Therapy-related myelodysplastic syndrome is a long-term complication of cancer treatment in patients receiving cytotoxic therapy, characterized by high-risk genetics and poor outcomes. Allogeneic ...hematopoietic cell transplantation is the only potential cure for this disease, but the prognostic impact of pre-transplant genetics and clinical features has not yet been fully characterized. We report here the genetic and clinical characteristics and outcomes of a relatively large cohort of patients with therapy-related myelodysplastic syndrome (n=67) who underwent allogeneic transplantation, comparing these patients to similarly treated patients with
disease (n=199). The 5-year overall survival was not different between patients with therapy-related and
disease (49.9%
53.9%;
=0.61) despite a higher proportion of individuals with an Intermediate-2/High International Prognostic Scoring System classification (59.7%
43.7%;
=0.003) and high-risk karyotypes (61.2%
30.7%; P<0.01) among the patients with therapy-related disease. In mutational analysis,
alteration was the most common abnormality in patients with therapy-related disease (n=18: 30%). Interestingly, the presence of mutations in
or in any other
the high-risk genes (
,
,
,
: n=29: 48%) did not significantly affect either overall survival or relapse-free survival. Allogeneic stem-cell transplantation is, therefore, a curative treatment for patients with therapy-related myelodysplastic syndrome, conferring a similar long-term survival to that of patients with
disease despite higher-risk features. While
alteration was the most common mutation in therapy-related myelodysplastic syndrome, the finding was not detrimental in our case-series.
In the current post-pandemic era, recipients of an allogeneic hematopoietic stem cell transplant (HCT) deserve special attention. In these vulnerable patients, vaccine effectiveness is reduced by ...post-transplant immune-suppressive therapy; consequently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) is often associated with elevated morbidity and mortality. Characterizing SARS-CoV-2 adaptive immunity transfer from immune donors to HCT recipients in the context of immunosuppression will help identify optimal timing and vaccination strategies that can provide adequate protection to HCT recipients against infection with evolving SARS-CoV-2 variants. We performed a prospective observational study (NCT04666025 at ClinicalTrials.gov) to longitudinally monitor the transfer of SARS-CoV-2-specific antiviral immunity from HCT donors, who were either vaccinated or had a history of COVID-19, to their recipients
T-cell replete graft. Levels, function, and quality of SARS-CoV-2-specific immune responses were longitudinally analyzed up to 6 months post-HCT in 14 matched unrelated donor/recipients and four haploidentical donor/recipient pairs. A markedly skewed donor-derived SARS-CoV-2 CD4 T-cell response was measurable in 15 (83%) recipients. It showed a polarized Th1 functional profile, with the prevalence of central memory phenotype subsets. SARS-CoV-2-specific IFN-γ was detectable throughout the observation period, including early post-transplant (day +30). Functionally experienced SARS-CoV-2 Th1-type T cells promptly expanded in two recipients at the time of post-HCT vaccination and in two others who were infected and survived post-transplant COVID-19 infection. Our data suggest that donor-derived SARS-CoV-2 T-cell responses are functional in immunosuppressed recipients and may play a critical role in post-HCT vaccine response and protection from the fatal disease.
clinicaltrials.gov, identifier NCT04666025.
Background
Despite recent approval of several new agents, relapsed acute lymphoblastic leukemia (ALL) remains challenging to treat. Sapanisertib (MLN0128/TAK‐228) is an oral TORC1/2 inhibitor that ...exhibited preclinical activity against ALL.
Methods
We conducted a single‐arm multi‐center Phase II study of sapanisertib monotherapy (3 mg orally daily of the milled formulation for 21 days every 28 days) in patients with ALL through the Experimental Therapeutics Clinical Trials Network (NCI‐9775).
Results
Sixteen patients, 15 of whom were previously treated (median 3 prior lines of therapy), were enrolled. Major grade 3–4 non‐hematologic toxicities included mucositis (3 patients) and hyperglycemia (2 patients) as well as hepatic failure, seizures, confusion, pneumonitis, and anorexia (1 patient each). Grade >2 hematological toxicity included leukopenia (3), lymphopenia (2), thrombocytopenia, and neutropenia (1). The best response was stable disease in 2 patients (12.5%), while only 3 patients (19%) were able to proceed to Cycle 2. Pharmacokinetic analysis demonstrated drug exposures similar to those observed in solid tumor patients. Immunoblotting in serially collected samples indicated limited impact of treatment on phosphorylation of mTOR pathway substrates such as 4EBP1, S6, and AKT.
Conclusion
In summary, single‐agent sapanisertib had a good safety profile but limited target inhibition or efficacy in ALL as a single agent. This trial was registered at ClinicalTrials.gov as NCT02484430.
Sapanisertib 3 mg daily was safe for patients with relapsed/refractory acute lymphoblastic leukemia. Its efficacy as single agent is limited.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
The Philadelphia chromosome is associated with a poor prognosis in acute lymphoblastic leukemia (ALL). While hematopoietic stem cell transplantation (HSCT) has been regarded as a favorable ...treatment option in adult Philadelphia‐positive (Ph+) ALL, its benefit is less clear in the era of newer generation tyrosine kinase inhibitors (TKIs) like dasatinib.
Methods
This was a retrospective study that analyzed the outcomes of adult patients with Ph+ ALL treated with either combination chemotherapy plus dasatinib or combination chemotherapy plus dasatinib followed by allogeneic HSCT.
Results
A total of 70 patients were included; 30 (42.9%) underwent allogeneic HSCT while 40 (57.1%) received only chemotherapy plus dasatinib. In comparing overall survival (OS) rates, results between the 2 groups were similar with a 1‐year OS of 93.3% versus 100% (P = 0.20), 2‐year OS of 89.8% versus 86.2% (P = 0.72), and 3‐year OS of 76% versus 71.3% (P = 0.56) in the transplant versus nontransplant groups, respectively. The 3‐year relapse‐free survival (RFS) rates were also similar at 70.5% in the transplant group and 80.1% in the nontransplant group (P = 0.94). Subgroup analyses were performed for patients with specific poor prognostic factors (higher white blood count, older age, positive minimal residual disease status), but results again showed no significant survival difference between transplant and nontransplant patients.
Conclusions
While HSCT has historically led to a survival advantage in Ph+ ALL, the results of our study demonstrate that it may have a less beneficial role in the era of newer generation TKIs such as dasatinib.
This retrospective cohort study demonstrates that chemotherapy plus dasatinib leads to comparable overall survival and relapse‐free survival rates as allogeneic hematopoietic stem cell transplantation for adult Philadelphia‐positive acute lymphoblastic leukemia. Given the potential morbidity and mortality associated with transplantation, it may serve a less beneficial role in this population in the era of newer generation tyrosine kinase inhibitors.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cancer care near the end of life (EOL) has become more aggressive over the years. Palliative care services (PCS) may decrease this aggressive cancer care in terminally ill cancer patients. Our ...objective was to observe the aggressiveness of cancer care near the EOL among Veterans Affairs cancer patients before and after the institution of a PCS team. We also assessed the time taken prior to death to initiate a PCS consultation and its effect on the aggressiveness of cancer care near the EOL.
This is a retrospective chart review analysis performed at the local Veterans Affairs hospital looking at the last 100 patients in each of the years, 2002 and 2008, who died with active cancer. Only patients in 2008 had access to a PCS team.
In the last 30 days of life, compared to 2002, patients in 2008 had a higher incidence of: chemotherapy administration, more than one hospital admission, more than 14 days of hospital stay, intensive care unit admissions, and in-hospital deaths. Patients with timely PCS consults in 2008 appeared to have a lower incidence of: chemotherapy administration, more than one emergency department visit, more than one hospital admission, more than 14-day hospital stays, intensive care unit admissions, and deaths in the hospital. Timely PCS consults were associated with earlier and more frequent hospice referral.
Cancer care near the EOL has become more aggressive with time at one of the hospitals in the Veterans Affairs healthcare system (VAHS). Institution of a PCS service was unable to completely decrease this trend of increasing aggressiveness of cancer care near the EOL. However, timely PCS consults may help attenuate this aggressiveness.
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