ALBERT

Description: Primary mediastinal B-cell lymphoma (PMBCL) is a relatively rare clinico-pathologic subtype of diffuse large B-cell lymohoma. The optimal management, the prognostic factors and the role of PET/CT scan in this entity remain a matter of debate. While several retrospective studies suggested that dose-dense regimens are more effective than standard CHOP, the impact of adding rituximab (R) on the outcome of patients (pts) with PMBCL has not been fully evaluated. In this retrospective analysis we reviewed the clinical and radiological records of 81 consecutive pts with PMBCL treated in Sheba Medical Center between August 1985 and October 2006. Chemotherapy in the pre-rituximab era (−R cohort) included VACOPB (n=47) or 6 courses of standard CHOP (n=5). Since October 2002, 6 cycles of R were added concurrent with the treatment in another 29 pts (+R cohort): R-VACOPB (n=21) and R-CHOP (n=8). Radiotherapy was not administered following initial chemotherapy to any of the pts. Median age at diagnosis was 31 years (yrs) (range 17–61). Stage I/II and bulky mediastinum (≥ 10 cm in diameter) were present in 88% and 33%, respectively, and extranodal involvement was evident in 44% of all pts. After a median follow-up of 85 months (range 9–240), the overall (OS) and progression-free (PFS) survival at 5 yrs for the entire cohort were 89% and 66%, respectively, with a plateau 1–2 yrs following treatment. PFS at 5 years was significantly better with +R (81%) than with -R cohort (58%, P=0.03). Five-year PFS in pts treated with R-VACOPB, R-CHOP, VACOP-B and CHOP were 84%, 74%, 62%, 20%, respectively (P=0.025). Yet, there was no significant difference in OS between +R and -R cohorts (96% vs. 88% at 5 yrs, p=0.29). Direct survival comparisons demonstrated that 5-yr OS and PFS were significantly better in VACOPB than in CHOP (P=0.04 and 0.05, respectively) and that R-VACOPB was significantly superior to VACOPB in terms of PFS (p=0.05). In contrast, there was no difference in 5-yr PFS between R-VACOPB and R-CHOP (p=0.44). Univariate analysis revealed that aaIPI was not predictive of OS (p=0.51). Age above 31 yrs (p=0.02) and pericardial effusion (p=0.04) were the only predictors of reduced OS. Furthermore, beginning in 2003, 16 consecutive pts in the +R cohort, who were scanned by PET/CT-FDG before starting and after completion of therapy, were also evaluated in the middle (mid-PET) of treatment. The estimated 3-year PFS rate for mid-PET negative pts (n=8) and for mid-PET positive pts (n=8) was 86% and 75%, respectively (P=0.48). In terms of treatment failure, the negative predictive value of mid-PET was 100%, while the positive predictive value was only 25%. In conclusion, our population-based historical comparison demonstrates that the addition of R to anthracycline-based therapy significantly improved PFS in pts with PMBCL. We observed superior PFS with VACOPB compared with CHOP, but this superiority was abrogated by the introduction of R as part of initial therapy. These findings merit further study in randomized prospective studies.

Description: High-dose chemotherapy and autologous stem-cell transplantation (autoSCT) have an established therapeutic role in patients (pts) with chemosensitive relapse of aggressive lymphoma. However, autoSCT has only limited success when performed in refractory or progressive stage of the disease and in heavily pretreated or multiply relapsed pts. The expected long-term progression-free survival (PFS) in this setting is less than 20%. This study was designed to explore the safety and outcome following inclusion of Zevalin in the conditioning regimen given prior to autoSCT in pts with refractory lymphoma expected to have poor outcome with standard autoSCT. Pts with aggressive lymphoma were eligible for this study if they did not achieve CR with prior chemotherapy (either as initial treatment or after relapse) and had active disease by PET-CT. Unlike standard treatment with Zevalin, extensive marrow involvement and pancytopenia were not contraindications for therapy. The study uncluded 23 pts, median age 55 years (range, 35–66), a median of 12 months (5–129) from diagnosis. Histology was diffuse large cell (n=15), transformed low grade (n=7) and mantle cell lymphoma (n=1). Disease status was primary refractory disease (n=11) or refractory relapse (n=12). Fourteen pts had bulky disease at autoSCT. The median number of prior therapies was 3 (range, 1–6). Rituximab 250 mg/m2 followed by Zevalin 0.4 mCi/kg were given on day -14 and high-dose BEAM chemotherapy started on day -6. All pts engrafted in a median of 10 days after autoSCT (9–22). Zevalin had no impact on engraftment kinetics although 9 pts became neutropenic on or prior to the day of autoSCT, an uncommon occurrence with standard BEAM. There were no early infusion reactions associated with Zevalin. Two pts died of multi-organ toxicities early after SCT. One died from infection and one died of bronchiolitis obliterans (infection related) 4 and 5 months after SCT, respectively. The day100 rate of non-relapse mortality in these heavily pretreated pts with refractory lymphoma is 9% (95% CI, 2–33) and it seems there was no additional toxicity related to Zevalin. Overall, 21 pts are evaluable for response; 11 achieved CR, 9 achieved PR, 5 of whom converted to CR with additional radiation therapy to residual disease (overall 16 pts achieved CR), 1 pt did not respond. In all, seven pts relapsed or did not respond. The 1-year cumulative incidence of relapse is only 32% (95% CI, 17–60%). As expected in refractory disease, all relapses occurred within 6 months of autoSCT. With a median follow-up of 15 months (range, 4–25), 15 pts are alive. The estimated 1-year overall and progression-free survival were 59% (95% CI, 36–83%) and 49%, respectively, compared with less than 20% expected with standard autoSCT in this setting. In conclusion, inclusion of Zevalin in the conditioning regimen prior to autoSCT is relatively safe and may improve outcome in pts with refractory lymphoma. Although excess non-relapse mortality can not be ruled out, relapse rate was relatively low, resulting in improved PFS. Zevalin in combination with autoSCT merits further study in larger scale randomized studies. Moreover, standard risk pts with chemosensitive disease may also benefit from Zevalin followed by autoSCT combination.

Description: Allogeneic stem cell transplantation (SCT) is a potentially curative approach in patients (pts) with AML and MDS. Intravenous busulfan (Busulfex, ivBu) was shown to reduce treatment-related mortality (TRM) and improve outcome after standard ablative conditioning. Reduced-intensity regimens allows SCT in pts not eligible for standard conditioning. It is not yet well established what are the dose intensities of ivBu predicting of better outcome in different settings. Eighty-six pts were included in this analysis; median age 50 years (range, 18–69). Seventy-one had AML; 31 of them had secondary AML following prior MDS (n=19) or prior chemotherapy (n=12, including 6 prior autologous SCT), and 15 had MDS (all with excess of blasts). The donors were HLA-matched siblings (n=42), 1-Ag mismatched relatives (n=6) or matched-unrelated (n=38). Thirty-six pts were in first or second remission at the time of SCT, or with less than 10% marrow blasts, 32 were chemo-refractory, and 18 had untreated MDS or relapsed AML and 〉 10% marrow blasts. Forty-two pts had myeloablative conditioning with ivBu (12.8 mg/kg) and cyclophosphamide. Forty-four pts considered not eligible for myeloablative therapy due to advanced age, comorbidities or extensive prior therapy were given fludarabine and reduced intensity doses of ivBu (6.4–12.8 mg/kg). With a median follow-up of 13 months, the 1-year overall (OS) and disease-free survival (DFS) rates of all pts were 47% and 44%, respectively. The cumulative incidence of TRM was relatively low at 17% and relapse rate was 40%. The most important predictive factor for survival in multivariant analysis was chemo-refractory disease at SCT (HR 3.2, p=0.001). Age, gender, secondary AML/MDS, donor type and conditioning regimen used were not significant. In particular there was no difference in survival between pts given different doses of ivBu. The OS and DFS of pts given 12.8 mg/kg (Bu16) (with cyclophosphamide or fludarabine) were 47% and 45%, compared with 50% and 45% in pts given 6.4–9.6 mg/kg (Bu8–12). Pts given Bu16 had higher risk of TRM (21% vs 7%) and lower relapse rate (33% vs 50%), not reaching statistical significance. However, the conditioning regimen had a significant influence when only pts with chemo-refractory disease were analyzed. OS, DFS, TRM and relapse rates were 39%, 38%, 26%, and 36% in pts given Bu16 compared with 0% (p=0.06), 0% (p=0.06), 19% (p=NS), and 81% (p=0.03) after Bu8–12, respectively. ivBu dose intensity did not influence outcome in chemo-sensitive disease. Pts previously untreated with 〉 10% marrow blasts had similar outcome to pts with chemo-sensitive disease if given Bu16, but similar to refractory disease if given Bu8–12. In conclusion, ivBu containing regimens are well tolerated with relatively low TRM rates, in particular in chemo-sensitive disease, and after reduced intensity conditioning. Busulfan dose intensity is not predictive of outcome in chemo-sensitive disease. However, pts with chemo-refractory or untreated disease could only be salvaged if given myeloablative doses of ivBu. Pts considered not eligible for standard ablative conditioning tolerated fludarabine and myeloablative doses of ivBu relatively well, and could be salvaged with this regimen even when treated for chemo-refractory disease. TRM remains acceptable even in these high-risk settings. Randomized studies will be needed to further determine the best dose-intensity in each setting.

Description: ABVD is widely considered as the gold standard treatment for advanced Hodgkin’s lymphoma (HL), although about 40% of patients relapse or do not respond to initial treatment. Recently, the HD9 trial of the German Hodgkin’s Lymphoma Study Group has shown that escalated (esc) BEACOPP regimen can achieve better disease control than ABVD, but has a high incidence of acute and long-term toxicities including high occurrence of AML/MDS. In an attempt to decrease toxicity while preserving the potential benefit of upfront intensive therapy, we conducted a pilot study, which tested the feasibility, toxicity and efficacy of combined escBEACOPP-ABVD regimen as therapy for newly diagnosed patients with high risk (IPS≥3) stage III–IV HL. Patients initially received 2 cycles of escBEACOPP followed by reevaluation with CT and gallium or PET/CT-FDG scans. When complete response (CR) or partial response (PR) was achieved, patients continued to receive 4 cycles of ABVD, while those failing to achieve a response were withdrawn from the study. Since August 2001, 21 patients entered the study and at the time of present analysis four of them are still receiving therapy. Three (18%) of 17 patients, who completed chemotherapy, received consolidative radiotherapy. Median age at diagnosis was 26 years (range 18–56) and 11 (57%) were males. Stage IV and B symptoms were evidenced in 19 (90%) and 17 (81%), respectively, and 7 (33%) had bulky mediastinal mass. Histology included nodular sclerosis in 18 patients (86%), mixed cellularity in 2 (10%) and lymphocyte predominance in 1 (5%). Following the first 2 cycles of escBEACOPP the overall response rate (CR+PR) was 100%. At the end of all therapy 15 patients (88%) were in CR, one patient in PR and only a single patient had progressive disease. With a median follow-up of 20 months no patient relapsed or died. Toxicity included WHO grade III–IV granulocytopenia in 15 patients (88%) and grade III–IV infection in one patient. Hospitalization for intravenous antibiotics was necessary in 10 patients (59%). Almost all of these events occurred during the first two cycles of escBEACOPP, while acute toxicity during the ABVD phase was mild. In conclusion, the combined escBEACOPP-ABVD regimen is well tolerated and is associated with a high CR rate when used in advanced HL patients with high IPS scores. Further follow-up is obviously required in order to determine long-term survival and late complications of this regimen.

Description: The expected 5-year freedom from progression of advanced stage Hodgkin’s lymphoma (HL) patients (pts) with IPS≥3, treated with COPP-ABVD, was reported as 55%. While the superiority of escalated (esc) BEACOPP regimen over COPP-ABVD was shown for all risk groups, it was more pronounced in pts with a poor IPS. However, pts receiving escBEACOPP had more acute and long-term toxicities including a higher incidence of MDS/AML. In an attempt to reduce this toxicity, while preserving improved initial tumor control in this high risk group of pts, we conducted a phase II study, which tested the feasibility, toxicity and efficacy of a regimen which utilized the combination of escBEACOPP and ABVD. Newly diagnosed HL pts, with unfavorable stage IIB or stages III–IV with IPS≥3 were initially received two cycles of escBEACOPP followed by reevaluation with FDG- PET/CT scans. When complete or partial response (CR, PR) was achieved, pts then continued to receive four cycles of ABVD, while pts who failed to obtain this response were planned to receive salvage therapy. Since starting in late 2001, 40 eligible pts received this regimen. Median age at diagnosis was 27 years (range 18–56) and 29 (73%) were males. Histology included nodular sclerosis (n=30), mixed cellularity (n=6) and unclassified (n=4). Stage IV, III and IIB were evident in 29 (73%), 8 (20%) and 3 (7%) pts, respectively and extranodal involvement was noted in 28 (70%). Following the first two cycles of escBEACOPP the overall response rate (CR+PR) was 100% and at the end of all therapy 36 (90%) pts were in CR, 2 (5%) in PR and 2 (5%) pts had progressive disease. After a median follow-up of 30 months (range 7–61), 38 pts are alive while two pts died from progressive HL. The estimated 5-year Progression free survival (PFS) and overall survival rates were 78% (95% CI, 64–92%) and 91% (95% CI, 78–100%), respectively. The 5-year cumulative incidence of relapse was 13% (95% CI, 5-33%). These survival rates are higher than those expected for ABVD containing regimens and comparable with the reported estimated long term survival rates achieved with the poor prognostic subgroup of pts, receiving eight cycles of escBEACOPP in the GHLSG HD9 trial. Furthermore, the estimated 5-year PFS rate for early PET negative pts (n=27) and for early PET positive pts (n=11) was 82% (95% CI, 66–98%) and 64% (95%, CI 35–92%), respectively (P=0.14) (in 2 pts early PET results were not conclusive). In terms of treatment failure, the positive predictive value was only 35%, while the negative predictive value was 85%. As expected, the incidence of acute hematologic toxicities was more common in the escBEACOPP than in the ABVD phase. Non hematologic adverse effects included grade III–IV infection (n=1), avascular necrosis of the hip (n=1) and cognitive impairment (n=1). In conclusion, combined escBEACOPP-ABVD therapy is well tolerated and may improve the outcome in pts with advanced HL who have high IPS scores. Larger scale randomized studies, comparing this combination regimen with previously reported dose-intensified chemotherapy regimens, are required in order to verify its true merit in this high risk subgroup of pts.

Description: Pyrimidine 5′ nucleotidase (P5′N-1) deficiency is an autosomal recessive condition causing hemolytic anemia characterized by marked basophilic stippling and the accumulation of high concentrations of pyrimidine nucleotides within the erythrocyte. It is implicated in the anemia of lead poisoning and is possibly associated with learning difficulties. Recently, a protein with P5′N-1 activity was analyzed and a provisional complementary DNA (cDNA) sequence published. This sequence was used to study 3 families with P5′N-1 deficiency. This approach generated a genomic DNA sequence that was used to search GenBank and identify the gene for P5′N-1. It is found on chromosome 7, consists of 10 exons with alternative splicing of exon 2, and produces proteins 286 and 297 amino acids long. Three homozygous mutations were identified in this gene in 4 subjects with P5′N-1 deficiency: codon 98 GAT→GTT, Asp→Val (linked to a silent polymorphism codon 92, TAC→TAT), codon 177, CAA→TAA, Gln→termination, and IVS9-1, G→T. The latter mutation results in the loss of exon 9 (201 bp) from the cDNA. None of these mutations was found in 100 normal controls. The DNA analysis was complicated by P5′N-1 pseudogenes found on chromosomes 4 and 7. This study is the first description of the structure and location of the P5′N-1 gene, and 3 mutations have been identified in affected patients from separate kindreds.

Description: An Arab family with three homozygotes for βδ-thalassemia is described. The single hemoglobin present in their red cells is fetal hemoglobin. A mild hemolytic condition was seen in the propositus, while the two other siblings are completely normal. The main differential diagnosis of this condition is homozygosity for persistent fetal hemoglobin gene.

Description: Abstract 2045 Poster Board II-22 Myeloid colony-stimulating factors (M-CSFs) are recommended as primary prophylaxis for the prevention of febrile neutropenia (FN) in patients who are at high risk for developing it. Since acute myeloid leukemia (AML) cells express functional growth factor receptors on their surface, concerns have been raised regarding the effect of M-CSFs on these cells. We assessed the safety of M-CSFs in AML patients. Systematic review and meta-analysis of all randomized controlled trials that compared the addition of M-CSFs during and following chemotherapy to chemotherapy alone in patients with AML was conducted. Trials evaluating the role of M-CSFs administered for the purpose of stem cell collection and/or priming e.g., before and/ or only for the duration of chemotherapy, were excluded. Both patients with and without neutropenia and/ or fever on admission were included. Two reviewers appraised the quality of trials and extracted data independently. The primary outcome was all-cause mortality at defined points in time. Secondary outcomes included complete remission (CR), disease free survival (DFS), relapse and infection rates. Relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. The search yielded 17 trials including 4800 patients (range 53-803 per trial). 14 trials included patients undergoing induction chemotherapy, two trials included patients undergoing consolidation and one trial included patients undergoing salvage chemotherapy. The addition of M-CSFs to chemotherapy yielded no difference in all-cause mortality at 30 days, 1 year and at the end of follow-up [RR 1.00 (95% CI.0.82-1.22), RR 1.07 (95% CI 0.97-1.19) and RR 1.02 (95% CI 0.98-1.05), respectively] (Fig.1). There was no difference with regard to CR [RR 1.03 (95% CI 0.98-1.07)], relapse [RR 0.99 (95% CI 0.91-1.08)] and DFS [HR 1.00 (95% CI 0.90-1.13)]. M-CSFs did not decrease the occurrence of bacteremias, RR 0.96 (95% CI 0.82-1.12) or invasive fungal infections, RR 1.40 (95% CI 0.90-2.19). The addition of M-CSFs to chemotherapy does not affect all-cause mortality and leukemia associated clinical end points, e.g. CR, relapse rate and DFS. Hence, the use of M-CSFs for prevention of FN in patients with AML is safe. However, since prevention of neutropenia does not result in improved survival, they should not be used on a routine basis. Their use in the individual patient can be considered according to the clinical situation. Fig. 1: All Cause Mortality Fig. 1:. All Cause Mortality Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 49 The optimal post-remission therapy in adults with acute lymphoblastic leukemia (ALL) is still a matter of debate. At present, it is uncertain whether patients achieving first complete remission (CR1) should receive intensive treatment with allogeneic hematopoietic stem cell transplantation (alloSCT), autologous stem cells transplantation (ASCT) or continue with conventional chemotherapy. The aim of this study was to compare between these therapeutic options for patients achieving CR1. We conducted a systematic review and meta-analysis of randomized trials including standard risk (SR) and high risk (HR) ALL patients receiving first post-remission therapy. Trials were assessed for methodological quality. Specifically, genetically randomized controlled trials were evaluated whether the trial was analyzed by intention-to-treat (ITT) methodology. Violation of ITT was considered as the solely, most important risk of bias domain. Outcomes assessed were all-cause mortality (ACM), relapse rate and non-relapse mortality (NRM). Relative risks (RRs) with 95% confidence intervals (CI) were estimated and pooled. We identified 13 trials (17 comparisons) conducted between the years 1986 and 2006 randomizing 2648 patients. Overall, there was a significant reduction in ACM in the alloSCT arm (RR=0.88 (95% CI 0.8–0.97)) compared with ASCT or conventional chemotherapy (Fig. 1). Results were similar when only trials reporting outcomes based on ITT analysis were included (RR 0.89 (95% CI 0.82–0.97)). The number needed to treat (NNT) to prevent one death with alloSCT for the ITT trials was 17 (95% CI 9 to 50). Subgroup analysis for the trials reporting outcomes based on ITT showed that the pattern for the SR patients was similar to that of the whole group with RR=0.82 (95% CI 0.7–0.98) and NNT of 11 (95% CI 6 – 100), while the advantage of alloSCT for the HR patients was non-significant (RR 0.91 (95% CI 0.8–1.04)) (Fig.1). Overall, there was an increase in NRM (RR 2.99 (1.37–6.53)) and a decrease in relapse rate in the alloSCT arm (RR 0.52 (0.33–0.83)). There was no difference in ACM and relapse rate between the ASCT and the conventional chemotherapy arms for the whole group (RR 1.02 (95%CI 0.88–1.19)) as well as for the SR and HR groups (RR 1.03 (95% CI 0.72–1.47) and RR 1.03 (95% CI 0.91–1.17), respectively). There was no difference in relapse rate between the two arms (RR 0.92 (95% CI 0.73–1.15)) but there was a significant increase in NRM in the ASCT arm in comparison to the conventional chemotherapy arm (RR 1.77 (95% CI 1.12–2.8)). We conclude that overall alloSCT is superior to ASCT or conventional chemotherapy for ALL patients in CR1. The survival advantage is of higher statistical significance for the SR than for the HR group. ASCT and conventional chemotherapy have similar ACM and relapse rate results with a higher NRM in the ASCT arm. Disclosures: No relevant conflicts of interest to declare.