High-dose melphalan has been the standard conditioning regimen for auto-SCT in multiple myeloma (MM) for decades. A more effective conditioning regimen may induce deeper responses and longer ...remission duration. It is especially needed in the setting of second auto-SCT, which rarely achieves comparable results with the first auto-SCT using the same conditioning regimen. Here we conducted a phase II study to investigate the efficacy and safety of a conditioning regimen V-BEAM (bortezomib-BEAM) before second auto-SCT for multiple myeloma. Ten patients were enrolled from September 2012 to May 2013. The CR rate at day +100 after auto-SCT was 75%; all except for one patient remained in remission after a median follow-up of 6 months. Three patients developed Clostridium difficile infection. Two patients died within the first 30 days of auto-SCT from neutropenic colitis and overwhelming sepsis, respectively. Due to the high rate of morbidity and mortality, the study was terminated after 10 patients. In summary, although the conditioning regimen V-BEAM before second auto-SCT for MM provided promising responses, it was associated with unexpected treatment-related toxicity and should not be investigated further without modifications.
In patients who had a relapse of acute myeloid leukemia after allogeneic hematopoietic stem-cell transplantation, no characteristic genetic lesions were detected, but alterations in expression of ...genes related to immune function were noted, particularly down-regulation of major histocompatibility complex class II genes.
Hematopoietic clones harboring specific mutations may expand over time. However, it remains unclear how different cellular stressors influence this expansion. Here we characterize clonal ...hematopoiesis after two different cellular stressors: cytotoxic therapy and hematopoietic transplantation. Cytotoxic therapy results in the expansion of clones carrying mutations in DNA damage response genes, including TP53 and PPM1D. Analyses of sorted populations show that these clones are typically multilineage and myeloid-biased. Following autologous transplantation, most clones persist with stable chimerism. However, DNMT3A mutant clones often expand, while PPM1D mutant clones often decrease in size. To assess the leukemic potential of these expanded clones, we genotyped 134 t-AML/t-MDS samples. Mutations in non-TP53 DNA damage response genes are infrequent in t-AML/t-MDS despite several being commonly identified after cytotoxic therapy. These data suggest that different hematopoietic stressors promote the expansion of distinct long-lived clones, carrying specific mutations, whose leukemic potential depends partially on the mutations they harbor.
Decitabine produced responses in patients with acute myeloid leukemia or myelodysplastic syndromes who had cytogenetic abnormalities associated with a poor prognosis, including 21 of 21 patients with ...tumors that contained
TP53
mutations.
Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are clonal disorders of myeloid hematopoiesis.
1
Adult patients with AML who have karyotypes that are associated with unfavorable risk and older patients with AML (≥60 years of age) have poor outcomes, with a median survival of approximately 1 year.
2
,
3
Patients with AML and
TP53
mutations tend to be older (median age, 61 to 67 years), and almost all have karyotypes that are associated with unfavorable risk; if they receive standard cytotoxic chemotherapy, these patients have especially poor outcomes (median survival, 4 to 6 months).
3
–
6
Decitabine (5-aza-2′-deoxycytidine) is commonly used as . . .
Profound differences exist in the replicative capacities of various human immunodeficiency virus 1 isolates in primary human monocytes. To investigate the molecular basis for these differences, ...recombinant full-length clones were constructed by reciprocal DNA fragment exchange between a molecular clone derived from a monocyte-tropic isolate (ADA) and portions of two full-length clones incapable of infection or replication in primary monocyte cultures (HXB2 and NL4-3). Virions derived from proviral clones that contained ADA sequences encoding vpu and the N and C termini of the surface envelope glycoprotein (gp120) were incapable of replication in monocytes. However, a 283-base-pair ADA sequence encoding amino acids 240-333 of the mature gp120 protein conferred the capacity for high-level virus replication in primary monocytes. The predicted amino acid sequence of this ADA clone differed from NL4-3 and HXB2 at 22 of 94 residues in this portion of gp120, which includes the entire third variable domain. Only 2 of 11 residues implicated in CD4 binding are located in this region of gp120 and are identical in HXB2, NL4-3, and ADA. Alignment of the ADA sequence with published amino acid sequences of three additional monocyte-replicative and three monocyte-nonreplicative clones indicates 6 discrete residues with potential involvement in conferring productive human immunodeficiency virus 1 infection of primary monocytes.
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