Allogeneic stem cell transplantation (allo-SCT) outcomes in patients with Hodgkin lymphoma (HL) remain poorly defined. We performed a meta-analysis of allo-SCT studies in HL patients. The primary ...endpoints were 6-month, 1-year, 2-year and 3-year relapse-free survival (RFS) and overall survival (OS). A total of 42 reports (1850 patients) was included. The pooled estimates (95% confidence interval) for 6-month, 1-year, 2-year and 3-year RFS were 77 (59-91)%, 50 (42-57)%, 37 (31-43)% and 31 (25-37)%, respectively. The corresponding numbers for OS were 83 (75-91)%, 68 (62-74)%, 58 (52-64)% and 50 (41-58)%, respectively. There was statistical heterogeneity among studies in all outcomes. In meta-regression, accrual initiation year in 2000 or later was associated with higher 6-month (P=0.012) and 1-year OS (P=0.046), and pre-SCT remission with higher 2-year OS (P=0.047) and 1-year RFS (P=0.016). In conclusion, outcomes of allo-SCT in HL have improved over time, with 5-10% lower non-relapse mortality and relapse rates, and 15-20% higher RFS and OS in studies that initiated accrual in 2000 or later compared with earlier studies. However, there is no apparent survival plateau, demonstrating the need to improve on current allo-SCT strategies in relapsed/refractory HL.
Patients 70 years of age or younger with previously untreated CLL were randomly assigned to receive ibrutinib plus rituximab or chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. ...The ibrutinib-based regimen led to prolonged progression-free and overall survival.
Traditional response criteria in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are based on bone marrow morphology and may not accurately reflect clonal tumor burden in patients ...treated with non-cytotoxic chemotherapy. We used next-generation sequencing of serial bone marrow samples to monitor MDS and AML tumor burden during treatment with epigenetic therapy (decitabine and panobinostat). Serial bone marrow samples (and skin as a source of normal DNA) from 25 MDS and AML patients were sequenced (exome or 285 gene panel). We observed that responders, including those in complete remission (CR), can have persistent measurable tumor burden (that is, mutations) for at least 1 year without disease progression. Using an ultrasensitive sequencing approach, we detected extremely rare mutations (equivalent to 1 heterozygous mutant cell in 2000 non-mutant cells) months to years before their expansion at disease relapse. While patients can live with persistent clonal hematopoiesis in a CR or stable disease, ultimately we find evidence that expansion of a rare subclone occurs at relapse or progression. Here we demonstrate that sequencing of serial samples provides an alternative measure of tumor burden in MDS or AML patients and augments traditional response criteria that rely on bone marrow blast percentage.
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.
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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.
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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).
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Decitabine (5-aza-2′-deoxycytidine) is commonly used as . . .
Currently, granulocyte colony stimulating factor (G-CSF) remains the standard mobilizing agent for peripheral blood stem cell (PBSC) donors, allowing the safe collection of adequate PBSCs from the ...vast majority of donors. However, G-CSF mobilization can be associated with some significant side effects and requires a multi-day dosing regimen. The other cytokine approved for stem cell mobilization, granulocyte-macrophage colony stimulating factor (GM-CSF), alters graft composition and may reduce the development of graft-versus-host disease, but a significant minority of donors fails to provide sufficient CD34+ cells with GM-CSF and some experience unacceptable toxicity. AMD3100 is a promising new mobilizing agent, which may have several advantages over G-CSF for donor mobilization. As it is a direct antagonist of the interaction between the chemokine stromal-derived factor-1 and its receptor CXCR4, AMD3100 mobilizes PBSCs within hours rather than days. It is also well tolerated, with no significant side effects reported in any of the clinical trials to date. Studies of autologous and allogeneic transplantation of AMD3100 mobilized grafts have demonstrated prompt and stable engraftment. Here, we review the current state of stem cell mobilization in normal donors and discuss novel strategies for donor stem cell mobilization.
The majority of patients with acute myeloid leukemia (AML) are elderly and have a poor prognosis despite induction therapy. Decitabine, a DNA-hypomethylating agent that induces differentiation and ...apoptosis of leukemic cells, is a well-tolerated alternative to aggressive chemotherapy. It is currently FDA-approved for myelodysplastic syndrome, including patients with 20%-30% bone marrow blasts. Recent clinical attention has focused on evaluating decitabine as frontline therapy for untreated high-risk elderly AML patients. A large randomized international phase III study comparing decitabine to supportive care and cytarabine in elderly AML patients demonstrated significantly improved complete remission rates, but the survival difference did not reach significance. Due to this, decitabine did not achieve FDA approval for AML, but continues to be used off-label. Current research is focused on further defining subgroups of elderly AML patients who may derive greater benefit from decitabine therapy and combining it with other low-intensity active agents for AML.
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