Impact of Blinatumomab Treatment on Bone Marrow Function in Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia

Association of blinatumomab treatment with myelosuppression was examined in this study. Peripheral blood counts were assessed prior to, during, and after blinatumomab treatment in patients with relapsed/refractory Philadelphia chromosome-negative (Ph−) B-cell precursor (BCP) acute lymphoblastic leukemia (ALL; n = 267) and Ph+ BCP-ALL (n = 45) from the TOWER and ALCANTARA studies, respectively, or chemotherapy in patients with Ph− BCP-ALL (n = 109) from the TOWER study; all the patients with relapsed/refractory BCP-ALL and responders achieving complete remission (CR) or CR with partial/incomplete hematological recovery (CRh/CRi) were evaluated. Event-free survival (EFS) and overall survival (OS) were assessed in patients achieving CR and CRh/CRi. Median leukocyte, neutrophil, and platelet counts increased during two blinatumomab cycles but remained low longer after chemotherapy. Among the responders, there was a trend that a greater proportion of patients achieved CR with blinatumomab (Ph−, 76.5%; Ph+, 77.8%) versus with chemotherapy (Ph−, 63.6%). In the TOWER study, the survival prognosis for patients achieving CRh/CRi versus CR with blinatumomab was more similar (median OS, 11.9 (95% CI, 3.9–not estimable (NE)) vs. 15.0 (95% CI, 10.4–NE) months, p = 0.062) than with chemotherapy (5.2 (95% CI, 1.6–NE) vs. 18.9 (95% CI, 9.3–NE) months, p = 0.013). Blinatumomab treatment, with only temporary and transient myelosuppression, resulted in a greater survival benefit than chemotherapy.

Alemtuzumab induced red cell aplasia and other immune cytopenias – not so ‘pure’

We report on the presentation and outcome of a 28-year-old female who developed red cell aplasia following alemtuzumab therapy for relapsing remitting multiple sclerosis. The patient also developed synchronous immune thrombocytopenia and immune neutropenia, but not aplastic anemia. This patient received high dose steroids, intravenous immunoglobulin (iv.Ig), rituximab, red cell transfusions, vincristine, G-CSF, cyclosporin and mycophenolate to treat the combination of cytopenias over a period of 6 months with subsequent improvement in bone marrow function. While alemtuzumab has several recognized autoimmune complications, little is known about the potential hematological side effects. The combination of red cell aplasia, immune thrombocytic purpura and autoimmune neutropenia has not previously been described in the literature following alemtuzumab immunotherapy and highlights the importance of monthly blood monitoring post alemtuzumab administration.

Recurrent CMV Viremia Portends Poor Prognosis and Results in Significant Resource Utilization in Patients with Poor Graft Function Post Allogeneic Stem Cell Transplantation

Introduction Poor Graft Function (PGF) characterized by 2 or more lineage cytopenias in the setting of complete donor chimerism is a recognized complication of allogeneic stem cell transplantation (alloSCT). Recurrent CMV viremia jeopardizes blood count recovery in PGF through direct effect of the virus on bone marrow function as well as myelosuppression/organ toxicity due to widely available antivirals such as val/ganciclovir or foscarnet. Methods To assess the clinical effect and resource utilization of recurrent CMV viremia on patients with PGF we performed a retrospective analysis of alloSCT recipients at our Centre from 2018-2019. Patients were classified as having PGF based on the following parameters: 1) Donor myeloid chimerism ≥95% at last assessment, 2) 2 or more lineage cytopenias defined by Hb ≤85g/L, Neutrophils ≤1.0x10 9/L, Platelets ≤60x10 9/L, 3) cytopenias present for 10 days after D30. CMV viral loads were monitored by q PCR twice weekly with reactivation defined as the first reading quantifiable above the threshold of detection of the assay. Recurrent CMV reactivation was defined as detectable CMV after an interval of 4weeks without detectable virus, with patients who reactivated within 4 weeks of an undetectable viral load defined as prolonged persisting infection. Patients who died before D60 or who relapsed within the 1 st 100 days or those who had a prior alloSCT were excluded. Baseline factors in the CMV seropositive PGF group were evaluated by Chi Squared and Kruskall-Wallis test for categorical and continuous variables respectively to establish any associations with recurrent or persisting CMV. Survival analysis of PGF patients was performed by the Kaplan Meier method with patients stratified by the following: Recurrent CMV/Prolonged persisting infection (RP-CMV), Single CMV reactivation (S-CMV), No CMV reactivations (N-CMV) and CMV sero-negativity (S-NCMV). A descriptive analysis of the number of hospital admissions in addition to the initial alloSCT admission (extra admissions) and total hospital days was also performed. Results There were 155 eligible patients of which 38 (24%) fulfilled criteria for PGF. The median follow-up of the cohort was 26 months (95%CI:23.1-28). The median overall survival (OS) of the cohort was not reached with an estimated 2 year OS of 73%. The 2 year OS of PGF patients was 59% compared to 78% in the non PGF group. There were no significant baseline associations found with RP-CMV (Table 1). Figure 1 demonstrates the survival of patients by nature of CMV reactivation. The 2 year OS by CMV reactivation was as follows: RP-CMV 25%, S-CMV 68%, N-CMV 70%, SN-CMV 87%. On univariate analysis, RP-CMV was significantly associated with mortality [HR 5.41; 95%CI 1.80-16.28; P=0.003]. This association remained significant when including Age and grade III-IV GVHD in multivariate analysis: RPCMV [HR 7.57; 95%CI 2.20-25.9;P=0.0013=], Age [HR 1.03; 95% CI 0.99-1.08; P=0.16] and GVHD [HR 2.91; 95%CI 0.87-9.75; P=0.08]. RP-CMV was not a risk factor for mortality within the NPGF population [HR 0.75; 95%CI 0.29-01.97; P=0.56]. Those with RP-CMV experienced an increase in their CMV viral load within a median of 4 days range (2-86) after achievement of an undetectable result. Those with PGF and RP-CMV had an average of 1.4 extra admissions with an average length of stay of 80 days, those with S-CMV reactivation had an average of 1.6 extra admissions with an average length of stay of 35 days, and those with N-CMV had an average of 1 extra admission with an average length of stay of 17 days. Those with SN-CMV had an average of 1 extra admission with an average length of stay of 23 days. CMV reactivation and CMV therapy contributed to 13/17 (76%) total readmissions for those with RP-CMV compared to 5/13 (38%) readmissions for those with S-CMV. Conclusion Patients with PGF and RP-CMV are at high risk of mortality as well as more lengthy hospital admissions of which CMV reactivation and CMV therapy is a potential contributor. Targeted use of novel therapies to prevent CMV reactivation in patients with PGF may improve both bone marrow function and survival leading to less resource utilization. Figure 1 Figure 1. Disclosures Chee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Koldej: CRISPR Therapeutics: Research Funding. Ritchie: BMS: Research Funding; Takeda: Research Funding; CRISPR Therapeutics: Research Funding; Amgen Inc: Honoraria, Research Funding; CSL: Honoraria; Novartis: Honoraria.

Polygenic basis and biomedical consequences of telomere length variation

Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally occurring variation in leukocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized UK Biobank participants. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 new). Genetically determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular and inflammatory pathologies. Finally, we estimated that, at the age of 40 years, people with an LTL >1 s.d. shorter than the population mean had a 2.5-year-lower life expectancy compared with the group with ≥1 s.d. longer LDL. Overall, we furnish new insights into the genetic regulation of LTL, reveal wide-ranging influences of LTL on physiological traits, diseases and longevity, and provide a powerful resource available to the global research community.

Polygenic basis and biomedical consequences of telomere length variation

Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence. Here we characterize the genetic architecture of naturally-occurring variation in leucocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized participants in UK Biobank. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 novel). Genetically-determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular, and inflammatory pathologies. Finally, we estimated that at age 40 years, people with >1-SD shorter compared to ≥1-SD longer LTL than the population mean had 2.5 years lower life expectancy. Overall, we furnish novel insights into the genetic regulation of LTL, reveal LTL's wide-ranging influences on physiological traits, diseases, and longevity, and provide a powerful resource available to the global research community.

The Impact of Tick-Borne Diseases on the Bone

Tick-borne infectious diseases can affect many tissues and organs including bone, one of the most multifunctional structures in the human body. There is a scarcity of data regarding the impact of tick-borne pathogens on bone. The aim of this review was to survey existing research literature on this topic. The search was performed using PubMed and Google Scholar search engines. From our search, we were able to find evidence of eight tick-borne diseases (Anaplasmosis, Ehrlichiosis, Babesiosis, Lyme disease, Bourbon virus disease, Colorado tick fever disease, Tick-borne encephalitis, and Crimean–Congo hemorrhagic fever) affecting the bone. Pathological bone effects most commonly associated with tick-borne infections were disruption of bone marrow function and bone loss. Most research to date on the effects of tick-borne pathogen infections on bone has been quite preliminary. Further investigation of this topic is warranted.

PSVIII-6 Cytomorphological features of the bone marrow of hypotrophic piglets

The experiment was conducted on newborn hypotrophic piglets obtained from sows of the 3rd–4th farrow on the farm in the Voronezh region. Bone marrow for histochemical and ultrastructural studies was selected from hypotrophic piglets with a body weight less than 800 g (n = 13). The material for electron microscopy was carried out in 2.5% glutaraldehyde in 0.114 M colloid buffer in the cold with postfixation in 1% solution of osmium tetroxide in the same buffer. The material was enclosed in epon-812. Semithin sections were stained with azur-2 in combination with the main fuchsin and were examined under Leica light microscope. Ultrathin sections were prepared on Ultracut (Leica) ultramicrotome, contrasted with lead citrate and uranyl acetate and examined under EM-208 (Philips) electron microscope. In hypotrophic piglets, the cells forming in the red bone marrow are located as islands. Hypoplasia of cells of the hemopoetic series occurred, proerythroblasts and megacaryoblasts were observed in insignificant quantity. Megakaryocytes were closely adjacent to sinusoidal capillaries, and a part of their cytoplasm penetrated into the lumen of blood vessels. Separating fragments of cytoplasm in the form of platelets were transferred to the blood flow. Light mitochondria with a few small electron-dense cristae were observed in the ultrastructure of cells of the bone marrow. The emergence of immature forms, which indicated bone marrow function disorder or its barrier damage, was also observed in the blood flow. At the same time there occurred a decrease in the number of differentiated cells and their differentiation disorder, which could lead to immunodeficiency state. Differentiation of cells in the bone marrow of hypotrophic piglets is impaired, and that is why the body is not provided with a sufficient number of blood cells. Blast cells, which appear in the blood flow, cannot fully perform their functions, resulting in immunodeficiency and anemia.

1146. Thrombocytosis in Infants with Congenital Cytomegalovirus Infection Being Treated with Valganciclovir

Background Congenital CMV (cCMV) is associated with sensorineural hearing loss and neurodevelopmental disabilities. Infants with symptomatic cCMV infection benefit from 6 months of oral valganciclovir (vGCV) therapy. Neutropenia, thrombocytopenia, and hepatotoxicity are adverse effects vGCV, for which we monitor. We observed a pattern that cCMV infants treated with vGCV developed an uptrend in platelets and/or thrombocytosis (platelet count >450,000/uL) while on therapy. This observation has not previously been reported. Methods Medical records and laboratory results from our multi-disciplinary cCMV clinic led by Infectious Diseases at Lurie Children’s Hospital were reviewed (2017-2020). Data included cCMV signs/symptoms, cCMV treatment prescribed, indication for ganciclovir/vGCV treatment, and complete blood count prior to, during, and post- vGCV therapy. Results Of 21 cCMV infants referred to clinic, 14 received >1 month of vGCV for symptomatic disease, 1 discontinued vGCV < 1 month due to perceived fussiness, and 1 was part of a clinical trial. Four infants were initially treated with ganciclovir for ≤1 month and transitioned to vGCV. Of the 14 patients treated with vGCV, 10 (71%) had sensorineural hearing loss (50% unilateral), 12 (86%) had central nervous system abnormalities (including cystic lesions on head ultrasound), 5 (36%) had thrombocytopenia, and 7 (50%) were intrauterine growth restricted [Table 1]. Eleven infants (79%) developed thrombocytosis. Thirteen infants (93%) had an uptrend in platelet count [not including normalization of initial thrombocytopenia (platelets < 150,000/uL)]. Figure 1 shows platelet counts by time with respect to vGCV treatment. Neutropenia (absolute neutrophil count < 500/uL) occurred in 1 patient that required temporary discontinuation of vGCV. Table 1 Figure 1 Conclusion We observed an interesting trend of rising platelet count and the development of thrombocytosis in the majority of our cCMV patients on vGCV. Platelet elevation associated with vGCV has not previously been described. This observation is limited by small number of patients and thrombocytosis is not a definitive association/adverse effect. With increasing use of vGCV and interest in its effect on bone marrow function, this observation is notable and warrants further study. Disclosures All Authors: No reported disclosures