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Background: As one of the major treatment obstacles in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), relapse of Ph+ALL may result from the persistence of leukemia-propagating cells (LPCs). Research using a xenograft mouse assay recently determined that LPCs were enriched in the CD34+CD38-CD58- fraction in human Ph+ALL. Additionally, a cohort study demonstrated that Ph+ALL patients with a LPCs phenotype at diagnosis exhibited a significantly higher cumulative incidence of relapse than those with the other cell phenotypes even with uniform front-line imatinib-based therapy pre- and post-allotransplant, thus highlighting the need for novel LPCs-based therapeutic strategies.Methods: RNA sequencing (RNA-Seq) and real-time quantitative polymerase chain reaction (qRT-PCR) were performed to analyze the gene expression profiles of the sorted LPCs and other cell fractions from patients with de novo Ph+ALL. In order to assess the effects of the selective BCR-ABL and/or Janus kinase (JAK)2 inhibition therapy by the treatment with single agents or a combination of ruxolitinib and imatinib or nilotinib on Ph+ALL LPCs, drug-induced apoptosis of LPCs was investigated in vitro, as well as in vivo using sublethally irradiated and anti-CD122-conditioned NOD/SCID xenograft mouse assay. Moreover, western blot analyses were performed on the bone marrow cells harvested from the different groups of recipient mice.Results: RNA-Seq and qRT-PCR demonstrated that JAK2 was more highly expressed in the sorted LPCs than in the other cell fractions in de novo Ph+ALL patients. Combination treatment with a selective JAK1/JAK2 inhibitor (ruxolitinib) and nilotinib more effectively eliminated LPCs than either therapy alone or both in vitro and in humanized Ph+ALL mice by reducing phospho-CrKL and phospho-JAK2 activities at the molecular level.Conclusions: In summary, this pre-clinical study provides a scientific rationale for simultaneously targeting BCR-ABL and JAK2 activities as a promising anti-LPCs therapeutic approach for patients with de novo Ph+ALL. [ABSTRACT FROM AUTHOR]

To investigate the impact of the combination of early molecular and cytogenetic responses on the achievement of MR4.5, 228 newly diagnosed chronic phase chronic myeloid leukemia patients treated with imatinib were categorized into 3-month and 6-month concordant optimal, discordant, concordant warning, and failure groups. Among them, 85.3% at 3 months and 78.1% at 6 months had concordant molecularly and cytogenetically defined responses. At both 3 and 6 months, patients with discordant, concordant warning and failure responses had similar 3-year MR4.5 rates, and all were significantly lower than the rate in patients with concordant optimal responses. Patients with concurrent 3-month and 6-month concordant optimal responses had a significantly higher 3-year MR4.5 rate than those with other responses, and 3-month and 6-month concurrent molecular optimal, but not cytogenetic optimal responses. Therefore, achieving concordant optimal molecular and cytogenetic responses at both 3 and 6 months with imatinib treatment are associated with MR4.5 achievement. [ABSTRACT FROM PUBLISHER]

The minimal residual disease (MRD) before and after a haploidentical hematopoietic stem cell transplantation (HSCT) of 86 patients with acute myeloid leukemia (AML) in complete remission (CR) was measured using flow cytometry (FCM) and Wilms tumor 1 (WT1). In all, 18 patients met the criteria of pre-MRD + before HSCT. The FCM + (p = .028) and the combinative criteria for positive MRD (MRDco+) (p = .022) post-transplantation were significantly correlated to relapse in univariate analysis. A multivariate analysis showed that only MRDco + post-transplantation was an independent risk factor of leukemia relapse (p = .022, HR = 4.653, 95% CI: 1.249–17.334). A significant difference in the cumulative incidence of relapse between patients with or without post-transplant MRDco + was observed (p < .001). However, the results suggested that the MRD status before transplantation might not affect leukemia relapse of patients with AML in CR after haploidentical HSCT. These types of patients might not need to receive further intensive chemotherapy or active intervention concerning HSCT. [ABSTRACT FROM PUBLISHER]

Abstract: The molecular response of chronic myeloid leukemia (CML) patients to tyrosine kinase inhibitor treatment can be evaluated either by BCR-ABL mRNA levels on international scale (IS) or by log reduction from the baseline level of the laboratory. Both methods were compared in 248 newly diagnosed chronic phase CML patients treated with imatinib. The major molecular responses (MMR) obtained by both methods predict progression-free survival (PFS, all P <0.0001). Thirty-six patients, who were identified as MMR patients by the IS method but as non-MMR patients by the log reduction method, had the same PFS as MMR patients identified by both methods. The molecular responses of patients at 3 and 6 months, as evaluated by the two methods, have similar predictive values on their cytogenetic responses at 12 months and on their molecular responses at 18 months. Both ≤10%IS and ≥1 log reduction at 3 months and ≤1%IS at 6 months were significantly associated with PFS (P =0.0011, 0.0090, and 0.0064). The percentages of patients with BCR-ABLIS of ≤1%, >1–10%, and of >10% at 3 months and 6 months in the German CML Study IV were similar with those with corresponding BCR-ABLIS in our center, but was significantly different with those evaluated by the log reduction method. Therefore, the molecular response evaluated by BCR-ABLIS has similar trends in PFS and in response prediction, but can better differentiate patients than that by the log reduction method. Furthermore, the IS method allows comparison among molecular response results from different laboratories. [Copyright &y& Elsevier]

PRAME and WT1 transcript levels were simultaneously measured in 312 bone marrow samples collected from patients with newly diagnosed myelodysplastic syndromes (MDS) and 111 samples collected during the treatment of 17 patients. Both the positive rate and the > 1-log increase expression frequency of PRAME were similar to those of WT1 (74.4 % vs. 77.6%; 51.6% vs. 49.0%), and 88.1% of patients overexpressed at least one marker. Moreover, the frequencies of PRAME expression with higher degrees of increase were significantly higher compared with those of WT1 expression (> 2-log increase: 30.8% vs. 3.8%; > 3-log increase: 9.0% vs. 0%; all p < 0.001). PRAME had a higher log increase than WT1 in 53.3% of the patients with overexpressed WT1. Both PRAME and WT1 transcript levels generally fluctuated within the normal range after hematopoietic stem cell transplant in all 10 patients in continuous complete remission. Six out of seven patients were predicted relapse by the combined detection: sustained positivity, or significant increase to be positive for both WT1 and PRAME in three patients, earlier by PRAME than WT1 or by PRAME alone in three patients. Thus, PRAME and WT1 transcripts constitute a good molecular marker combination for monitoring minimal residual disease in MDS. [ABSTRACT FROM AUTHOR]

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