No abstract

Although inotuzumab ozogamicin (InO) is recognized as an effective agent in relapsed acute lymphoblastic leukemia (ALL) in adults, data on safety and efficacy in pediatric patients are scarce. We report the use of InO in 51 children with relapsed/refractory ALL treated in the compassionate use program. In this heavily pretreated cohort, complete remission was achieved in 67% of patients with overt marrow disease. The majority (71%) of responders were negative for minimal residual disease. Responses were observed irrespective of cytogenetic subtype or number or type of prior treatment regimens. InO was well-tolerated; grade 3 hepatic transaminitis or hyperbilirubinemia were noted in 6 (12%) and grade 3/4 infections in 11 (22%) patients. No patient developed sinusoidal obstruction syndrome (SOS) during InO therapy; however, 11 of 21 (52%) patients who underwent hematopoietic stem cell transplantation (HSCT) following InO developed SOS. Downregulation of surface CD22 was detected as a possible escape mechanism in three patients who developed a subsequent relapse after InO. We conclude that InO is a well-tolerated, effective therapy for children with relapsed ALL and prospective studies are warranted. Identification of risk factors for developing post-HSCT SOS and strategies to mitigate this risk are ongoing.

Arsenic trioxide (As 2 O 3 ) exhibits potent antitumor effects in vitro and in vivo, but the precise mechanisms by which it generates such responses are not well understood. We provide evidence that As 2 O 3 is a potent inducer of autophagy in leukemia cells. Such induction of autophagy by As 2 O 3 appears to require activation of the MEK/ERK pathway but not the AKT/mammalian target of rapamycin or JNK pathways. In efforts to understand the functional relevance of arsenic-induced autophagy, we found that pharmacological inhibitors of autophagy or molecular targeting of beclin 1 or Atg7 results in reversal of the suppressive effects of As 2 O 3 on leukemic cell lines and primary leukemic progenitors from acute myelogenous leukemia patients. Altogether, our data provide direct evidence that autophagic cell death is critical for the generation of the effects of As 2 O 3 on acute myelogenous leukemia cells and raise the potential of modulation of elements of the autophagic machinery as an approach to enhance the antitumor properties of As 2 O 3 and possibly other heavy metal derivatives. Arsenic trioxide (As 2 O 3 )2 is a metalloid that exhibits potent antineoplastic effects in vitro and in vivo (1-3). This arsenic derivative induces apoptosis and suppresses the growth of various types of malignant cells of diverse origin in vitro (1-3). Different mechanisms by which As 2 O 3 promotes cell death of target cells have been extensively studied and described (reviewed in Refs. 1-3). As 2 O 3 -dependent generation of reactive oxygen species leads to activation of pro-apoptotic pathways in different types of cells (1-3). In addition, there is evidence for mechanisms involving As 2 O 3 -dependent cell typespecific targeting of malignant cells with distinct molecular abnormalities (reviewed in Ref.3). For instance, there is evidence for As 2 O 3 -dependent specific targeting of cells expressing AML1/MDS1/EVI1 involving degradation of the abnormal fusion protein (4), evidence for arsenic-dependent BCR-ABL ubiquitination and proteasomal degradation (5), and eradication of leukemia-initiating cells in acute promyelocytic leukemia via As 2 O 3 -inducible PML-RAR␣ degradation (6).Despite extensive research over the years, the precise mechanisms of action of arsenic trioxide in malignant cells are not well understood. In particular, the specific cellular events that account for differential sensitivity of malignant cells to As 2 O 3 remain to be precisely defined. Notably, arsenic trioxide treatment induces responses in patients with acute promyelocytic leukemia in vivo (7,8), and it is an agent approved by the United States Food and Drug Administration for the treatment of this leukemia. The unusually high sensitivity of acute promyelocytic leukemia cells to the effects of arsenic trioxide likely reflects the requirement of lower As 2 O 3 concentrations for induction of leukemic cell differentiation seen in these cells versus apoptotic cell death (3), but other mechanisms may be involved as well.Autophagy is a cell death mechani...

Background Studies show superior outcomes for adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) treated following pediatric versus adult ALL therapeutic regimens. Whether adult oncologists in the United States have adopted this approach to AYA ALL is currently unknown. We sought to provide a population-based description of AYA ALL treatment patterns over the past decade. Methods Data on AYAs 15-39 years and diagnosed with ALL during 2004-2014 while living in the Greater Bay Area were obtained from the Greater Bay Area Cancer Registry (GBACR). Treating facilities were designated as pediatric or adult centers; induction treatment regimens were abstracted from registry text data fields. Results Of 304 patients diagnosed in the GBACR catchment region, complete treatment data was available for 229 (75%). Location of care was identified for 296 (97%) patients treated at 31 unique centers. 70% of AYAs received induction therapy at an adult center. All AYAs treated at pediatric centers received pediatric ALL regimens. Among AYAs treated by adult oncologists with complete treatment data, none received a pediatric regimen prior to 2008. From 2008-2012, while the adult intergroup C10403 pediatric-inspired ALL protocol was open to accrual, 31% of AYAs treated by adult oncologists received pediatric regimens. This fell to 21% in 2013-2014. Adult facilities treating ≥2 AYA ALL GBACR patients per year were more likely to administer pediatric regimens than lower volume centers (P= 0.03). Conclusion As of 2014, only a minority of AYAs with ALL received pediatric ALL regimens at adult cancer centers.