Immunoparesis recovery in newly diagnosed transplant ineligible multiple myeloma patients, an independent prognostic factor that complements minimal residual disease.

Information on the prognostic value of immunoparesis (IP) recovery in multiple myeloma (MM) patients has been only generated in some observational and retrospective studies. We have evaluated the prognostic impact of IP recovery and its association with minimal residual disease (MRD) in a series of 113 newly diagnosed transplant-ineligible (NDTI) patients, that received fix duration treatment (18 cycles of VMP/lenalidomide-dexamethasone) within the PETHEMA/GEM2010MAS65 trial and who achieved CR or VGPR. Immunoglobulin levels were measured at diagnosis, at the end of treatment (after cycle 18th) and during subsequent follow up whereas MRD was analyzed only at the end of the treatment (after cycle 18th). We found that patients who had IP at diagnosis and recovered it during or after treatment had longer progression free survival (PFS) [p < 0.001; HR 0.32 (0.19-0.52)] and longer overall survival (OS) [p = 0.007; HR 0.40 (0.20-0.80)] compared to those who failed to recover it. When we analyzed IP recovery in MRD negative patients, we found that those cases with IP recovery had longer PFS [p = 0.007; HR 0.31 (0.13-0.76)] and longer OS [p = 0.012; HR 0.21 (0.06-0.80)] as compared to MRD negative patients but without IP recovery. In conclusion, IP recovery confers better prognosis in NDTI-MM patients with fixed duration treatment who achieve CR or VGPR and the prognostic value of MRD can be complemented when combined with IP recovery.

Omicron SARS-CoV-2 infection management and outcomes in patients with hematologic disease and recipients of cell therapy.

Introduction: Scarce real-life data exists for COVID-19 management in hematologic disease (HD) patients in the Omicron era. Purpose: To assess the current clinical management and outcome of SARS-CoV-2 infection diagnosed, identify the risk factors for severe outcomes according to the HD characteristics and cell therapy procedures in a real-world setting. Methods: A retrospective observational registry led by the Spanish Transplant Group (GETH-TC) with 692 consecutive patients with HD from December 2021 to May 2023 was analyzed. Results: Nearly one-third of patients (31%) remained untreated and presented low COVID-19-related mortality (0.9%). Nirmatrelvir/ritonavir was used mainly in mild COVID-19 cases in the outpatient setting (32%) with a low mortality (1%), while treatment with remdesivir was preferentially administered in moderate-to-severe SARS-CoV-2 infection cases during hospitalization (35%) with a mortality rate of 8.6%. The hospital admission rate was 23%, while 18% developed pneumonia. COVID-19-related mortality in admitted patients was 14%. Older age, autologous hematopoietic stem cell transplantation (SCT), chimeric antigen receptor T-cell therapy, corticosteroids and incomplete vaccination were factors independently associated with COVID-19 severity and significantly related with higher rates of hospital admission and pneumonia. Incomplete vaccination status, treatment with prior anti-CD20 monoclonal antibodies, and comorbid cardiomyopathy were identified as independent risk factors for COVID-19 mortality. Conclusions: The results support that, albeit to a lower extent, COVID-19 in the Omicron era remains a significant problem in HD patients. Complete vaccination (3 doses) should be prioritized in these immunocompromised patients. The identified risk factors may help to improve COVID-19 management to decrease the rate of severe disease, ICU admissions and mortality.

Low dose lenalidomide versus placebo in non-transfusion dependent patients with low risk, del(5q) myelodysplastic syndromes (SintraREV): a randomised, double-blind, phase 3 trial.

BACKGROUND: Lenalidomide is the standard of care for patients who are transfusion dependent with chromosome 5q deletion (del[5q]) myelodysplastic syndromes. In the SintraREV trial, we aimed to investigate whether an early intervention of low lenalidomide doses for 2 years could delay transfusion dependency in patients with anaemia who were not transfusion dependent. METHODS: This randomised, double-blind, phase 3 trial, was conducted at 22 sites (University Hospitals) in Spain, France, and Germany. Eligible patients were aged 18 years or older diagnosed with low-risk or intermediate-1-risk del(5q) myelodysplastic syndromes with non-transfusion-dependent anaemia (according to the IPSS), were erythropoietin-stimulating agents naive, and had an ECOG performance status of 2 or less. Patients were randomly assigned (2:1) by means of a telephone system to receive lenalidomide 5 mg daily in 28-day cycles versus placebo for 2 years. The primary endpoint was time to transfusion dependency based on blinded independent central review. Analysis were by intent-to-treat (ITT) and evaluable population. Safety analyses included all participants who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov (NCT01243476) and EudraCT (2009-013619-36) and is complete. FINDINGS: Between Feb 15, 2010, and Feb 21, 2018, 61 patients were randomly assigned to receive lenalidomide (n=40; two did not receive treatment) or placebo (n=21). The median age was 72·2 (IQR 65·4-81·9) years, 50 (82%) patients were female, and 11 (18%) were male. The median follow-up time was 60·6 (IQR 32·1-73·9) months. Regarding primary endpoint, median time to transfusion dependency was not reached (95% CI not applicable) in the lenalidomide group versus 11·6 months (95% CI 0·00-30·11) in the placebo group (p=0·0027). Lenalidomide significantly reduced the risk of transfusion dependency by 69·8% (hazard ratio 0·302, 95% CI 0·132-0·692; p=0·0046). The most frequent treatment-related adverse event was neutropenia, occurring in 24 (63%) of 38 patients in the lenalidomide group (grade 3 and 4 in 17 [45%] patients and one [3%], respectively) and in four (19%) of 21 patients in the placebo group (grade 3 in one [5%] patient). Thrombocytopenia was detected in seven (18%) of 38 patients receiving lenalidomide (grade 3 in two [5%] patients). Regarding the non-haematological toxicity, skin disorders (rash nine [23%] of 38 patients) were the most frequently described toxicities among patients receiving lenalidomide, being grade 3 in one (3%) of 38 patients. 19 serious adverse events were reported in 13 patients, 18 in the lenalidomide group and one in the placebo group, five of which were potentially related to the study drug. No treatment-related deaths were identified. INTERPRETATION: An early approach with low doses of lenalidomide across two years delays the time to transfusion dependency and improves the rate and quality of the responses, with a manageable safety profile in patients who are non-transfusion dependent with del(5q) low-risk myelodysplastic syndromes. FUNDING: Bristol Myers Squibb.

Immune response against the SARS-CoV-2 spike protein in cancer patients after COVID-19 vaccination during the Omicron wave: a prospective study.

BACKGROUND: Cancer patients often have weakened immune systems, resulting in a lower response to vaccines, especially those receiving immunosuppressive oncological treatment (OT). We aimed to assess the impact of OT on the humoral and T-cell response to the B.1 lineage and Omicron variant following COVID-19 vaccination in patients with solid and hematological neoplasms. METHODS: We conducted a prospective study on cancer patients, stratified into OT and non-OT groups, who received a two-dose series of the COVID-19 mRNA vaccine and a booster six months later. The outcomes measured were the humoral (anti-SARS-CoV-2 S IgG titers and ACE2-S interaction inhibition capacity) and cellular (SARS-CoV-2 S-specific T-cell spots per million PBMCs) responses against the B.1 lineage and Omicron variant. These responses were evaluated four weeks after the second dose (n = 98) and eight weeks after the booster dose (n = 71). RESULTS: The humoral response after the second vaccine dose against the B.1 lineage and Omicron variant was significantly weaker in the OT group compared to the non-OT group (q-value<0.05). A booster dose of the mRNA-1273 vaccine significantly improved the humoral response in the OT group, making it comparable to the non-OT group. The mRNA-1273 vaccine, designed for the original Wuhan strain, elicited a weaker humoral response against the Omicron variant compared to the B.1 lineage, regardless of oncological treatment or vaccine dose. In contrast, T-cell responses against SARS-CoV-2, including the Omicron variant, were already present after the second vaccine dose and were not significantly affected by oncological treatments. CONCLUSIONS: Cancer patients, particularly those receiving immunosuppressive oncological treatments, should require booster doses and adapted COVID-19 vaccines for new SARS-CoV-2 variants like Omicron. Future studies should evaluate the durability of the immune response and the efficacy of individualized regimens.

Ibrutinib followed by ofatumumab consolidation in previously untreated patients with chronic lymphocytic leukemia (CLL): GELLC-7 trial from the Spanish group of CLL (GELLC).

Background: BTK inhibitors have been concurrently administered with anti-CD20 monoclonal antibodies (mAbs) in chronic lymphocytic leukemia (CLL). However, the optimal regimen for combining these two drugs remains pending. Methods: This multi-center phase 2 study aimed to analyze whether consolidation with ofatumumab improved the response in patients with CLL receiving front-line treatment with ibrutinib. Patients received 12 cycles of ibrutinib monotherapy. Those who achieved CR after this induction were maintained on ibrutinib. Conversely, those who did not attain CR continued with ibrutinib in addition to a consolidation, which involved 7 doses of ofatumumab. The primary objective was the complete response (CR) rate at cycle 20. This study is registered within the EU Clinical Trials Register (EudraCT 2016-004937-26). Findings: Between September 8, 2017, and May 21, 2018, 84 patients (median age, 69 years) were included. After completion of 12 cycles of ibrutinib (n = 80), 4 patients (5%) were in CR, 67 (84%) in partial response (PR), and 6 patients (7%) had a PR with lymphocytosis (PRL). After consolidation with ofatumumab, 20 patients improved the response from PR to CR and 6 patients with PRL obtained a PR. Seventy-one patients (85%) completed 20 cycles of treatment, with a CR rate of 24/71 (34%). According to the intention-to-treat analysis at cycle 20, the ORR was 69/84 (82.2%), with a CRR of 24/84 (28.6%). Progression-free survival and overall survival at 48-months were 89.9% (CI: 82.4-95.5) and 92.2% (CI: 85.3-97.1), respectively. Interpretation: These findings underscore the potential for a consolidation strategy in CLL, wherein the addition of a mAb in patients with low tumor burden might enhance the quality of the response. Funding: The study was funded by Janssen that also supplied ibrutinib, whereas ofatumumab was supplied by Novartis.

Association of Cytogenetics Aberrations and IGHV Mutations with Outcome in Chronic Lymphocytic Leukemia Patients in a Real-World Clinical Setting.

Immunoglobulin heavy chain variable ( IGHV ) region mutations, TP53 mutation, fluorescence in situ hybridization (FISH), and cytogenetic analysis are the most important prognostic biomarkers used in chronic lymphocytic leukemia (CLL) patients in our daily practice. In real-life environment, there are scarce studies that analyze the correlation of these factors with outcome, mainly referred to time to first treatment (TTFT) and overall survival (OS). This study aimed to typify IGHV mutation status, family usage, FISH aberrations, and complex karyotype (CK) and to analyze the prognostic impact in TTFT and OS in retrospective study of 375 CLL patients from a Spanish cohort. We found unmutated CLL (U-CLL) was associated with more aggressive disease, shorter TTFT (48 vs. 133 months, p < 0.0001), and shorter OS (112 vs. 246 months, p < 0.0001) than the mutated CLL. IGHV3 was the most frequently used IGHV family (46%), followed by IGHV1 (30%) and IGHV4 (16%). IGHV5-51 and IGHV1-69 subfamilies were associated with poor prognosis, while IGHV4 and IGHV2 showed the best outcomes. The prevalence of CK was 15% and was significantly associated with U-CLL. In the multivariable analysis, IGHV2 gene usage and del13q were associated with longer TTFT, while VH1-02, +12, del11q, del17p, and U-CLL with shorter TTFT. Moreover, VH1-69 usage, del11q, del17p, and U-CLL were significantly associated with shorter OS. A comprehensive analysis of genetic prognostic factors provides a more precise information on the outcome of CLL patients. In addition to FISH cytogenetic aberrations, IGHV and TP53 mutations, IGHV gene families, and CK information could help clinicians in the decision-making process.

COVID-19 Outcomes in Patients with Hematologic Malignancies in the Era of COVID-19 Vaccination and the Omicron Variant.

A greater understanding of clinical trends in COVID-19 outcomes among patients with hematologic malignancies (HM) over the course of the pandemic, particularly the Omicron era, is needed. This ongoing, observational, and registry-based study with prospective data collection evaluated COVID-19 clinical severity and mortality in 1818 adult HM patients diagnosed with COVID-19 between 27 February 2020 and 1 October 2022, at 31 centers in the Madrid region of Spain. Of these, 1281 (70.5%) and 537 (29.5%) were reported in the pre-Omicron and Omicron periods, respectively. Overall, patients aged ≥70 years (odds ratio 2.16, 95% CI 1.64-2.87), with >1 comorbidity (2.44, 1.85-3.21), or with an underlying HM of chronic lymphocytic leukemia (1.64, 1.19-2.27), had greater odds of severe/critical COVID-19; odds were lower during the Omicron BA.1/BA.2 (0.28, 0.2-0.37) or BA.4/BA.5 (0.13, 0.08-0.19) periods and among patients vaccinated with one or two (0.51, 0.34-0.75) or three or four (0.22, 0.16-0.29) doses. The hospitalization rate (75.3% [963/1279], 35.7% [191/535]), rate of intensive care admission (30.0% [289/963], 14.7% [28/191]), and mortality rate overall (31.9% [409/1281], 9.9% [53/536]) and in hospitalized patients (41.3% [398/963], 22.0% [42/191]) decreased from the pre-Omicron to Omicron period. Age ≥70 years was the only factor associated with higher mortality risk in both the pre-Omicron (hazard ratio 2.57, 95% CI 2.03-3.25) and Omicron (3.19, 95% CI 1.59-6.42) periods. Receipt of prior stem cell transplantation, COVID-19 vaccination(s), and treatment with nirmatrelvir/ritonavir or remdesivir were associated with greater survival rates. In conclusion, COVID-19 mortality in HM patients has decreased considerably in the Omicron period; however, mortality in hospitalized HM patients remains high. Specific studies should be undertaken to test new treatments and preventive interventions in HM patients.

Other malignancies in the history of CLL: an international multicenter study conducted by ERIC, the European Research Initiative on CLL, in HARMONY.

Background: Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work. Methods: We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022. Findings: In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs).The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC ± R) (OR = 3.7; 95% CI = 2.79-4.91; p < 0.001). STs were more frequent in males and patients with unmutated immunoglobulin heavy variable genes (OR = 1.77; 95% CI = 1.49-2.11; p < 0.001/OR = 1.89; 95% CI = 1.6-2.24; p < 0.001).CLL-directed treatment was associated with non-melanoma skin and prostate cancers (OR = 1.8; 95% CI = 1.36-2.41; p < 0.001/OR = 2.11; 95% CI = 1.12-3.97; p = 0.021). In contrast, breast cancers were more frequent in untreated patients (OR = 0.17; 95% CI = 0.08-0.33; p < 0.001).Patients with CLL and an OM had inferior overall survival (OS) than those without. AML and MDS conferred the worst OS (p < 0.001). Interpretation: OMs in CLL impact on OS. Treatment for CLL increased the risk for AML/MDS, prostate cancer, and NMSC. FCR was associated with increased risk for AML/MDS. Funding: AbbVie, and EU/EFPIAInnovative Medicines Initiative Joint Undertaking HARMONY grant n° 116026.

Remdesivir or Nirmatrelvir/Ritonavir Therapy for Omicron SARS-CoV-2 Infection in Hematological Patients and Cell Therapy Recipients.

BACKGROUND: Scarce data exist that analyze the outcomes of hematological patients with SARS-CoV-2 infection during the Omicron variant period who received treatment with remdesivir or nirmatrelvir/ritonavir. METHODS: This study aims to address this issue by using a retrospective observational registry, created by the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group, spanning from 27 December 2021 to 30 April 2023. RESULTS: This study included 466 patients, 243 (52%) who were treated with remdesivir and 223 (48%) with nirmatrelvir/ritonavir. Nirmatrelvir/ritonavir was primarily used for mild cases, resulting in a lower COVID-19-related mortality rate (1.3%), while remdesivir was preferred for moderate to severe cases (40%), exhibiting a higher mortality rate (9%). A multivariate analysis in the remdesivir cohort showed that male gender (odds ratio (OR) 0.35, p = 0.042) correlated with a lower mortality risk, while corticosteroid use (OR 9.4, p < 0.001) and co-infection (OR 2.8, p = 0.047) were linked to a higher mortality risk. Prolonged virus shedding was common, with 52% of patients shedding the virus for more than 25 days. In patients treated with remdesivir, factors associated with prolonged shedding included B-cell malignancy as well as underlying disease, severe disease, a later onset of and shorter duration of remdesivir treatment and a higher baseline viral load. Nirmatrelvir/ritonavir demonstrated a comparable safety profile to remdesivir, despite a higher risk of drug interactions. CONCLUSIONS: Nirmatrelvir/ritonavir proved to be a safe and effective option for treating mild cases in the outpatient setting, while remdesivir was preferred for severe cases, where corticosteroids and co-infection significantly predicted worse outcomes. Despite antiviral therapy, prolonged shedding remains a matter of concern.

The evolving landscape of COVID-19 and post-COVID condition in patients with chronic lymphocytic leukemia: A study by ERIC, the European research initiative on CLL.

In this retrospective international multicenter study, we describe the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders (small lymphocytic lymphoma and high-count monoclonal B lymphocytosis) infected by SARS-CoV-2, including the development of post-COVID condition. Data from 1540 patients with CLL infected by SARS-CoV-2 from January 2020 to May 2022 were included in the analysis and assigned to four phases based on cases disposition and SARS-CoV-2 variants emergence. Post-COVID condition was defined according to the WHO criteria. Patients infected during the most recent phases of the pandemic, though carrying a higher comorbidity burden, were less often hospitalized, rarely needed intensive care unit admission, or died compared to patients infected during the initial phases. The 4-month overall survival (OS) improved through the phases, from 68% to 83%, p = .0015. Age, comorbidity, CLL-directed treatment, but not vaccination status, emerged as risk factors for mortality. Among survivors, 6.65% patients had a reinfection, usually milder than the initial one, and 16.5% developed post-COVID condition. The latter was characterized by fatigue, dyspnea, lasting cough, and impaired concentration. Infection severity was the only risk factor for developing post-COVID. The median time to resolution of the post-COVID condition was 4.7 months. OS in patients with CLL improved during the different phases of the pandemic, likely due to the improvement of prophylactic and therapeutic measures against SARS-CoV-2 as well as the emergence of milder variants. However, mortality remained relevant and a significant number of patients developed post-COVID conditions, warranting further investigations.

The Five "Ws" of Frailty Assessment and Chronic Lymphocytic Leukemia: Who, What, Where, Why, and When.

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, but chronological age does not accurately discriminate frailty status at the inter-individual level. Frailty describes a person's overall resilience. Since CLL is a stressful situation, it is relevant to assess the patient´s degree of frailty, especially before starting antineoplastic treatment. We are in the era of targeted therapies, which have helped to control the disease more effectively and avoid the toxicity of chemo (immuno) therapy. However, these drugs are not free of side effects and other aspects arise that should not be neglected, such as interactions, previous comorbidities, or adherence to treatment, since most of these medications are taken continuously. The challenge we face is to balance the risk of toxicity and efficacy in a personalized way and without forgetting that the most frequent cause of death in CLL is related to the disease. For this purpose, comprehensive geriatric assessment (GA) provides us with the opportunity to evaluate multiple domains that may affect tolerance to treatment and that could be improved with appropriate interventions. In this review, we will analyze the state of the art of GA in CLL through the five Ws.

Molnupiravir compared to nirmatrelvir/ritonavir for COVID-19 in high-risk patients with haematological malignancy in Europe. A matched-paired analysis from the EPICOVIDEHA registry.

INTRODUCTION: Molnupiravir and nirmatrelvir/ritonavir are antivirals used to prevent progression to severe SARS-CoV-2 infections and decrease hospitalisation and mortality rates. Nirmatrelvir/ritonavir was authorised in Europe in December 2021, whereas molnupiravir is not yet licensed in Europe as of February 2022. Molnupiravir may be an alternative to nirmatrelvir/ritonavir because it is associated with fewer drug-drug interactions and contraindications. A caveat for molnupiravir is the mode of action induces viral mutations. Mortality rate reduction with molnupiravir was less pronounced than that with nirmatrelvir/ritonavir in patients without haematological malignancy. Little is known about the comparative efficacy of the two drugs in patients with haematological malignancy at high-risk of severe COVID-19. Thus, molnupiravir and nirmatrelvir/ritonavir were compared in a cohort of patients with haematological malignancies. METHODS: Clinical data from patients treated with molnupiravir or nirmatrelvir/ritonavir monotherapy for COVID-19 were retrieved from the EPICOVIDEHA registry. Patients treated with molnupiravir were matched by sex, age (±10 years), and severity of baseline haematological malignancy to controls treated with nirmatrelvir/ritonavir. RESULTS: A total of 116 patients receiving molnupiravir for the clinical management of COVID-19 were matched to an equal number of controls receiving nirmatrelvir/ritonavir. In each of the groups, 68 (59%) patients were male; with a median age of 64 years (interquartile range [IQR] 53-74) for molnupiravir recipients and 64 years (IQR 54-73) for nirmatrelvir/ritonavir recipients; 56.9% (n=66) of the patients had controlled baseline haematological malignancy, 12.9% (n=15) had stable disease, and 30.2% (n=35) had active disease at COVID-19 onset in each group. During COVID-19 infection, one third of patients from each group were admitted to hospital. Although a similar proportion of patients in the two groups were vaccinated (molnupiravir n=77, 66% vs. nirmatrelvir/ritonavir n=87, 75%), more of those treated with nirmatrelvir/ritonavir had received four vaccine doses (n=27, 23%) compared with those treated with molnupiravir (n=5, 4%) (P<0.001). No differences were detected in COVID-19 severity (P=0.39) or hospitalisation (P=1.0). No statistically significant differences were identified in overall mortality rate (P=0.78) or survival probability (d30 P=0.19, d60 P=0.67, d90 P=0.68, last day of follow up P=0.68). Deaths were either attributed to COVID-19, or the infection was judged by the treating physician to have contributed to death. CONCLUSIONS: Hospitalisation and mortality rates with molnupiravir were comparable to those with nirmatrelvir/ritonavir in high-risk patients with haematological malignancies and COVID-19. Molnupiravir is a plausible alternative to nirmatrelvir/ritonavir for COVID-19 treatment in patients with haematological malignancy.

Real-World Evidence on the Clinical Characteristics and Management of Patients with Chronic Lymphocytic Leukemia in Spain Using Natural Language Processing: The SRealCLL Study.

The SRealCLL study aimed to obtain real-world evidence on the clinical characteristics and treatment patterns of patients with chronic lymphocytic leukemia (CLL) using natural language processing (NLP). Electronic health records (EHRs) from seven Spanish hospitals (January 2016-December 2018) were analyzed using EHRead® technology, based on NLP and machine learning. A total of 534 CLL patients were assessed. No treatment was detected in 270 (50.6%) patients (watch-and-wait, W&W). First-line (1L) treatment was identified in 230 (43.1%) patients and relapsed/refractory (2L) treatment was identified in 58 (10.9%). The median age ranged from 71 to 75 years, with a uniform male predominance (54.8-63.8%). The main comorbidities included hypertension (W&W: 35.6%; 1L: 38.3%; 2L: 39.7%), diabetes mellitus (W&W: 24.4%; 1L: 24.3%; 2L: 31%), cardiac arrhythmia (W&W: 16.7%; 1L: 17.8%; 2L: 17.2%), heart failure (W&W 16.3%, 1L 17.4%, 2L 17.2%), and dyslipidemia (W&W: 13.7%; 1L: 18.7%; 2L: 19.0%). The most common antineoplastic treatment was ibrutinib in 1L (64.8%) and 2L (62.1%), followed by bendamustine + rituximab (12.6%), obinutuzumab + chlorambucil (5.2%), rituximab + chlorambucil (4.8%), and idelalisib + rituximab (3.9%) in 1L and venetoclax (15.5%), idelalisib + rituximab (6.9%), bendamustine + rituximab (3.5%), and venetoclax + rituximab (3.5%) in 2L. This study expands the information available on patients with CLL in Spain, describing the diversity in patient characteristics and therapeutic approaches in clinical practice.

Impact of SARS-CoV-2 vaccination and monoclonal antibodies on outcome post-CD19-directed CAR T-cell therapy: an EPICOVIDEHA survey.

Patients with previous CD19-directed chimeric antigen receptor (CAR) T-cell therapy have a prolonged vulnerability to viral infections. Coronavirus disease 2019 (COVID-19) has a great impact and has previously been shown to cause high mortality in this population. Until now, real-world data on the impact of vaccination and treatment on patients with COVID-19 after CD19-directed CAR T-cell therapy are lacking. Therefore, this multicenter, retrospective study was conducted with data from the EPICOVIDEHA survey. Sixty-four patients were identified. The overall mortality caused by COVID-19 was 31%. Patients infected with the Omicron variant had a significantly lower risk of death due to COVID-19 compared with patients infected with previous variants (7% vs 58% [P = .012]). Twenty-six patients were vaccinated at the time of the COVID-19 diagnosis. Two vaccinations showed a marked but unsignificant reduction in the risk of COVID-19-caused mortality (33.3% vs 14.2% [P = .379]). In addition, the course of the disease appears milder with less frequent intensive care unit admissions (39% vs 14% [P = .054]) and a shorter duration of hospitalization (7 vs 27.5 days [P = .022]). Of the available treatment options, only monoclonal antibodies seemed to be effective at reducing mortality from 32% to 0% (P = .036). We conclude that survival rates of CAR T-cell recipients with COVID-19 improved over time and that the combination of prior vaccination and monoclonal antibody treatment significantly reduces their risk of death. This trial was registered at www.clinicaltrials.gov as #NCT04733729.

COVID-19 Severity and Survival over Time in Patients with Hematologic Malignancies: A Population-Based Registry Study.

Mortality rates for COVID-19 have declined over time in the general population, but data in patients with hematologic malignancies are contradictory. We identified independent prognostic factors for COVID-19 severity and survival in unvaccinated patients with hematologic malignancies, compared mortality rates over time and versus non-cancer inpatients, and investigated post COVID-19 condition. Data were analyzed from 1166 consecutive, eligible patients with hematologic malignancies from the population-based HEMATO-MADRID registry, Spain, with COVID-19 prior to vaccination roll-out, stratified into early (February-June 2020; n = 769 (66%)) and later (July 2020-February 2021; n = 397 (34%)) cohorts. Propensity-score matched non-cancer patients were identified from the SEMI-COVID registry. A lower proportion of patients were hospitalized in the later waves (54.2%) compared to the earlier (88.6%), OR 0.15, 95%CI 0.11-0.20. The proportion of hospitalized patients admitted to the ICU was higher in the later cohort (103/215, 47.9%) compared with the early cohort (170/681, 25.0%, 2.77; 2.01-3.82). The reduced 30-day mortality between early and later cohorts of non-cancer inpatients (29.6% vs. 12.6%, OR 0.34; 0.22-0.53) was not paralleled in inpatients with hematologic malignancies (32.3% vs. 34.8%, OR 1.12; 0.81-1.5). Among evaluable patients, 27.3% had post COVID-19 condition. These findings will help inform evidence-based preventive and therapeutic strategies for patients with hematologic malignancies and COVID-19 diagnosis.

SARS-CoV-2-reactive antibody waning, booster effect and breakthrough SARS-CoV-2 infection in hematopoietic stem cell transplant and cell therapy recipients at one year after vaccination.

The kinetics of SARS-CoV-2 reactive IgG antibodies after full vaccination and booster in allogeneic and autologous stem cell transplantation (allo-HSCT, ASCT) and chimeric antigen receptor T-cell therapy (CAR-T) are of utmost importance for estimating risk of infection. A prospective multicenter registry-based cohort study, conducted from December 2020 to July 2022 was used to analyze antibody waning over time, booster effect and the relationship of antibody response and breakthrough infection in 572 recipients (429 allo-HSCT, 121 ASCT and 22 CAR-T cell therapy). A significant decline in antibody titers was observed at 3 and 6 months after full vaccination in recipients without pre-vaccine SARS-CoV-2 infection, whereas recipients infected prior to vaccination showed higher and stable antibody titers over time. In poor responders, a booster dose was able to increase antibody titers in 83% of allo-HSCT and 58% of ASCT recipients but not in CART-T cell recipients [0%] (p < 0.01). One-year cumulative incidence of breakthrough infection was 15%, similar among cell therapy procedures. Immunosuppressive drugs at the time of vaccination [hazard ratio (HR) 1.81, p = 0.0028] and reduced intensity conditioning (HR 0.49, p = 0.011) were identified as the only conditions associated with different risk of breakthrough infection in allo-HSCT recipients. Antibody titers were associated with breakthrough infection and disease severity. No death was observed among the 72 breakthrough infections. Antibody level decay after the first two vaccine doses was common except in recipients with pre-vaccination SARS-CoV-2 infection. Poorly responding allo-HSCT recipients showed a response advantage with the booster as compared to ASCT and, especially, the null response found in CAR-T cell recipients. Antibody titers were positively correlated with the risk of breakthrough SARS-CoV-2 infection which was mainly driven by the immunosuppression status.