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Treatment of acute lymphoblastic leukemia with an rGel/BLyS fusion toxin.

ABSTRACT: Acute lymphoblastic leukemia (ALL) is the most common malignancy affecting children and a major cause of mortality from hematopoietic malignancies in adults. A substantial number of patients become drug resistant during chemotherapy, necessitating the development of alternative modes of treatment. rGel (recombinant Gelonin)/BlyS (B-lymphocyte stimulator) is a toxin-cytokine fusion protein used for selective killing of malignant B-cells expressing receptors for B-cell-activating factor (BAFF/BLyS) by receptor-targeted delivery of the toxin, Gelonin. Here, we demonstrate that rGel/BLyS binds to ALL cells expressing BAFF receptor (BAFF-R) and upon internalization, it induces apoptosis of these cells and causes downregulation of survival genes even in the presence of stromal protection. Using an immunodeficient transplant model for human ALL, we show that rGel/BLyS prolongs survival of both Philadelphia chromosome-positive and negative ALL-bearing mice. Furthermore, we used AMD3100, a CXCR4 antagonist, to mobilize the leukemic cells protected in the bone marrow (BM) microenvironment and the combination with rGel/BLyS resulted in a significant reduction of the tumor load in the BM and complete eradication of ALL cells from the circulation. Thus, a combination treatment with the B-cell-specific fusion toxin rGel/BLyS and the mobilizing agent AMD3100 could be an effective alternative approach to chemotherapy for the treatment of primary and relapsed ALL.

SUBMITTER: Parameswaran R

PROVIDER: S-EPMC3376225 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Treatment of acute lymphoblastic leukemia with an rGel/BLyS fusion toxin.

Parameswaran R R Yu M M Lyu M-A MA Lim M M Rosenblum M G MG Groffen J J Heisterkamp N N

Leukemia 20120229 8

Acute lymphoblastic leukemia (ALL) is the most common malignancy affecting children and a major cause of mortality from hematopoietic malignancies in adults. A substantial number of patients become drug resistant during chemotherapy, necessitating the development of alternative modes of treatment. rGel (recombinant Gelonin)/BlyS (B-lymphocyte stimulator) is a toxin-cytokine fusion protein used for selective killing of malignant B-cells expressing receptors for B-cell-activating factor (BAFF/BLyS ...[more]

PMID: 22373785

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Project description:Comprehensive studies on neutropenia and infection-related complications in patients with acute lymphoblastic leukemia (ALL) are lacking.We evaluated infection-related complications that were grade??3 on National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0) and their risk factors in 409 children with newly diagnosed ALL throughout the treatment period.Of the 2420 infection episodes, febrile neutropenia and clinically or microbiologically documented infection were seen in 1107 and 1313 episodes, respectively. Among documented infection episodes, upper respiratory tract was the most common site (n?=?389), followed by ear (n?=?151), bloodstream (n?=?147), and gastrointestinal tract (n?=?145) infections. These episodes were more common during intensified therapy phases such as remission induction and reinduction, but respiratory and ear infections, presumably viral in origin, also occurred during continuation phases. The 3-year cumulative incidence of infection-related death was low (1.0±0.9%, n?=?4), including 2 from Bacillus cereus bacteremia. There was no fungal infection-related mortality. Age 1-9.9 years at diagnosis was associated with febrile neutropenia (P?=?0.002) during induction and febrile neutropenia and documented infection (both P?<?0.001) during later continuation. White race was associated with documented infection (P?=?0.034) during induction. Compared with low-risk patients, standard- and high-risk patients received more intensive therapy during early continuation and had higher incidences of febrile neutropenia (P?<?0.001) and documented infections (P?=?0.043). Furthermore, poor neutrophil surge after dexamethasone pulses during continuation, which can reflect the poor bone marrow reserve, was associated with infections (P?<?0.001).The incidence of infection-related death was low. However, young age, white race, intensive chemotherapy, and lack of neutrophil surge after dexamethasone treatment were associated with infection-related complications. Close monitoring for prompt administration of antibiotics and modification of chemotherapy should be considered in these patients.

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Treatment of acute lymphoblastic leukemia with an rGel/BLyS fusion toxin.

Publications

Treatment of acute lymphoblastic leukemia with an rGel/BLyS fusion toxin.

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