Lance Sieger

High-Dose Melphalan, Etoposide, Total-Body Irradiation, and Autologous Stem-Cell Reconstitution as Consolidation Therapy for High-Risk Ewing’s Sarcoma Does Not Improve Prognosis

PURPOSEnTo determine whether consolidation therapy with high-dose melphalan, etoposide, and total-body irradiation (TBI) with autologous stem-cell support would improve the prognosis for patients with newly diagnosed metastatic Ewings sarcoma (ES).nnnPATIENTS AND METHODSnThirty-two eligible patients with newly diagnosed ES metastatic to bone and/or bone marrow were enrolled onto this study. Treatment was initially comprised of five cycles of induction chemotherapy (cyclophosphamide, doxorubicin, and vincristine alternating with ifosfamide and etoposide) and local control. Peripheral-blood stem-cell collection was performed after the second cycle of chemotherapy, with delay if the bone marrow was persistently involved. If patients had a good response to initial therapy, they proceeded to consolidation therapy with melphalan, etoposide, TBI, and stem-cell support.nnnRESULTSnOf the 32 eligible patients, 23 proceeded to high-dose therapy consolidation. Of the nine patients who did not proceed to consolidation, four were secondary to progressive disease and two were secondary to toxicity. Three patients died from toxicity during the high-dose phase of the therapy. The majority of the patients who underwent high-dose consolidation therapy experienced relapse and died with progressive disease. Two-year event-free survival (EFS) for all eligible patients is 20%. The 2-year post-stem-cell reconstitution EFS for the subset of 23 patients who received consolidation therapy is 24%. Analysis of peripheral-blood stem-cell collections by molecular techniques for minimal residual disease showed contamination of at least some samples by tumor cells in all three patients with available data.nnnCONCLUSIONnConsolidation with high-dose melphalan, etoposide, TBI, and autologous stem-cell support failed to improve the probability of EFS in this cohort of patients with newly diagnosed metastatic ES.

Identification of Eleven Human Hemoglobin Variants by High-Performance Liquid Chromatography: Additional Data on Functional Properties and Clinical Expression

Eleven abnormal hemoglobins were detected in the course of cord blood screening or in the evaluation of evident hematological problems in individual cases. Identification of the variant in each case was done by high-performance liquid chromatography (HPLC); HPLC provides a rapid, sensitive means for the examination of abnormal hemoglobins. Some of the 11 variants that were identified have been described repeatedly and are included to provide information on the HPLC behavior of tryptic peptides. Others are much rarer. Additional information is provided about the hematological and clinical expression as well as ethnic and geographical distribution of the abnormal hemoglobin.

Considerations in the evaluation of haemophilia patients for short‐term prophylactic therapy: a paediatric and adult case study

Summary.u2002 The long‐term prophylactic administration of clotting factor concentrate in patients with haemophilia reduces bleeding events, slows joint deterioration, and improves quality of life. Prophylaxis can also be effective when used short‐term to prevent or reduce bleeding associated with trauma, surgery, and athletic activities. While clinical trials are needed to establish the optimal length of prophylaxis following injury, several weeks and possibly months of treatment may be needed. Discontinuing therapy prematurely can result in rebleeding in the injured area.

Inhibitor challenges in the paediatric setting

As the management of children with alloantibodies that inhibit or neutralize the function of factor VIII (FVIII) differs from that in adults, a group of clinicians who treat haemophilia met to discuss the challenges of treating inhibitors in the paediatric setting. The group agreed that there is a clear preference for the exclusive use of recombinant products in children – but not in adults – with inhibitors. This preference is often driven by parents, who are concerned about the safety of plasmaderived products. Consequently, recombinant activated factor VII (rFVIIa; NovoSeven , Novo Nordisk A/S, Bagsvaerd, Denmark) is routinely used to treat serious bleeding events in hospitalized children with high-titre inhibitors, whereas adults may be treated with either NovoSeven or FVIII inhibitor bypass activity (FEIBA) VH AICC (Baxter Healthcare Corporation, Westlake Village, CA, USA) the only activated prothrombin complex concentrate currently available. The group noted that this approach is not based on the most recent safety data and cautioned that it could jeopardize outcomes. The potential for plasma-derived agents to transmit infection is cited as a primary reason for selecting recombinant products. Yet not a single incident of disease transmission has resulted from infusions of human-derived, viral-inactivated products since 1985 in the US and 1987 in Canada. Moreover, despite the widespread use of plasma-derived and blood products, no patient with haemophilia or thalassaemia has developed a new variant Creutzfeldt-Jakob disease (CJD). Another argument against the use of FEIBA is that it causes thrombotic events. Thrombosis is a rare but well-recognized potential complication of FEIBA, particularly when used in higher than recommended doses [1–3]. Nonetheless, recent reports indicate that thrombotic risk is similar with NovoSeven [4], and is extremely low with either of these bypassing agents [1,4]. Finally, because FEIBA contains trace amounts of FVIII [5], anamnesis, defined as an increase of >50% of pre-infusion inhibitor titre level [6] may occur following FEIBA administration. Elevated titres typically decline over time, however, and the anamnestic response has no impact on the haemostatic efficacy of either FEIBA or NovoSeven [5,7]. The panel agreed that immediately after a child is diagnosed with an inhibitor, the clinician must have a conversation with the parents delineating the realities of the situation. Specifically, the development of an alloantibody is a life-threatening complication of haemophilia, and only two products are currently available to treat bleeding events in patients with high-titre inhibitors. Haemostasis cannot be guaranteed with either FEIBA or NovoSeven, and response varies depending on the bleeding episode and the patient and may even change during a single bleeding event. Thus, treaters must have the parents permission to use whatever works to halt bleeding, as eliminating a plasma-derived product as a therapeutic option may have significant clinical consequences. In the opinion of the group, the adjunctive use of aminocaproic acid (Amicar ; Xanodyne Pharmaceuticals, Florence, KY, USA) is safe in children receiving either FEIBA or NovoSeven and is especially helpful in controlling mucosal bleeding associated with dental procedures. To minimize the potential for thrombotic complications, it was recommended that Amicar be administered 2 h after NovoSeven and 12 h after FEIBA dosing. Because patients with high-responding, high-titre inhibitors are at increased risk of developing devastating joint disease [8], immune tolerance induction (ITI) is usually attempted using one of several protocols, all modifications of the original Bonn protocol first described by Brackmann and Gormsen [9]. However, approximately 30–40% of patients Correspondence: Lance Sieger, MD, Department of Pediatrics, David Geffen School of Medicine of UCLA and Harbor/UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90502. Tel.: 310-222-4158 e-mail: lsieger@labiomed.org

PULMONARY WASHINGS AND BLOOD IN PULMONARY ALVEOLAR PROTEINOSIS (PAP)

Pulmonary alveolar proteinosis is a diffuse pulmonary disease of obscure etiology characterized by abnormal accumulations of phospholipids in the lung. Despite severe pulmonary disabilities there is a striking absence of inflammatory cells and fibrosis in the lungs of these patients. We have examined the lung washings and blood from five patients with this disease in an attempt to discover whether there are any inhibitors of the normal inflammatory responses locally or systemically. The complete peripheral blood counts and numbers of T and B lymphocytes and monocytes were entirely normal in all patients. The cellular components of the lung washings were primarily mononuclear cells which exhibited histochemical and surface characteristics typical of alveolar macrophages (AM). Morphologically, these AM were many times larger than AM from control patients and were filled with amorphous material. The lung washings of the patients inhibited Con A and pokeweed mitogen stimulation of allogenic peripheral blood lymphocytes by >90%, but had no significant effects on PHA stimulation. Their sera inhibited stimulation by all three mitogens >95%. This inhibition was not due to cytotoxicity. When the lung washings were injected into normal rabbit peritoneal cavities, there was no inhibition of accumulation of either PMNs or peritoneal macrophages as stimulated by mineral oil. In addition, the lung washings stimulated RNA synthesis in vitro by rabbit AM.

Dasatinib Plus Intensive Chemotherapy in Children, Adolescents, and Young Adults With Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia: Results of Children’s Oncology Group Trial AALL0622

Purpose Addition of imatinib to intensive chemotherapy improved survival for children and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Compared with imatinib, dasatinib has increased potency, CNS penetration, and activity against imatinib-resistant clones. Patients and Methods Childrens Oncology Group (COG) trial AALL0622 (Bristol Myers Squibb trial CA180-204) tested safety and feasibility of adding dasatinib to intensive chemotherapy starting at induction day 15 in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia age 1 to 30 years. Allogeneic hematopoietic stem-cell transplantation (HSCT) was recommended for patients at high risk based on slow response and for those with a matched family donor regardless of response after at least 11 weeks of therapy. Patients at standard risk based on rapid response received chemotherapy plus dasatinib for an additional 120 weeks. Patients with overt CNS leukemia received cranial irradiation. Results Sixty eligible patients were enrolled. Five-year overall (OS) and event-free survival rates (± standard deviations [SD]) were 86% ± 5% and 60% ± 7% overall, 87% ± 5% and 61% ± 7% for standard-risk patients (n = 48; 19% underwent HSCT), and 89% ± 13% and 67% ± 19% for high-risk patients (n = 9; 89% underwent HSCT), respectively. Five-year cumulative incidence (± SD) of CNS relapse was 15% ± 6%. Outcomes (± SDs) were similar to those in COG AALL0031, which used the same chemotherapy with continuous imatinib: 5-year OS of 81% ± 6% versus 86% ± 5% ( P = .63) and 5-year disease-free survival of 68% ± 7% versus 60% ± 7% ( P = 0.31) for AALL0031 versus AALL0622, respectively. IKZF1 deletions, present in 56% of tested patients, were associated with significantly inferior OS and event-free survival overall and in standard-risk patients. Conclusion Dasatinib was well tolerated with chemotherapy and provided outcomes similar to those with imatinib in COG AALL0031, where all patients received cranial irradiation. Our results support limiting HSCT to slow responders and suggest a potential role for transplantation in rapid responders with IKZF1 deletions.

PULMONARY ALVEOLAR MACROPHAGES IN PRE-AND POST-NATAL RABBITS

Pulmonary alveolar macrophages (PAM) are the most important phagocytic cells in the lung. We have studied a fetal rabbit model to show whether functioning PAM are present in normal numbers in the fetus or whether air breathing is required for their formation and/or migration to the lung. Broncho-pulmonary washings, with 37°C. normal saline, were examined from a). 30 day fetal rabbits delivered by hysterotomy with tracheas ligated prior to first breath, b). spontaneously breathing neonatal rabbits born normally, and c). adult rabbits. The cells contained in all the washings were >99% PAM and the PAM from all rabbits appeared to be similar when stained with Wrights and α-napthol acetate. There were no significant differences in the total numbers of PAM per rabbit when corrected for wet lung weights. The PAM from all the rabbits phagocytized P. aeruginosa and S. aureus equally well. These findings indicate that functioning PAM are present in equivalent numbers in intra- and extrauterine life. The susceptibility of neonates to serious pulmonary infections may be due to factors other than diminished numbers of functioning PAM.

1341 WHOLE BLOOD PLATELET VOLUME MEASUREMENTS IN NEONATES

The MPV(mean platelet volume)and FLP(fraction of large platelets)were determined for 31 non-thrombocytopenic and 11 thrombocytopenic neonates. Samples were obtained by heel stick, by venipuncture, from cord blood, or from indwelling catheters. 0.1 ml unfractionated anticoagulated whole blood samples were analyzed using a Coulter model S+ cell counter, which determines MPV by direct measurement.The FLP was calculated by determining the fraction of platelets on a platelet volume histogram between 13 and 28μm3. There was no difference between MPV and FLP of capillary blood compared to catheter arterial blood samples. The platelets of 4 thrombocytopenic premature infants(< 100,000) were significantly larger(MPV=9.80, FLp=21.45) than the platelets from 7 non-thrombocytopenic premature infants (MPV=8.20, FLp=10.11). The platelets of 7 thrombocytopenic full-term infants were also significantly larger(MPV=9.61, FLp=28.34) than the platelets of 25 non-thrombocytopenic full-term infants (MPV=8.51, FLp=11.90) Nine of the thrombocytopenic neonates had proved or suspected sepsis; 1 had DIC with severe acidemia; and 1 had aortic thrombosis. This simplified method of platelet volume determination is particularly useful in neonates because of the small volume of blood required and suggests that thrombocytopenia associated with neonatal sepsis is due to increased destruction rather than decreased production.