In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849 .).

Minimal residual disease (MRD) is an im- IntroductionThe presence of minimal residual disease (MRD) following therapy for acute lymphoblastic leukemia (ALL) has been shown to be an important prognostic marker in many studies. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] MRD is typically detected either by polymerase chain reaction (PCR) amplification of clonotypic immunoglobulin or T-cell receptor gene rearrangements [20][21][22][23][24][25][26] or by flow cytometry, 27-41 the latter based on the principle that leukemic cells express combinations of antigens that are different from those present on normal bone marrow cells. The former technique can be more sensitive, though to achieve adequate sensitivity it is necessary to synthesize optimized clonespecific reagents. As a consequence, it is difficult to obtain real-time data that could be used for early intervention.Molecular detection of MRD has been well standardized. 25,[42][43][44] Though less widely standardized, 37,45 flow cytometry is faster, generally less expensive, and provides informative results in a higher percentage of patients than molecular methods. For these reasons, flow-based MRD assessment has the potential for rapidly identifying patients at increased risk of relapse, allowing for prompt changes in therapy, including earlier intensification. 7 Both PCR and flow have successfully been used to help risk-stratify patients, and while there is generally concordance between the methods in direct comparisons, 46,47 individual patients may not always be classified in the same way by each method. 48 Although the prognostic significance of MRD in ALL is well established, and is used as a criterion for risk stratification in many current studies, 49,50 most published studies have been relatively small. In childhood ALL in particular, the value of MRD must be weighed against other well-established prognostic variables, including age, white blood cell count, cytogenetic features of blasts, and conventional assessment of response to therapy. [50][51][52][53][54][55][56][57] Although MRD has been shown to retain prognostic significance after adjusting for some common risk factors, 4,6,19 the relationship between MRD and other prognostic factors has been incompletely explored. It is not clear if MRD by itself is all that is needed to predict outcome, if other risk factors add additional information to that obtained by MRD, or whether there are complex interactions between MRD and other factors. For example, we previously showed a difference between the frequency of positive MRD results at end induction in patients with the 2 most common The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 12, 2018. by guest www.bloodjournal.org From favorable genetic lesions: the TEL-AML1 translocation and simultaneous trisomies of chromosomes 4 and 10, w...

The occurrence of hepatic veno-occlusive disease (VOD) has been reported in up to 60% of patients following stem cell transplantation (SCT), with incidence varying widely between studies depending on the type of transplant, conditioning regimen, and criteria used to make the diagnosis. Severe VOD is characterized by high mortality and progression to multiorgan failure (MOF); however, there is no consensus on how to evaluate severity. This review and analysis of published reports attempts to clarify these issues by calculating the overall mean incidence of VOD and mortality from severe VOD, examining the effect of changes in SCT practice on the incidence of VOD over time, and discussing the methods used to evaluate severity. Across 135 studies performed between 1979 and October 2007, the overall mean incidence of VOD was 13.7% (95% confidence interval [CI] = 13.3%–14.1%). The mean incidence of VOD was significantly lower between 1979–1994 than between 1994–2007 (11.5% [95% CI, 10.9%–12.1%] vs 14.6% [95% CI, 14.0%–15.2%]; P < .05). The mortality rate from severe VOD was 84.3% (95% CI, 79.6%–88.9%); most of these patients had MOF, which also was the most frequent cause of death. Thus, VOD is less common than early reports suggested, but the current incidence appears to be relatively stable despite recent advances in SCT, including the advent of reduced-intensity conditioning. The evolution of MOF in the setting of VOD after SCT can be considered a reliable indication of severity and a predictor of poor outcome.

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Class III genes require multiple cellular factors for transcription by RNA polymerase III; these genes form stable transcription complexes, which in the case of Xenopus 5S genes are correlated with differential expression in vivo. The minimal number and identity of the factors required to form both stable and metastable complexes on three class III genes (encoding, respectively, 5S RNA, transfer RNA, and adenovirus VA RNA species) were determined. Stable complex formation requires one common factor, whose recognition site was analyzed, and either no additional factors (the VA gene), a second common factor (the transfer RNA gene), or a third gene-specific factor (the 5S gene). The mechanism of stable complex formation and its relevance to transcriptional regulation were examined in light of the various factors and the promoter sequences recognized by these factors.