ALBERT

Description: Multiple Myeloma (MM) is the most frequent indication for autolografting and allografting. Autografting (AutoSCT) represents the most effective palliation for these patients. Even the double AutoSCT where there is demonstrated good long-term control in a minority of patients do not appear to result in cure of disease. Myeloablative AlloSCT is penalized by excessive transplant-related mortality (TRM) and toxicity.The introduction of reduced-intensity conditioning for allografting (RICT) has renewed interest in the use of AlloSCT for MM. Recent studies have reported encouraging results with tandem AutoSCT followed shortly thereafter by RICT in MM patients as compared to AutoSCT or myeloablative AlloSCT alone. Here we present the results achieved in our Unit in patients receiving AutoSCT (single or double) compared to patients receiving tandem AutoSCT/RICT. The major results are summarized in the table. In the AutoSCT/RICT group the risk of disease progression was reduced for those patients who achieved full chimerism, acute and/or chronic GVHD. This finding confirms the existence of a graft-versus-myeloma effects. Since the first clinical signs of response of remitters patients were noted between 70 and 120 days and maximum response between 160 and 200 days after RICT (and after DLI in 2 patients) these responses should be considered immunological responses. In conclusion, these data suggest that AutoSCT/RICT significantly reduces the incidence of disease progression but did not impact on overall survival with respect to single or double AutoSCT. Single Double AutoSCT AutoSCT AutoSCT + RICT (n=15) (n=35) (n=24) Age, median 64 (range 48–73) 62 (range 35–73) 50 (range 34–63) No. prior cycle chemoth., median 5 (range 3–8) 4 (range 3–6) 4 (range 3–6) Conditioning regimen for AutoSCT Melph. 200 mg/m2 Melph. 200 mg/m2 Melph. 200 mg/m2 Conditioning regimen for RICT ==== ==== TBI-Flu (19 pts) Flu-Melph. (5 pts) Days from Dx to AutoSCT, median 210 (range 120–390) 320 (range 120–840) Days from AutoSCT to RICT ==== ==== 80 Overall Survival 73,3% (11/15) 60% (21/35) 66% (16/24) Median Overall Survival 37 (range 10–132) 51 (range 13–147) 28 (range 6–87) Pts alive in CR 1 (6,6%) 4 (26,6%) 10 (41,6%) CR duration, median 20 mo. 56 mo. (range 28–70) 67 mo. (range 8–78) TRM 1 ==== 3

Description: Abstract 4109 Imatinib has become an integral part of front-line therapy for Ph+ ALL, with remission rate exceeding 90% irrespective of whether Imatinib is given alone or combined with chemotherapy. Treatment outcome with Imatinib-based regimens has improved survival compared with historic controls, but most patients who do not undergo allogeneic stem cell transplantation (SCT) eventually relapse. Second generation TKI, e.g. Nilotinib and Dasatinib, show activity against most of the BCR-ABL tyrosine kinase domain mutations involved in acquired Imatinib resistance, but clinical benefit is generally short lived. In the attempt to improve the prognosis of these patients, we started a new intensive protocol consisting of induction phase with Imatinib (600 mg po, daily) in combination with conventional chemotherapy; moreover, two intrathecal methotrexate will be administered at the day +8 and +22. As known, this approach will determine an high number of complete hematologycal (CHR) and cytogenetic remissions (CcyR). Soon after, Imatinib will be discontinued and a 2nd TKI (Nilotinib or Dasatinib) will be offered to the patients. The idea is to reduce/eliminate as soon as possible the mutations generating under Imatinib. The primary objective of the study will be to assess the activity of sequential TKI to induce molecular remission; secondary objectives will be DFS, relapse rate, OS. This protocol will be designed for patients 〉18 years. Recruitment started in June 2008. Minimal residual disease will be investigate by RQ-PCR at day +30, +60, +90, +120, +150 and so on. The protocol has been designed for 20 patients. Three evaluable patients entered until now this trial; the median age was 47 years (range, 39-64 years). All 3 patients achieved CHR and CCyR at a median of 26 days (range, 18-31 days) and 46 days (range, 39-59 days), respectively. Monitoring RQ-PCR, a marked clearance of leukemic cells was found at d+60; when CCyR was achieve, Imatinib was discontinued and 2nd TKI was started: 2 patients received Dasatinib 100 mg po daily and 1 patient Nilotinib 800 mg po twice daily. Between d+100 and d+120, RQ-PCR became negative in the peripheral blood of all patients. One patient with an HLA+ sibling donor is waiting to receive an allograft; the other 2 patients, who did not find an HLA+ donor, received an autograft with molecular negative PBPC. The conditioning regimen consisted of the BU-Cy regimen. Both patients are alive and in CMR at 3 and 10 months after autografting. More patients and more time will confirm the efficacy of this new approach. Disclosures: No relevant conflicts of interest to declare.

Description: Reduced-intensity conditioning for transplant (RICT) aims to exploit graft vs lymphoma (GvLy) effects while reducing conditioning-related toxicity. Because GvLy responses might be insufficient when HL are bulky and lymphoma growth is rapid, we pionered that intensive cytoreduction prior to RICT may allow GvLy reaction to be exploited (Carella et al. JCO2000; 18:3918). Thirty-eight patients with relapsed (n=26) or refractory (n=12) HL underwent RICT from an HLA-identical sibling preceeded by ASCT. Previous therapy consisted of 2–6 lines. High-dose therapy with ASCT consisted of BEAM protocol (n=29) or melphalan 200 mg/m2 (n=9). RICT consisted of fludarabine-cyclophosphamide (n=30) or fludarabine-melphalan (n=8). The two groups had similar prognostic factors. The median time to neutrophils and platelets recovery was 10 days and 16 days, respectively. Chimerism studies indicated 100% donor-derived engraftment. Day 100 and cumulative (2 yrs) TRM were 5,3 % (2 pts) and 18% (7 pts), respectively. Seventeen patients (44%) are alive (12 in complete remission and 5 with stable disease) with a median follow-up of 41 months (7–110 months). Twenty-one patients expired (TRM n=7, disease progression n=14). In conclusion, tandem ASCT/RICT is feasible and effective salvage therapy for patients with advanced HL. The long-term results obtained appear encouraging.

Description: Anagrelide treatment is considered potentially responsible of cardiovascular toxicity and side effects. For this reason, we have retrospectively evaluated 130 patients (pts) with Essential Thrombocythemia (ET) treated with Anagrelide in 10 Italian Hematological Centres belonging to the GIMEMA Group. The pts, 55 males and 75 females, had at diagnosis a mean age of 43 years (range 13–82) and a mean platelet (PLT) count of 1086x10(e)9/L. The Anagrelide treatment was started after a mean of 47 months from diagnosis(range 0–196). A previous treatment with cytoreductive drugs (mainly HU and IFN) and antiplatelet agents (mainly ASA), was performed in 65% and 98% of cases, respectively. The mean Anagrelide dose was 1 mg/day at start and 1.7 mg/day in the maintenance phase (mean PLT count below 500x10(e)9/L). Twenty-five patients (19%) discontinued the treatment after a mean of 27 months (range 1–85) for the following reasons: compliance loss (n8), no satisfactory response (n7), palpitations and tachycardia (n6), other side effects (n4), anemia (n1), renal toxicity (n1), thromboembolism (n1). During the follow-up (median 28 months) 4 thrombotic complications (1.15/100 pt-yrs) and 2 minor hemorrhages (0.57/100 pt-yrs) were registered. Moreover, 15 pts showed non lethal cardiovascular events: angina (n6), cardiomiopathy (n4), arrhythmia (n3), AMI (n2). An instrumental cardiovascular evaluation with Echocardiography (ECHO) and ECG was performed at Anagrelide start in 58 pts: the Ejection Fraction (EF) was abnormal in only one pt (EF 47%). The instrumental monitoring was done in 28 pts every 6–12 months. Four out of these 28 pts showed a decrease of the EF below the level of 50% (43%,45%,47%, and 49%), and only 1 pt discontinued Anagrelide for this reason (see table). The clinical and instrumental cardiovascular evaluation in ET patients receiving Anagrelide is becaming of routinary application and an observational prospective study of the Registro Italiano Trombocitemia (RIT) is now in progress. ECHO EF

Description: Althought favourable results with ASCT in patients with AML in first CR have been reported, there are no definitive data indicating that this approach is superior to chemotherapy alone. We have recently reviewed our 23 years experience with ASCT in AML in Genoa. From January 1984 to December 2007, 79 patients in first CR, aged 18–65 years, who did not have a sibling donor, were autografted. These patients had been previously treated in induction with Ara-C 200 mg/m2/d × 7 days and DNR 50 mg/m2/d × 3 days. Soon after, they had received consolidation therapy with 4 courses of DAT therapy (DNR 50 mg/m2/d1, Ara-C 200 mg/m2 c.i. day 2–5, thioguanine 80 mg/m2 days 2–5). Fifty patients were autografted with bone marrow and 29 patients with peripheral blood stem cells. High-dose therapy consisted of Cyclophosphamide and single dose TBI (n=50) or high-dose busulfan and cyclophosphamide (n=29). At a median of 11 years, 15 patients (19%) are still alive and well. At that time genetic aberrations combined or not with cytogenetics were not available; therefore we have retrospectively analyzed the patients according to age, sex, WBC count, time to CR and conditioning regimen. None of these factors was predictive for long-term remission. On the contrary, we found that late platelets recovery was predictive. The median time to recover platelets 〉 50 × 109/L was 72 days (45–115 days) in long-term remission patients versus ≤ 30 days in the other patients who relapsed. During the presentation details of this retrospective study will be discussed. In conclusion, the late recovery of platelets after autografting is in our experience the most predictive factor for long-term remission duration in autografted AML patients.

Description: Multiple Myeloma (MM) is still an incurable disorder despite the numerous attempts to exploit new therapy approaches for it. The better understanding of its molecular pathogenesis has led to the development of effective, novel therapeutic agents like thalidomide and the proteasome inhibitor bortezomib. High-dose therapy with stem cell transplantation and novel targeted therapies represent two approaches to overcome resistance of multiple myeloma cells to conventional treatments. Autografting (AutoSCT) has been limited by high-relapse rates and conventional allografting (AlloSCT) by excessive TRM and toxicity. Reduced intensity conditioning for transplant (RICT), a less toxic procedure for AlloSCT that aims to exploit graft versus tumor effect, has been shown to achieve remissions in MM. High-dose therapy/AutoSCT followed shortly thereafter by RICT might improve outcomes in MM as compared to AutoSCT or conventional AlloSCT used alone. We compared two retrospective cohort of patients who underwent either tandem AutoSCT (HDT consisted of Melphalan 200 mg/m2) or AutoSCT followed closely by related RICT (patients with HLA-matched siblings). The two groups were matched for pre-transplant therapy, disease status at transplant, time from diagnosis to transplant. GVHD prophylaxis for RICT patients consisted of CyA/MTX. The major results are summarized in the Table. In the AutoSCT/RICT group the complete remission rate was higher (p=0.004) and the risk of disease progression after transplant was significantly reduced. All patients who reached CR responded after full chimerism and GVHD developed. This finding confirms the existence of a graft-versus-myeloma effect. Since the first clinical signs of response in remitters patients were noted between 70 and 120 days and maximum response between 160 and 200 days after RICT (after DLI in one patient), these responses should be considered immunological responses. Our data demonstrated that RICT following an AutoSCT can mediate a potentially curative graft-versus-myeloma effect and reduces the incidence of disease progression. Tandem ASCT (N=35) ASCT+RICT (n=20) Age, median 56 (range, 38–66) 51 (range, 34–63 Median number of prior cycles of Chemoth. 4 (range, 3–6) 4 (range, 3–6) Time from Dx to 1st AutoSCT (median mo.) 6 (range, 5–60) 9 (range, 7–42) Conditioning Regimen for AutsoSCT Melphalan (200mg/m2) Melphalan (200mg/m2) Conditioning regimen for RICT --- TBI/Fludarabine Median days from AutoSCT to RICT --- 80 Complete Remission rate 14% 50% Disease-free Survival at 4 yrs 14% 45% Overall Survival at 4 yrs 28% 40% Transplant-Related Mortality 0% 0%