Co-infections and superinfections complicating COVID-19 in cancer patients: A multicentre, international study.

BACKGROUND: We aimed to describe the epidemiology, risk factors, and clinical outcomes of co-infections and superinfections in onco-hematological patients with COVID-19. METHODS: International, multicentre cohort study of cancer patients with COVID-19. All patients were included in the analysis of co-infections at diagnosis, while only patients admitted at least 48 h were included in the analysis of superinfections. RESULTS: 684 patients were included (384 with solid tumors and 300 with hematological malignancies). Co-infections and superinfections were documented in 7.8% (54/684) and 19.1% (113/590) of patients, respectively. Lower respiratory tract infections were the most frequent infectious complications, most often caused by Streptococcus pneumoniae and Pseudomonas aeruginosa. Only seven patients developed opportunistic infections. Compared to patients without infectious complications, those with infections had worse outcomes, with high rates of acute respiratory distress syndrome, intensive care unit (ICU) admission, and case-fatality rates. Neutropenia, ICU admission and high levels of C-reactive protein (CRP) were independent risk factors for infections. CONCLUSIONS: Infectious complications in cancer patients with COVID-19 were lower than expected, affecting mainly neutropenic patients with high levels of CRP and/or ICU admission. The rate of opportunistic infections was unexpectedly low. The use of empiric antimicrobials in cancer patients with COVID-19 needs to be optimized.

Predictors of multidrug-resistant Pseudomonas aeruginosa in neutropenic patients with bloodstream infection.

OBJECTIVES: To assess risk factors for multidrug-resistant Pseudomonas aeruginosa (MDR-PA) infection in neutropenic patients. METHODS: Single-centre retrospective analysis of consecutive bloodstream infection (BSI) episodes (2004-2017, Barcelona). Two multivariate regression models were used at BSI diagnosis and P. aeruginosa detection. Significant predictors were used to establish rules for stratifying patients according to MDR-PA BSI risk. RESULTS: Of 661 Gram-negative BSI episodes, 190 (28.7%) were caused by P. aeruginosa (70 MDR-PA). Independent factors associated with MDR-PA among Gram-negative organisms were haematological malignancy (OR 3.30; 95% CI 1.15-9.50), pulmonary source of infection (OR 7.85; 95% CI 3.32-18.56), nosocomial-acquired BSI (OR 3.52; 95% CI 1.74-7.09), previous antipseudomonal cephalosporin (OR 13.66; 95% CI 6.64-28.10) and piperacillin/tazobactam (OR 2.42; 95% CI 1.04-5.63), and BSI occurring during ceftriaxone (OR 4.27; 95% CI 1.15-15.83). Once P. aeruginosa was identified as the BSI aetiological pathogen, nosocomial acquisition (OR 7.13; 95% CI 2.87-17.67), haematological malignancy (OR 3.44; 95% CI 1.07-10.98), previous antipseudomonal cephalosporin (OR 3.82; 95% CI 1.42-10.22) and quinolones (OR 3.97; 95% CI 1.37-11.48), corticosteroids (OR 2.92; 95% CI 1.15-7.40), and BSI occurring during quinolone (OR 4.88; 95% CI 1.58-15.05) and ß-lactam other than ertapenem (OR 4.51; 95% CI 1.45-14.04) were independently associated with MDR-PA. Per regression coefficients, 1 point was assigned to each parameter, except for nosocomial-acquired BSI (3 points). In the second analysis, a score >3 points identified 60 (86.3%) out of 70 individuals with MDR-PA BSI and discarded 100 (84.2%) out of 120 with non-MDR-PA BSI. CONCLUSIONS: A simple score based on demographic and clinical factors allows stratification of individuals with bacteraemia according to their risk of MDR-PA BSI, and may help facilitate the use of rapid MDR-detection tools and improve early antibiotic appropriateness.

Home management of acute medical complications in cancer patients: a prospective pilot study.

BACKGROUND: The development of reliable alternatives to conventional hospitalization in patients with cancer would have great clinical and economical value. The aim of the present study was to assess the feasibility of a home-based nursing intervention model as a safe alternative for the management of acute medical complications in cancer patients who would otherwise require conventional hospitalization. PATIENTS AND METHODS: From October 2013 to October 2014, we prospectively evaluated the outcomes of consecutive acute medical episodes treated at home under the home-based intervention program named the Bridge Project (BP). Episodes were classified as "avoided hospitalization in outpatients" (AHO) vs. "reduced hospitalization in inpatients" (RHI). The primary end-point was to assess the rate and causes of BP intervention failure (unplanned hospital readmission or death). RESULTS: Two hundred and forty-six consecutive episodes (52 % AHO and 48 % RHI) involving 203 patients (55 % male; mean age 63 years) were enrolled. The main conditions managed at home were non-neutropenic infections (40 %), febrile neutropenia (20 %), and cancer-related complications (28 %). The median duration of the BP intervention was 5 days (range 1-16 days). No deaths were reported at home. Unplanned hospital readmissions occurred in 9 % of episodes (14 % in AHO vs. 4 % in RHI; p = 0.001). Five of the 22 readmitted patients (22.7 % of the BP failures; 2.5 % of the whole series) died during hospitalization. The BP intervention burden was 1353 days, representing a potential saving of 14 % of days of hospitalization during the study period. CONCLUSIONS: The BP is a safe intervention which can potentially avoid or reduce the length of hospitalization in selected cancer patients with acute medical complications. Our findings support further development of innovative home-based clinical approaches to promote potentially avoidable hospitalization in this setting.

Allogeneic hematopoietic SCT in multiple myeloma: long-term results from a single institution.

The role of allogeneic hematopoietic SCT (allo-HCT) in multiple myeloma (MM) remains controversial. A total of 58 patients received an allo-HCT (25 of them with myeloablative conditioning-allo-MAC-and 33 with reduced-intensity conditioning-allo-RIC) at our institution over a 28-year period. The CR rate for allo-MAC was 36%. The incidence of grade III-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) was 28% and 39%, respectively The TRM at any time was 60% and the main causes of death were aGVHD or infectious complications not directly related to GVHD. The estimated PFS and OS at 15 years were 8% and 15%, respectively. The CR rate with allo-RIC was 45%. The incidence of grade III-IV aGVHD and cGVHD were 24% and 41%, respectively. The TRM at any time was 33% and was mainly related to aGVHD. The estimated PFS and OS at 5 years were 22% and 38%, respectively. Despite its high TRM, a proportion of patients with high-risk myeloma (early relapse and newly diagnosed ultrahigh risk) may obtain long-term disease control with allo-HCT. New approaches aimed at decreasing the incidence of aGVHD, and consequently to decrease the TRM, are needed.

Fungal and viral infections after allogeneic hematopoietic transplantation from unrelated donors in adults: improving outcomes over time.

Umbilical cord blood (CB) is increasingly used as an alternative source of stem cells in adult unrelated transplantation. Although registry studies report similar overall outcomes in comparison with BM/PB, comparative studies focusing on severe infections and infection-RM (IRM) with a long follow-up are scarce. A total of 434 consecutive unrelated transplants (1997-2009) were retrospectively analyzed to compare overall outcomes, incidence and risk factors of severe viral and invasive fungal infections in CB (n=65) vs BM/PB recipients (n=369). The 5-year OS was 38 vs 43%, respectively (P=0.2). CB transplantation (CBT) was associated with a higher risk of invasive aspergillosis (100-days-cumulative incidence 16 vs 6%, P=0.04) and CMV infection without differences in RM. No statistically significant differences were found regarding NRM (NRM of 38% in CB vs 37% in BM/PB at 1 year) nor IRM (30% in CB vs 27% in BM/PB at 1 year). In the overall population, NRM and IRM improved in more recent years. In adults who receive a single CBT, the risk of severe infections is increased when compared with unrelated BM/PB recipients, but mortality from infections is similar, leading to similar NRM and survival.

Pattern of relapse and progression after autologous SCT as upfront treatment for multiple myeloma.

The achievement of CR is the crucial step for a prolonged PFS and OS after an autologous SCT in multiple myeloma (MM). Unfortunately, even with the use of new regimens and the current high CR rates, most, if not all, patients will ultimately relapse or progress. We analyzed the type of relapse or progression (asymptomatic vs symptomatic), clinical features including the presence of extramedullary involvement and time to next treatment in 211 patients who underwent melphalan-based autologous SCT over an 18-year period at our institution. After autologous SCT, serological or asymptomatic relapse/progression was observed in about one half of the patients. The treatment-free interval was significantly longer in patients relapsing from CR than in those progressing from PR (P=0.017). Patients with serological relapse/progression had a significantly longer OS than those relapsing from symptomatic disease (P=0.002). The relapse pattern was similar to the initial clinical presentation. Survival after relapse/progression was shorter in those patients with a 24-h urine M-protein excretion of at least 200 mg (P=0.048). Extramedullary involvement was frequent (24%), being the highest risk in patients with extramedullary involvement at diagnosis (P=0.001).

A variant in IRF3 impacts on the clinical outcome of AML patients submitted to Allo-SCT.

Allo-SCT has a strong curative potential for AML patients mainly due to a GVL effect. Unfortunately, GvL and GVHD are intimately linked. IFN regulatory factor-3 (IRF3), by modulating innate immune reactions, could impact on the incidence and intensity of GVL and GVHD. We analyzed two gene variants in IRF3 (rs7251 and rs2304205) on the clinical outcome of 249 AML patients submitted to HLA-identical sibling allo-SCT. Patients with a donor carrying the dominant GG gene variant in rs7251 had, as compared with GC and CC variants, a lower acute GVHD (aGVHD) III-IV incidence (4% vs 11% vs 27%; P=0.0078), a higher relapse incidence (49% vs 35% vs 26%; P=0.018), and lower TRM (7% vs 24% vs 18%; P=0.0065). In functional studies, the GG variant was associated with lower production of IFN-γ, decreased lymphocyte proliferation after antigen presentation by DCs, and lower cytotoxic response of mature natural killer cells. Patients carrying the AA dominant variant in rs2304205 had higher relapse incidence (50% vs 39% vs 18%, P=0.0068). The presence of both variants (GG in rs7251 and AA in rs2304205) in donors and patients resulted in a stronger clinical impact.

Incidence, characteristics and risk factors of marked hyperbilirubinemia after allogeneic hematopoietic cell transplantation with reduced-intensity conditioning.

To analyze the incidence, characteristics and risk factors of hyperbilirubinemia after allogeneic hematopoietic cell transplantation with reduced-intensity conditioning (allo-RIC), we conducted a retrospective study in three Spanish centers. We analyzed 452 consecutive patients receiving allo-RIC. Of these, 92 patients (20%) developed marked hyperbilirubinemia (>4 mg/day or >68.4 µM) after allo-RIC. The main causes of marked hyperbilirubinemia after transplant were cholestasis due to GVHD or sepsis (n=57, 62%) and drug-induced cholestasis (n=13, 14%). A total of 22 patients with marked hyperbilirubinemia (24%) underwent liver biopsy. The most frequent histological finding was iron overload alone (n=6) or in combination with other features (n=6). In multivariate analysis, the risk factors for marked hyperbilirubinemia after allo-RIC were non-HLA-identical sibling donors (hazard ratio (HR) 2.2 (95% confidence interval (CI) 1.4-3.6) P=0.001), female donors to male recipients (HR 2.1 (95% CI 1.3-3.3) P=0.003) and high levels of bilirubin and γ-glutamyl transpeptidase before transplant (HR 4.5 (95% CI 2.5-8.4) P<0.001 and HR 4.6 (95% CI 2.6-8.1) P<0.001, respectively). Patients with marked hyperbilirubinemia showed higher 4-year nonrelapse mortality (HR 1.3 (95% CI 1-1.7), P=0.02) and lower 4-year OS (HR 1.4 (95%CI 1.3-1.7), P<0.001) than patients without. In conclusion, we confirm that marked hyperbilirubinemia is frequent and diverse after allo-RIC. Development of marked hyperbilirubinemia after allo-RIC is associated with worse outcome of the procedure.

A constitutional variant in the transcription factor EP300 strongly influences the clinical outcome of patients submitted to allo-SCT.

An adequate response of the innate immune system after allo-SCT is crucial for the clinical outcome of patients submitted to this procedure. EP300 is one of the key genes of the innate immune system (IIS). We evaluated the influence of gene variant A>G rs20551 in EP300 in donor and/or recipient on clinical results after HLA-identical sibling allo-SCT. Patients with AA gene variant had a lower relapse incidence (31 vs 48%, P=0.025; odds ratio (OR)=1.6, P=0.05), attained better disease-free survival (AA: 53% vs AG+GG: 24%, P=0.001; OR=1.8, P=0.01), and better OS (AA: 53% vs AG+GG: 34%, P=0.001; OR=1.9, P=0.007). This beneficial association was more evident when AA gene variant was present in both donor and patient. In healthy individuals, AA gene variant was associated with lower IL2 production after a mitogenic stimuli, higher CD4+ cell response after CMV infection, and higher expression of innate immune genes (IRF-3 and MIF), cell cycle genes (AURKB, CCNA2 and CCNB1), lymphocyte survival genes (NFAT5 and SLC38A2), and with a lower expression of P53 compared with recessive GG gene variant. These findings suggest a beneficial effect of the AA gene variant in rs20551 on clinical outcome after allo-SCT.

Serial intestinal endoscopic examinations of patients with persistent diarrhea after allo-SCT.

Gastrointestinal (GI) GVHD after allo-SCT is diagnosed on the basis of symptoms and findings in endoscopic mucosal biopsy specimens. However, GI symptoms often persist despite treatment and whether a second endoscopy may be helpful in determining the most suitable therapy is not established. We identified 31 patients with persistent diarrhea who underwent more than one endoscopic study. All cases underwent serial microbiological stool analysis and CMV-detecting assays on serum and biopsies. Of the 31 initial GI biopsies, 20 (64.5%) were classified as GVHD, two (6.5%) as GVHD with CMV, four (13%) as non-CMV infection, and five (16%) as normal or unspecific. The second GI biopsies were diagnostic of GVHD in nine cases (29%), GVHD simultaneously with CMV infection in four (13%), regenerative changes post-GVHD in five (16%), CMV infection in four (13%), and normal or unspecific in nine (29%). In 22 of the 31 patients (71%), the histological findings of the second/third endoscopic biopsies differed from the findings of the first endoscopy and led to a therapy change in 77%. In conclusion, serial GI endoscopies are of reliable diagnostic value and can impact on therapeutic decision-making for patients with persistent diarrhea after allo-SCT.

MTX or mycophenolate mofetil with CsA as GVHD prophylaxis after reduced-intensity conditioning PBSCT from HLA-identical siblings.

Mycophenolate mofetil (MMF) in combination with CsA seems to lead to earlier post transplant hematological recovery and less mucositis than MTX, with a similar incidence of GVHD. In this study we analyzed the post transplant outcomes of two cohorts of patients who underwent an HLA-identical sibling reduced intensity conditioning transplantation (allo-RIC) with GVHD prophylaxis consisting of CsA in combination with either MMF or a short course of MTX. We included 145 consecutive allo-RIC transplants performed between April 2000 and August 2007. The median follow-up for survivors was 41 months (4-105 months). The study group included 91 males. Median age was 55 years (range 18-71 years). Diagnoses included myeloid (n=65) and lymphoid (n=80) malignancies. GVHD prophylaxis consisted of CsA/MMF in 52 and CsA/MTX in 93 patients. The conditioning regimen was based on fludarabine in combination with BU (n=59) or melphalan (n=86). The occurrence of grade 2-4 mucositis was higher in the CsA/MTX group than in the CsA/MMF group (57 vs 23%, P=0.001). The cumulative incidence of acute and chronic GVHD was similar, 48 vs 50% and 71 vs 68%, respectively (P>0.7). The 2-year relapse and OS were similar in the CsA/MTX and CsA/MMF groups (29 vs 21%, P=0.3 and 52 vs 51%, P=0.7, respectively). Our results support further prospective studies comparing the use of the CsA/MMF combination with CsA/MTX as GVHD prophylaxis in HLA-identical sibling donor allo-RIC recipients.

Engraftment syndrome after auto-SCT: analysis of diagnostic criteria and risk factors in a large series from a single center.

Engraftment syndrome (ES) is increasingly observed in patients who receive auto-SCT. To investigate this fact, validate the clinical criteria for ES diagnosis and analyze the risk factors for this complication, we reviewed 328 consecutive peripheral blood auto-SCT performed during the past 7 years. A total of 43 patients presented with clinical or biological data suggestive of ES. Of the total, 41 (95%) and 22 (51%) could be diagnosed with ES using the Maiolino criteria (MC) and the Spitzer criteria (SC), respectively. The SC were less sensitive as they do not consider some relevant clinical data and limit the observation time after engraftment. All ES cases had high C-reactive protein (CRP) values not observed in the remaining patients at engraftment (median +/- s.d.: 17.5 +/- 7.3 vs 2.4 +/- 3.4 mg per 100 ml; P=0.0001). Multivariate analysis showed a higher risk of ES in SCT performed in recent years (relative risk (RR) 2.3, 95% confidence interval (CI 1.0-4.7), female patients (RR 2.5, 95% CI 1.2-5.2), and absence of intensive chemotherapy before SCT (RR 8.8, 95% CI 3.3-20.5). All patients except one improved after treatment with corticosteroids. The MC seem to be the best tool to establish a diagnosis of ES. In doubtful cases, the diagnosis could be confirmed by evaluating CRP. Auto-SCT in patients not receiving previous chemotherapy could explain the increasing incidence of ES in the past years.

Salvage chemotherapy with alternating MINE-ESHAP regimen in relapsed or refractory Hodgkin's lymphoma followed by autologous stem-cell transplantation.

BACKGROUND: High-dose chemotherapy (HDT) followed by autologous stem-cell transplantation (ASCT) is considered the gold standard in the treatment of patients with relapsed or refractory Hodgkin's lymphoma (HL). However, the optimal salvage regimen has not yet been established. PATIENTS AND METHODS: We retrospectively analyzed the efficacy and toxicity of MINE (mesna, ifosfamide, mitoxantrone, and etoposide) alternated with ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin) in the treatment of 61 relapsed or refractory HL patients after ABVD-based chemotherapy. RESULTS: Overall, 25 patients (41%) achieved a complete response (CR), 23 (38%) a partial response (PR), 4 (7%) a stable disease, and 8 (13%) progressed for an overall response rate of 79%. Response to first-line chemotherapy was the most important prognostic factor for response to MINE-ESHAP (P = 0.041). No grade 4 extrahematologic toxic effects or toxic deaths were observed. Adequate peripheral blood stem-cell collection was achieved in 56 of 59 (95%) mobilized patients. Overall survival and event-free survival after HDT and ASCT were significantly higher for patients achieving CR/PR in comparison with those refractory to MINE-ESHAP (46% and 35% versus 74% and 69%, respectively). CONCLUSION: MINE-ESHAP results in a high response rate with acceptable toxicity in patients with HL having failed ABVD-based treatment.

G-CSF increases the number of peripheral blood dendritic cells CD16+ and modifies the expression of the costimulatory molecule CD86+.

Dendritic cells (DC) play a key role in initiating immune reactions after allogeneic stem cell transplantation. The two main peripheral blood DC populations are myeloid (DC1) and lymphoplasmacytoid (DC2). A new subset of myeloid DC, expressing CD16, has been identified. We analyzed the number and CD86 expression of DC subsets in peripheral blood of 18 healthy donors, before and after granulocyte colony-stimulating factor (G-CSF) and in the inoculum of allogeneic peripheral blood transplants (allo-PBT; n=100) and allogeneic bone marrow transplants (allo-BMT; n=22). Granulocyte colony-stimulating factor administration increased the median number of DC1 (P=0.0007), of DC2 (P<0.0001) and of DC CD16+ (P=0.0001). Granulocyte colony-stimulating factor administration was also associated with a significant decrease of CD86 expression on DC1 (P=0.0003) and with a trend for an increase on DC CD16+ (P=0.07). Recipients of allo-PBT received similar quantities of DC1 and higher doses of DC2 and DC CD16+ than recipients of allo-BMT (P=0.5; P=0.0001; P<0.0001, respectively). Granulocyte colony-stimulating factor modifies the number of DC in peripheral blood and the expression of the costimulatory molecule CD86. This resulted in a different composition of DC2 and especially of DC CD16+ in the harvests, which might explain some of the differences observed in allogeneic reactions after allo-PBT with respect to allo-BMT.

High-dose therapy/autologous stem cell transplantation in patients with chemosensitive multiple myeloma: predictors of complete remission.

High-dose therapy (HDT) followed by autologous stem cell support is widely used as intensification treatment in patients with multiple myeloma (MM) responsive to the initial chemotherapy. However, there is growing evidence that only the subset of patients who achieve complete remission (CR) actually benefit from this approach. The aim of this study was to identify pretransplant predictors of CR in responding myeloma patients intensified with HDT. A total of 59 patients with chemosensitive disease received myeloablative therapy. The intensification regimen consisted of MEL-200 (23), MEL-140/TBI 12 Gy (21) or busulfan-based regimens (15). Serum and urine negative immunofixation were required for CR. After HDT, the CR rate increased from 8 to 37%. For the overall series, the median event-free survival (EFS) and overall survival (OS) from the initiation of therapy were 41 and 68 months, respectively. Patients who achieved CR had an EFS (median 47 vs 36 months; P=0.023) as well as an OS (median not reached vs 60 months; P=0.006) significantly longer than those attaining a lower degree of response. Finally, the pretransplant features significantly associated to CR were a low M-protein size (serum