Even if now we have available the weapon of vaccination against SARS-CoV-2, the patients with cancer remains a very frail population in which frequently the immunologic response to vaccination may be ...impaired. In this setting, the SARS-CoV-2 infection screening retains a great value. However, there are still limited data on the feasibility and efficacy of combined screening procedures to assess the prevalence of SARS-CoV-2 infection (including asymptomatic cases) in cancer outpatients undergoing antineoplastic therapy.
From May 1, 2020, to June 15, 2020, during the first wave of SARS-CoV-2 pandemic, 860 consecutive patients, undergoing active anticancer therapy, were evaluated and tested for SARS-CoV-2 with a combined screening procedure, including a self-report questionnaire, a molecular nasopharyngeal swab (NPS) and a rapid serological immunoassay (for anti-SARS-CoV-2 IgG/IgM antibodies). The primary endpoint of the study was to estimate the prevalence of SARS-CoV-2 infection (including asymptomatic cases) in consecutive and unselected cancer outpatients by a combined screening modality. A total of 2955 SARS-CoV-2 NPS and 860 serological tests, in 475 patients with hematologic cancers and in 386 with solid tumors, were performed. A total of 112 (13%) patients self-reported symptoms potentially COVID-19 related. In 1/860 cases (< 1%) SARS-CoV-2 NPS was positive and in 14 cases (1.62%) the specific serological test was positive (overall prevalence of SARS-CoV-2 infection 1.62%). Of the 112 cases who declared symptoms potentially COVID-19-related, only 2.7% (3/112) were found SARS-CoV-2 positive.
This is the largest study reporting the feasibility of a combined screening procedure (including triage, NPS and serologic test) to evaluate the prevalence of SARS-CoV-2 infection in cancer patients receiving active therapy, during the first epidemic wave and under the restrictive lockdown measures, in one of the active areas of the SARS-CoV-2 circulation. Lacking specific recommendations for the detection of asymptomatic SARS-CoV-2 cases, a combined diagnostic screening might be more effective to detect the exact prevalence of SARS-CoV-2 in neoplastic patient population. The prevalence can obviously change according to the territorial context, the entity of the restrictive measures adopted and the phase of the epidemic curve. However, its exact and real-time knowledge could be important to balance risks/benefits of oncologic treatments, avoiding (if the prevalence is low) the reduction of dose intensity or the selection of less intensive (but also less effective) anti-cancer therapies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Therapy-related myeloid neoplasms (t-MNs), which develop after cytotoxic, radiation, or immunosuppressive therapy for an unrelated disease, account for 7%-8% of acute myeloid leukemia (AML). Worse ...outcomes and consequently shortened survival are associated with t-MNs as compared with
AML. Therapy-related MNs are being reported with increasing frequency in successfully treated acute promyelocytic leukemia (APL), in particular, before the introduction of all-
retinoic acid (ATRA) plus arsenic trioxide (ATO). Considering the high curability of APL, t-MNs represent one of the prognosis-limiting factors in this setting of leukemia. We report our experience with a patient who developed t-AML 15 years after treatment for APL. Treatment included three cycles of chemotherapy with CPX-351 (Vyxeos, Jazz Pharmaceuticals) followed, as in remission, by an allogeneic hematopoietic stem cell transplant. A review of available literature was also included.
Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by genetic and clinical heterogeneity and high mortality. Despite the recent introduction of novel pharmaceutical ...agents in hemato-oncology, few advancements have been made in AML for decades. In the last years, the therapeutic options have rapidly changed, with the approval of innovative compounds that provide new opportunities, together with new challenges for clinicians: among them, on 1 September, 2017 the Food and Drug Administration granted approval for Gemtuzumab Ozogamicin (GO) in combination with daunorubicin and cytarabine for the treatment of adult patients affected by newly diagnosed CD33+ AML. Benefits of GO-based regimens were also reported in the pre- and post-transplantation settings. Moreover, several biomarkers of GO response have been suggested, including expression of CD33 and multidrug resistance genes, cytogenetic and molecular profiles, minimal residual disease and stemness signatures. Among them, elevated CD33 expression on blast cells and non-adverse cytogenetic or molecular risk represent largely validated predictors of good response.
We conducted a retrospective multicenter study including pediatric and adult patients with acute leukemia (AL) who received donor lymphocyte infusions (DLIs) after allogeneic hematopoietic stem cell ...transplantation (HCT) between January 1, 2010 and December 31, 2015, in order to determine the efficacy and toxicity of the immune treatment. Two hundred fifty-two patients, median age 45.1 years (1.6–73.4), were enrolled from 34 Italian transplant centers. The underlying disease was acute myeloid leukemia in 180 cases (71%). Donors were HLA identical or 1 locus mismatched sibling (40%), unrelated (40%), or haploidentical (20%). The first DLI was administered at a median time of 258 days (55–3,784) after HCT. The main indication for DLI was leukemia relapse (73%), followed by mixed chimerism (17%), and pre-emptive/prophylactic use (10%). Ninety-six patients (38%) received one single infusion, whereas 65 (26%), 42 (17%), and 49 patients (19%) received 2, 3, or ≥4 infusions, respectively, with a median of 31 days between two subsequent DLIs. Forty percent of evaluable patients received no treatment before the first DLI, whereas radiotherapy, conventional chemotherapy or targeted treatments were administered in 3, 39, and 18%, respectively. In informative patients, a few severe adverse events were reported: grade III–IV graft versus host disease (GVHD) (3%), grade III–IV hematological toxicity (11%), and DLI-related mortality (9%). Forty-six patients (18%) received a second HCT after a median of 232 days (32–1,390) from the first DLI. With a median follow-up of 461 days (2–3,255) after the first DLI, 1-, 3-, and 5- year overall survival (OS) of the whole group from start of DLI treatment was 55, 39, and 33%, respectively. In multivariate analysis, older recipient age, and transplants from haploidentical donors significantly reduced OS, whereas DLI for mixed chimerism or as pre-emptive/prophylactic treatment compared to DLI for AL relapse and a schedule including more than one DLI significantly prolonged OS. This GITMO survey confirms that DLI administration in absence of overt hematological relapse and multiple infusions are associated with a favorable outcome in AL patients. DLI from haploidentical donors had a poor outcome and may represent an area of further investigation.
Adrenomedullin (ADM) is a hypotensive and vasodilator peptide belonging to the calcitonin gene-related peptide family. It is secreted
in vitro
by endothelial cells and vascular smooth muscle cells, ...and is significantly upregulated by a number of stimuli. Moreover, ADM participates in the regulation of hematopoietic compartment, solid tumors and leukemias, such as acute myeloid leukemia (AML). To better characterize ADM involvement in AML pathogenesis, we investigated its expression during human hematopoiesis and in leukemic subsets, based on a morphological, cytogenetic and molecular characterization and in T cells from AML patients. In hematopoietic stem/progenitor cells and T lymphocytes from healthy subjects,
ADM
transcript was barely detectable. It was expressed at low levels by megakaryocytes and erythroblasts, while higher levels were measured in neutrophils, monocytes and plasma cells. Moreover, cells populating the hematopoietic niche, including mesenchymal stem cells, showed to express
ADM
.
ADM
was overexpressed in AML cells
versus
normal CD34
+
cells and in the subset of leukemia compared with hematopoietic stem cells. In parallel, we detected a significant variation of
ADM
expression among cytogenetic subgroups, measuring the highest levels in inv(16)/t(16;16) or complex karyotype AML. According to the mutational status of AML-related genes, the analysis showed a lower expression of
ADM
in
FLT3
-ITD,
NPM1
-mutated AML and
FLT3
-ITD/
NPM1
-mutated cases compared with wild-type ones. Moreover,
ADM
expression had a negative impact on overall survival within the favorable risk class, while showing a potential positive impact within the subgroup receiving a not-intensive treatment. The expression of 135 genes involved in leukemogenesis, regulation of cell proliferation, ferroptosis, protection from apoptosis, HIF-1α signaling, JAK-STAT pathway, immune and inflammatory responses was correlated with
ADM
levels in the bone marrow cells of at least two AML cohorts. Moreover,
ADM
was upregulated in CD4
+
T and CD8
+
T cells from AML patients compared with healthy controls and some
ADM
co-expressed genes participate in a signature of immune tolerance that characterizes CD4
+
T cells from leukemic patients. Overall, our study shows that
ADM
expression in AML associates with a stem cell phenotype, inflammatory signatures and genes related to immunosuppression, all factors that contribute to therapy resistance and disease relapse.
1 Division of Hematology and Cellular Therapies Unit Carlo Melzi, Dept. of Morphological and Medical Research, University of Udine
2 II Hematology Division, San Martino Hospital, Genoa
3 Statistics ...Institute, Dept. of Morphological and Medical Research, University of Udine
4 Hematology Division, La Sapienza University, Rome
5 Hematology Department, Pescara Hospital, Oncohematology Unit
6 La Maddalena Hospital, Palermo
7 Internal Medicine and Hematology Division, S. Gerardo de Tintori Hospital, Monza
8 Division of Hematology, Pesaro Hospital
9 Division of Hematology, Reggio Calabria Hospital
10 Hematology Division, Azienda Ospedaliera Careggi, University of Florence, Italy
Correspondence: Francesca Patriarca, MD, Division of Hematology and Cellular Therapies Unit Carlo Melzi, Azienda Ospedaliera-Universitaria p.zale S. Maria della Misericordia 1, 33100 Udine, Italy. E-mail: patriarca.francesca{at}aoud.sanita.fvg.it
Background: Allogeneic stem cell transplantation is a potentially curative treatment for myelofibrosis, although its use is limited by a high rate of transplant-related mortality. In this study, we evaluated the outcome of patients with myelofibrosis who underwent allogeneic stem cell transplantation, and the impact of prognostic factors.
Design and Methods: One hundred patients were transplanted in 26 Italian centers between 1986 and 2006. We analyzed the influence of the patients characteristics and the clnical features of their disease before stem cell transplantation and of transplant procedures on transplant-related mortality, overall survival, and relapse-free survival by means of univariate and multivariate analyses.
Results: The median age of the patients at the time of stem cell transplantation was 49 years (range, 21–68) and 90% of them had an intermediate or high Dupriez score. Forty-eight percent received a myeloablative conditioning regimen and 78% received stem cells from matched sibling donors. The cumulative incidence of engraftment at day 90 after transplant was 87% (95% CI, 0.87–0.97). The cumulative 1-year and 3-year incidences of transplant-related mortality were 35% and 43%, respectively. The estimated 3-year overall and relapse-free survival rates after stem cell transplantation were 42% and 35%, respectively. In multivariate analysis, negative predictors of transplant-related mortality were year of stem cell transplantation before 1995, unrelated donor, and a long interval between diagnosis and transplantation. There was a trend towards longer overall and relapse-free survival in patients receiving peripheral blood stem cells rather than bone marrow as the source of their graft ( p =0.070 and p =0.077, respectively). The intensity of the conditioning regimen (myeloablative versus reduced intensity regimens) did not significantly influence the outcome.
Conclusions: We conclude that the outcome of myelofibrosis patients who underwent allogeneic stem cell transplantation significantly improved after 1996 due to the reduction in transplant-related mortality. We observed that a reduction in transplant-related mortality was associated with the choice of a matched sibling donor, whereas longer overall survival was associated with the use of peripheral blood as the source of stem cells.
Key words: primary myelofibrosis, allogeneic stem cell transplantation, prognostic factors, reduced-intensity regimens.
Related Article
Allogeneic hematopoietic stem cell transplantation for myelofibrosis
Damiano Rondelli
Haematologica 2008 93: 1449-1450.
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It has now been ascertained that acute myeloid leukemias-as in most type of cancers-are mixtures of various subclones, evolving by acquiring additional somatic mutations over the course of the ...disease. The complexity of leukemia clone architecture and the phenotypic and/or genotypic drifts that can occur during treatment explain why more than 50% of patients-in hematological remission-could relapse. Moreover, the complexity and heterogeneity of clone architecture represent a hindrance for monitoring measurable residual disease, as not all minimal residual disease monitoring methods are able to detect genetic mutations arising during treatment. Unlike with chemotherapy, which imparts a relatively short duration of selective pressure on acute myeloid leukemia clonal architecture, the immunological effect related to allogeneic hematopoietic stem cell transplant is prolonged over time and must be overcome for relapse to occur. This means that not all molecular abnormalities detected after transplant always imply inevitable relapse. Therefore, transplant represents a critical setting where a measurable residual disease-based strategy, performed during post-transplant follow-up by highly sensitive methods such as next-generation sequencing, could optimize and improve treatment outcome. The purpose of our review is to provide an overview of the role of next-generation sequencing in monitoring both measurable residual disease and clonal evolution in acute myeloid leukemia patients during the entire course of the disease, with special focus on the transplant phase.
BACKGROUND: In the past two decades peripheral blood stem cells (PBSCs) have increasingly replaced marrow as stem cells source for allogeneic transplantation. The PBSC donation initially applied only ...to related donors; later, due to the safety of the procedure, it was extended to unrelated donors.
STUDY DESIGN AND METHODS: We have retrospectively collected data regarding mobilization, collection, and short‐ and long‐term follow‐up of 190 consecutive donors, 174 related and 16 unrelated. All donors followed a standard protocol for mobilization and underwent at least one PBSC collection. Follow‐up in related donors was performed every 4 months in the first year and then annually, with no time limits, while unrelated donors were monitored for 10 years.
RESULTS: All 190 donors completed the established mobilization protocol. The mobilizing capacity was significantly greater in males and in donors less than 60 years old. No case of major toxicity by granulocyte–colony‐stimulating factor was found, nor thromboembolic events. The total dose of CD34+/recipient (median 5.8 × 106/kg recipient/body weight) was statistically correlated with age, CD34+ before and after mobilization, and collection efficiency. Compliance to follow‐up was 66%, with a significant difference between related and unrelated (63% vs. 100%, p = 0.03). During follow‐up no significant abnormalities in hematologic variables or hematologic malignancies were reported.
CONCLUSION: Our study allowed us to define the PBSC donation as “a safe procedure for the donors,” with short‐ and long‐term effects limited to a small percentage of donors and “effective for the recipient,” due to the dose of collected CD34+, adequate for transplantation in almost all recipients.
Patients who undergo hematopoietic stem cell transplants (HSCT) are at major risk of C. difficile (CD) infection (CDI), the most common cause of nosocomial diarrhea. We conducted a retrospective ...study, which enrolled 481 patients who underwent autologous (220) or allogeneic HSCT (261) in a 5-year period, with the aim of identifying the incidence, risk factors and outcome of CDI between the start of conditioning and 100 days after HSCT. The overall cumulative incidence of CDI based upon clinical evidence was 5.4% (95% CI, 3.7% to 7.8%), without any significant difference between the two types of procedures. The median time between HSCT and CDI diagnosis was 12 days. Out of 26 patients, 19 (73%) with clinical and symptomatic evidence of CDI were positive also for enzymatic or molecular detection of toxigenic CD; in particular, in 5 out of 26 patients (19%) CD binary toxin was also detected. CDI diagnoses significantly increased in the period 2018–2019, since the introduction in the microbiology lab unit of the two-step diagnostic test based on GDH immunoenzymatic detection and toxin B/binary toxin/027 ribotype detection by real-time PCR. Via multivariate analysis, abdominal surgery within 10 years before HSCT (p = 0.002), antibiotic therapy within two months before HSCT (p = 0.000), HCV infection (p = 0.023) and occurrence of bacterial or fungal infections up to 100 days after HSCT (p = 0.003) were significantly associated with a higher risk of CDI development. The 26 patients were treated with first-line vancomycin (24) or fidaxomicine (2) and only 2 patients needed a second-line treatment, due to the persistence of stool positivity. No significant relationship was identified between CDI and the development of acute graft versus host disease (GVHD) after allogeneic HSCT. At a median follow-up of 25 months (range 1–65), the cumulative incidence of transplant related mortality (TRM) was 16.6% (95% CI 11.7% to 22.4%) and the 3-year overall survival (OS) was 67.0% (95% CI 61.9% to 71.6%). The development of CDI had no significant impact on TRM and OS, which were significantly impaired in the multivariate analysis by gastrointestinal and urogenital comorbidities, severe GVHD, previous infections or hospitalization within two months before HSCT, active disease at transplant and occurrence of infections after HSCT. We conclude that 20% of all episodes of diarrhea occurring up to 100 days after HSCT were related to toxigenic CD infection. Patients with a history of previous abdominal surgery or HCV infection, or those who had received broad spectrum parenteral antibacterial therapy were at major risk for CDI development. CDIs were successfully treated with vancomycin or fidaxomicin after auto-HSCT as well as after allo-HSCT.
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