The outcomes of patients with acute lymphoblastic leukaemia (ALL) presenting relapse after allogeneic stem cell transplant (allo‐SCT) are poor, with few data available in this setting.
Objective and ...Methods
To evaluate the outcomes of patients with ALL presenting relapsed after allo‐SCT, we performed a retrospective study including 132 from 11 centres in Spain.
Results
Therapeutic strategies consisted of palliative treatment (n = 22), chemotherapy (n = 82), tyrosine kinase inhibitors (n = 26), immunotherapy with inotuzumab and/or blinatumumab (n = 19), donor lymphocyte infusions (n = 29 pts), second allo‐SCT (n = 37) and CAR T therapy (n = 14). The probability of overall survival (OS) at 1 and 5 years after relapse was 44% (95% confidence interval CI: 36%; 52%) and 19% (95% CI: 11%; 27%). In the 37 patients undergoing a second allo‐SCT, the 5‐year estimated OS probability was 40% 22%; 58%. Younger age, recent allo‐SCT, late relapse, 1st complete remission at 1st allo‐SCT and chronic graft‐versus‐host disease confirmed their positive impact on survival in the multivariable analysis.
Conclusion
Despite the poor prognosis of patients with ALL presenting relapse after a first allo‐SCT, some can be satisfactorily rescued and a second allo‐SCT still remains a valid option for selected patients. Moreover, emerging therapies really might improve ALL patients outcome when relapsing after an allo‐SCT.
Azacitidine (AZA) is a DNA hypomethylation agent administered in myeloid neoplasms; however, there is still a lack of established predictors of response. We studied 113 patients with myelodysplastic ...syndromes (
n
= 85) or acute myeloid leukemia (
n
= 28) who received AZA to assess the predictive value on response of clinical features, cytogenetics, and molecular markers. Overall, 46 patients (41%) responded to AZA. Platelet doubling after the first AZA cycle was associated with a better response (68% vs. 32% responders,
P
= 0.041). Co-occurrence of chromosome 7 abnormalities and 17p deletion was associated with a worse response (
P
= 0.039). Pre-treatment genetic mutations were detected in 98 patients (87%) and methylation of
CDKN2B
and
DLC-1
promoters were detected in 50 (44%) and 37 patients (33%), respectively. Patients with
SF3B1
mutations showed a better response to AZA (68% vs. 35% responders,
P
= 0.008). In contrast, subjects with mutations in transcription factors (
RUNX1
,
SETBP1
,
NPM1
) showed a worse response (20% vs. 47% responders,
P
= 0.014).
DLC-1
methylation pre-treatment was associated with poor clinical features and its reduction post-treatment resulted in a better response to AZA in MDS patients (
P
= 0.037). In conclusion, we have identified several predictors of response to AZA that could help select the best candidates for this treatment.
Androgens represent the historical therapeutic backbone of bone marrow failure (BMF) syndromes. However, their role has rarely been analyzed in a prospective setting, and systematic and long-term ...data regarding their usage, effectiveness and toxicity in both acquired and inherited BMF are currently unavailable. Here, taking advantage of a unique disease-specific international dataset, we retrospectively analyzed the largest cohort so far of BMF patients who received androgens before or in the absence of an allogeneic hematopoietic cell transplantation (HCT), re-evaluating their current use in these disorders. We identified 274 patients across 82 European Society for Blood and Marrow Transplantation (EBMT) affiliated centers: 193 with acquired (median age 32 years) and 81 with inherited (median age 8 years) BMF. With a median duration of androgen treatment of 5.6 and 20 months, respectively, complete and partial remission rates at 3 months were 6% and 29% in acquired and 8% and 29% in inherited disorders. Five-year overall survival and failure-free survival (FFS) were respectively 63% and 23% in acquired and 78% and 14% in inherited BMF. Androgen initiation after second-line treatments for acquired BMF, and after >12 months post diagnosis for inherited BMF were identified as factors associated with improved FFS in multivariable analysis. Androgen use was associated with a manageable incidence of organ-specific toxicity, and low rates of solid and hematologic malignancies. Sub-analysis of transplant-related outcomes after exposure to these compounds showed probabilities of survival and complications similar to other transplanted BMF cohorts. This study delivers a unique opportunity to track androgen use in BMF syndromes and represents the basis for general recommendations on this category of therapeutics on behalf of the Severe Aplastic Anemia Working Party of the EBMT.
To investigate the multi-drug resistant bacteria (MDRB) colonization rate in hematological patients hospitalized for any cause using a multi-body-site surveillance approach, and determine the extent ...to which this screening strategy helped anticipate MDRB bloodstream infections (BSI).
Single-center retrospective observational study including 361 admissions documented in 250 adult patients. Surveillance cultures of nasal, pharyngeal, axillary and rectal specimens (the latter two combined) were performed at admission and subsequently on a weekly basis. Blood culture samples were incubated in an automated continuous monitoring blood culturing instrument (BACTEC FX).
In total, 3463 surveillance cultures were performed (pharyngeal, n = 1201; axillary-rectal, n = 1200; nasal, n = 1062). MDRB colonization was documented in 122 out of 361 (33.7%) admissions corresponding to 86 patients (34.4%). A total of 149 MDRB were isolated from one or more body sites, of which most were Gram-negative bacteria, most frequently non-fermenting (n = 83) followed by Enterobacterales (n = 51). BSI were documented in 102 admissions (28%) involving 87 patients. Overall, the rate of BSI caused by MDRB was significantly higher (p = 0.04) in the presence of colonizing MDRB (16 out of 47 admissions in 14 patients) than in its absence (9 out of 55 admissions in 9 patients). Colonization by any MDRB was independently associated with increased risk of MDRB-BSI (HR, 3.70; 95% CI, 1.38-9.90; p = 0.009).
MDRB colonization is a frequent event in hematological patients hospitalized for any reason and is associated with an increased risk of MDRB BSI. The data lend support to the use of MDRB colonization surveillance cultures for predicting the occurrence of MDRB BSI in this cohort.
The long-term clinical efficacy of SARS-CoV-2 vaccines according to antibody response in immunosuppressed patients such as hematological patients has been little explored. A prospective multicenter ...registry-based cohort study conducted from December 2020 to July 2022 by the Spanish Transplant and Cell Therapy group, was used to analyze the relationship of antibody response over time after full vaccination (at 3-6 weeks, 3, 6 and 12 months) (2 doses) and of booster doses with breakthrough SARS-CoV-2 infection in 1551 patients with hematological disorders. At a median follow-up of 388 days after complete immunization, 266 out of 1551 (17%) developed breakthrough SARS-CoV-2 infection at median of 86 days (range 7-391) after full vaccination. The cumulative incidence was 18% 95% confidence interval (C.I.), 16-20%. Multivariate analysis identified higher incidence in chronic lymphocytic leukemia patients (29%) and with the use of corticosteroids (24.5%), whereas female sex (15.5%) and more than 1 year after last therapy (14%) were associated with a lower incidence (p < 0.05 for all comparisons). Median antibody titers at different time points were significantly lower in breakthrough cases than in non-cases. A serological titer cut-off of 250 BAU/mL was predictive of breakthrough infection and its severity. SARS-CoV-2 infection-related mortality was encouragingly low (1.9%) in our series. Our study describes the incidence of and risk factors for COVID-19 breakthrough infections during the initial vaccination and booster doses in the 2021 to mid-2022 period. The level of antibody titers at any time after 2-dose vaccination is strongly linked with protection against both breakthrough infection and severe disease, even with the Omicron SARS-CoV-2 variant.
The performance of a plasma real-time PCR (cytomegalovirus CMV PCR kit; Abbott Diagnostics) was compared with that of the antigenemia assay for the surveillance of active CMV infection in 42 ...allogeneic hematopoietic stem cell transplantation (Allo-SCT) recipients. A total of 1,156 samples were analyzed by the two assays. Concordance between the two assays was 82.2%. Plasma DNA levels correlated with the number of pp65-positive cells, particularly prior to the initiation of preemptive therapy. Fifty-seven episodes of active CMV infection were detected in 37 patients: 18 were defined solely by the PCR assay and four were defined on the basis of the antigenemia assay. Either a cutoff of 288 CMV DNA copies/ml or a 2.42-log₁₀ increase of DNAemia levels between two consecutive PCR positive samples was an optimal value to discriminate between patients requiring preemptive therapy and those not requiring therapy on the basis of the antigenemia results. The real-time PCR assay allowed an earlier diagnosis of active CMV infection and was a more reliable marker of successful clearance of CMV from the blood. Analysis of the kinetics of DNAemia levels at a median of 7 days posttreatment allowed the prediction of the response to CMV therapy. Two patients developed CMV colitis. The PCR assay tested positive both before the onset of symptoms and during the disease period. The plasma real-time PCR from Abbott is more suitable than the antigenemia assay for monitoring active CMV infection in Allo-SCT recipients and may be used for guiding preemptive therapy in this clinical setting.
Erythropoiesis stimulating agents (ESAs) are the first-line therapy in patients with lower-risk myelodysplastic syndromes (LR-MDS). Some predictive factors for ESAs response have been identified. ...Type and number of somatic mutations have been associated with prognosis and response to therapies in MDS patients.
The objective was to evaluate the outcomes after ESAs in patients with LR-MDS and to address the potential predictive value of somatic mutations in ESAs-treated patients.
Multi-center retrospective study of a cohort of 722 patients with LR-MDS included in the SPRESAS (Spanish Registry of Erythropoietic Stimulating Agents Study) study. Retrospective analysis of 65 patients with next generation sequencing (NGS) data from diagnosis.
ESAs' efficacy and safety were evaluated in patients receiving ESAs and best supportive care (BSC). To assess the potential prognostic value of somatic mutations in erythroid response (ER) rate and outcome, NGS was performed in responders and non-responders.
ER rate for ESAs-treated patients was 65%. Serum erythropoietin (EPO) level <200 U/l was the only variable significantly associated with a higher ER rate (odds ratio, 2.45;
= 0.036). Median overall survival (OS) in patients treated with ESAs was 6.7
3.1 years in patients receiving BSC (
< 0.001). From 65 patients with NGS data, 57 (87.7%) have at least one mutation. We observed a trend to a higher frequency of ER among patients with a lower number of mutated genes (40.4% in <3 mutated genes
22.2% in ⩾3;
= 0.170). The presence of ⩾3 mutated genes was also significantly associated with worse OS (hazard ratio, 2.8;
= 0.015), even in responders. A higher cumulative incidence of acute myeloid leukemia progression at 5 years was also observed in patients with ⩾3 mutated genes
<3 (33.3% and 10.7%, respectively;
< 0.001).
This large study confirms the beneficial effect of ESAs and the adverse effect of somatic mutations in patients with LR-MDS.
Background:
The consequences of infectious toxicity of hypomethylating agents (HMAs) on overall survival (OS) of patients diagnosed with high-risk myeloid neoplasms have not been thoroughly ...investigated.
Objectives:
We aimed to evaluate whether infectious events (IEs) negatively influenced the results of HMA treatment in a real-world setting.
Design:
Observational study.
Methods:
We obtained data from 412 non-selected consecutive patients from 23 Spanish hospitals who were diagnosed with high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, or acute myeloid leukemia and were treated with HMA. HMAs received after chemotherapy or stem cell transplant were excluded. All IEs were recorded. Outcomes included OS, modifications to the pre-planned treatment, incidence and characteristics of IEs, hospitalization, red blood cell transfusions, and factors associated with infection.
Results:
The rate of infection was 1.2 per patient/year. Next-cycle delay (p = 0.001) and hospitalizations (p = 0.001) were significantly influenced by IEs. Transfusion requirements during each cycle were significantly higher after infection compared with cycles without infection (coefficient = 1.55 95% confidence interval (CI) = 1.26–1.84, p < 0.001). The median number of cycles was lower in patients experiencing any infection during the first four cycles (5 3–8 versu 8 5–16, p < 0.001). In the multivariable analysis, factors associated with lower OS were having any infection during the first four cycles (hazard ratio (HR) = 1.43 95% CI = 1.09–1.88, p = 0.01), bone marrow blasts ⩾30% (HR = 2.13 95% CI = 1.14–3.96, p = 0.01), adverse cytogenetics (HR = 1.70 95% CI = 1.30–2.24, p < 0.001), and platelet count <50 × 109/l (HR = 1.69 95% CI = 1.3–2.2, p < 0.001). BM blasts >20% (HR = 1.57 95% CI = 1.19–2.01, p < 0.001) and adverse cytogenetics (HR = 1.7 95% CI = 1.35–2.14, p < 0.001) were associated with infection, whereas hemoglobin >9 g/dl (HR = 0.65 95% CI = 0.51–0.82, p < 0.001) and higher platelet count (HR = 0.997 95% CI = 0.996–0.998, p = 0.016) protected from it.
Conclusion:
HMA infectious toxicity worsens OS, hinders the adherence to antineoplastic treatment and results in significant morbidity. Preventive strategies are fundamental in vulnerable patients.
Approval of hypomethylating agents in patients with chronic myelomonocytic leukaemia is based on trials done in patients with myelodysplastic syndromes. We aimed to investigate whether ...hypomethylating agents provide a benefit in subgroups of patients with chronic myelomonocytic leukaemia compared with other treatments.
For this retrospective cohort study, data were retrieved between Nov 30, 2017, and Jan 5, 2019, from 38 centres in the USA and Europe. We included non-selected, consecutive patients diagnosed with chronic myelomonocytic leukaemia, who received chronic myelomonocytic leukaemia-directed therapy. Patients with acute myeloid leukaemia according to 2016 WHO criteria at initial diagnosis (ie, ≥20% blasts in the bone marrow or peripheral blood) or with unavailability of treatment data were excluded. Outcomes assessed included overall survival, time to next treatment, and time to transformation to acute myeloid leukaemia. Analyses were adjusted by age, sex, platelet count, and Chronic myelomonocytic leukaemia-Specific Prognostic Scoring System (CPSS). Patients were grouped by first received treatment with either hydroxyurea, hypomethylating agents, or intensive chemotherapy, and stratified by risk according to blast count, French-American-British subtype, CPSS, WHO 2016 subtype, and the eligibility criteria of the DACOTA trial (NCT02214407).
949 patients diagnosed with chronic myelomonocytic leukaemia between April 13, 1981, and Oct 26, 2018, were included. Median follow-up was 23·4 months (IQR 11·5-42·3) from diagnosis and 16·2 months (6·6-31·6) from start of first-line treatment. 412 (43%) of 949 patients received hypomethylating agents as first treatment, 391 (41%) hydroxyurea, and 83 (9%) intensive chemotherapy. Adjusted median overall survival for patients treated with hydroxyurea versus hypomethylating agents was 15·6 months (95% CI 13·1-17·3) versus 20·7 months (17·9-23·4); hazard ratio (HR) 1·39 (1·17-1·65; p=0·0002) and 14·0 months (9·8-17·2) versus 20·7 months (17·9-23·4; HR 1·55 1·16-2·05; p=0·0027) for those treated with intensive chemotherapy versus hypomethylating agents. In patients with myeloproliferative chronic myelomonocytic leukaemia (myeloproliferative CMML), median overall survival was 12·6 months (10·7-15·0) versus 17·6 months (14·8-21·5; HR 1·38 1·12-1·70; p=0·0027) for patients treated with hydroxyurea versus hypomethylating agents, and 12·3 months (8·4-16·6) versus 17·6 months (14·8-21·5; HR 1·44 1·02-2·03; p=0·040) for intensive chemotherapy versus hypomethylating agents. Hypomethylating agents did not confer an overall survival advantage for patients classified as having lower-risk disease (ie, myelodysplastic chronic myelomonocytic leukaemia with <10% blasts, CMML-0, or lower-risk CPSS).
These data suggest hypomethylating agents as the preferred therapy for patients with higher-risk chronic myelomonocytic leukaemia and those with myeloproliferative CMML. Our findings also suggest that CPSS is a valuable tool to identify patients who are most likely to benefit from hypomethylating agents. Further evidence from prospective cohorts would be desirable.
The Austrian Group for Medical Tumor Therapy.
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