ALBERT

Description: In this randomized multicenter study of 136 patients, 6 courses of CHOP (cyclo-phosphamide/doxorubicin/vincristine/prednisone) followed by rituximab (CHOP-R) were compared with rituximab-supplemented high-dose sequential chemotherapy with autografting (R-HDS) to assess the value of intensified chemo-therapy as a first-line treatment for high-risk follicular lymphoma (FL) after the introduction of monoclonal antibodies. The analysis was intention to treat with event-free survival (EFS) as the primary endpoint. Complete remission (CR) was 62% with CHOP-R and 85% with R-HDS (P 〈 .001). At a median follow-up (MFU) of 51 months, the 4-year EFS was 28% and 61%, respectively (P 〈 .001), with no difference in overall survival (OS). Molecular remission (MR) was achieved in 44% of CHOP-R and 80% of R-HDS patients (P 〈 .001), and was the strongest independent outcome predictor. Patients relapsing after CHOP-R underwent salvage R-HDS in 71% of cases. Salvage R-HDS had an 85% CR rate and a 68% 3-year EFS (MFU, 30 months). We conclude that (1) achieving MR is critical for effective disease control, regardless of which treatment is used; (2) R-HDS ensures superior disease control and molecular outcome than CHOP-R, but no OS improvement; and (3) CHOP-R failures have a good outcome after salvage R-HDS, suggesting that relapsed/refractory FL could be the most appropriate setting for R-HDS–like treatments. This trial was registered at www.clinicaltrials.gov as no. NCT00435955.

Description: Abstract 4446 Life expectancy of CML patients has greatly improved in tyrosine-kynase inhibitor (TKI) era, but still some questions remain about the management of suboptimal responders (SR) to imatinib standard dose. This group of patients appears to be heterogeneous, with significant differences in terms of event-free survival between cytogenetic SR and molecular SR (Alvarado et al, Cancer 2009) European Leukemia Net (ELN) recommendations did not clarify those differences and there isn't a clear agreement on SR: maintaining imatinib at standard or higher dose or switching to another TKI are all considered acceptable options (Baccarani et al, JCO 2009). We retrospectively analyzed 63 CML patients, diagnosed in chronic phase between 1988 and 2011, SR to imatinib 400 mg/d, treated according to the 3 different ELN options. Fifty-two patients received imatinib front line and 11 had been previously treated with an interferon based therapy. Sokal score, evaluable in 44 patients, was high in 7, intermediate in 24 and low in 12, respectively. Twenty-five patients were cytogenetic SR and 38 molecular SR. The median follow-up from diagnosis was 76 months (range 10–292). At suboptimal response detection 47 patients (74%) continued imatinib 400 mg/d (30 of them afterword switched to high dose imatinib or new TKI), 12 patients (19%) increased imatinib dose to 600 mg/d (7) or 800 mg/d (5) (8 of them later changed TKI) and only 4 patients switched immediately to new TKI. Twenty-three percent of the 47 patients who continued imatinib 400 mg/d obtained a stable complete cytogenetic response (CCyR) and major molecolar response (MMR) while 27% underwent to a failure. Globally thirty-tree SR patients increased imatinib dose, 36% at suboptimal response detection and 64% after a median of further 12 months of standard dose treatment (range 3–50): 48% of them obtained a durable CCyR and MMR. Twenty-six evaluable patients switched to new TKI (9 to nilotinib and 17 to dasatinib), 13 after high dose imatinib: 62% of the patients achieved a stable CCgR and MMR. Both high dose imatinib and new TKI were significantly more effective in achieving CCyR and MMR than maintaining imatinib 400 mg/d (p

Description: Decitabine is a pyrimidine nucleoside analogue of cytidine and with azacytidine has been approved for treatment of MDS and non-proliferative CMML. Anyhow, few CMML cases were included in the registrative studies and CMML treatment still remains very arduous, being CMML an heterogenous disease by itself, with characteristics of both MDS and MPN and with a variable prognosis. Decitabine has been suggested to be particularly effective in CMML in a few studies. We evaluated efficacy and safety of decitabine 20mg/m2/day for 5 days every 28 days for a minimum of 6 cycles in a group of pretreated CMML patients. Evaluation of response was performed after 4 and 6 cycles of therapy, according to IWG 2006 criteria. Morphological diagnosis, evaluation of dysplastic signs and monocytic component was performed centrally after first on-site diagnosis. The mononuclear cell expression of decitabine metabolizing enzymes CDA, hENT1, DCK, and CN-II was determined. Between April 2010 and October 2011, 44 patients were enrolled from 15 Italian Hematology centers, 43 had a confirmed centralized diagnosis of CMML (M/F 30/13), and 42 were finally evaluable. According to WHO 27/42 pts were classified CMML-I with organomegaly and 15/42 CMML-II. Among these patients, 46% had received previous therapy. Proliferative CMML was diagnosed in 32/42 cases. Median age was 71 (42-84) yrs, median number of cycles 6 (1-28). Eleven patients received 〈 4 cycles, 16 from 4 to 6 cycles and 15 〉 6 cycles. Eighty one percent of patients with CMML-I received 〉 4 cycles. All cycles were administered in an out-patient basis. Overall response rate (ORR) was 33%, mCR in 19%, CR in 14.3 %, PR 2.3% and SD in 34.9% and at 3 year-observation time 31% of patients are still alive (13/42). Median duration of response was 9 months. At present, 16.3% (7/42) of patients are still in treatment. Splenomegaly was significantly reduced in 28% of cases. No significative difference in response rate was present in CMML I vs CMML II, nor in proliferative CMML vs dysplastic ones. At analysis of karyotype, 57% of cases had no cytogenetic abnormality and there was no difference in RR between normal and abnormal cases, among which only 5% had complex karyotype. Median OS is 19 months (2-39). For CMML I cases OS is 26 months vs 15 months for CMML II (p

Description: Abstract 3124 Background. Outcome of aggressive HIV-associated NHL (HIV-NHL) with adverse prognostic features is not satisfactory with standard therapy. High dose therapy (HDT) and autologous stem cell transplantation (ASCT) has been demonstrated safe and active in HIV-NHL in the salvage setting. Aims. To define the role of HDT and ASCT in the upfront treatment of HIV-NHL at high risk, in terms of efficacy and toxicity. We report the interim results of a multicenter study including HDT and ASCT as consolidation after first-line treatment of HIV-NHL at high-risk. Patients and methods. Inclusion criteria: untreated aggressive HIV-NHL (including DLBCL, plasmablastic, anaplastic lymphoma), aa-IPI 2–3, age 18–60, CD4+ count 〉50/mcl and availability of effective HAART. Burkitt and CNS lymphoma are excluded. Patients (pts) receive R-CHOP-21 (CHOP-21 or CHOP-14 for CD20 negative lymphoma) for 6 cycles and, if responsive, undergo stem cells mobilization and collection after Cyclophosphamide 4gr/ms + G-CSF followed by HDT with BEAM and ASCT. Involved-field radiotherapy on previous bulky or residual disease is recommended. Pts receive HAART during the entire treatment program. Overall survival (OS) at 2 years is the primary endpoint. Results. Since January 2007 to July 2012, 23 pts were registered and 20 entered the study. Median age was 47.5 years (range, 27–62). Fifteen pts (75%) had DLBCL, 4 (20%) plasmablastic and 1 (5%) anaplastic lymphoma. ECOG PS was 〉1 in 11 pts (55%); Ann-Arbor stage III/IV, 5(25%)/15(75%); B symptoms, 12 (60%); LDH 〉 n.v., 18 (90%); aaIPI 2/3, 10 (50%)/10(50%). Fourteen pts (70%) had a prior history of HIV-positivity and 13 (65%) were on HAART at NHL diagnosis; thirteen (65%) had detectable HIV-viremia. Median CD4+ count was 283/mcl (58–571). Nine pts (45%) had HCV infection. Seventeen pts received (R)-CHOP-21 and 3 pts with plasmablastic histology received CHOP-14. One pt is still on treatment and 19/20 are evaluable for (R)-CHOP response. One had toxic death (due to hepatic failure), 2 had prolonged cytopenia (1 with severe hepatic toxicity) that lead to withdrawal of therapy and 16 completed (R)-CHOP therapy: 11 pts had complete remission (CR), 4 partial remission (PR) and 1 disease progression (PD) (ORR 79%,CR 58%, PR 21%, according to intention to treat). One pt is ongoing and 14 collected CD34+ cells after Cyclophosphamide + G-CSF (median CD34+ cells 7.35 × 10e6/Kg, range 2.65–10.0). Two pts had early disease progression after collection, 1 did not receive HDT because of cardiac ejection fraction 〈 50% at evaluation before BEAM and 1 is ongoing. So far, 10 pts received ASCT according to the protocol. Moreover, three pts received radiotherapy (2 on previous bulky and 1 on testicular disease). HDT-related toxicities included 2 grade II and 5 grade III GI and 1 grade III hepatic toxicity. Prior to engraftment 1 VZV infection, 1 Clostridium difficile colitis, 1 sigmoiditis and 5 episodes of FUO were registered. There were no transplant-related deaths. One case of CMV reactivation and no opportunistic infections were registered during observation. All transplanted pts are alive and relapse-free after a median of 43 ms (range, 4–58) after transplant (Figure 1). In the entire series, with a median f-up of 29.5 ms (range, 4–65), the 2-years PFS and OS of the entire series from study entry were 73% (+10.3%) and 76% (+10.6%), respectively (Figure 2). Conclusions. This is the first prospective trial addressing the role of HDT and ASCT in first line treatment of HIV-LNH. The procedure was well tolerated and the clinical results highly encouraging. Interim evaluation of OS in this very high risk series of pts is satisfactory and accrual is ongoing. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Elderly patients (pts) with FL do worse than younger ones and the aim of the treatment is usually palliation rather than cure. In order to outline a treatment plan specifically devised for elderly pts with a reduced amount of chemotherapy, we investigated the efficacy and safety of a brief chemo-immunotherapy FND plus Rituximab. Patients and methods: from March 1999 to March 2003, 80 elderly pts (age 〉60) with advanced stage FL at diagnosis were enrolled. Treatment plan was: 4 courses of FND (Fludarabine 25 mg/m2 days 1–3, Mitoxantrone 10 mg/m2 day 1 and Dexamethasone 20 mg days 1–3) followed by 4 Rituximab infusions at 375 mg/m2/week; pts in partial remission received 2 further FND and 2 Rituximab infusions. PCR molecular monitoring for the presence of IgH/Bcl2 and/or Ig heavy chain gene rearrangement was performed at the beginning of the treatment, after FND, after Rituximab and during follow-up time on bone marrow (BM) samples. Results: median age was 66 (range 60–78); 42 males and 38 females; 16% had stage II, 12% stage III and 72% stage IV disease; 61% had BM involvement; 41% had bulky disease and 24% were at high risk according to IPI score. PCR molecular analysis was performed in 46 pts at diagnosis: 63% were Bcl2 rearranged and 37% were not; IgH rearrangement was detected in 24% of Bcl2 negative pts. Up to date, 70 pts are evaluable. Overall response at the end of treatment was achieved in 63 pts (90%) with 58 pts (83%) in complete remission (CR) and 5 pts (7%) in partial remission (PR). Six pts (9%) did not respond and one patient (1%) died of neutropenic sepsis during a FND course. The addition of Rituximab allowed to increase CR rate from 44% (31 pts) after FND to 83% (58 pts); 73% of responding pts did so with a brief treatment program (4 FND + 4 Rituximab). Patients with adverse prognostic features at diagnosis responded as well as those with more favorable ones with no significant differences in CR rates: BM+ 89%, BM- 79%; low IPI 83%, high IPI 82%; Bulky+ 85%, Bulky- 79%; stage II 90%, III 87%, IV 84%. A thorough molecular analysis is ongoing; to date a molecular marker was detectable in 26 pts. After FND 9/26 pts (35%) did not show anymore BM molecular disease, while PCR negativity was achieved in 23/26 pts (88%) after Rituximab treatment. With a median follow-up of 30 months, 3-yr failure free survival was 50% for the whole series of pts. Failures were observed more frequently in PCR+ pts: all 3 PCR+ pts failed compared to only 7/23 PCR- pts (p=.01). The toxicity was mild with grade 3–4 neutropenia reported in 22% of FND courses, but only 3 pts developed grade 3–4 infections. The whole program was performed in an outpatient setting. Rituximab toxicity was as expected. Conclusions: a brief course of chemo-immunotherapy is able to achieve high clinical and molecular response rates in elderly pts with low toxicity. The sequential use of FND and Rituximab induces a CR rate 〉80% also in unfavorable subsets of pts. The achievement of PCR negative status correlates with a lower risk of failure.

Description: 5-Azacytidine (AZA) is an hypomethylating agent approved in US for the treatment of all FAB subtypes of myelodysplastic syndromes (MDS). Some recent reports have raised the question of a possible efficacy of AZA in selected patients with acute myeloid leukaemia (AML). In September 2007, we started a retrospective study aiming to register and analyse all Italian patients with MDS or AML who had received AZA for the treatment of their disease outside of clinical trials, on the basis of a national patient named program. Among a total of 246 patients treated in 31 different Italian Institutions since 2005, 55 AML diagnosed according to WHO criteria were collected. Median age was 72 years (range 29–87) and 28 patients were male. Poor karyotype was present in 11 patients (20%), while 14 patients (25%) had secondary AML. Median time from diagnosis was 5 months (range 0–72). Eighteen patients (33%) received AZA as front-line treatment, as they were considered not eligible for intensive chemotherapy due to age, co-morbidities or poor performance status. Thirty-seven patients (67%) were pre-treated with growth factors (3 patients) or with one or more lines of chemotherapy (11 and 23 patients, respectively); most of the pre-treated patients (22 out of 34) had received high dose chemotherapy, including autologous or allogeneic stem cell transplantation. Low dose chemotherapy had been employed in the remaining cases. The median number of monthly AZA cycles administered was 4 (range 1–22). Thirty-nine patients (71%) received AZA at the fixed dose of 100 mg/d s.c., 16 patients (29%) received a dose of 75 mg/sqm/d s.c.. A seven-day per month schedule was employed in 43 patients (78%), while 11 patients (20%) received AZA for more than 7 days and one patient for 5 days. Twenty-nine patients (52.8%) received AZA alone, twenty-six (47.2%) in various combinations with growth factors (1), valproic acid +/− ATRA (21) or gentuzumab-ozogamycin (4).The most relevant toxicities observed (grade 3–4) were represented by further myelosuppression (15%), infections (24%: in particular, 1 fungal lung infection, 3 pneumonia and 1 septic shock) and gastrointestinal adverse events (20%). The overall response rate was 35.3% (18/51): 8 patients achieved a complete remission (CR) (15.7%), while a partial response (PR) was observed in 5 patients (9.8%). Five haematological improvements were also seen (9.8%). Response rate was significantly higher in untreated patients compared to pre-treated ones (p=0.02). A statistically significant difference (p=0.04) in response rate in favour of 75 mg/sqm/d versus 100 mg fixed dose was also observed. The actuarial probability of overall survival (OS) at 16 months was 45% for patients responding to AZA and 10% for those non responding (p=0.0027). In conclusion, our data show that: AZA can induce significant responses in about one third of AML patients; the “standard” dose of 75 mg/sqm/d seems to be more effective than 100 mg/d (one single vial) fixed dose; AZA is more effective in de novo as compared to pre-treated (refractory and/or relapsed) disease; AML patients responding to AZA have a significant survival advantage compared to non responders.

Description: The prognosis for elderly patients with acute myeloid leukaemia (AML) is dismal. Intensive chemotherapy is offered only to fit patients. The complete remission is obtained usually in 50% of the patients. The remission duration is short and the majority of patients will relapse within one year, with a poor quality of life. In this study we have evaluated the outcome of sixty-eight elderly patients (mean age 69.2 years) with AML or high-risk myelodysplasia (HR-MDS) treated with an induction program with fludarabine (30 mg/sqm/day for 4 days), cytarabine (1 gr/sqm/day for 4 days) and interspaced continuous infusion of idarubicin (12 mg/sqm/day on days 1,3,5), followed by lenograstim (FLAIG). Thirty-six patients (53%) were in CR after the first course. Thirty-four received a second reduced outpatient course. To account for the “guarantee time” required to survive the induction and retain the CR until the beginning of the post-remissional treatment, we used a landmark analysis at three months from CR to evaluate the disease-free survival (DFS), therefore excluding from the analysis early relapses and deaths in CR. In the first cohort, 13 patients received a post-remissional treatment with thioguanine and weekly cytarabine until relapse. In the second cohort, 14 patients received gemtuzumab ozogamicin (GO) at 3 mg/sqm every 3 months for 1 year or until relapse. The two cohorts were comparable for age, WHO classification, karyotype and CD33 expression. No difference in the median overall survival (OS) was observed between the two cohorts (7.4 vs. 12.3 months; p=0.1).. The landmark analysis showed an improvement of the DFS in patients receiving a post-remissional treatment with GO in confront to those treated with maintenance chemotherapy. (12.5 vs. 6.73 months; p=0.04). Although not influencing survival, the prolongation of DFS without hospitalisation or complications may improve the quality of life of elderly AML patients. The post-remissional therapy with low-dose GO deserves further evaluation in prospective randomized studies.

Description: Background. A leukaemic evolution is evident in less than 50% of myelodysplastic patients. They can often die of age-related problems which are independent of myelodysplastic syndrome (MDS) itself, and the best therapy is difficult to define for this group of old patients, in which aggressive strategies are at high risk and supportive care can constitute the most useful option. A systematic analysis of causes of death is so far lacking. Aim of the work. To analyse the prognosis of a large group of myelodysplastic syndromes with particular reference to the causes of death. Patients and methods. From January 1999 to June 2005, data from 783 new cases of MDS were prospectively recorded into the Piedmont MDS register through our web site. Thirty two and 68 cases were excluded because RAEB-t and CMMoL respectively. The remaining 680 patients, who are the object of the present analysis, can be subdivided according to the WHO classification as follows: 99 RAEB-II; 160 RAEB-I; 104 RCMD; 317 MDS other than RAEB and RCMD. Data regarding co-morbidity and IPSS score are available for 457 and 404 patients respectively. At the moment of the analysis, 157 deaths were recorded and causes of death were registered for 153 patients. Results. Median age was 73 (range 27–95), with 151 patients (22%) older than 80. One or more co-morbidities were present at diagnosis in 399/457 (87%). The prognostic role of both IPSS scoring system and WHO classification were confirmed. The causes of death were subdivided as follows: complications due to cytopenia and/or leukaemic transformation in 57 patients (37%); infections in 20 patients (13%); other age or co-morbidity related causes in the remaining 76 patients (50%). No significant differences of causes of death were seen according to sex, while deaths from unrelated causes increased with increasing age from 29% under 60 years up to of 61% over 80 years (test for linear trend: p=0.02). Deaths due to cytopenia, and/or leukaemic transformations, and/or infections were more frequent in patients with no co-morbidities (75%), while no differences were seen according to the number of co-morbidities: 44%, 39% and 55% for patients with respectively one, two and three associated diseases. A significant relationship was evident between diagnostic subgroups and deaths from unrelated causes: 21% for RAEB-II; 51% for RAEB-I; 53% for RCMD; 76% for MDS other than RAEB and RCMD (p

Description: Histone deacetilase inhibitors (HDCAi) have been shown to modulate gene expression with pro-differentiative effects. Valproic acid (VPA) has HDCAi activity and synergizes with Ara-C to differentiate AML blasts in vitro. VPA is orally applicable and has a low toxicity prophile. We tried to assess the therapeutic activity of VPA in combination with low-dose Ara-C in elderly/frail AML/RAEB patients. We enrolled in this study 31 patients with Myeloid Pathologies. Fifteen pts had diagnosis of oligoblastic AML (M0:2, M1: 7, M2: 1, M4:1, M5: 4); 13 patients had RAEB (RAEB 1: 2, RAEB 2: 11) with the following IPSS: int-1=2, int-2= 2, high= 6. Three other patients had progression from previous MPS (1 from ET, 2 from LMMC). Median age was 70 yrs (range: 53 to 84). Median time from Diagnosis to treatment was 15 months (range 1 to 79). Clinical status at start of protocol was: at Diagnosis = 13 pts, Resistant after induction =6 pts, Relapsed after CR =11 pts, Relapsed after allogeneic transplant =1 pt). All patients were excluded from conventional chemotherapy for age and multiple comorbidities. In 27 out of 31, these comorbidities required therapy or periodic controls (grade 3), other 2 pts had one of G4 grade (life-threatening). Thirteen patients were defined “frail” because they presented 3 of G3 comorbidities or at least a G4 one. Twenty-nine pts were evaluated for autosufficiency with ADL score, 5 of them didn’t reach the score of 6, showing impairment in their autosufficiency. Assessing functional autonomy, IADL score showed deficiency in 17 of 29 patients. In our protocol, VPA was administered in continuum to reach serum concentration of 50–100μg/ml. Ara-C was given in cycles of 8 days, 40 mg/day. Ammonium and valproic acid serum level was routinely checked. Bone marrow examination was done at the enrollement in the study, after sixth cycle of Ara-C and/or if improvement of blood counts were observed. In two patients that were in CR at the end of sixth cycle, VPA was maintained; other six cycles of Ara-C were given monthly and thereafter every third month until relapse. Six patients received the treatment for at least 6 cycles, the other patients had a median of 2 cycles, (range 1 to 4). Ten patients are still in treatment, 17 dropped out for progression/death, one patient underwent reduced intensity allotransplant while in remission. From the start of protocol, median overall survival was 4 mths, range 1 to 33 mths. Fifteen pts are alive now. Overall, 11 of 31 patients (35%) had hematological improvement (according to IWG, 2008), including 7 CR (22%) with clearing of blasts in the marrow and normalization of blood counts. The median cycle of improvement was 2 (range 1 to 4) and the median duration of improvement was 2 months (range 1 to 23 months), including two pts that lasted in CR for 10 and 23 months; 3 pts are still in CR at 5,8 and 10 mths from the starting of response, one patient is in Hematological Improvenment at 2 mths. Hematological toxicity requiring platelet transfusion was seen in 17 patients, while 10 pts required red cell transfusion. Transient hyperammoniemia was seen in one patient; liver toxicity in another patient. Neutropenia-related infections were seen in 3 pts. Adding VPA to low-dose Ara-C, some complete responses and some improvements in peripheral cytopenias can be achieved without a significant increase in toxicity. Therefore this therapeutic protocol is feasible for elderly/frail oligoblastic AML/RAEB patients who cannot have aggressive therapy.