Absolute monocyte count at diagnosis could improve the prognostic role of early FDG-PET in classical Hodgkin lymphoma patients

Recently published international guidelines suggested that positron emission tomography (PET)-computed tomography (CT) could be utilized for response assessment using the Deauville criteria in fluorodeoxyglucose (FDG)-avid lym- phomas (Meignan et al, 2012). Interim PET (I-PET) scan- ning seems highly predictive of treatment failure in Hodgkin Lymphoma (HL) patients. We recently showed that the absolute monocyte count (AMC) has prognostic value in patients with classical HL (cHL) (Tadmor et al, 2015). Here, we show that the com- bined use of I-PET and AMC at diagnosis enables a more accurate projection of patient outcome in cHL. The present study is an ancillary branch of the analysis reported by Tadmor et al, (2015). Patients with histopatho- logical diagnosis of cHL previously enrolled in the Gruppo Italiano Studio Linfomi trials were eligible if data on all clini- cal and laboratory features and treatments, reported I-PET results, treatment response and follow-up were available. Response was defined according to the revised International Working Group guidelines (Cheson et al, 1999). An absolute lymphocyte count <06 9 10 9 /l and AMC > 075 9 10 9 /l were used as cut-off points. I-PET was performed after 2 cycles of treatment. A positive or negative I-PET was defined by the local investigators’ interpretation of the nuclear physi- cian’s scan report, which was based on a visual qualitative assessment. The principal end-point of the study was the impact of I-PET and AMC on progression-free survival (PFS); their impact on overall survival (OS) was the secondary end-point. Survival functions were estimated using the Kaplan–Meier method. Statistical comparisons between curves were per- formed with log-rank test, and the effect of the covariate was reported as hazard ratios (HR), from Cox regression. All patients had a diagnosis of cHL; 76% of cases had the nodular sclerosis (NS) subtype. Seventy-six patients (64%) were treated with classical ABVD (doxorubicin, bleomycin, vincristine, dacarbazine), and 23 (19%) and 19 (16%) with the more intensive BEACOPP (bleomycin, etoposide, doxoru- bicin, cyclophosphamide, vincristine, procarbazine, pred- nisone) and COPPEBVCAD (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, procarbazine, vinblastine, bleomycin) regimens (Federico et al, 2009), respectively. Of the entire cohort, 104 patients (88%) achieved complete remission. Twenty-six patients had a positive I-PET (22%) and 28 (24%) had AMC > 075 9 10 9 /l at diagnosis. The median follow-up of the entire cohort was 88 months (range 5–142 months). The estimated 5-year OS was 91% (95% confidence interval [CI]: 84–95%). The 5-year PFS was 80% (95% CI: 71–86%). Patients with positive I-PET showed a worse PFS compared to patients with negative I-PET (51% and 88%, respectively; HR 587 [95% CI: 256–135]). Patients with AMC > 075 9 10 9 /l at diagnosis had a worse PFS compared to patients with AMC ≤ 075 9 10 9 /l (58% and 87%, respectively; HR 373 [95% CI: 161–864]). Multi- ple Cox proportional hazards (PH) regression, adjusted for International Prognostic Score 3–7, confirmed the prognostic role of I-PET (HR 532 [95% CI: 230–123]; P < 0001) and AMC >075 9 10 9 /l (HR 319 [95% CI: 132–768]; P = 0010). Figure 1A, B shows the PFS for I-PET and AMC, and Table I shows the uni- and multivariate Cox PH regres- sion for PFS. The prognostic role of I-PET and AMC on OS was also confirmed. Given the strong predictive value of both I-PET and AMC, we stratified patients by positive or negative I-PET and AMC > 075 9 10 9 /l or ≤075 9 10 9 /l into 3 groups with different levels of risk. The low risk level (negative I- PET and AMC ≤ 075 9 10 9 /l; n = 73, 62%) had a 5-year PFS of 90% (95% CI: 80–96%), the intermediate level (I-PET positive or AMC > 075 9 10 9 /l; n = 36, 51%) had a 5-year PFS of 73% (95% CI: 55–85%), and the high risk level (I-PET positive and AMC > 075 9 10 9 /l; n = 9, 8%) had a 5-year PFS of 17% (95% CI: 1–49%). The log-rank test between the intermediate and low levels and between the high and intermediate levels were significant (P = 0 007, P = 0001, respectively). For OS, the difference between the intermediate and low risk levels tended to narrow (P = 0232), while the difference between the high and inter- mediate levels was significantly different (P < 0001). Fig- ure 1C, D shows the PFS and OS stratified by risk group. The test for trend in PFS and OS was significant (P < 0001). The rationale for using AMC as a prognostic parameter in cHL is relevant because immunohistochemical and molecular data, including the gene expression profile, have identified a key role for monocytes and macrophages in the biology of cHL (Steidl et al, 2010; Porrata et al, 2012; Tan et al, 2012; Koh et al , 2015; Tadmor et al, 2015). It might therefore bepossible that AMC is associated with the number of tumour- associated macrophages (TAMs) in the microenvironment. If so, then it could be considered as a biomarker of reactive cells that is easily detectable in peripheral blood. The FDG- PET scan is currently considered the most precise staging method and may also be used to provide an early prediction of treatment efficacy There is a strong suggestion that reactive cells are respon- sible for the increased FDG uptake at baseline, as they account for 99% of Hodgkin tumours (Gallamini, 2010). Furthermore, early responses to treatment have been sug- gested to demonstrate the elimination of reactive cells, or at least the disappearance of their activity, and are indirect surrogates of tumour chemo-sensitivity (Gallamini & Kostakoglu, 2012). Thus, the FDG-PET scan could be considered a biomarker of the extent and activity of the tumour microenvironment. However, in clinical practice, patients with negative I-PET can rapidly progress during induction treatment, while other patients with positive I-PET may eventually achieve a CR. Therefore, there is a need to further improve the predictive power of I-PET. By combining the AMC at diagnosis with the I-PET results, we showed that it is possible to increase the discriminatory power of I-PET alone in identifying cHL patients with poor PFS and OS. We are fully aware that our study has many weaknesses, such as its retrospective nature, the small number of patients and the lack of use of the Deauville criteria. However, our results suggest that it is pos- sible to further improve the already high predictive power of PET by combining it with a simple and inexpensive surrogate biomarker of reactive cells that are easily detectable in peripheral blood

Absolute monocyte count and lymphocyte-monocyte ratio predict outcome in nodular sclerosis Hodgkin lymphoma: Evaluation based on data from 1450 patients

Objective: To verify whether absolute monocyte count (AMC) and lymphocyte-monocyte ratio (LMR) at diagnosis are valid prognostic parameters in classical Hodgkin lymphoma (cHL). Patients and Methods: Data were collected from 1450 patients with cHL treated in Israel and Italy from January 1, 1988, through December 31, 2007. Results: The median age of the patients was 33 years (range, 17-72 years), and 70% (1017) of the patients had nodular sclerosis (NS); the median follow-up duration was 87 months. The best cutoff value for AMC was 750 cells/mm3, and the best ratio for LMR was 2.1. The adverse prognostic impact of an AMC of more than 750 cells/mm(3) was confirmed for the entire cohort, and its clinical significance was particularly evident in patients with NS histology. The progression-free survival (PFS) at 10 years for an AMC of more than 750 cells/mm(3) was 65% (56%-72%), and the PFS at 10 years for an AMC of 750 cells/mm(3) or less was 81% (76%-84%; P<.001). The overall survival (OS) at 10 years for an AMC of more than 750 cells/mm3 was 78% (70%-85%), and the OS at 10 years for an AMC of 750 cells/mm(3) or less was 88% (84%-90%; P=.01). In multivariate analysis, both AMC and LMR maintained prognostic significance for PFS (hazard ratio [HR], 1.54, P=.006, and HR, 1.50, P=.006) after adjusting for the international prognostic score, whereas the impact on OS was confirmed (HR, 1.56; P=.04) only in patients with NS and an AMC of more than 750 cells/mm(3). Conclusion: This study confirms that AMC has prognostic value in cHL that is particularly significant in patients with NS subtype histology. This finding links the known impact of macrophages and monocytes in Hodgkin lymphoma with routine clinical practice

Neutrophil-lymphocyte ratio at diagnosis is an independent prognostic factor in patients with nodular sclerosis Hodgkin lymphoma: Results of a large multicenter study involving 990 patients

Several studies have demonstrated the prognostic value of neutrophil-lymphocyte ratio (NLR) in patients with solid tumors and non-Hodgkin lymphoma. In contrast, there is only sparse data on its prognostic role in patients with classical Hodgkin lymphoma (cHL). The aim of our study was to establish whether NLR could serve as an independent prognostic factor in a cohort of 990 patients with nodular sclerosis (NS)-cHL. After analysis of the log hazard ratio (HR) as a function of NLR, we chose the value 6 as cutoff. Patients with NLR &gt;6 had a worse progression-free survival and overall survival compared to those with NLR ≤6; 84% vs 75% and 92% vs 88%, at 5 years, with an HR of 1.65 and 1.82, respectively. Multivariate analysis showed that the risk remained high with HR 1.44 and HR 1.54 in progression-free survival and overall survival, respectively. In summary, our study shows that NLR is a robust and independent prognostic parameter in NS-cHL, both in early and advanced disease. It is inexpensive and simple to apply. Thus, we conclude that NLR, possibly in combination with the international prognostic score and absolute monocyte count, is a useful guide for physicians treating NS-cHL patients

The prognostic role of end of treatment FDG-PET-CT in patients with diffuse large B cell lymphoma can be improved by considering it with absolute monocyte count at diagnosis

AbstractIt is well established that some patients with diffuse large B-cell lymphoma (DLBCL) and the negative end of treatment PET-CT (EOT-PET-CT) will relapse, while a proportion with positive upt..

Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia

Background: chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. Methods: we randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee. Results: the median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib. Conclusions: ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.)

COVID-19 severity and mortality in patients with CLL: an update of the international ERIC and Campus CLL study

Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p < 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41–0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02–1.04; HR = 1.79, 95% CI:1.04–3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated

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

Richter Transformation in Chronic Lymphocytic Leukemia: Update in the Era of Novel Agents

Richter transformation (RT) is a poorly understood complication of chronic lymphocytic leukemia (CLL) with a dismal prognosis. It is associated with a switch in histopathology and biology, generally with a transformation of the original CLL clone to diffuse large B-cell lymphoma (DLBCL) or less frequently to Hodgkin’s variant of Richter transformation (HVRT). It occurs in 2–10% of CLL patients, with an incidence rate of 0.5–1% per year, and may develop in treatment-naïve patients, although it is more common following therapy. In recent years, there has been a deeper understanding of the molecular pathogenesis of RT that involves the inactivation of the TP53 tumor suppressor gene in 50–60% of cases and the activation of aberrations of NOTCH1 and MYC pathways in about 30% of cases. Compared to the preceding CLL, 80% of cases with DLBCL-RT and 30% of HVRT harbor the same IGHV-D-J rearrangements, indicating a clonal evolution of the disease, while the remaining cases represent de novo lymphomas that are clonally unrelated. Despite advances in understanding the molecular variations and the pathogenesis of the disease, there is still no significant improvement in patient outcomes. However, if no clinical trials were designed for patients with RT in the past, now there many studies for these patients that incorporate new drugs and novel combinations that are being explored. In this review, we summarize the new information accumulated on RT with special emphasis on results involving the novel therapy tested for this entity, which represents an unmet clinical need