Autologous bone marrow transplantation for acute leukemia using transplant chemopurified with metabolite of oxazaphosphorines (ASTA Z 7557, INN mafosfamide)

Summary The contamination of autologous marrow with clonogenic tumor cells has been the main argument against ABMT in acute leukemia.In a preclinical study we evaluated an active cyclophosphamide derivative named ASTA Z 7557. We observed that the toxic effect of this drug on CFU-GM growth was dependent on nucleated cell concentration as well as on red blood cell contamination. The potency of the drug was in close relationship with the incubation temperature.The growth of leukemic CFU was inhibited with an ASTA Z dose higher than 30 g/ml. In our system, beyond 40 g/ml more than 95% of committed stem cells are destroyed.Fifteen patients had autotransplant because of AML for 10 patients and because of ALL for 5 patients (4 patients were grafted in relapse and 11 patients in remission).We demonstrated that the marrow take was possible although the inoculum is CFU-GM depleted.Five of the 10 AML patients are alive and remain disease-free at 45 +, 65 +, 190 +, 345+ and 570 + days from ABMT without any maintenance treatment. Four of the 5 ALL patients are alive, three of them in complete remission (404+, 110+, 250+ days).The number of patients reported in this clinical study was relatively small and more cases should be evaluated to be conclusive. Nevertheless the feasibility of chemopurified ABMT was demonstrated.     

Sugar's introduction in apothecary

In ancient times, the medicaments used to be sweetened with honey. Subsequently, the Arab apothecaries progressively replaced it by sugar, as witnessed by their formularies, that were known as grabadins. These were introduced to the West as from the XIth century A.D. The latin world also produced its very own formularies, of which the Antidotarium magnum (circa 1100) and the Antidotarium Mesuae (appearing at around the same period) are the most famous. The latter accords to sugar a place of honour and has recourse to it for the best part of the formulae intended for internal usage (namely syrops, julebs, electuaries, loochs, aromatic powders, condita, conservae, etc.) whilst not abandoning the use of honey.     

Results of 58872 and 58921 trials in acute myeloblastic leukemia and relative value of chemotherapy vs allogeneic bone marrow transplantation in first complete remission: the EORTC Children Leukemia Group report.

The first EORTC (European Organization of Research and Treatment of Cancer) acute myeloblastic leukemia (AML) pilot study (58872) was conducted between January 1988 and December 1991. Out of 108 patients, 78% achieved complete remission (CR), and event-free survival (EFS) and survival rates (s.e., %) at 7 years were 40 (5) and 51% (6%), respectively. It indicated that mitoxantrone could be substituted for conventional anthracyclines in the treatment of childhood AML without inducing cardiotoxicity. The aim of the next EORTC 58921 trial was to compare the efficacy and toxicity of idarubicin vs mitoxantrone in initial chemotherapy courses, further therapy consisting of allogeneic bone marrow transplantation (alloBMT) in patients with an HLA-compatible sibling donor or chemotherapy in patients without a donor. Out of 177 patients, recruited between October 1992 and December 2002, 81% reached CR. Overall 7-year EFS and survival rates were 49 (4) and 62% (4%), respectively. Out of 145 patients who received the first intensification, 39 had a sibling donor. In patients with or without a donor, the 7-year disease-free survival (DFS) rate was 63 (8) and 57% (5%) and the 7-year survival rate was 78 (7) and 65% (5%), respectively. Patients with favorable, intermediate and unfavorable cytogenetic features had a 5-year EFS rate of 57, 45 and 45% and a 5-year survival rate of 89, 67 and 53%, respectively.     

Systemic allergic vasculopathy after naproxen (author's transl)]

The authors report a case of hypersensitivity angiitis presenting with cutaneous, muscular, articular, and renal signs. They suggest a possible etiological mechanism for such disorders: a circulating immune-complex disease, and criticize the often improper interpretation of the results of lymphoblast transformation tests. Hypersensitivity angiitis, "ground base disease", requires investigation for possible underlying immunity abnormalities or neoplasms.     

Total body irradiation–high-dose cytosine arabinoside and melphalan followed by allogeneic bone marrow transplantation from HLA-identical siblings in the treatment of children with acute lymphoblastic leukaemia after relapse while receiving chemotherapy: a Société Française de Greffe de Moelle study

We investigated the use of a new conditioning regimen followed by allogeneic bone marrow transplantation (BMT) for treating children with acute lymphoblastic leukaemia (ALL) after relapse within 6 months of the completion of therapy. One hundred and sixteen children with acute lymphoblastic leukaemia in second or subsequent complete remission (CR) underwent allogeneic bone marrow transplantation from HLA-identical siblings after a preparative regimen comprising total body irradiation (TBI), high-dose cytosine arabinoside and melphalan (TAM regimen). The Kaplan-Meier product-limit estimate (mean ± SE) of disease-free survival (DFS) at 7 years was 59.5 ± 9% (95% confidence interval). The estimated chance of relapse was 22.5 ± 15% with a median follow-up of 88.5 months (range 51–132). 26 patients (22.4%) died with no evidence of recurrent leukaemia, mainly from interstitial pneumonitis, veno-occlusive disease or acute graft-versus-host disease (GVHD). Three factors significantly affected DFS: acute GVHD, site of relapse and, for children in second remission after a marrow relapse, the disease status at the time of transplantation. The DFS were 59.02 ± 12.6%, 37.5 ± 19.8% and 77.4 ± 15% among patients in CR2 after a marrow relapse, in CR3 or in untreated partial marrow relapse, and in CR2 after an isolated CNS relapse, respectively. The lowest DFS was seen in children with acute GVHD grades 3–4. Two significant factors were associated with relapse: the marrow status at the time of transplantation and chronic GVHD. The relapse rate was lower among children in CR2 or with chronic GVHD. We conclude that transplantation after the TAM regimen is an effective therapy for this population with acceptable toxicity, particularly for children in second remission after a very early marrow relapse, or those with early isolated CNS involvement.     

Neurologic effects of acyclovir after an allogenic marrow graft

On the 4th day of acyclovir treatment for Herpes simplex pneumonia, a 28 month-old girl who had received allogenic marrow transplant for stage IV neuroblastoma presented with severe neurologic disorders including coma and choreic movements. These symptoms disappeared 9 days after acyclovir was stopped. The disturbance in acyclovir kinetics because of acute renal failure and/or a cerebral cortex atrophy might explain the poor neurologic tolerance of acyclovir. This reversible neurologic involvement on a prone patient should be known as a differential diagnosis of Herpes simplex encephalitis.     

Soluble CD8, IL-2 receptor, and tumor necrosis factor-alpha levels in steroid-resistant acute graft-versus-host disease. Relation with subsequent response to anti-IL-2 receptor monoclonal antibody treatment

Serial determination of soluble CD8 (sCD8), soluble IL-2 receptors (sIL-2R), and tumor necrosis factor-alpha serum levels were performed in bone marrow transplant patients upon initiation, day 0 (D0) and at D10 of an anti-IL-2 receptor (alpha chain) monoclonal antibody (B-B10) in vivo treatment for steroid-resistant grade greater than or equal to 2 acute graft-versus-host disease (aGVHD). D0 and D10 sCD8 serum levels correlated strongly with response to B-B10 treatment (p = .003 and .001, respectively); 76% of the patients with D0 sCD8 levels less than 500 U/ml responded favorably to B-B10 treatment, versus only a 30% response if the sCD8 levels were greater than 500 U/ml (p = .02). Likewise, D0 tumor necrosis factor-alpha levels significantly correlated with subsequent response to B-B10 treatment (p = .03). D0 sIL-2R levels were not significantly different in B-B10-responsive and nonresponsive aGVHD patients. These results suggest that the serial determination of sCD8 and TNF serum levels could provide valuable predictive information as to steroid-resistant aGVHD responsiveness to anti-IL-2R treatment.