs 13–52 months) remission and the duration of response (11 months, range 4–42 vs 10 months, range 7–46 and 2–19 vs 3–13+ months, respectively) between the two groups. Finally, no relationship was evident between the type of additional karyotypic anomalies and sensitivity to treatment. In fact, clones bearing complex translocations (2), isoPh’ (2), trisomy 8 (2), translocations other than Ph’ (2), partial chromosome monosomy (11-q, 1) or loss of chromosome Y alone (1) or associated with other anomalies (−6 and −14 or −21 or isoPh’) (3) all responded to therapy. In conclusion, although the small sample size, these findings suggest that the presence of karyotypic abnormalities additional to Ph’ in CML is not associated to disease resistance to therapy.

Description: Introduction Progressive improvement has been observed in CKR and survival of CML patients (pts) in response to interferon (IFN)a-based regimens, or imatinib. The purpose of this study is the evaluation of: rate of, time to and duration of CKR in accordance to first line therapy employed and Sokal score; impact on overall survival of CKR, and Sokal score, separately considered or combined together. Patients. 109Ph’+ and 5Ph’−, (BCR-ABL positive), CML pts were treated at diagnosis with allogeneic transplantation (3 pts), hydroxyurea (HU) (19 pts), INFa (51pts, G1), INFa associated with ARA-C (20 pts, G2), imatinib alone (18 pts, G3), or imatinib combined with INFa (3 pts, G4). INFa was employed as second line therapy in 12 pts initially treated with hydroxyurea (G5), while INFa/ARA-C combination or imatinib alone was given to 24 (G6) and 23 (G7) pts with de novo or acquired resistance or intolerance to INFa. Third line therapy, consisting of the combination of imatinib with IFNa, was employed in 11 (G8) pts with no CKR (5 pts) or in complete cytogenetic, but not in molecular remission (6 pts). Results. 40 of 94 Ph’+ evaluable non-allotransplanted pts obtained one or more (overall 47) CKRs to INFa-based regimens or imatinib. CKR rate, median time to CKR and response duration are shown in table 1. In the analysis according to Sokal score 82/94 pts, with complete prognostic data at diagnosis, were included. The percentage of responders was higher in the low compared to the non-low Sokal risk group (57% vs. 31%). Irrespective of the treatment, median duration value of the first CKR was also better in the former [18+mths(1–64)] than in the latter group [6mths(2–54)] with 16 vs.4 pts still in first or subsequent remission. Overall survival for CKRs was 68+mths(5–275) vs. 52mths(5–270) for CKRs with 35 vs. 6 pts still alive respectively. Overall survival according to Sokal score at diagnosis was 61+ mths(5–275) for low vs 53mths(5–212) for non-low risk patients. The impact on survival of CKR and Sokal risk were then analyzed simultaneously. The median survival of 27 CKRs and 20 not CKRs with low Sokal risk were 61+mths(5–275)and 63 mths(14–270) respectively as compared to 73+mths(11–212) of 11 CKRs and 36mths(5–139) of 24 not CKRs with unfavourable characteristics at diagnosis. The number of patients still alive in these 4 groups were 24/27, 3/20, 8/11, 3/24 respectively at the time when this analysis was performed. Conclusions. The present data not only confirm the effectiveness of imatinib-over the INFa-based regimens in inducing CKR, but also suggest that response to treatment may be better than Sokal risk in predicting patient survival. Rate,time to and duration of CKR according to treatment PT Group CKR rate(%) time to CKR( months) Duration of CKR (months) N° of pts in cCKR Median Range Median Range G1 17 16 (3–28) 6 (2–53) 0 G2 30 11 (3–24) 15,5 (2–33) 0 G3 85 6 (2–14) 10+ (1–44) 11 G4 100 4 (4–5) 48 (2–50) 1 G5 0 0 G6 9 9,5 (7–12) 40,5 (17–64) 1 G7 54 9 (4–38) 21,5+ (3–54) 6 G8 80 3 (2–4) 26+ (4–48) 9

Description: Cancer is often accompanied by worsening of the patient’s iron profile, and the resulting anemia could be a factor that negatively impacts antineoplastic treatment efficacy and patient survival. The first line of therapy is usually based on oral or intravenous iron supplementation; however, many patients remain anemic and do not respond. The key might lie in the pathogenesis of the anemia itself. Cancer-related anemia (CRA) is characterized by a decreased circulating serum iron concentration and transferrin saturation despite ample iron stores, pointing to a more complex problem related to iron homeostatic regulation and additional factors such as chronic inflammatory status. This review explores our current understanding of iron homeostasis in cancer, shedding light on the modulatory role of hepcidin in intestinal iron absorption, iron recycling, mobilization from liver deposits, and inducible regulators by infections and inflammation. The underlying relationship between CRA and systemic low-grade inflammation will be discussed, and an integrated multitarget approach based on nutrition and exercise to improve iron utilization by reducing low-grade inflammation, modulating the immune response, and supporting antioxidant mechanisms will also be proposed. Indeed, a Mediterranean-based diet, nutritional supplements and exercise are suggested as potential individualized strategies and as a complementary approach to conventional CRA therapy.