ALBERT

Description: Myelodysplastic syndromes (MDS) form a heterogeneous group of clonal hematopoietic disorders with unfavourable prognosis. Allogeneic bone marrow transplantation is the only potentially curative treatment, but remains limited to a small subgroup of younger patients with HLA- compatible donors. As autologous stem cell transplantation is currently being explored as an alternative treatment strategy for MDS, more information needs to be acquired regarding the clonal nature of the progenitor cells in these autografts. Therefore, we have analyzed the clonal patterns of highly purified hematopoietic progenitors and their mature daughter cells in mobilized peripheral blood collections produced from five female patients with high-risk MDS in complete hematologic remission. X-chromosome activation patterns of flow-sorted immature (CD34 + 38low, CD34 + 33low) and committed (CD34 + 38high, CD34 + 33high) progenitors were studied with the polymerase chain reaction-based HUMARA assay. In four patients, a polyclonal remission was shown in all stem cell subpopulations and their mature daughter cells whereas one patient was found to remain skewed in all fractions, except T lymphocytes. This study provides strong evidence that polyclonal immature hematopoietic progenitors can be mobilized and harvested in patients high-risk MDS after treatment with high-dose chemotherapy.

Description: Background. Oral mucositis (OM) is a common complication of high-dose (HD) chemotherapy conditioning regimens used with peripheral blood stem-cell transplantation (PBSCT). Severe grades of OM are associated with higher morbidity such as infections, need for total parenteral nutrition (TPN), opioid analgesics and prolonged hospitalization and has been historically underreported. Recent epidemiology reveals an incidence of severe OM of 50–60%. Moreover, OM is reported by patients as the worst and most debilitating complication of PBSCT. The keratinocyte growth factor, palifermin, stimulates the growth, differentiation, migration, and survival of epithelial cells. Palifermin is now approved in the US and the EU to decrease the incidence, duration, and severity of OM in patients (pts) with hematological malignancies requiring autologous PBSCT. Objective. This report describes the treatment of 60 pts who received palifermin through an early access program in Belgium. We evaluated the effect of palifermin on OM in pts with multiple myeloma or non-Hodgkin’s lymphoma receiving HD melphalan (HD Mel) or BEAM conditioning regimen, respectively, prior to autologous PBSCT. Methods. The pts received palifermin (IV bolus: 60 μg/kg/day) for 3 days before and 3 days after HD Mel or BEAM. The common OM prevention strategy included basic oral hygiene, mouth washes and oral cryotherapy during HDM administration (n=9). For each patient, follow-up data were collected on mucositis grading, duration of hospitalization, neutropenic fever, treatment with G-CSF, IV antibiotics, opioids, and TPN. The grade of OM during treatment was assessed according to the WHO oral-toxicity scale (grade 0 to 4). Drug-related adverse events were also recorded. Results. Thirty pts received HD Mel and 30 pts received BEAM before PBSCT. All 60 pts received at least 3 palifermin bolus injections; the scheduled doses (6 bolus) were administered to 55 (91%) of 60 pts. Analysis of the follow-up data revealed that 10 (16%) pts experienced no OM. Furthermore, a low incidence (31%) of severe (grade 3 and 4) OM was observed with each conditioning regimen. The median duration of severe OM with the HD Mel regimen was 7 days (range 3–27) contrasting with a median OM duration of 3 days (range 2–12) with the BEAM regimen. Two pts in each regimen required prolonged hospitalization due to OM. With either regimen, neutropenic fever and use of IV antibiotics were common (70% of pts), while bacteremia was infrequent (20% of pts). Myeloid growth factors were administered post PBSCT to the majority of pts. Forty percent (40%) of HD Mel-treated pts and 26% of BEAM-treated pts required opioid analgesics. The percentages of pts receiving TPN were similar in the 2 conditioning regimens (66% of all pts). TPN was used in 16 (84%) pts with severe OM and in 24 (58%) pts with no or grade 1–2 OM. Adverse events clearly related to palifermin were reported in 25 (41%) of 60 pts. The most common adverse events included rash (18 events, 8 severe), disorders of tongue and oral mucosa (13 events, 2 severe), edema (10, no severe) and pruritus (7, no severe). Conclusions. These results indicate that palifermin use prior to HD Mel or BEAM and immediately following the transplantion may provide effective support in the prophylaxis of severe OM in pts undergoing autologous PBSCT, without major toxicity.

Description: Abstract 323 Event-free survival (EFS) at 5 years in pediatric ALL is 〉 80% with dose intensive multi-agent chemotherapy. In contrast, adult ALL still has an unsatisfactory outcome, which may partly be due to less cumulative dosing of chemotherapeutic agents and less strict adherence to timing of successive cycles of chemotherapy. Given the earlier reported feasibility of pediatric schedules in adolescent patients, the HOVON group performed a prospective multicenter phase II trial to evaluate the feasibility and efficacy of an intensified treatment regimen in adult patients with newly diagnosed ALL aged 18–40 years. The treatment regimen was based on the French FRALLE-2000 protocol, including dose intensification for steroids, vincristine, L-asparaginase, and high dose methotrexate (MTX). Fifty-four patients, median age 26 years (range 17–39) were enrolled in 15 centres in the Netherlands and Belgium between December 2005 and August 2007. After a prednisolon prephase and a multidrug remission-induction (prednisolon, daunorubicin, vincristine, cyclophosphamide and L-asparaginase), patients received consolidation containing 5000 mg/m2 MTX twice, two intensifications with intensified L-asparaginase, interspersed by an interphase with again two times high dose MTX, and maintenance chemotherapy (oral MTX and 6-mercaptopurine (6-MP) with reinduction with vincristine and prednisolon) for two years. CNS prophylaxis with MTX was delivered intrathecally 18 times. Standard risk patients with an HLA-identical sibling stem cell donor proceeded to allogeneic stem cell transplantation (alloSCT) after the first intensification, high risk patients received alloSCT from either sibling or unrelated donors. Adherence to the treatment schedule was urged by defining a strict timetable. Feasibility was defined by completion of chemotherapeutic and alloSCT protocol treatment within this a pre-defined timeframe. Thirty-five patients (65%) had B-cell phenotype ALL, 17 (31%) had T-cell phenotype and 2 (4%) had biphenotypic leukemia. Moreover, 23 patients (43%) had high risk disease, of whom 9 patients with BCR-ABL positive ALL. In total 33 patients fully completed treatment as scheduled, including 18 alloSCT recipients. Complete remission (CR) was achieved in 91% (95% CI: 80–97). After a median follow-up of 26 months (range 15–36 months), 2-year event-free-survival (EFS) is 68% (95% CI: 53–78), 2-year disease free survival (DFS) 74% (95% CI: 59–84) and the 2-year overall survival (OS) 70% (95% CI: 55–81). Fifteen patients (28%) died, including 8 due to relapsed/refractory ALL, 3 due to infection, 3 due to toxicity and 1 due to graft versus host disease. CTC grade 4-5 toxicities (mainly liver/kidney function abnormalities and peripheral neuropathy) were observed in 15% during induction and 13% during consolidation. Severe infections (CTC grade 3-4) primarily occurred during induction (41%) and consolidation (39%). Failures were due to not reaching CR in 5 patients, early relapse in 2, severe extramedullary drug toxicity in 3, excessive delay in 7 and other reasons not otherwise specified (but most likely due to toxicity) in 4 patients. In conclusion, these data show that a dose-intensified chemotherapeutic regimen based on a pediatric schedule is safe and feasible in most adult ALL patients up to the age of 40, although a delay of subsequent cycles was frequently observed. Early efficacy data suggest a high CR rate and favourable DFS and OS. Based on this experience, a randomised phase III trial has recently been initiated. This trial was supported by the Dutch Cancer Foundation (CKTO 2005-08), EudraCT number 2005-000919-96 Disclosures: No relevant conflicts of interest to declare.

Description: Cytogenetic data were studied in 26 patients with de novo acute myeloid leukemia (AML) with minimal myeloid differentiation, corresponding to the M0 subtype of the French-American-British classification, in correlation with cytoimmunologic and clinical findings. Clonal abnormalities were detected in 21 cases (80.7%), 12 of which had a complex karyotype. Partial or total monosomy 5q and/or 7q was found, either as the sole aberration or in all abnormal metaphases, in 11 patients; in 8 cases, additional chromosome changes were present, including rearrangements involving 12p12–13 and 2p12–15 seen in 3 cases each. Five patients had trisomy 13 as a possible primary chromosome change; in 5 cases, nonrecurrent chromsome abnormalities were observed. Comparison of these findings with chromosome data from 42 patients with AML-M1 shows that abnormal karyotypes, complex karyotypes, unbalanced chromosome changes (-5/5q- and/or -7/7q- and +13) were observed much more frequently in AML-M0 than in AML-M1. Patients with abnormalities of chromosome 5 and/or 7 frequently showed trilineage myelodysplasia and low white blood cell count. Despite their relatively young age, complete remission was achieved in 4 of 11 patients only. Patients with +13 were elderly males with frequent professional exposure to myelotoxic agents. Unlike patients with clonal abnormalities, most AML-M0 patients with normal karyotype showed 1% to 2% peroxidase-positive blast cells at light microscopy and frequently achieved CR. It is concluded that (1) AML-M0 shows a distinct cytogenetic profile, partially recalling that of therapy-related AML, (2) different cytogenetic groups of AML-M0 can be identified showing characteristic clinicobiologic features, and (3) chromosome rearrangements may partially account for the unfavorable outcome frequently observed in these patients.