Autologous bone marrow transplantation in high-risk remission T-lineage acute lymphoblastic leukemia using immunotoxins plus 4- hydroperoxycyclophosphamide for marrow purging

Abstract

Fourteen patients with high-risk T-lineage acute lymphoblastic leukemia (ALL) in complete remission underwent autologous bone marrow transplantation (BMT) in an attempt t o eradicate their residual disease burden. A combined immunochemotherapy protocol using a cocktail of t w o immunotoxins directed against CD5/Tp67 and CD7/Tp41 T-lineage differentiation antigens in combination with the in vitro active cyclophosphamide congener 4hydroperoxycyclophosphamide (4-HC) was used t o purge autografts. Despite high dose pretransplant radiochemotherapy and effective purging of autografts. 9 of 14 patients relapsed at a median of 2.5 months (range. 1.2 t o 16.8 months) post BMT. Two patients remain alive and disease free at 26 and 28 months post BMT. We used a novel quantitative minimal residual disease (MRD) detection assay, which combines fluorescence activated multiparameter flow cytometry and cell sorting with leukemic progenitor cell (LPC) assays, t o analyze remission bone marrow (BM) samples from T-lineage ALL patients for the presence of residual LPCs. ODERN MULTI-AGENT intensive chemotherapyM results in long-term disease-free survival (DFS) in 50% to 80% of patients with acute lymphoblastic leukemia (ALL), and a substantial proportion of these patients are cured of their di~ease.'.~ However, some ALL patients are at high risk for relapse following the currently available firstline chemotherapeutic regimens. Although a prolonged second remission can be attained by intensive salvage chemotherapy in patients who relapse while off treatment, patients who experience a medullary relapse during or shortly after their first-line chemotherapy have a poor outcome.' A number of centers have investigated the role of high-dose radiochemotherapy followed by allogeneic or autologous bone marrow transplantation (BMT) for the treatment of high-risk remission ALL.4-" Recent reports indicate that BMT may be more effective than chemotherapy in a number of high risk ALL patients, especially those who relapse within 18 months after first-line chemotherapy.ls6 More than two thirds of otherwise eligible BMT candidates with high risk remission ALL do not have a matched sibling donor for allogeneic BMT. For these patients autologous BMT has emerged as a potentially curative alternative therapy.'."This report details our preclinical and clinical data in 14 consecutive patients with high-risk remission T-lineage ALL who were prepared for BMT with either high dose cytarabine (ARA-C) in combination with total body irradiation (TBI) or hyperfractionated TBI followed by cyclophosphamide, and who received autografts that were purged ex vivo using the anti-CD5 (Tp67) immunotoxin T101-Ricin plus the anti-CD7 (Tp41) immunotoxin G3.7-Ricin combined with 4-hydroperoxycyclophosphamide (4-HC). Remission bone marrow (BM) samples were analyzed for the presence of residual T-lineage leukemic progenitor cells (LPCs) using a quantitative minimal residual disease (MRD) detection assay system, which combines fluorescence activated multipa-Notably, high numbers ...

Phenotypic perturbation of B cells in the Wiskott–Aldrich syndrome

“…To characterize the CD21 – patient B‐cells, we measured CD10, a marker of immature B‐cells primarily confined to bone marrow [19]. A small number of CD21 – CD10 bright cells were found in infant patients and were also present in normal infants (Fig.…”

Therapy with CD7 monoclonal antibody TH‐69 is highly effective for xenografted human T‐cell ALL

“…Whereas Wang et al (1992) purging with CD7 bound to magnetic beads, others used CD7-ricin A immunoconjugates (Preijers et al, 1989) or such conjugates plus hydroperoxycyclophosphamide (Uckun et al, 1990). Studies with CD7 in T-cell leukaemias have focused on immunotoxins and have been investigated for intrathecal application in rhesus monkeys (Hertler et al, 1989).…”

Engraftment of Human T‐Cell Acute Lymphoblastic Leukemia in Immunodeficient NOD/SCID Mice Which Have Been Preconditioned by Injection of Human Cord Blood

“…Leukemic progenitor cells have been implicated in the maintenance and expansion of leukemic blast populations [6, 7]. These clonogenic blast cells comprise only 0.05% to 1.5% of the bulk marrow or peripheral blood blasts from ALL patients [6, 8], identified on the basis of their ability to proliferate and form colonies in semisolid media in response to specific growth factors [8, 9].…”