Presence Of Cytopenias Research Articles

Molecular mechanisms promoting long-term cytopenia after BCMA CAR-T therapy in multiple myeloma

AbstractHematologic toxicity is a common side effect of chimeric antigen receptor T-cell (CAR-T) therapies, being particularly severe among patients with relapsed or refractory multiple myeloma (MM). In this study, we characterized 48 patients treated with B-cell maturation antigen (BCMA) CAR-T cells to understand kinetics of cytopenia, identify predictive factors, and determine potential mechanisms underlying these toxicities. We observed that overall incidence of cytopenia was 95.7%, and grade >3 thrombocytopenia and neutropenia, 1 month after infusion, was observed in 57% and 53% of the patients, respectively, being still present after 1 year in 4 and 3 patients, respectively. Baseline cytopenia and high peak inflammatory markers were highly correlated with cytopenia that persisted up to 3 months. To determine potential mechanisms underlying cytopenias, we evaluated the paracrine effect of BCMA CAR-T cells on hematopoietic stem and progenitor cell (HSPC) differentiation using an ex vivo myeloid differentiation model. Phenotypic analysis showed that supernatants from activated CAR-T cells (spCAR) halted HSPC differentiation, promoting more immature phenotypes, which could be prevented with a combination of interferon γ, tumor necrosis factor α/β, transforming growth factor β, interleukin-6 (IL-6) and IL-17 inhibitors. Single-cell RNA sequencing demonstrated upregulation of transcription factors associated with early stages of hematopoietic differentiation in the presence of spCAR (GATA2, RUNX1, CEBPA) and a decrease in the activity of key regulons involved in neutrophil and monocytic maturation (ID2 and MAFB). These results suggest that CAR-T activation induces HSPC maturation arrest through paracrine effects and provides potential treatments to mitigate the severity of this toxicity.

Clonal hematopoiesis and inflammation in the vasculature: CHIVE, a prospective, longitudinal clonal hematopoiesis cohort and biorepository

AbstractClonal hematopoiesis (CH) is an age-associated phenomenon leading to an increased risk of both hematologic malignancy and nonmalignant organ dysfunction. Increasingly available genetic testing has made the incidental discovery of CH clinically common yet evidence-based guidelines and effective management strategies to prevent adverse CH health outcomes are lacking. To address this gap, the prospective CHIVE (clonal hematopoiesis and inflammation in the vasculature) registry and biorepository was created to identify and monitor individuals at risk, support multidisciplinary CH clinics, and refine taxonomy and standards of practice for CH risk mitigation. Data from the first 181 patients enrolled in this prospective registry recapitulate the molecular epidemiology of CH from biobank-scale retrospective studies, with DNMT3A, TET2, ASXL1, and TP53 as the most commonly mutated genes. Blood counts across all hematopoietic lineages trended lower in patients with CH. In addition, patients with CH had higher rates of end organ dysfunction, in particular chronic kidney disease. Among patients with CH, variant allele frequency was independently associated with the presence of cytopenias and progression to hematologic malignancy, whereas other common high-risk CH clone features were not clear. Notably, accumulation of multiple distinct high-risk clone features was also associated with cytopenias and hematologic malignancy progression, supporting a recently published CH risk score. Surprisingly, ∼30% of patients enrolled in CHIVE from CH clinics were adjudicated as not having clonal hematopoiesis of indeterminate potential, highlighting the need for molecular standards and purpose-built assays in this field. Maintenance of this well-annotated cohort and continued expansion of CHIVE to multiple institutions are underway and will be critical to understanding how to thoughtfully care for this patient population.

Prediction of Risk for Myeloid Malignancy in Clonal Hematopoiesis

BackgroundClonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS) are defined by somatic mutations in genes associated with myeloid neoplasms (MN) at a variant allele fraction (VAF) of 0.02 or greater in the absence and presence of cytopenia, respectively. CHIP/CCUS is highly prevalent in adults, and defining predictors of MN risk would aid clinical management and research.MethodsWe analyzed sequenced exomes of healthy U.K. Biobank participants (N=438,890) in separate derivation and validation cohorts. Genetic mutations, laboratory values, and MN outcomes were used in conditional probability–based recursive partitioning and Cox regression to determine predictors of incident MN. Combined statistical weights were used to define a clonal hematopoiesis risk score (CHRS). Independent CHIP/CCUS patient cohorts were used to test the prognostic capability of the CHRS in the clinical setting.ResultsRecursive partitioning distinguished patients with CHIP/CCUS with 10-year probabilities of MN ranging from 0.0077 to 0.85. Multivariable analysis validated partitioning variables as predictors of MN. Key features, including single DNMT3A mutations, high-risk mutations, two or more mutations, a VAF of 0.2 or more, 65 years of age or older, having CCUS versus CHIP, and red blood cell indices, influenced MN risk in a variable direction. CHRS was used to define low-risk (n=10,018 [88.4%]), intermediate-risk (n=1196 [10.5%]), and high-risk (n=123 [1.1%]) groups. In clinical cohorts, most MN events occurred in high-risk patients with CHIP/CCUS.ConclusionsThe CHRS provides a simple prognostic framework for CHIP/CCUS, distinguishing a high-risk minority from the majority of CHIP/CCUS, which has a minimal risk of progression to MN. (Funded by the National Institutes of Health, the Harold Amos Medical Faculty Development Program, and others.)

Patterns of Cytopenias Associated with Methotrexate Treated Rheumatoid Arthritis Patients

Objective: To determine the frequency of various patterns of cytopenias with Methotrexate-treated rheumatoid arthritis patients and the correlation of pancytopenia with various factors.
 Study Design: Cross-sectional study.
 Place and Duration of Study: Rheumatology/General Medicine Department, Pak Emirates Military Hospital Rawalpindi from May 2019 to Mar 2020.
 Methodology: Patients with rheumatoid arthritis who were managed with Methotrexate for more than six months were included in the study. Full blood counts were performed for all the patients from the laboratory of the hospital. The frequency of monocytopenia, bi-cytopenia and pancytopenia were calculated.
 Results: Mean age of the study participants was 37.41±5.72 years. One hundred and sixty-eight 168(84%) patients had the presence of any cytopenia, while 32 (16%) did not show the presence of any cytopenia on full blood count. The advancing age and use of polypharmacy had a statistically significant association with cytopenias among patients with rheumatoid arthritis managed with Methotrexate (p-value <0.05).
 Conclusion: The presence of cytopenia emerged as a relatively common finding among rheumatoid arthritis patients managed with Methotrexate. Advanced age of the patient and patients who required more than one medication to control the symptoms of RA were found at a higher risk for developing pancytopenia while being managed with Methotrexate for rheumatoid arthritis.

The presence of a chromosomal abnormality in cytopenia without dysplasia identifies a category of high-risk clonal cytopenia of unknown significance.

Myelodysplastic syndromes (MDS) are hematological malignancies classically defined by the presence of cytopenia(s) and dysmorphic myeloid cells. It is now known that MDS can be preceded by a pre-malignant condition called clonal cytopenia of unknown significance (CCUS), which associates a clonality marker with cytopenia in the absence of criteria of dysplasia. However, to date, it is not clear whether chromosomal abnormalities should be considered in the definition of CCUS or if they carry a prognostic impact in CCUS patients. In this study, we analyzed the clinico-biological features and outcomes of 34 patients who presented with one or more cytopenias, an absence of significant dysplasia, and a presence of a chromosomal abnormality (CA). We named this entity chromosomal abnormality with cytopenia of undetermined significance (CACtUS). We show that these patients are slightly older than MDS patients and that they more frequently presented with normocytic anemia. Most CACtUS patients exhibited only one unbalanced CA. The number and type of mutations were comparable between CACtUS patients and MDS patients. Regardless of the cytogenetic abnormality, the clinicobiological characteristics, overall survival, and risk of progression to high-risk (HR) MDS were similar between CACtUS patients and low-risk MDS patients. Thus, we suggest that CACtUS patients can be considered as HR-CCUS and should receive the follow-up regimen recommended for MDS patients.

Utility of Peripheral Blood Flow Cytometric Blast Enumeration Reporting in Patients without Prior Hematologic Malignancy

Background: The significance of documenting the enumerated data of low levels of blast events (CD34+/CD117+) by peripheral blood flow cytometry studies is largely unaddressed in the literature. The presence of a blast population in peripheral blood of individuals without documented appropriate explanation (such as treatment with a colony-stimulating factor) can be the very first indication of an evolving hematolymphoid neoplastic process. We aim to identify a threshold of quantified blast events on peripheral blood flow cytometric studies that may alert medical professionals of a possible disease process affecting the bone marrow. Methods and materials: Peripheral blood flow cytometry studies performed by the clinical flow cytometry laboratory at the University of California Davis Medical Center between 2015 and 2020 that were detected to have less than or equal to 1% blast population were evaluated. Patients with a history of a known hematologic malignancy at the time of the aforementioned peripheral blood flow cytometry study were excluded. The remaining cases from patients without a known hematological malignancy were investigated. All flow cytometry events were analyzed by multiparametric 10-color flow cytometry using an extensive panel of monoclonal antibodies. The data events were analyzed with Kaluza® software. Percentages of blasts in patients with progression to a hematologic malignancy were compared with the group of patients without progression to a hematologic malignancy. The results of this comparison were utilized to establish a threshold of the presence of CD34+/CD117+ blasts that may warrant formal reporting and recommendations of additional studies. Results: A total of 165 flow cytometry cases from 2015-2020 were evaluated. The patients' electronic medical records were reviewed in order to determine the presence of a prior hematolymphoid malignancy and to evaluate for the progression of a malignancy after the flow study. Of the cases reviewed, 110 were excluded due to the presence of a prior hematolymphoid malignancy. The remaining 55 cases were separated into a group who on follow up had no progression to a hematolymphoid malignancy (n=50), and a second group who developed a hematolymphoid malignancy (n=5) (see figure). The mean percent of CD34+/CD117+ events in the group of patients who progressed to a hematolymphoid malignancy was higher than the non-malignancy control group (0.80% vs 0.40% of total flow cytometry events respectively). The mean percent of CD34+ events in the group of patients who had a malignancy was slightly higher than the control non-malignant group mean percent CD34+ events (0.248% vs 0.220% of total flow cytometry events respectively). Conclusions: We identified a small percentage of patients with no known hematolymphoid malignancy and low levels of blasts on peripheral blood flow cytometry study who later developed a hematolymphoid malignancy (5/55 = 9%). On further investigation, a slightly elevated level of CD34+/CD117+ blast events in these patients was noted. Of the patients who did not develop hematolymphoid malignancies, a significant percentage had non-malignant inflammatory conditions. Based on our current assessment, some patients with low levels of circulating blasts detected by flow cytometry may necessitate follow-ups, including bone marrow evaluation. The presence of cytopenias and/or elevated inflammatory markers may further assist in the decision to proceed with additional hematologic work-up. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hemophagocytic lymphohistiocytosis as an etiology of bone marrow failure.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of multiorgan system dysfunction that is caused by hypercytokinemia and persistent activation of cytotoxic T lymphocytes and macrophages. A nearly ubiquitous finding and a diagnostic criterion of HLH is the presence of cytopenias in ≥ 2 cell lines. The mechanism of cytopenias in HLH is multifactorial but appears to be predominantly driven by suppression of hematopoiesis by pro-inflammatory cytokines and, to some extent, by consumptive hemophagocytosis. Recognition of cytopenias as a manifestation of HLH is an important consideration for patients with bone marrow failure of unclear etiology.

VERY COMPLEX KARYOTYPE IN YOUNG MYELODYSPLASTIC SYNDROME PATIENT AFTER CHRONIC EXPOSURE TO CHLOROFORM

Myelodysplastic Syndrome (MDS) is marked by biological and clinical heterogeneity, characterized by dysplasia in the bone marrow and blood cells with the presence of cytopenias. MDS is recognized as a disease in elderly individuals. About 86% of MDS cases are diagnosed at age ≥ 60 and less than 10% of patients are younger than 50. Recurrent cytogenetic abnormalities are present in 40% to 60% of cases. Cytogenetic analysis plays an important role, whether in the diagnosis or classification of the disease. Recently, the new international molecular prognostic score system (IPSS-M) reinforces the valuable prognostic contribution of cytogenetics in MDS in both survival and leukemic evolution. To report a chronic chloroform exposure as a trigger capable of inducing DNA damage. Chronic exposure to a genotoxic agent has been linked to MDS chromosomal abnormality. Among these, chloroform, and an inorganic halide derivative of hydrocarbons can induce the DNA lesion. A 24-year-old male patient with a marked history of 10-year chloroform exposure sought medical attention for anemia, fainting, and unintentional weight loss. He was diagnosed with Myelodysplastic Syndrome and refractory anemia with excess blasts (RAEB II) with initial tests: Hb = 5 g/dL; neutrophils=320/mm3; platelets= 18 x 109/L. Bone marrow aspiration showed 15% myeloblasts, immunohistochemistry profile showed CD34+, CD117+ in blasts and cytogenetic analysis showed a very complex karyotype: 45,XY,del(6)(q22),-7,add(9) (q12),del(12)(p11.2),del(17)(p13),del(20)(q12),add(21(p13)[17]/46, XY[3]. Chemotherapy with azacitidine was performed as a bridge to bone marrow transplantation, but the patient evolved into sepsis, dying eight months after diagnosis. The pathogenesis of MDS reflects the heterogeneity of the disease, thus, comprises multiple steps and includes factors that can be endogenous and/or exogenous. Therefore, this unusual case shows the extreme importance of investigating possible recurrent and/or occupational exposures in these patients combined with cytogenetics analyses.

COVID-19 infection in hematopoietic stem cell transplant recipients

Objective. To assess the course and outcomes of COVID-19 in recipients of allogeneic and autologous hematopoietic stem cell transplant (HSCT). Materials and Methods. The retrospective study included 44 adult recipients (allogeneic – 33 [75%] and autologous – 11 [25%] of HSCT who diagnosed with COVID-19 after transplantation. Group mostly represented by acute leukemia – 18 (41%) and lymphoma – 10 (22.7%). The median follow-up time since the development of COVID-19 was 231 days (1–818 days), after HSCT – 507.5 days (14–3723 days). Overall and progression-free survival was assessed using the Kaplan–Meier and Log-Rank method. We also evaluated the characteristics of the course of a new coronavirus infection. Results. Median time for the development of COVID-19 from the moment of HSCT was 122.5 days (-1–3490 days). Twelve patients (27.2%) were in grade 3–4 neutropenia at the time of COVID-19 diagnosis, 16 (36.4%) patients were in grade 1–2 neutropenia. Sixteen (48.4%) allo-HSCT recipients had active graft-versus-host disease (GVHD) at the time of COVID-19 development. Disease severity was mild in 19 (43.2%) and moderate in 13 (29.5%) patients. Overall, 200-day survival from the onset of COVID-19 was 78.8% (95% CI [63.1–88.4]). Anemia (p = 0.02) and thrombocytopenia (p = 0.01) significantly decrease OS in patients with COVID-19 after HSCT. Patients with GVHD at the time of COVID-19 onset had a better survival rate (p = 0.02). The timing of COVID-19 development after HSCT did not affect outcomes. Conclusions. The key points of the course of COVID-19 in HSCT recipients are the presence of cytopenia and graft-versus-host disease. Overall survival was 78.8%.

Relmacabtagene Autoleucel CD19 CART Therapy for Adults with Heavily-Pretreated Relapsed/Refractory Large B-Cell Lymphoma in China

IntroductionPrognosis for relapsed and refractory large B-cell lymphoma (r/r LBCL) is poor, and treatment remains challenging. Relmacabtagene autoleucel (relma-cel) is a CD19-directed 4-1BB/CD3z chimeric antigen receptor T cell (CAR-T) product manufactured in China. RELIANCE study is the first CAR-T study with CD19 as target that got IND approved by the authority in China. Initial findings of the pivotal Phase 2 single-arm, multicenter RELIANCE trial demonstrated high response rates and low rates of CAR-T-associated toxicity with relma-cel treatment in heavily pretreated patients (pts) with r/r LBCL (NCT04089215; Ying et al. Cancer Med 2020;10:999-1011). Long-term follow-up data for the RELIANCE study are presented.Materials & MethodsFifty-nine adults (age ≥18 years) with heavily pretreated (≥2 prior therapies), measurable and histologically confirmed r/r LBCL were randomized to receive lymphodepletion chemotherapy (LDC: fludarabine 25 mg/m 2 + cyclophosphamide 250 mg/m 2 daily×3) followed by a single infusion of autologous CAR+ T cells at a dose of 100×10 6 or 150×10 6. Pts were evaluated for efficacy using Lugano criteria and for toxicity using Common Terminology Criteria for Adverse Events v4.03 and for cytokine release syndrome (CRS) using Lee et al. (Blood 2014;124(2):188-95). Primary endpoint was 3-month objective response rate (ORR); key secondary endpoints included complete response rate (CRR) at 3 months, duration of response (DOR), progression-free survival (PFS), overall survival (OS) and treatment-emergent adverse event (TEAE) profile. The data cutoff date was December 31, 2020.ResultsAt the time of analysis, all 59 pts (median age 56.0 years, range 18-75 years) were at least 15 months post-treatment with relma-cel (7 pts completed trial, 34 pts on study, 18 pts withdrew). Among the modified intent-to-treat (mITT) population of 58 efficacy-evaluable pts, best ORR was 77.6%, with a best CRR of 51.7%; ORR and CRR at 3-month-postdose landmark were 60.3% and 44.8%, respectively. With a median follow-up of 17.9 months (range 0.3-25.6 months), median PFS (mITT) was 7.0 months (95% CI 4.8-not reached [NR]). Median PFS was NR (95% CI 8.8 months-NR) for pts with compete response (CR) at 3 months, the 6-, 12-, 18- and 24-month PFS rates were 80.8%, 69.2%, 69.2% and 69.2%, respectively (Figure). PFS was associated with objective response or CR at 1, 3, 6, and 12 months (log-rank test, p≤0.002). Median OS was NR (95% CI NR-NR) for both the mITT population and pts with CR at 3 months (12-month OS rate, 76.8% and 92.3%, respectively). Median DOR was NR (95% CI 4.9 months-NR) for the mITT population and (95% CI 8.0 months-NR) for pts with CR at 3 months. Levels of CAR-T cells declined to below the level of quantification (BLQ) in 41 (69.5%) pts, among whom nearly 40% had sustained response. Median time from documentation of CAR-T BLQ to disease progression was 6.1 months (95% CI 1.8-NR). Treatment-related TEAEs were reported in 93.2% of pts and were primarily grade 1-2 (89.8% pts); 54.2% of pts had grade ≥3 TEAEs. Pyrexia was the most common TEAE, reported in 59.3% of pts (all grade 1-2). The most common grade ≥3 treatment-related TEAEs were neutrophil count decrease (30.5%) and white blood cell (WBC) count decrease (13.6%). Presence of cytopenia at day 29 (78.0%) was significantly associated with WBC count after LDC, change in serum albumin between days 1 and 4 and serum interleukin 8 after LDC (p<0.05). The incidence of CRS and neurotoxicity (NT) was 47.5% and 20.3%, respectively, both primarily grade 1-2. There were no CRS- or NT-related deaths. Occurrence of grade ≥2 CRS or NT (11.9% and 6.8%, respectively) was significantly associated with fold-change of platelet count on day 4 compared with baseline and day 1 absolute neutrophil count (p<0.03). There were no treatment-related deaths.ConclusionsThese are the first data of long-term follow-up CD19 CAR-T study with IND approval in China reported. With nearly 18 months of median follow-up, the RELIANCE pivotal registered study demonstrated durable responses, high rates of OS and PFS, and no new safety profile found in r/r LBCL pts. Based on these data, relma-cel is undergoing approval in China. Figure: Kaplan-Meier estimates of (A) PFS and (B) OS by 3-month tumor responsePR, partial response [Display omitted] DisclosuresZhang: JW Therapeutics: Current Employment. Yang: JW Therapeutics: Current Employment. Zhou: JW Therapeutics: Current Employment. Zheng: JW Therapeutics: Current Employment.

Is Hematopoietic Clonality of Indetermined Potential a Risk Factor for Pulmonary Embolism?

Background Unprovoked pulmonary embolism (uPE) is a severe and frequent condition. Identification of new risk factors is mandatory to identify patients that would benefit from a long-term treatment. Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the acquisition of somatic mutations that drive clonal expansion in the absence of cytopenia. Its prevalence is estimated of 5% in the population above 65 years. Since inflammation and endothelial dysfunction may share a pathophysiological pathway(1), we hypothesized that CHIP, may be a risk factor for uPE. Methods We conducted a pilot retrospective observational study. Patients with iPE between 18 to 65 years old were included. PE was considered as unprovoked, when no transient nor persistant risk factor was present and when thrombophilia testing was negative. We excluded documented atherosclerosis, personal or familial history of VTE and presence of cytopenias. CHIP proportion in uPE patients were analyzed using next generation sequencing of the coding sequence of a custom panel composed by DNMT3A, ASXL1, SF3B1, TET2 and TP 53 . Results Upon 61 patients with uPE consecutively included, a total of 19 somatic mutations were found in 12 patients (20%) IC95% [10 - 20]. 15 mutations were found in DNMT3A gene, 3 in ASXL1 and one in TET2 . There was no diference in terms of age, PE location, DVT presence and risk stratification in CHIP carriers and non carriers. Conclusion We report for the first time, the presence of high rates of CHIP in patients presenting with uPE. Thus, CHIP may be a new risk factor for VTE. These results need to be confirmed in an ongoing prospective case-control study including more patients and using a more diverse gene panel to better determine CHIP incidence in uPE.

Clinical Complications of Iron Overload in Patients with Myelodysplastic Syndromes: a literature review

Myelodysplastic Syndromes (MDS) are a group of heterogeneous hematologic disorders characterized by bone marrow involvement. Iron overload is the result of multiple transfusions and high levels of apoptosis. Based on a literature review, ferritin was identified as an important marker of iron accumulation in organs such as liver, heart and pancreas in patients with MDS. Some studies also demonstrated that iron overload caused cell cycle arrest causing apoptosis and progression to leukemia, high levels of reactive oxygen species and low levels of HIF-1a, causing apoptosis, being related to the presence of cytopenia in MDS.

Leukocytoclastic vasculitis as a previously unreported paraneoplastic manifestation of acute lymphoblastic leukemia in adults

Although leukocytoclastic vasculitis (LCV) is often idiopathic or secondary to benign diseases, it sometimes accompanies malignancies. Besides being more common in hematological cancers compared to solid tumors, the association of acute lymphoblastic leukemia (ALL) with LCV is extremely rare. In this study, we present a 22-year-old woman presenting with palpable petechiae, purpura, and ecchymoses on her limbs. Bone marrow and skin biopsy of the patient with bicytopenia revealed precursor B cell ALL and LCV, respectively. This case is the first adult ALL case with paraneoplastic LCV. In this study, it is emphasized that hematological malignancies should be considered in patients presenting with cutaneous vasculitis, especially in the presence of cytopenia.

PS1116 LATE ONSET NEUTROPENIA ASSOCIATED WITH RITUXIMAB. FREQUENCY AND RISK FACTORS IN A COHORT OF PATIENTS WITH NON HODGKIN LYMPHOMA AT INSTITUTO NACIONAL DE CANCEROLOGÍA MÉXICO

Background:Late onset neutropenia (LON) has been recognized as a side effect of therapy with rituximab, defined as grade III‐IV neutropenia (CTCAE) 3–4 weeks after the last dose with rituximab without any other aetiology. The post‐commercialization rate has been reported 0.02% in over 30,000 patients, but according to different studies, the rate of LON is considerably higher. It's necessary to distinguish between this adverse effect and another dreaded complication as therapy related Myelodysplastic syndromes.Aims:is to describe the prevalence of late onset neutropenia in a population of NHL patients treated with rituximabMethods:Two cohorts including patients with Diffuse Large B‐Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL) diagnosed between January 2011 and December 2015 were reviewed. Patients were were eligible if they were treated with chemotherapy + rituximab, achieved complete hematologic recovery(at the end of chemotherapy), lasting for at least 4 months, and thereafter developed cytopenias In all patients: infectious causes were requested (HIV, HBV; HCV), abdomen US, and if none peripheral comorbidity was documented, a bone marrow aspiration with cytogenetic analysis was done, to search t‐MDS. The following factors were analyzed as risk factors to develop cytopenias: history of febrile neutropenia during chemotherapy, number of cycles with rituximab, bone marrow infiltration, IPI, clinical stage, ECOG, B symptoms, number of nodal sites, and the presence of cytopenias at diagnosis. Descriptive and Cox‐regression analysis was done.Results:840 patients (DLBCL = 696 and FL = 145) were treated with schemas including rituximab, and achieved complete hematologic recovery. From them: 33 developed late onset cytopenias (66.7% with DLBCL and 33.35 with FL), 22 females and 11 males, with a median age of 60 years. At the end of treatment 12.1% developed LON (lowest absolute neutrophil count 400mm3) and 9.1% thrombocytopenia (lowest platelet count = 8,000/K). Interestingly, 91% of the patients with cytopenia had complete response compared with 58.9% of complete responses in patients without cytopenia which could be associated with the effectiveness of rituximab as reported in previous studies. The presences of Hb &lt;12 g/dl and &gt;6 nodal sites were related to the development of LON in patients with FL. Thrombocytopenia has also been described in patients receiving rituximab, and 9.1% of our patients developed only thrombocytopenia (15% of the patients developed combinations of thrombocytopenia with anemia or lymphopenia), with 9.1% requiring platelet transfusions; there are still no prospective studies which can help to define it as an entity as LON.Summary/Conclusion:Due to the spectacular benefits of the treatment with rituximab it is now considered as a standard of care for multiple lymphomas, we are able to recognize multiple complications associated as cytopenias in increasing frequency, and morbidity associated to infections that require hospitalization must be considered. Interestingly, the development of LON was associated with an increase in complete response and reduced rate of relapse, for reasons still to be discovered.

PS1340 ABSOLUTE MONOCYTE COUNT AFFECTS PROGNOSIS IN MYELODYSPLASTIC SYNDROMES INDEPENDENTLY FROM THE IPSS‐R

Background:Monocytopenia is a hallmark of some inherited bone marrow failure syndromes, e.g. in case of germline GATA2 mutations. Its prevalence and potential prognostic impact in Myelodysplastic Syndromes (MDS) is less well studiedAims:To define the prognostic role of the absolute monocyte count (AMC) in MDSMethods:The Düsseldorf MDS‐registry was screened for patients with information about the IPSS‐R and the AMC at diagnosis. Cases with a white blood cell count (WBC) ≥13 G/l or an AMC ≥1 G/l were excluded. The influence of the AMC on overall survival (OS) was determined by Kaplan‐Meier analysis and by uni‐ and multivariate Cox regression models.Results:976 patients with a median follow‐up of 28.5 months (mo) were identified, with a median AMC of 0.189 G/l (SD 0.239; range 0–0.996). Within higher IPSS‐R categories, lower median AMCs were observed: very‐low 0.309 G/l (range 0–0.966), low 0.232 G/l (range 0–0.996), intermediate 0.183 G/l (range 0–0.98), high 0.156 G/l (range 0–0.990) and very‐high 0.126 G/l (range 0–0.992) together with a highly significant difference between lower‐risk (IPSS‐R very‐low and low) compared to higher risk (IPSS‐R intermediate or [very] high) MDS (median AMC 0.241 vs. 0.155, p &lt; 0.001).Survival analyses were restricted to patients not having received allogeneic stem cell transplantation or induction chemotherapy (n = 771; IPSS‐R‐risk categories: very low n = 50 [median OS 102 mo], low n = 269 [median OS 67 mo], intermediate n = 201 [median OS 42 mo], high n = 139 [median OS 22 mo] and very high n = 112 [median OS 8 mo]).An AMC below the median was associated with a lower OS (HR for death 1.29, 95% CI 1.08–1.54, p = 0.004 and median OS 36 vs. 51 mo, p = 0.004) in univariate analysis, but without additional prognostic impact (HR 0.92, 95% CI 0.77–1.11, p = 0.397) after inclusion into a multivariate Cox regression model together with the cytogenetic risk categories according to IPSS‐R, bone marrow blast count (&lt; or ≥5%) and presence of cytopenias (haemoglobin &lt; or ≥10 g/dl, absolute neutrophil count &lt; or ≥1.8 x 109/l and platelets &lt; or ≥100 x 109/l).An AMC within the third quartile (0.190–0.379 G/l) was associated with a significantly longer OS compared to the first (0–0.076 G/l), second (0.077–0.189 G/l) and fourth (0.379–0.996 G/l) quartile (Q) [median OS 63 mo (Q3) versus 31 mo (Q1), 42 mo (Q2) and 41 mo (Q4), p = 0.002] and retained its independent prognostic value after inclusion into multivariate Cox regression models either together with the cytogenetic risk categories according to IPSS‐R, bone marrow blast count and presence of cytopenias as mentioned above (p = 0.015; HR 0.77, 95% CI 0.62–0.95) as well as together with the IPSS‐R categories as covariates (p = 0.001, HR 0.69, 95% CI 0.56–0.85). After stratification according to the IPSS‐R, the additional prognostic value of an AMC within Q3 was restricted to the IPSS‐R intermediate group (median OS 75 vs. 38 mo, p = 0.005).The WBC and the relative monocyte proportion were significantly higher in Q4 compared to Q1/2/3 (median 5.1 G/l vs. 3.0 G/l and 12% vs. 4%, respectively, p &lt; 0.001).Summary/Conclusion:Monocytopenia is an additional risk factor in MDS, but an AMC in the upper range of normal (0.38–0.99 G/l, Q4 of the cohort) is associated with an inferior survival as well. The biological basis of this unexpected phenomenon remains to be elucidated, but the significantly higher monocyte percentage suggests an accumulation of borderline cases between MDS and chronic myelomonocytic leukaemia in this subgroup. Further studies are needed to define the AMC best suitable for prognostication in MDS.

Prognostic and Predictive Impact of Small PNH Clones in a Large Cohort of Patients with Myelodysplastic Syndromes and Aplastic Anemia: A Single-Center Experience

▪Background: the use of high sensitive FLAER in the last 10 years improved the detection of very small PNH clones (<1%) in various hematologic conditions, including aplastic anemia (AA)/myelodysplastic syndromes (MDS). Although generally considered unremarkable, the recent observation of asymptomatic end-organ damage due to undiagnosed thrombosis even in patients without overt hemolysis questions the assertion that small PNH clones are of subclinical value.Aim: To evaluate the prevalence of PNH clones ≥0.01% in AA/MDS patients tested at a single tertiary center, and to assess their impact on disease prognosis (leukemic evolution, death), occurrence of thrombosis, and response to current therapies.Methods: We retrospectively collected clinical (diagnosis, stage, therapy, complications and outcome) and laboratory features (complete blood counts, LDH, PNH clone size) of 869 MDS and 531 AA patients tested from March 1998 till October 2017.Results: Figure 1 shows clinical and laboratory characteristics of MDS and AA patients, divided according to the presence/absence of PNH clones. A PNH clone was less frequently found in MDS cases versus AA (20.3% vs 61%). Focusing on MDS, PNH+ cases were significantly more hypoplastic, mainly displayed IPSS low/int-1 score, and showed deeper cytopenias (significantly for Hb and PLT) and higher LDH levels. Dividing patients according to clone size (negative, 0.01-1%, 1.01-10%,10.01-50%, and >50% on granulocytes), we observed a significant worsening of cytopenia and raise of LDH along with clone size increase. Likewise, lower IPSS risk patients more frequently displayed a greater clone size. As regards therapy, PNH+MDS showed significantly higher response rates to immunosuppressive therapies (ATG and CyA, 84% vs 44.7%, p=0.01) and to HSCT (71% vs 56.6%, p=0.09) compared to PNH-, and the cumulative probability of response to any treatment significantly improved along with clone size increase (from 52 to 100%, p=0.03). In addition, PNH+MDS showed lower rate of progression and AML evolution, and a longer OS [mean 11.9+0.7 years (10.5-13.3) vs 7.3+0.3 (6.6-7.9), p<0.0001] compared to PNH- ones. Interestingly, we observed a significant reduction of death frequency along with clone size increase (56% in PNH- vs 24% in PNH+ with clone size 0.01-1%, p<0.0001). However, PNH+MDS had a higher incidence of thrombotic events, with greater frequency along with clone size increase (from 5% in PNH- to 50% in PNH+ with clone size >50%, p<0.0001). As expected, worse OS also significantly correlated with older age, male gender, transfusion dependence, MDS progression/AML evolution, higher IPSS score, and non-response to therapy.Regarding AA, together with a higher frequency of PNH clones, we also found a higher frequency of large clones (>10%) compared to MDS (p=0.04, bars chart). PNH+AA showed deeper thrombocytopenia, higher reticulocyte counts and LDH values. As observed for MDS, we found a significant worsening of cytopenia and raise of LDH along with clone size increase. In addition, PNH+ AA showed higher response rates compared to PNH- (97 vs 77% for HSCT, p=0.01; 78 vs 50% for IST, p<0.0001; and 88% vs 65% considering any treatment, p<0.0001). PNH+AA also showed lower rate of MDS progression and death (p=0.01 and p<0.0001), and longer OS [mean 15.8+0.43 years (14.9-16.7) vs 6.5+0.35 (5.8-7.21), p<0.0001]. Also in AA, we observed a significant reduction of death frequency along with clone size increase (32.1% in PNH- vs 9.2% in PNH+ with clone size 0.01-1%, p<0.0001). Worse OS also correlated with older age, male gender, presence of cytopenia, and non-response to therapy.Conclusions: Prevalence of PNH clones of any size is high in patients with MDS and AA. We firstly show a positive impact of PNH clone positivity on response to IST and HSCT in MDS. The presence of a PNH clone also correlated with lower disease progression and better OS. Furthermore, we confirm the known favourable prognostic and predictive value of PNH clones in a large AA cohort. Clone size analysis suggests that even small clones (0.01-1%) have a clinical and prognostic significance. [Display omitted] DisclosuresKassam:AbbVie: Equity Ownership. Yallop:Pfizer: Consultancy; Servier: Other: Travel funding. Mufti:Celgene: Research Funding. Kulasekararaj:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support .

Myelodysplastic Syndromes, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology.

The myelodysplastic syndromes (MDS) comprise a heterogenous group of myeloid disorders with a highly variable disease course. Diagnostic criteria to better stratify patients with MDS continue to evolve, based on morphology, cytogenetics, and the presence of cytopenias. More accurate classification of patients will allow for better treatment guidance. Treatment encompasses supportive care, treatment of anemia, low-intensity therapy, and high-intensity therapy. This portion of the guidelines focuses on diagnostic classification, molecular abnormalities, therapeutic options, and recommended treatment approaches.

11q Deletion (del11q) Is Not a Prognostic Factor for Adverse Outcomes for Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treated with Ibrutinib: Pooled Data from 3 Randomized Phase 3 Studies

11q Deletion (del11q) Is Not a Prognostic Factor for Adverse Outcomes for Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treated with Ibrutinib: Pooled Data from 3 Randomized Phase 3 Studies

Laboratory and clinical risk assessment to treat myelodysplatic syndromes.

Myelodisplastic syndromes (MDS) are heterogeneous myeloid disorders characterized by peripheral cytopenias and increased risk of transformation into acute myelogenous leukemia (AML). MDS are generally suspected in the presence of cytopenia on routine analysis and the evaluation of bone marrow cells morphology and cellularity leads to correct diagnosis of MDS. The incidence of MDS is approximately five cases per 100,000 people per year in the general population, but it increases up to 50 cases per 100,000 people per year after 60 years of age. Typically MDS affect the elderly, with a median age at diagnosis of 65-70 years. Here the current therapeutic approaches for MDS are evaluated by searching the PubMed database. Establishing the prognosis in MDS patients is a key element of therapy. In fact an accurate estimate of prognosis drives decisions about the choice and timing of the therapeutic options. Therapy is selected based on prognostic risk assessment, cytogenetic pattern, transfusion needs and biological characteristics of the disease, comorbidities and clinical condition of the patients. In lower-risk patients the goals of therapy are different from those in higher-risk patients. In lower-risk patients, the aim of therapy is to reduce transfusion needs and transformation to higher risk disease or AML, improving the quality of life and survival. In higher-risk patients, the main goal of therapy is to prolong survival and to reduce the risk of AML transformation. Current therapies include growth factor support, lenalidomide, immunomodulatory and hypomethylating agents, intensive chemotherapy, and allogenic stem cell transplantation. The challenge when dealing with MDS patients is to select the optimal treatment by balancing efficacy and toxicity.

Clinical Factors Associated with Long-Term Complete Remission versus Poor Response to Chemotherapy in HIV-Infected Children and Adolescents with Kaposi Sarcoma Receiving Bleomycin and Vincristine: A Retrospective Observational Study.

Kaposi sarcoma (KS) is the most common HIV-associated malignancy in children and adolescents in Africa. Pediatric KS is distinct from adult disease. We evaluated the clinical characteristics associated with long-term outcomes. We performed a retrospective observational analysis of 70 HIV-infected children and adolescents with KS less than 18 years of age diagnosed between 8/2010 and 6/2013 in Lilongwe, Malawi. Local first-line treatment included bleomycin and vincristine plus nevirapine-based highly active anti-retroviral therapy (HAART). Median age was 8.6 years (range 1.7–17.9); there were 35 females (50%). Most common sites of presentation were: lymph node (74%), skin (59%), subcutaneous nodules (33%), oral (27%), woody edema (24%), and visceral (16%). Eighteen (26%) presented with lymphadenopathy only. Severe CD4 suppression occurred in 28%. At time of KS diagnosis, 49% were already on HAART. Overall, 28% presented with a platelet count < 100 x 109/L and 37% with hemoglobin < 8 g/dL. The 2-year event-free (EFS) and overall survival (OS) were 46% and 58% respectively (median follow-up 29 months, range 15–50). Multivariable analysis of risk of death and failure to achieve EFS demonstrated that visceral disease (odds ratios [OR] 19.08 and 11.61, 95% CI 2.22–163.90 and 1.60–83.95 respectively) and presenting with more than 20 skin/oral lesions (OR 9.57 and 22.90, 95% CI 1.01–90.99 and 1.00–524.13 respectively) were independent risk factors for both. Woody edema was associated with failure to achieve EFS (OR 7.80, 95% CI 1.84–33.08) but not death. Univariable analysis revealed that lymph node involvement was favorable for EFS (OR 0.28, 95% CI 0.08–0.99), while T1 TIS staging criteria, presence of cytopenias, and severe immune suppression were not associated with increased mortality. Long-term complete remission is achievable in pediatric KS, however outcomes vary according to clinical presentation. Based on clinical heterogeneity, treatment according to risk-stratification is necessary to improve overall outcomes.