Epidemiology and Risk Factors of Invasive Fungal Infections Among 795 Patients with Chronic Lymphocytic Leukemia from the Padua University

Abstract Background Invasive fungal infections (IFI) are serious and life-threatening complications of hematological malignancies particularly in patients affected by acute myeloid leukemia and following hematopoietic stem cell transplantation. However, only few epidemiological data concerning fungal infections in chroniclymphoproliferativedisorders are available. In this work we aimed to identify the clinical and biological features of patients with chronic lymphocytic leukemia (CLL) affected by IFI. Methods We performed a single-center retrospective study based on the CLL patients referred to the Hematology Unit of University of Padua from 1983 to 2015. IFI were defined as infective events caused by yeasts ormouldsthat required inpatient management and/or intravenous antifungal therapies. We included only proven and probable IFI. Time to IFI (TIFI) and overall survival (OS) were calculated from the date of CLL diagnosis to IFI development or death (event), respectively, or last available follow-up (censored). Diagnostic work-up of fungal infection included blood cultures, serumgalactomannanantigen test for 3 consecutive days (cut-off 0.5), β-1,3-(D)-glucanand high resolution chest computed tomography andbronchoalveolarlavages when clinically indicated. We also collected the closest immunoglobulin (IG) levels data before the onset of each IFI or serious bacterial infective events. IGs measured during infections were not included in the analysis, because they could have been influenced by the infectious event. The last available serum IG levels were considered for patients who did not suffer from any IFI. Results 795 patients with CLL were recruited in this study. 60% were male and the median age at diagnosis and at IFI onset were 65 and 68 years, respectively. The median follow-up was 8.5 years and 316 patients required treatment during the follow-up. 11 out of 795 (1.4%) patients developed IFI during the follow-up. Among them, 7 patients (64%) had probable Aspergillosisand 4 had proven IFI (3 Aspergillusspp and 1 Candida kruseii) based on histological confirmation and/or microbiological isolation of the specific fungal agent. 9 patients wereBinet stage A, 2Binet B and noneBinet C at CLL diagnosis. The median lines of treatment were 5 ranging from 2 to 9. Six out of 11 (55%) patients showed high-risk cytogenetic by FISH analysis (11q or 17p deletion), 2 harbored complex karyotypes, 62% (5/8) hadunmutated IGVH gene. By Kaplan-Meyer analysis we showed that IFI occurred in 2.1% and 7.0% of the cohort after 10 and 20 years of follow-up, respectively (Figure 1A). However, considering the number of chemotherapy regimens, the estimated cumulative incidence of IFI was higher in patients who were treated with at least 4 lines of chemo-immunotherapy (10-year TIFI were 9.0% and 0.3%, p<0.0001, Figure 1B). IFI occurrence was associated with a very poor prognosis. In fact, the median overall survival of patients who developed IFI was 125 months as compared to 250 months of the remaining cohort (Log-rank test, p=0.0001, Figure 1C). Since IFI was itself the main cause of death of these subjects. In multivariable analysis, patients with IFI had almost 10 times higher-risk of death (HR 10, p=0.0012) that other patients. We demonstrated that, at the time of IFI events, patients had lower levels of IG as compared to a group of 72 patients who had serious bacterial infections or to 712 subjects who did not have any infections. The medianIgGlevels were 4.11, 6.38 and 8.38 g/L for patients with IFI, bacterial infections and without history of infections, respectively (ANOVA test, p<0.0001, Figure 1D). The median IgA levels were 0.35, 0.78 and 1.39 g/L for patients with IFI, bacterial and none infections, respectively (ANOVA test, p<0.0001, Figure 1E). The medianIgMlevels were 0.28, 0.59 and 0.65 g/L for patients with IFI, bacterial and none infections, respectively (ANOVA test, p=0.0038, Figure 1F). Conclusions Herein, we described the epidemiology of invasive fungal infections among a large cohort of CLL patients from a single institution over 32 years. We demonstrated that IFI significantly impacts on the survival of CLL patients and we provided evidence of the importance of previous chemo-immunotherapy and IG levels on the risk of developing IFI. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Prognostic importance of serum soluble CD23 level in chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v88.11.4259.4259 ◽

1996 ◽

Vol 88 (11) ◽

pp. 4259-4264 ◽

Cited By ~ 116

Author(s):

M Sarfati ◽

S Chevret ◽

C Chastang ◽

G Biron ◽

P Stryckmans ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Disease Progression ◽

Early Stage ◽

Lymphocytic Leukemia ◽

Study Entry ◽

Clinical Staging ◽

Soluble Cd23

Abstract Prognosis of B-cell chronic lymphocytic leukemia (CLL) is based on clinical staging whose limitation is the failure to assess whether the disease will progress or remain stable in early stage (Binet A, or Rai 0, I, II) patients. We previously reported that soluble CD23 (sCD23), a protein derived from the B-cell membrane CD23 Ag, is selectively elevated in the serum of CLL patients. This prospective study assessed the predictive value of serum sCD23 level measured at study entry on the overall survival of all CLL patients and on disease progression of stage Binet A patients. Prognostic value of repeated measurements of sCD23 over time in stage A patients was also analyzed. One hundred fifty-three CLL patients were prospectively followed with a median follow-up of 78 months. Eight clinical or biological parameters were collected from the date of the first sCD23 measurement. At study entry, by Cox model, Binet staging (P = .0001) and serum sCD23 level (P = .03) appeared as prognostic factors for survival. Patients with sCD23 level above median value (> 574 U/mL) had a significantly worse prognosis than those with lower values (median survival of 53 v 100+ months, P = .0001). During follow-up, sCD23 doubling time increased by 3.2 the risk of death (P = .001). Among stage A patients (n = 100), sCD23 determination at study entry was the sole variable predictive of disease progression, patients with sCD23 level above 574 U/mL had a median time progression of 42 months versus 88 months for those with lower levels (P = .0001). Stage A patients who doubled their sCD23 level exhibited a 15-fold increased risk of progression (P = .0001) and, in addition, the sCD23 increase preceded by 48 months disease progression. We conclude that in CLL patients, serum sCD23 level provides significant additional prognostic information in terms of overall survival. Most interestingly, among early stage patients, sCD23 determination at diagnosis and during the course of the disease may help to the early identification of patients who will rapidly progress to upper stages.

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Revelance of Gammaglobulin Levels at Diagnosis and during Disease Course in Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v128.22.5561.5561 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5561-5561

Author(s):

Erin Streu ◽

Jayce Bi ◽

Mandy DeSousa ◽

Versha Banerji ◽

Dhali H.S. Dhaliwal ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Replacement Therapy ◽

Lymphocytic Leukemia ◽

Age At Diagnosis ◽

Disease Course ◽

Β2 Microglobulin ◽

Igg Replacement Therapy ◽

Over Time

Abstract Introduction: Hypogammaglobulinemia is commonly observed in chronic lymphocytic leukemia (CLL), likely worsens over time and with chemoimmunotherapy, and eventually leads to infections which are a major cause of death in this disease. Unfortunately, newer therapies, such as ibrutinib, may not prevent the ongoing immunosuppression in CLL as a major cause of discontinuing this drug is increased infections. Nowadays, most patients present with early stage CLL, with an increasing number having monoclonal B cell lymphocytosis (MBL) and being followed for many years. CLL treatment is typically intensive, using chemoimmunotherapy with the therapeutic goal being to minimize tumor load. For these reasons, a reassessment of Ig levels in a CLL Clinic at diagnosis and during disease course in the 'real-life' setting has been carried out, along with an assessment of the need for Ig replacement. Methods: All CLL/SLL/MBL cases referred to the CLL clinic at CancerCare Manitoba, Winnipeg, Canada from 2007 to 2011 were included in this study. Immunoglobulin (Ig) levels (G, A, and M) were measured at the time of referral/diagnosis (baseline) and annually thereafter. Ig levels were correlated with patient characteristics (age at diagnosis, gender, comorbidities), CLL prognostic indicators (Rai stage, lymphocyte doubling time, creatinine, LDH, β2- microglobulin, IGHV mutational status, ZAP-70, CD38) and time to first treatment (TTFT). A subset analysis of patients treated with replacement gammaglobulin was also conducted. Results: There were 293 patents in this cohort with median age at diagnosis of 68 years. Of these, 62.5% were male, 38% had received treatment, and 24% died during the follow up time (median follow up of 71 months). Seventy percent of patients had CLL (of those 85% were diagnosed with Rai 0/I), 15% MBL and 15% SLL. At baseline, 41% had normal Ig levels while 59% had a reduced level of one or more Ig (32% had reduced levels of one Ig type, 18% two, and 9% all three). Overall, 53% of patients had low IgM, 24% low IgG and 17% low IgA. However, no consistent correlation was found between the Ig levels at diagnosis and any of the prognostic markers outlined above. Hypogammaglobulinemia (at least two consecutive values < normal) was associated with need for CLL treatment (HR 3.45, 95% CI 1.63-7.30, p=0.0012), while hypogammaglobinemia at diagnosis predicted a shorter TTFT (p=0.0008). Baseline IgA was also predictive of TTFT as well as overall survival, with patients with normal IgA having a longer TTFT, patients with high/low IgA a shorter TTFT (p=0.0012) and those with high IgA a shorter overall survival (p=0.0032). Furthermore, there was a positive correlation between baseline IgG and number of comorbidities (r=0.17, p = 0.0057) as measured by the Cumulative Index Rating Scale (CIRS) and β2-microglobulin levels. Eighteen patients (6.14%) required Ig replacement therapy, of those 13 (72%) were male and 13 (72%) had received chemotherapy. These patents also had a shorter overall survival than those not requiring IgG replacement therapy (p=0.0006). CLL cases with high baseline IgG are seven times more likely to require IgG replacement therapy (HR 6.92, 95% CI 1.78 - 29.91, p=0.0052) while cases with low baseline IgG are 5 times more likely (HR 4.99, 95% CI 1.59 - 9.43, p=0.0254) as compared to those with normal baseline IgG. Baseline IgA and IgM were not predictive of need for IgG replacement therapy. Interestingly, over a median follow-up of 4 years, one-third of patients with normal baseline IgG developed a low IgG and this was unrelated to receiving chemotherapy (Figure 1). Summary This study demonstrates that baseline Ig levels in CLL are informative of the underlying biology of this disease, and could provide valuable information regarding disease progression, survival and need for subsequent IgG replacement therapy or CLL treatment. Importantly, Ig levels may be elevated in CLL and this is associated with increased CIRS and a high β2-microglobulin level, suggesting that the increase is related to underlying comorbidities. Further studies are required to examine the cause for the progressive decline in Ig levels over time, despite an otherwise stable disease, and to determine whether this decline can be eliminated by earlier treatment with novel new therapies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Chemoimmunotherapy With Fludarabine and Rituximab Produces Extended Overall Survival and Progression-Free Survival in Chronic Lymphocytic Leukemia: Long-Term Follow-Up of CALGB Study 9712

Journal of Clinical Oncology ◽

10.1200/jco.2010.31.1811 ◽

2011 ◽

Vol 29 (10) ◽

pp. 1349-1355 ◽

Cited By ~ 93

Author(s):

Jennifer A. Woyach ◽

Amy S. Ruppert ◽

Nyla A. Heerema ◽

Bercedis L. Peterson ◽

John G. Gribben ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Variable Region ◽

Progression Free Survival ◽

Lymphocytic Leukemia ◽

Free Survival ◽

Mutational Status ◽

Long Term Follow Up

Purpose The addition of rituximab to fludarabine-based regimens in chronic lymphocytic leukemia (CLL) has been shown to produce high response rates with extended remissions. The long-term follow-up of these regimens with respect to progression, survival, risk of secondary leukemia, and impact of genomic risk factors has been limited. Methods We report the long-term follow-up of the chemoimmunotherapy trial CALGB 9712 from the Cancer and Leukemia Group B, for which treatment regimen was previously reported, to examine end points of progression-free survival (PFS), overall survival (OS), impact of genomic features, and risk of therapy-related myeloid neoplasm (t-MN). Results A total of 104 patients were enrolled on this study and now have a median follow-up of 117 months (range, 66 to 131 months). The median OS was 85 months, and 71% of patients were alive at 5 years. The median PFS was 42 months, and 27% were progression free at 5 years. An estimated 13% remained free of progression at almost 10 years of follow-up. Multivariable models of PFS and OS showed that immunoglobulin heavy chain variable region mutational status was significant for both, whereas cytogenetic abnormalities were significant only for OS. No patient developed t-MN before relapse. Conclusion Long-term follow-up of CALGB 9712 demonstrates extended OS and PFS with fludarabine plus rituximab. Patients treated with fludarabine plus rituximab administered concurrently or sequentially have a low risk of t-MN. These long-term data support fludarabine plus rituximab as one acceptable first-line treatment for symptomatic patients with CLL.

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Cerebral Invasive Aspergillosis in a Case of Chronic Lymphocytic Leukemia with Bruton Tyrosine Kinase Inhibitor

Current Oncology ◽

10.3390/curroncol28010081 ◽

2021 ◽

Vol 28 (1) ◽

pp. 837-841

Author(s):

Omar Alkharabsheh ◽

Alhareth Alsayed ◽

Diana M. Morlote ◽

Amitkumar Mehta

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Tyrosine Kinase ◽

Kinase Inhibitor ◽

Fungal Infections ◽

Case Reports ◽

Invasive Fungal Infections ◽

Lymphocytic Leukemia ◽

High Morbidity ◽

Bruton Tyrosine Kinase ◽

Btk Inhibitors

Bruton tyrosine kinase (BTK) inhibitors have become an important therapy for untreated and previously treated patients with chronic lymphocytic leukemia (CLL). Despite improved outcomes, rare adverse events, such as invasive fungal infections, have been reported with the use of first-generation BTK inhibitors. Invasive fungal infections carry a high morbidity and mortality risk. There have been several case reports describing the association between aspergillosis and ibrutinib treatment, but none with acalabrutinib, to our knowledge. In this case report, we describe a patient with CLL who developed an intracranial Aspergillus fumigatus infection while receiving acalabrutinib.

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Retrospective Non-Interventional Assessment of the Use of Idelalisib in Relapsed/Refractory Chronic Lymphocytic Leukemia Patients in Spain

Blood ◽

10.1182/blood-2019-126588 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5473-5473 ◽

Cited By ~ 1

Author(s):

Christelle M Ferra ◽

Manuel Perez Encinas ◽

Javier Lopez Jimenez ◽

Macarena Ortiz ◽

Santiago Osorio-Prendes ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Adverse Events ◽

Real World ◽

Research Funding ◽

Fungal Infections ◽

Lymphocytic Leukemia ◽

Cumulative Probability ◽

Pneumocystis Jirovecii Pneumonia ◽

Grade 3

Background Idelalisib is a PI3-kinase inhibitor specific for the delta isoform, approved (in combination with rituximab or ofatumumab) for the treatment of adult patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL). Although the efficacy of idelalisib was reported in clinical trials, it is unclear how this translates into Real World. Methods A non-interventional retrospective study was conducted in Spain to describe the clinical characteristics and outcomes of patients diagnosed with R/R CLL that started treatment with idelalisib between 1 February 2015 and 31 December 2017. The Time from start of idelalisib treatment to either the start of a new anti CLL therapy or death (Time to Next Treatment or Death - TNTD) was defined as primary endpoint. Secondary endpoints included overall survival (OS), time to discontinuation (TTD) and safety, especially Adverse Events of Special Interest (AESI): ≥ grade 3 transaminase elevations, diarrhea /colitis, pneumonitis, neutropenia,Cytomegalovirus, bacterial, fungal and respiratory virus infections (RVI),Pneumocystis jirovecii pneumonia (PjP). Results Investigators from 21 centers included 77 patients in the study. The median age was 72.1 years (48-86) and 67.5% (n=52) were male. The main baseline characteristics were: Binet stage B-C in 32.5% (n=25), 17p deletion or TP53 mutation in 35.1% (n=27) and the median number previous lines of therapy was 4 (1-16). With a median follow up time of 14.4 months (1.2-44.4), 27 patients (35.1%) had started a new treatment and 19 (24.7%) had died. The median TNTD was 17.1 months (95% CI 14.0-22.3) in the overall population and 13.8 months (95% CI 7.9-15.2) in patients that discontinued idelalisib. The median OS has not been reached, with a cumulative probability of surviving at 1 and 2 years of 0.84 (95% CI 0.73-0.91) and 0.67 (95% CI 0.52-0.78). During follow-up 54 patients (70.1%) discontinued idelalisib: 39 (72.3%) due to toxicity and 10 (18.5%) due to disease progression. The median TTD was 13.0 months (95% CI 7.7-15.8); 5.3 months (95%CI 3.8-8.0) in patients who discontinued treatment due to serious adverse events (SAE) or AESI and 10.5 months (95% CI 0.5-16.0) in those who did so due to progressive disease. A total of 355 AEs were reported, of which 29.0% (n=103) were SAE. 181 AESIs were recorded: the most frequent were neutropenia (n=67; 22 grade >3), diarrhea/colitis (n=37; 14 grade >3) and bacterial infections (n=24; 14 grade >3). Other AESI were CMV infections (n=11), grade ≥ 3 pneumonitis (n=7), RVI (n=6), fungal infections (n=5), grade ≥ 3 transaminase elevations (n=3) and PjP (n=1). The median time from Idelalisib start to first AESI was 9.5 months (95%CI 5.5-15.3). During follow-up, 19 deaths were registered, 10 of which were caused by idelalisib-related SAEs (4 respiratory infections, 2 pneumonitis, 1 diarrhea/colitis). The time from SAE related to idelalisib that led to death, to death was 0.8 months (95% CI 0.7-1.7). Conclusions This real world study shows results of effectiveness of idelalisib consistent with the efficacy findings of the 312-0116 clinical trial. Toxicity was the most common reason for idelalisib discontinuation. Findings of adverse events were consistent with the known safety profile of idelalisib and no new drug-related adverse events were identified. This is a Gilead Sciences sponsored study. Disclosures Perez Encinas: GILEAD SCIENCES: Research Funding; CELGENE: Consultancy; JANSSEN: Consultancy. Lopez Jimenez:GILEAD SCIENCES: Honoraria, Other: Education funding. Ortiz:GILEAD SCIENCES: Research Funding. Cordoba:Pfizer: Consultancy; Celgene: Consultancy, Honoraria, Speakers Bureau; FUNDACION JIMENEZ DIAZ UNIVERSITY HOSPITAL: Employment; Roche: Honoraria, Speakers Bureau; Kyowa-Kirin: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Ramirez Payer:GILEAD SCIENCES: Research Funding. González-Barca:Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celtrion: Consultancy; AbbVie: Consultancy, Honoraria; Kiowa: Consultancy; Takeda: Honoraria; Celgene: Consultancy. Martín Sánchez:GILEAD SCIENCES: Research Funding. Sanchez:Gilead Sciences: Research Funding. Baltasar Tello:JANSSEN: Consultancy, Honoraria; ABBVIE: Honoraria; ROCHE: Honoraria; GILEAD: Honoraria. Amutio:NOVARTIS: Consultancy; JANSSEN: Consultancy, Honoraria; CELGENE: Consultancy, Honoraria; ROCHE: Honoraria; GILEAD SCIENCES: Consultancy, Honoraria; TAKEDA: Consultancy; GSK: Honoraria; BMS: Honoraria; JAZZ PHARMACEUTICALS: Honoraria; MUNDIPHARMA: Consultancy. Vidal Maceñido:GILEAD SCIENCES: Research Funding. Fernandez:GILEAD SCIENCES: Research Funding. Loscertales:Gilead: Honoraria; AbbVie: Honoraria; AstraZeneca: Honoraria; Janssen: Honoraria; Roche: Honoraria. Rodríguez:GILEAD SCIENCES: Research Funding. Alaez:ROCHE: Consultancy. Ramroth:Gilead Sciences: Employment. Palla:Gilead Sciences: Employment.

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Faculty Opinions recommendation of Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.10936958.11872056 ◽

2011 ◽

Author(s):

Tadeusz Robak ◽

Krzysztof Jamroziak

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Progression Free Survival ◽

Lymphocytic Leukemia ◽

Free Survival ◽

Long Term Follow Up

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Allogeneic Stem Cell Transplantation (allo-SCT) for Chronic Lymphocytic Leukemia: a Long Term Analysis From the Societe Francaise De Greffe De Moelle Et De Therapie Cellulaire (SFGM-TC).

Blood ◽

10.1182/blood.v114.22.201.201 ◽

2009 ◽

Vol 114 (22) ◽

pp. 201-201

Author(s):

Mohamad Mohty ◽

Jean-Paul Vernant ◽

Ibrahim Yakoub-Agha ◽

Didier Blaise ◽

Gérard Socié ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Chronic Lymphocytic Leukemia ◽

Stem Cell Transplantation ◽

Disease Progression ◽

Acute Gvhd ◽

Disease Status ◽

Lymphocytic Leukemia

Abstract Abstract 201 Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with a heterogeneous natural history. While some patients never require treatment or can be managed effectively with conventional chemotherapy, others experience early disease progression and death. Allo-SCT is increasingly considered as a therapeutic option for younger patients with poor-risk CLL. This multicenter retrospective analysis assessed the long term outcome of 160 CLL patients who received allo-SCT between 1987 and 2005, and were reported to the SFGM-TC registry. This series included 127 males (79%) and 33 females (20.6%) with a median age at CLL diagnosis of 45.5 (range, 24.4–65.1) y. The median age at time of allo-SCT was 50.9 (range, 29.8–68.3) y. Before allo-SCT, 26 patients (16.3%) received previous stem cell transplantation in the course of their disease. Patients received either a standard myeloablative conditioning regimen (n=58; 38%; Cy-TBI in 90% of cases) or a so-called reduced-intensity conditioning. A matched-related donor was used in 142 cases (89%) and PBSCs were used as source of stem cells in 92 cases (57.5%). At time of allo-SCT, only 10 patients (6.3%) were in CR1, 17 in CR2 and CR3 (10.6%), 27 in first PR (16.9%) and 106 (66.2%) in more advanced phases, including 46 patients (28.8%) in progressive disease. With a median follow-up of 60 (range, 1.6–208) months for surviving patients, 96% of patients engrafted (ANC>500/μL) at a median of 18 (range, 1–41) days after allo-SCT. 71 patients (44.4%) experienced grade 2–4 acute GVHD, including 28 cases (17.5%) of grade 3–4 acute GVHD. 73 patients (56.2%) experienced some form of chronic GVHD. At time of last follow-up, 70 patients (43.8%) were still alive, of whom 24 (34%) were in continuous CR. Disease progression accounted for 24 deaths, while transplant-related causes (infections, n=23; GVHD, n=13; MOF, n=12; other causes, n=18) were observed in 66 cases, for a TRM rate of 41%. The KM estimates of disease-free survival (DFS) at 2, 5, and 10 years after allo-SCT were 44.3%, 39.6%, and 30.5%, respectively. Estimates of overall survival (OS) were 54.4%, 46.2%, and 35.8.1%, respectively. In a Cox multivariate analysis for OS (including demographic features, transplant and donor types, and disease status at time of allo-SCT), disease status at time of allo-SCT (CR or PR) was the most significant parameter associated with improved OS (RR=0.56; 95%CI, 0.36–0.89). We conclude that allo-SCT has the potential to induce long-term disease control and overall survival in patients with high risk or advanced CLL. Disclosures: No relevant conflicts of interest to declare.

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Targeting Chronic Lymphocytic Leukemia with Cord Blood NK Cells In NSG Model

Blood ◽

10.1182/blood.v116.21.2453.2453 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2453-2453

Author(s):

Dongxia Xing ◽

William Decker ◽

Sufang Li ◽

Simon Robinson ◽

Nina Shah ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Cord Blood ◽

Nk Cells ◽

Adoptive Transfer ◽

Nk Cell ◽

Interleukin 2 ◽

Lymphocytic Leukemia ◽

Hematopoietic Stem ◽

Nsg Mice

Abstract Abstract 2453 The incompatibility between donor killer cell immunoglobulin-like receptors (KIRs) and their corresponding ligands has been reported to reduce the risk of relapse after haploidentical and human leukocyte antigen (HLA) mismatched hematopoietic stem cell transplantation in patients with acute myeloid leukemia. We tested this KIR-ligand mismatch hypothesis in the context of allogeneic cord blood NK cells as an adoptive transfer of lymphocytes treating residual chronic lymphocytic leukemia (CLL). As a model for targeting malignant B cells in CLL, we examined allogeneic cord blood NK cell function in NOD scid gamma (NSG) mice, which carry the null interleukin-2 receptor gamma chain mutation, as the mice developed leukemia. Positively selected CD56+ cord blood NK cells were expanded ex vivo with interleukin-2 for 14 days. CLL cells were established in the NSG model by infusion of CLL cells obtained from patients. The leukemia that develops in NSG mice resembles human CLL, with a proliferating CD19+CD23+CD5+ B-cell population detected in the bone marrow, spleen, lymph nodes, and peripheral blood. Subsequently, expanded cord blood NK cells (5 × 106 per mouse) were intravenously infused into NSG-CLL mice. The NK cells that were infused into the CLL mice were typed for HLA and KIR (four main KIRs: KIR2DL2, KIR2DL3, KIR3DL1, and KIR2DL1). The CLL patients' samples that had been used in the NSG models were genotyped for KIR ligands (HLA-C group or HLA-Bw4 group and HLA-A3). In the six pairs of cord blood NK and CLL cells typed, all were HLA mismatched. Five pairs were KIR-ligand mismatched; these mice showed robust NK cell–mediated killing of CLL cells 7 days after NK cell infusion. Of interest, although no KIR-ligand mismatch was seen between the cord blood NK cells and CLL cells in one pair, we still observed NK cell–mediated killing of CLL cells in the mice. In this instance, NK cell–mediated cell killing could have been attributed to possible lower expression of HLA ligands by leukemic cells. Overall survival was significantly improved in CLL-NSG mice that had received cord blood NK cell treatment compared with overall survival in untreated mice (Kaplan-Meier analysis, p < 0.03). These results showed that adoptive transfer of allogeneic cord blood NK cells can be effective in killing CLL, and will be explored in the clinic. Disclosures: Gribben: Roche: Consultancy; Celgene: Consultancy; GSK: Honoraria; Napp: Honoraria.

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Invasive Fungal Infections in Adults with Newly Diagnosed AML Undergoing Intensive Chemotherapy: Characterization, Risk Factors, and Outcomes in a Single Institution

Blood ◽

10.1182/blood.v118.21.4254.4254 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4254-4254

Author(s):

Kit Lu ◽

Dionissios Neofytos ◽

Amanda Blackford ◽

Amy Seung ◽

Judith E. Karp

Keyword(s):

Risk Factors ◽

Overall Survival ◽

Bacterial Infections ◽

Conflicts Of Interest ◽

Fungal Infections ◽

Significant Risk ◽

Invasive Fungal Infections ◽

Myelogenous Leukemia ◽

Newly Diagnosed ◽

European Organization

Abstract Abstract 4254 Background: Invasive fungal infections (IFI) are a significant cause of morbidity and mortality in patients with acute myelogenous leukemia (AML) undergoing chemotherapy treatment. However, the epidemiology, risk factors, and outcomes of IFI in these patients have been poorly described. Methods: A single-center retrospective analysis was performed to study the epidemiology, risk factors, clinical outcomes, and mortality predictors of IFIs in AML patients undergoing intensive, multi-agent induction timed sequential therapy (TST) between January 2005 and June 2010. Newly diagnosed AML patients, with exception of acute promyelocytic leukemia, were studied. IFIs were defined using the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria. Results: 254 consecutive patients (57% male; median age 54, range 20–78) were analyzed. 123 (48%) of patients had an IFI; of which, 15 patients (12%) had a proven candidal infection, and 108 patients (88%) had a mould infection (5 proven/probable (5%) and 103 (95%) possible mould infections). 237 (93%) patients received antifungal therapy during their treatment course (median day 8, range day -15 to 30). Of those, 63 (27%) received monotherapy (46% liposomal amphotericin, 44% voriconazole) and the rest received multiple antifungal agents. Significant risk factors and trends for developing +IFI shown from univariate analyses are listed in Table 1. Prolonged neutropenia, duration of mucositis, and concurrent bacterial infections did not significantly affect the development of +IFI. Using multivariate analyses, mortality was impacted by patients’ baseline organ function (p=0.002 [1.3,3.1]), specifically, by bilirubin < 2 mg/dL (p=0.003 [1.38,4.57]) and creatinine < 1.5 mg/dL (p=0.01 [1.23,5.4]). Patients with +IFI did not significantly impact overall survival. However, patients with candidal IFIs had a significantly lower overall survival compared to patients with mould IFIs and no IFI (HR 2.01 [1.06, 3.8]) (Figure 1). Candida colonization prior to or during the first week of chemotherapy, and development of mucositis were associated with the development of candidal IFIs (p=0.07). Conclusion: IFIs, particularly mould infections, remain a significant problem in patients with AML. Although overall survival did not appear to be significantly affected by mould infections, patients with candidal infections were more likely to die. Identification of risk factors for each type of IFIs may help to develop effective targeted preventive antifungal strategies. Disclosures: No relevant conflicts of interest to declare.

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