Autologous Haemopoietic Stem Cell Transplantation Research Articles

Australian rheumatologists' perception of autologous haemopoietic stem cell transplantation for the treatment of systemic sclerosis: a cross-sectional survey.

Autologous haemopoietic stem cell transplantation (AHSCT) is an effective treatment for systemic sclerosis (SSc); however, treatment-related toxicity remains a key issue. To investigate the perceptions of rheumatologists on the use of AHSCT for SSc. Australian rheumatologists were asked for their opinion on the role of AHSCT, the indications for treatment and the barriers to the use of AHSCT for SSc. A secondary analysis assessed what factors influenced the perception of AHSCT. A total of 77.8% rheumatologists agreed or strongly agreed with the statement that AHSCT is an accepted treatment for SSc. While 65.1% agreed or strongly agreed that treatment-associated mortality was a significant barrier to referral for AHSCT, only 15.2% agreed or strongly agreed that this risk was unacceptable. Progressive lung or skin disease, or lack of response to other therapies, were considered the main referral criteria. A total of 92.0% of respondents agreed or strongly agreed that reduction of treatment toxicity would increase their likelihood to refer patients for AHSCT. Rheumatologists who were aware of the correct evidence base were more likely to consider AHSCT an acceptable treatment for SSc (4.21 ± 0.7 vs 3.64 ± 0.9, P = 0.007). Rheumatologists desire improved patient selection criteria and access to treatment. In this national survey of rheumatologists, AHSCT is considered an accepted therapy. However, concern about toxicity remains a potential barrier to patient referral. Access, studies to refine patient selection and development of AHSCT protocols that improve safety were identified as key areas of need.

Co-Occurrence of Familial Mediterranean Fever and Hematologic Malignancies: Case Report Series

Introduction: Familial Mediterranean Fever (FMF) is an autosomal recessive genetic disorder primarily found among individuals of Mediterranean descent, including Armenians, Italians, Greeks, Arabs, Turks and Jews. In the Armenian population, approximately 90% of FMF cases are associated with three main mutations (M694V, V726A, and M680I) in two alleles of MEFV gene, while more than 300 MEFV variants have been reported worldwide. The homozygous M694V genotype is associated with frequent renal failure due to amyloidosis. Clinical manifestations of FMF include periodic attacks of diffuse serositis with pain and fever that are treated with colchicine or biologic therapy. There is a scarcity of data on patients with FMF and hematologic malignancies. Limited data makes it difficult to generate evidence-based recommendations for the management of these patients, which is mostly based on expert opinions or few case reports. Here we report the case series of patients from Armenia with simultaneous presence of FMF and hematologic malignancies (FMFHM) and evaluate their management challenges. Methods: Data was collected from the Armenian National Registry of Blood Disorders, at the Hematology Center after Prof. R. Yeolyan, and through personal interviews conducted with each patient. Hematology Center is the only institution in Armenia managing hematologic malignancies. We have analyzed 8 patients diagnosed with both FMFHM during 2000-2020, treated in the pediatric (1 patient) and adult (7 patients) hematology departments. Results: 8 patients with FMFHM were identified, from which 4 were diagnosed with myeloproliferative neoplasms (MPN), 2 with acute leukemia (AL), and 2 with non-Hodgkin lymphoma (NHL). The median age of patients was 46, range 20-60 years. Only 5 (62.5%) of patients were regularly taking colchicine for FMF, while the rest refused it. Four MPN patients received treatment only with oral medications (tyrosine kinase inhibitors, hydroxyurea). Autologous hemopoietic stem cell transplantation (auto-HSCT) was performed in 1 NHL patient after indicated 1 st and 2 nd line immuno-chemotherapy. Another 2 AL patients and one NHL patient received protocol-based respective chemotherapy regimens. Moderate gastrointestinal (GI) complications (e.g., epigastric pain, nausea, vomiting, intestinal discomfort) was experienced by 7 (87.5%) patients. Allergic reactions (e.g., moderate skin rash, itching) were seen in 5 patient (62.5%), of which one developed severe anaphylactic shock. A patient with FMF and PMF had ischemic stroke caused by thrombi. Arterial hypertension occurred in 3 (37.5%). Only in one patient reduction of colchicine dosage was performed (1mg/day was reduced to 0.6mg/d), because of interaction with imatinib. The rest of patients received chemotherapy and colchicine treatment as indicated. All 8 patients are alive, 5 of them are in hematologic or molecular remission, two of which received concurrent colchicine treatment. One patient in remission developed renal failure due to FMF (colchicine was refused). Two patients with MPN treated with colchicine experienced disease stabilization. Conclusion: In conclusion, the concurrent appearance of FMFHM may potentially increase the risk of GI side effects, allergic complications, and arterial hypertension, however definitive conclusions require further investigations in larger patient cohorts. While the overall treatment responses were largely positive, the association between MEFV and HM mutations warrants deeper exploration to provide more precise drug administration recommendations for colchicine and cancer medications. Future studies in this area will contribute to a better understanding of the interplay between these conditions and guide optimal treatment strategies.

Survival of Hodgkin Lymphoma Patients Treated with Novel Immunotherapies after Autologous Stem Cell Transplantation Failure: A Retrospective Analysis of the Italian Lymphoma Foundation (FIL)

Background: Classical Hodgkin lymphoma (HL) is considered a highly curable disease and nearly 80-90% of patients (pts) may achieve complete remission (CR) with standard chemotherapy (Engert et. al. NEJM 2010).However up to 30% of HL pts experience primary refractory disease or eventually relapse after first-line treatment (Barrington et. al. Blood 2016, Press O et al. Clin Oncol 2016). High-dose chemotherapy followed by autologous hemopoietic stem cell transplantation (autoHSCT) has been showed to be an active salvage treatment in approximately 50% pts with chemosensitive relapse. Before the advent of novel immunotherapies, the median survival duration for pts failing autoHSCT was only 10 months (Vose et. al. Blood 1992). In this setting the introduction of Brentuximab Vedotin (BV) (Younes et. al. JCO 2012) and of the checkpoint inhibitors (CPI) Nivolumab (nivo) (Herrera et. al. Blood 2018) or Pembrolizumab (Chen et.al. Blood 2019) have shown to significant therapeutic active. Aims: To assess the therapeutic effects of BV and CPI in prolonging PFS and OS in patients with HL r/r post autoHSCT. Methods: This is an observational, retrospective, multicentric study from 15 centers of the Fondazione Italiana Linfomi (FIL). Adult patients who received salvage treatment with BV or CPI for post autoHSCT r/r HL from January 2015 to June 2018 were included in the analysis; the times of observation was censored in December 2020. Patients that had received pre-autoHSCT BV or CPI, were excluded from the analysis. Results: 40 pts, 25 treated with BV and 15 with nivo were included into the study. Patients' main characteristics at diagnosis are summarize in Table 1. Overall response was achieved in 23 (56%) pts treated with BV and in 9 (60%) with nivo, respectively. 14 (35%) out of 40 responsive to BV (10 pts) or nivo (4 pts) received allogeneic hemopoietic stem cell transplantation (alloHSCT) consolidation. The median follow-up time from the time of autoHSCT failure of the entire cohort was 36 months (range 2-70). At last follow-up, 32 (80%) pts were in CR, 1 (2%) in PR, while 2 (5%) and 5 (13%) were in SD and PD, respectively. 34 (85%) pts were alive and 6 (15%) have died. In the entire cohort, the median PFS and OS from the time of autoHSCT failure was 36 months and not reached, respectively; the 36-months projected PFS and OS of 50% and 86%, respectively. The median PFS and the 36-months projected OS of pts who received or not received alloHSCT were superimposable (Figure 1). Conclusion: In this retrospective analysis of pts with HL failing autoHSCT, BV or nivo resulted very active therapeutic salvage therapies. The comparison with historical results of the pre BV/CPI era suggests a major significant improvement both in PFS and OS. A significant proportion of pts received post BV or nivo alloHSCT but the effect of this treatment in prolonging PFS and OS should be further evaluated.

MRI graph parameters are longitudinal markers of neuronal integrity in multiple sclerosis

PurposeWe sought to determine if structural network parameters add to traditional markers of MS treatment response following immunoablation and autologous haemopoietic stem cell transplantation (IAHSCT). The post-IAHSCT paradigm afforded us the opportunity to study MS patients after relapsing biology had been effectively suppressed, enabling us to study the cortical substrate of progressive MS in a less confounded manner. MethodsIn this analysis of data from a phase 2 prospective study, associations between magnetic resonance graph parameters, N-acetylaspartate to creatine ratio (NAA/Cr), and serum neurofilament light chain (sNfL), amongst other markers, were assessed at 3 months pre-and 12 months post-IAHSCT. Correlations between graph parameter score changes and markers of brain health were calculated. Predictive factors of NAA/Cr or sNfL levels were calculated, adjusting for reference models. Model improvements were evaluated using the G2 likelihood-ratio test. Results24 patients (aged 18–38) were evaluated. Post-IAHSCT, high NAA/Cr and low sNfL (both measures of neuronal injury) were respectively associated with more favourable degree, density, clustering and path lengths, and degree, γ, and path length. Post-IAHSCT, absolute change in degree, path length and γ were associated with NAA/Cr and sNfL. Multivariate analysis demonstrated that the relative change in network parameters after IAHSCT accounted for 14% and 35% more variance in NAA/Cr and sNfL levels respectively than the reference model alone. ConclusionsCross-sectionally and longitudinally, network parameters demonstrate added utility as markers of disease severity in MS. These measures have the potential to capture cortical changes relevant to progressive non-relapsing biology in MS.

A PREDICTIVE MODEL FOR ULTRA‐HIGH RISK IN PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA: A SINGLE‐CENTER STUDY IN CHINA

Introduction: Although novel therapies have significantly improved the prognosis of multiple myeloma (MM) patients, there are still a subgroup of MM patients experienced early relapse or disease progression. To early identify the patients with compromised prognosis in our center, the study aimed to establish a predictive model for ultra-high risk (UHR) in MM. Methods: A study from a tertiary hospital in western China analyzed the patients with newly diagnosed MM (NDMM) receiving bortezomib and/or lenalidomide-included regimens from January 2015 to June 2021. The last follow-up date was December 31, 2022. The patients were randomly divided (2:1) into training and validation cohorts, and the patients with progression-free survival (PFS) less than 12 months were defined as UHR. Univariate and multivariate Cox regression analyses were performed for clinical feature selection. Independent baseline factors were incorporated and scored to develop the predictive model. The UHR group was then defined beyond the optimal cut-off value of total scores. Results: A total of 314 MM patients were enrolled and 102 (32.5%) patients underwent autologous hemopoietic stem cell transplantation (ASCT). The median time of follow-up was 36.6 months. Disease progression and death occurred in 178 (56.7%) and 69 (22.0%) patients. The median PFS (mPFS) was 36.5 months, and the median overall survival (mOS) was not reached. The mPFS of patients stratified into R-ISS III, R2-ISS III, R2-ISS IV, IMWG high-risk and mSMART double/triple hit was 23.8, 25.6, 10.0, 17.2 and 10.5 months, respectively. Among 54 patients at UHR, less than half of them could be identified by the aboved stratification systems. In the training cohort, elevated LDH, hypercalcemia, 1q21 gain/amplification (1q+) and the presence of extramedullary disease (EMD) showed significant association with UHR in NDMM. Referring to the results, the UHR predictive model was developed as 5 points for elevated LDH, 6 points for hypercalcemia, 7 points for 1q+ and 10 points for EMD. Patients with total scores of more than 12 points can be predicated as UHR. This model identified UHR and non-UHR groups with significantly different mPFS (9.8 v.s. 37.5 months, HR = 3.24, 95% CI:2.09-5.03, P < 0.001) and 5-year OS (63.3% vs. 83.8%, HR = 2.92, 95% CI: 1.47-5.81, P = 0.002). The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was 0.77, and in the validation cohort, the UHR model kept good discrimination (AUC: 0.79) at the latest follow-up. Conclusions: In this study, elevated LDH, hypercalcemia, 1q+ and EMD were selected and scored to develop the UHR model for NDMM patients. At present, the extension of follow-up time and expansion of sample size in the validation cohort are still ongoing. External validity is also designed to verify the generalizability of the model. The research was funded by: Natural Science Foundation of Sichuan Province, China, Grant/Award Number: 2022NSFSC1299 Keywords: Risk Models, Multiple Myeloma No conflicts of interests pertinent to the abstract.

Septic shock in patient undergoing hemopoietic stem cell transplantation. A case report

. Septic shock in patient undergoing hemopoietic stem cell transplantation. A case-report. This case on septic shock is the last contribution proposed on oncology emergencies. It is the case of a 66-year-old man who undergoes an autologous hemopoietic stem-cell transplantation for a multiple myeloma. The case follows the update on hemopoietic stem cell transplantation published in issue 1, 2023. The readers are invited to read the update for a useful guide to answering learning questions.

A Self-Help Manual for Psychological Distress and Quality of Life During a Haemopoietic Stem-Cell Transplant: An Effectiveness and Acceptability Pilot.

Haemopoietic stem-cell transplantation (HSCT) can be a highly distressing procedure that negatively impacts quality of life (QoL). Self-help interventions can help improve psychopathology and wellbeing in patients with physical illness, but have rarely been trialled with HSCT recipients. This study aimed to pilot the utility of a self-help manual intervention during the acute phase of HSCT. Forty autologous and allogeneic HSCT candidates were randomly assigned to a self-help manual intervention or treatment as usual (TAU). Psychological distress (BSI-18) and QoL (FACT-BMT-Vs4) were measured pre-, 2-3weeks and 3months post-HSCT. Linear mixed-effects analyses showed no significant group-time interaction for global QoL (p = .199) or global distress (p = .624). However, highlighting a protective role during admission, manual participants showed minimal QoL or somatic distress change at 2-3weeks post-transplant compared with moderate-large effects for reduced QoL (d = 0.62) and increased somatic distress (d = -0.81) for TAU patients. Thematic analysis suggests the manual helped prepare patients for transplant and provided strategies to improve distress and QoL. This pilot provides preliminary evidence for the benefit of a self-help manual during hospitalisation for a HSCT. More intensive, recovery-focussed care, however, may be needed to improve psychological health in the post-hospital period. Retrospectively registered trial (ANZCTR No. 12620001165976, 6th November 2020).

Post-Transplant Nivolumab Plus Unselected Autologous Lymphocytes in Refractory Hodgkin Lymphoma: A Feasible and Promising Salvage Therapy Associated with Expansion and Maturation of NK Cells

ABSTRACT Background. Hodgkin Lymphoma (HL) Hodgkin Lymphoma (HL) is a B-Cell neoplasia characterized by a high degree of response to chemotherapy and an overall favourable outcome in responding patients. Despite the efficacy of first line therapy, however, about 30% of patients affected by HL are either refractory or eventually relapse (R/R) after first or second line therapy followed by autologous hemopoietic stem cell transplantation (ASCT). Immune checkpoint inhibitors (CI) have demonstrated clinical activity in HL patients relapsing after ASCT, although only 20% complete response (CR) rate are usually observed. The efficacy of CI is strictly related to the host immune competence, which is impaired in heavily pre-treated HL patients. Aims. Here, we aimed to enhance the activity of early post-ASCT CI (nivolumab) administration with the infusion of autologous lymphocytes (ALI) and to investigate the lymphocyte subpopulation involved in the mechanism of response to CI in HL. Results. Seventeen patients with relapse/refractory (R/R) HL (median age 29 years; range 18-65), underwent lymphocyte apheresis after first line chemotherapy and then proceeded to salvage therapy. Subsequently, 12 patients with progressive disease at ASCT received early post-transplant CI supported with four ALI, whereas 5 responding patients received ALI alone, as a control cohort. Most patients showed CMV seropositivity at the time of enrolment, without signs of active infection (positive anti-CMV IgG, negative IgM and undetectable CMV DNA). No adverse events were recorded, specifically, no immune-related toxicity was observed and none of the patients showed CMV reactivation. All patients receiving ALI + CI (treated patients) achieved negative PET scan CR and 11/12 are alive and disease-free after a median follow-up of 33 months. The only relapse occured 23 months after last ALI. Six of the responding patients underwent subsequent allogeneic SCT in a CR status and 1 patients are currently waiting for transplantation. Two of the patients in the control arm relapsed after a median of 6 months (4-8 months) Phenotypic analysis of circulating cells showed a faster expansion of highly differentiated NK cells in ALI plus nivolumab-treated patients as compared to control patients (Fig.1). In detail, different patterns of NK cell development could be identified. Indeed, starting from one month after transplantation, in the group of patients undergoing ALI plus nivolumab, a relevant fraction of NK cells displayed a mature phenotype characterized by a CD56dimCD16bright expression (Fig. 1). On the contrary, in control patients, NK cells were characterized by a more immature phenotype (high frequencies of CD56brightCD16neg/dim NK cells) even at late time points (three months) after transplantation (Fig. 1). This event occurred in all the treated (ALI + nivolumab) patients analyzed (Fig. 1). Finally, PB from patients undergoing ALI + nivolumab was enriched in unconventional CD56dimCD16dim NK cells (Fig. 1). One month after transplantation, CD94/NKG2A+ KIR- NK cells were largely predominant in all patients, whereas CD94/NKG2A- KIR+ NK cells were present in low proportions. An increase of CD94/NKG2A- KIR+ subset occurred primarily in treated patients starting from t2. At t3, the significant increase of CD94/NKG2A- KIR+ NK cells occurred in the treated group but not in the control group . This event occurred in all the treated (ALI + nivolumab) patients analyzed, regardless of their serological status for HCMV, but was more evident in treated patients who were seropositive for HCMV. Remarkably, PB from HCMV seropositive patients undergoing ALI + nivolumab became enriched over time in differentiated NK cells characterized by high expression of NKG2C receptor (the activating counterpart of NKG2A), as compared to HCMV+ control patients. This subset represents the so-called "adaptive" NK cell population that usually increases during HCMV infection/reactivation. In this case, however, this event occurred in the absence of HCMV reactivation, and only in HCMV seropositive patients treated with ALI + nivolumab. Conclusions. Our data show anti-tumour activity with good tolerability of ALI + CI for R/R HL and suggest that this setting may accelerate NK cell development/maturation and favour the expansion of the "adaptive" NK cell compartment, especially in patients with CMV seropositivity, in the absence of CMV reactivation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Thromboembolic Complications PICC-Related in Adult Patients Affected By Hematologic Diseases: A 13-Years Monocentric Experience

Background: Currently, Peripheral Insertion Central Venous Catheters (PICCs) represents the device of choice for the treatment of hematologic patients because of lower risk of complications, easier management in outpatient population compared to Centrally Inserted Central Venous Catheters (CICCs) and effectiveness in performing high-risk therapy as hematopoietic stem cell transplantation. Introduction: PICC insertion and use could be characterized by the occurrence of complications, whose most dangerous are the systemic and local infections and thromboembolic (TE) manifestations. The aim of this study is to evaluate the incidence of TE complications and the risk factors associated to their development. Methods: Since the 2007, a PICC team, consisting of a hematology physician and three dedicated nurses has carried out a prospective study to evaluate complication rate and usefulness of PICC device in the hematology clinical practice. Inclusion criteria included all hematologic inpatient and outpatient who needed program of chemo-radiotherapy, support treatment and HSCT, regardless of white blood cells (WBC) and platelets (PLT) counts. All patients underwent a previous evaluation of arms vascular anatomy by ultrasonography. All implantation procedures were performed under ultrasound guide with radiographic control following insertion. The TE complications were diagnosed in clinical suspicion with venous color-doppler ultrasound and, if necessary, vascular CT scan. The therapy was performed according to local guidelines. The duration of PICC life is reported as 1000 days/PICC. The statistical analysis were performed with R software (R core team 2021). Results: From March 2007 to June 2020, 1132 PICC implantation were performed in 983 hematologic patients (545 male and 438 females). Median age was 56 years, range 15-94. The most representative diseases were non-Hodgkin Lymphoma (NHL) (332 patients, 33,8%), Hodgkin Lymphoma (HL) (276 patients, 28%), Multiple Myeloma (MM) (127 patients, 12,9%), Acute Myeloid Leukemia (AML) (107 patients, 11%). Seven hundred and eighten PICCs (63.4%) were inserted in patients that underwent a previous therapy. Nine hundred and ten PICCs (80,4%) were used for chemo-radiotherapy courses, 95 (8,4%) for support treatment, 111 (9,8%) for autologous hemopoietic stem cell transplantation (HSCT), 15 (1,3%) for allogenic HSCT, 1 for auto-allo HSCT (0.09%). PICC median life was 133 days (range 1-1257) for a total of 156485 days. Forty-two PICCs were lost at follow up and for this reason the analysis about duration and complication was performed on 1090 devices. At the time of this analysis 25 PICCs (2,3%) are still in situ and in use, 754 (69,2%) were removed for end of therapy, 94 (8,6%) for accidental withdrawals, 130 (11,9%) for death, 1 (0,1%) for patient decision. Only 86 PICCs (7,9%) were removed because of catheter related complications: 4 (0,36%) for catheter rupture, 25 (2,3%) for malfunctioning/occlusion, 11 (1%) for malposition, 7 (0,64%) for local infection, 3 (0,3%) for confirmed PICC-related sepsis 36 (3,3%) for suspected PICC-related sepsis. There were only 30 episodes (2,7%; 0,19/1000 days/PICC) of symptomatic PICC-related thrombotic complications, without need of removal. The TE complications were described in PICC inserted in patients affected by HL (11 PICCs, 36.3%), NHL (9, 30%), MM (5, 16,7%), AML (2, 6,7%), promyelocitic leukemia (2, 6,7%), non neoplastic anemia (1, 3,4%). The univariate analysis shown a strong association between the TE complications and the duration of PICC life (Tab. 1). The multivariate analysis confirm this data with a demonstration that a diagnosis of HL and the age at time of insertion could be considered as risk factors for the onset of TE disease (Tab.1). Conclusions. These data shown that the rate of TE complications in our experience in adult hematologic patients is very low, no impacting on the safety of patients and usefulness of the devices. The advanced age of patients, duration of PICC life and HL diagnosis seem to be risk factor for the onset of TE manifestations PICC-related. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Incidence of chronic renal injury in patients undergoing autologous stem cell transplant therapy.

Haemopoietic stem cell transplant (HSCT) is a well-established treatment option for many haematologic immunologic and oncologic diseases, allowing the safe administration of high-dose chemotherapy. Increased risk of acute renal injury is associated with HSCT; however, the risk of chronic kidney injury in autologous HSCT remains unclear. This cohort study investigates the incidence of chronic renal injury and its predisposing factors in a single-centre population of 139 patients who underwent autologous HSCT. Estimated glomerular filtration rate (eGFR) was measured at baseline and at 3, 6, 12 and 24 months following autologous stem cell reinfusion and used as a marker of renal dysfunction. A significant reduction in mean eGFR of patients was observed from baseline (80.62 ± 2.97 mL/min) to 24 months (71.54 ± 4.14 mL/min), independent of primary diagnosis (P= 0.0019). At baseline, 12% of the cohort had stage 3 or worse chronic renal injury and this increased to 38% by 24 months. By univariate analysis, age at baseline greater than the mean of 58 years and the occurrence of acute kidney injury during the peritransplant period emerged as predictive factors for the development of chronic kidney disease at 24 months. The current results indicate there is an increased incidence of chronic renal injury in patients who have undergone autologous peripheral blood haemopoietic stem cell transplantation therapy and this injury is potentiated by the autologous stem cell transplant procedure.

Relationship Between Markers of the Acute Phase of Inflammation, Parameters of Blood Lipid Composition and Intracardiac Hemodynamics During Chemotherapy in Patients With Multiple Myeloma.

Aim To evaluate in a pilot study time-related changes in the clinical state, indexes of the acute phase of inflammation, parameters of blood lipid profile, intracardiac hemodynamics, and disorders of cardiac rhythm/conduction in patients who are not candidates for autologous hemopoietic stem cell transplantation, during three bortezomib-containing chemotherapy courses (VCD) followed by a correlation analysis.Material and methods This pilot study included 20 patients diagnosed with myeloma, who were not candidates for autologous hemopoietic stem cell transplantation and who had undergone three courses of VCD chemotherapy (bortezomib, cyclophosphamide and dexamethasone). In addition to mandatory examinations, measurement of blood lipid profile, transthoracic echocardiography (EchoCG), and 24-h Holter electrocardiogram (ECG) monitoring were performed for all participants before and after a specific therapy.Results Following three bortezomib-containing courses of chemotherapy, patients of the study group had significant increases in the neutrophil-lymphocyte ratio (NLR) (1.6±0.2 and 2.5±0.4; р=0.05), cholesterol concentration (4.8±1.1 and 5.6±1.1 mmol/l, р=0.05), and low-density lipoprotein concentration (2.8±0.4 and 3.5±0.8 mmol/l, р=0.02). In comparing the changes in parameters of intracardiac hemodynamics, criteria for genuine cardiotoxicity were not met, however, a tendency to emergence/progression of myocardial diastolic dysfunction was noted. No clinically significant disorders of cardiac rhythm/conduction were observed. The correlation analysis performed prior to the start of chemotherapy, showed significant strong, direct correlations between the C-protein concentration and left atrial (LA) volume (r=0.793; p=0.006), right atrial (RA) volume (r=0.857; p=0.002), left ventricular (LV) end-diastolic dimension (EDD) (r=0.589; p=0.043), and LV end-diastolic volume (EDV) (r=0.726; p=0.017). Following the specific treatment, significant, medium-power and strong correlations were found between NLR and EDV (r= -0.673; p=0.033), NLR and end systolic volume (ESV) (r= -0.710; p=0.021), respectively. Significant direct correlations were found between the bortezomib dose per one injection and the serum concentration of triglycerides following the treatment (r=0.78; p=0.05); a single bortezomib dose and parameters of intracardiac hemodynamics: LA (r=0.71; p=0.026), RA (r=0.74; p=0.014), EDD (r=0.837; p=0.003), EDV (r=0.749; p=0.013), ESV (r=0.553; p=0.049).Conclusion For the first time, a comprehensive evaluation was performed in patients with multiple myeloma, including the dynamics of blood lipid profile, intracardiac hemodynamics and disorders of cardiac rhythm/conduction during bortezomib-containing antitumor therapy, with an analysis of correlation with levels of acute inflammation phase markers. Although in the observation window for genuine cardiotoxicity, clinically significant cardiovascular complications were not detected, the found correlations may evidence a potential role of systemic inflammation activity in myocardial remodeling in the studied patient cohort.

Strategies for Potentiating NK-Mediated Neuroblastoma Surveillance in Autologous or HLA-Haploidentical Hematopoietic Stem Cell Transplants.

Simple SummaryHigh-risk neuroblastomas (HR-NB) are malignant tumors of childhood that are treated with a very aggressive and life-threatening approach; this includes autologous hemopoietic stem cell transplantation (HSCT) and the infusion of a mAb targeting the GD2 tumor-associated antigen. Although the current treatment provided benefits, the 5-year overall survival remains below 50% due to relapses and refractoriness to therapy. Thus, there is an urgent need to ameliorate the standard therapeutic protocol, particularly improving the immune-mediated anti-tumor responses. Our review aims at summarizing and critically discussing novel immunotherapeutic strategies in HR-NB, including NK cell-based therapies and HLA-haploidentical HSCT from patients’ family.High-risk neuroblastomas (HR-NB) still have an unacceptable 5-year overall survival despite the aggressive therapy. This includes standardized immunotherapy combining autologous hemopoietic stem cell transplantation (HSCT) and the anti-GD2 mAb. The treatment did not significantly change for more than one decade, apart from the abandonment of IL-2, which demonstrated unacceptable toxicity. Of note, immunotherapy is a promising therapeutic option in cancer and could be optimized by several strategies. These include the HLA-haploidentical αβT/B-depleted HSCT, and the antibody targeting of novel NB-associated antigens such as B7-H3, and PD1. Other approaches could limit the immunoregulatory role of tumor-derived exosomes and potentiate the low antibody-dependent cell cytotoxicity of CD16 dim/neg NK cells, abundant in the early phase post-transplant. The latter effect could be obtained using multi-specific tools engaging activating NK receptors and tumor antigens, and possibly holding immunostimulatory cytokines in their construct. Finally, treatments also consider the infusion of novel engineered cytokines with scarce side effects, and cell effectors engineered with chimeric antigen receptors (CARs). Our review aims to discuss several promising strategies that could be successfully exploited to potentiate the NK-mediated surveillance of neuroblastoma, particularly in the HSCT setting. Many of these approaches are safe, feasible, and effective at pre-clinical and clinical levels.

PB2193: IS HYPERHYDRATION NECESSARY FOR HIGH DOSE MELPHALAN CONDITIONING REGIMEN IN AUTOLOGOUS HAEMATOPOIETIC STEM CELL TRANSPLANTATION?

Background: Single-agent Melphalan or combined with Bortezomib is often used as a conditioning regimen in autologous haemopoietic stem cell transplantation (HSCT) for multiple myeloma (MM) and primary amyloidosis (AL). In order to prevent nephrotoxicity, Melphalan is often administrated with hyperhydration (HH) consisting of 4-6 Litres (L) 0.9% saline which has a potential fluid overload risk, mainly in elderly patients. Given the potential morbility of HH, some institutions use a less intensive hydration regimen consisting of 2-3L 0.9% saline the day Mephalan is administrated. Aims: This study aimed to retrospectively analyze the safety of not using hyperhydration (NHH) in our center. Methods: This study used a retrospective cohort design, reviewing patients from Guadalajara University Hospital diagnosed with MM or AL who underwent autologous HSCT between January 2017 and December 2021. Cohorts were defined by HH (6L/24h 0.9% saline) or NHH (2L/24h 0.9% saline) the day Melphalan was administrated. The primary endpoint of this study was the incidence of acute renal impairment, the secondary endpoints were fluid overload and other adverse effects. Comparisons were assessed using Student t-test or Fisher’s exact test, considering a p-value <0.05 statistically significant. Results: The sample included 50 patients: 11 with HH (100% MM) and 39 NHH (87.18% MM, 12.82% AL). Patient’s gender (HH 45.45% women; NHH 61.54% women) was similar in both cohorts. Median age in HH cohort was 71, while in NHH it was 61. The prevalence of kidney disease due to MM at diagnosis was higher in NHH cohort (HH 9.1%, NHH 17.9%; p=0.48) but not statistically significant. Baseline creatinine (HH 0.79, NHH 0.78; p=0.92) and the prevalence of cardiovascular risk factors (HH 63.6%, NHH 66.7%; p=0.31) were comparable. The incidence of acute renal failure (HH 18.1%, NHH 7.7%; p=0.31) was higher in HH but statistically non-significant, while median creatinine increase from Melphalan administration to day 7 after haemopoietic stem cell infusion was similar in both groups (HH 0.38, NHH 0.18; p=0.08). All patients who developed acute renal failure had a history of chronic kidney disease or a baseline creatinine >1 before HSCT and it was always reversible. Likewise, all patients developed mild kidney injury (AKIN stage 1) except for one (1/5) from the HH cohort (AKIN stage 3). Concerning the presence of clinical fluid overload, it was significantly more frequent in the HH cohort (36.6%) in opposition to the NHH cohort (7.7%) (p = 0.02) as expected due to the greater volume administrated, but no patients developed acute pulmonary edema. Regarding other adverse effects as hepatic toxicity (HH 0%, NHH 17.9%; p=0.13), rash (HH 9.1%, NHH 5.1%; p=0.63) or grade IV mucositis (HH 81.8%, NHH 64.1%; p=0.07), they were similar in both cohorts with no statistically significant difference between both groups. Neutrophil engraftment was reached at day +10 in HH group and at day +14 in NHH group. This difference is probably due to the elimination of G-CSF from the protocol in the last years in order to avoid engraftment syndrome. There were limitations in this study such as the small sample size and retrospective analysis. Image:Summary/Conclusion: Hyperhydration did not demonstrate to protect the kidney compared to non-hyperhydration regimes, with a significantly greater incidence of fluid overload. Consequently, HH may not be necessary for melphalan conditioning regimen in autologous haemopoietic stem cell transplantation as our protocol demonstrates an adequate safety profile.

Высокодозная химиотерапия с аутологичной трансплантацией гемопоэтических стволовых клеток при ретинобластоме у детей. Обзор литературы и демонстрация клинических случаев

Высокодозная химиотерапия с аутологичной трансплантацией гемопоэтических стволовых клеток при ретинобластоме у детей. Обзор литературы и демонстрация клинических случаевHigh-dose chemotherapy with autologous hemopoietic stem cell transplantation in children with retinoblastoma. Literature review and case series

Acute Hematological Toxicity during Cranio-Spinal Proton Therapy in Pediatric Brain Embryonal Tumors.

Simple SummaryEmbryonal tumors include a heterogeneous group of tumors that need multimodal and multidisciplinary treatments in which craniospinal irradiation (CSI) plays a major role, with a known impact on the acute toxicity and future quality of life of patients. Neutropenia represents one of the most common acute hematological side effects and is responsible for infections and treatment delays that can affect the effectiveness of therapy. To better describe hematological acute toxicity during proton beam radiation treatment, we retrospectively examined 20 subsequent pediatric patients affected by high-risk embryonal tumors subjected to CSI with dual-phase proton therapy after a chemotherapy regimen. Our data suggest that the dual-phase technique is safe and feasible in this setting of pediatric patients with a significant baseline hematological toxicity. Despite all patients having undergone chemotherapy prior to irradiation, no serious hematological toxicity was reported at the end of the treatment with proton therapy, and, therefore, no treatment was discontinued or delayed.Background: Embryonal tumors represent a heterogeneous entity of brain tumors that need a multidisciplinary treatment including cranio-spinal irradiation (CSI), with a known impact on the acute toxicity. Proton therapy (PT) boasts a reduction in acute hematological toxicity. Methods: We retrospectively examined 20 pediatric patients affected by high-risk medulloblastoma and other rare embryonal brain tumors subjected to CSI with PT from September 2016 to April 2020. Before CSI, all patients received induction chemotherapy, and three patients additionally received two high-dose courses with thiotepa, followed by an autologous haemopoietic stem cell transplantation. We recorded the total white blood cell count, absolute neutrophil count, platelets, and hemoglobin levels for all patients during PT. Results: Leucocytes and neutrophils decreased directly after the beginning of treatment, reaching a complete recovery at the end of treatment. Hemoglobin values remained constant over the treatment course. The median platelet value decreased until reaching a plateau around halfway through therapy, followed by a slow increase. No cases of febrile neutropenia or severe infections were reported. No treatment discontinuation due to hematological toxicity was necessary. Conclusions: CSI with PT was proven to be safe in this setting of pediatric patients. Our study showed that despite all patients having undergone chemotherapy prior to irradiation, no serious hematological toxicity was reported at the end of the treatment with PT, and, therefore, no treatment was discontinued or delayed.

Management and Outcome of Patients with Diffuse Large B-Cell Lymphoma Relapsed after Autologous Hemopoietic Stem Cell Transplantation (auto-HSCT): A Retrospective Analysis of the Lymphoma Working Party (LWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Abstract Introduction: The standard therapy for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients is salvage immuno-chemotherapy followed by high-dose therapy and auto-HSCT, but 50%-70% of them will have recurrence of the disease. There is no consensus on further therapy at this point. The present study is intended to analyze management and outcome of patients with DLBCL relapsing after auto-HSCT and reported to the EBMT database. Patients and Methods: Adult patients (age ≥ 18 years) diagnosed with DLBCL who underwent a first auto-HSCT between Jan/2003 and Dec/2013 and who relapsed after the auto-HSCT, were included in the analysis. Five hundred and forty-three patients (pts) were identified, but therapy after auto-HSCT relapse was not reported in 164 pts. This group of pts was more heavily pretreated before auto-HSCT [3 or more lines in 65 (40%); p Results: 229 (60%) pts were male, with a median age at auto-HSCT of 54 years (range: 19-75); at relapse: 34% had an R-IPI 3-5, 28% had B symptoms, 55% raised LDH, 33% bulky disease ≥5 cm and 76% Karnosfsky score above 80. Auto-HSCT was performed after one line of chemotherapy in 91 pts (24%), after two lines in 203 pts (54%), and after three or more lines in 85 pts (22%). Median time from first auto-HSCT to relapse was 5.7 mo (range: 0.4-75), 113 pts (30%) relapsed more than 1 year after auto-HSCT. The most frequent therapy combinations at relapse were: platinum containing regimens in 134 pts (35%), other active combinations (doxorubicin, cytosine arabinoside, ifosfamide, gemcitabine) in 97 pts (26%), lenalidomide / bendamustine containing regimens in 26 pts (7%), palliative (steroids, single agent, radiotherapy alone) in 77 pts (20%), other treatments in 45 pts (12%). Response after therapy was complete remission (CR) in 86 pts (23%), partial remission (PR) in 42 pts (11%), stable/progressive disease (SD/PD) in 171 pts (45%), unknown in 73 pts (19%) and death without response assessment in 7 pts (2%). Ninety-six (25%) pts underwent a second HSCT [allogeneic HSCT (allo-HSCT) in 82 patients]; 37 of them were in CR, 16 in PR, 39 with active disease, and in 4 status was unknown. Median follow-up of alive pts was of 42 mo (range: 26-65), 288 pts (76%) died: 239 (63%) of disease progression, 32 (8.4%) due to transplant related mortality, 5 (1.3%) of secondary malignancies, and 12 from other causes. OS at 36 mos for the whole cohort was 26% (95% CI 21-31). Results were significantly more favorable in pts who relapsed more than 1 year after auto-HSCT, with an OS at 36 mo of 43% (95% CI 34-53) compared with those who relapsed less than 1 year after auto-HSCT, with an OS at 36 mo of 18% (95% CI 14-24) (p Conclusions: In our series, 76% of pts who received therapy for relapse after auto-HSCT maintained a good performance status, in spite of the fact that relapse after auto-HSCT was an early event (median time from auto-HSCT to relapse, less than six months). Around 35% of the pts who received therapy responded, and 25% underwent a second HSCT, mainly allo-HSCT. The outcome of pts who relapsed longer than 1 year after auto-HSCT was relatively good, with a 36-mo OS of 43%, supporting consideration of active, curative approaches for these pts at relapse. In contrast, pts relapsing less than 1 year after auto-HSCT have significantly worse outcomes. These patients remain an unmet clinical need, and novel therapies and strategies are required. Disclosures Gonzalez-Barca: Roche: Speakers Bureau; Janssen: Speakers Bureau; Sandoz: Consultancy; Gilead: Consultancy. Trněný: BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Snowden: Sanofi: Honoraria. Bishton: Roche: Other: Travel Sponsorship. Janikova: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Leleu: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sureda: Janssen: Honoraria.

Single-dose MGTA-145/plerixafor leads to efficient mobilization and in vivo transduction of HSCs with thalassemia correction in mice

We have developed an in vivo hemopoietic stem cell (HSC) gene therapy approach without the need for myelosuppressive conditioning and autologous HSC transplantation. It involves HSC mobilization and IV injection of a helper-dependent adenovirus HDAd5/35++ vector system. The current mobilization regimen consists of granulocyte colony-stimulating factor (G-CSF) injections over a 4-day period, followed by the administration of plerixafor/AMD3100. We tested a simpler, 2-hour, G-CSF–free mobilization regimen using truncated GRO-β (MGTA-145; a CXCR2 agonist) and plerixafor in the context of in vivo HSC transduction in mice. The MGTA-145+plerixafor combination resulted in robust mobilization of HSCs. Importantly, compared with G-CSF+plerixafor, MGTA-145+plerixafor led to significantly less leukocytosis and no elevation of serum interleukin-6 levels and was thus likely to be less toxic. With both mobilization regimens, after in vivo selection with O6-benzylguanine (O6BG)/BCNU, stable GFP marking was achieved in >90% of peripheral blood mononuclear cells. Genome-wide analysis showed random, multiclonal vector integration. In vivo HSC transduction after mobilization with MGTA-145+plerixafor in a mouse model for thalassemia resulted in >95% human γ-globin+ erythrocytes at a level of 36% of mouse β-globin. Phenotypic analyses showed a complete correction of thalassemia. The γ-globin marking percentage and level were maintained in secondary recipients, further demonstrating that MGTA145+plerixafor mobilizes long-term repopulating HSCs. Our study indicates that brief exposure to MGTA-145+plerixafor may be advantageous as a mobilization regimen for in vivo HSC gene therapy applications across diseases, including thalassemia and sickle cell disease.

The outcome of relapsed/refractory hodgkin's lymphoma patients post autologous bone marrow transplantation in a Baghdad Medical City Complex Center

BACKGROUND: Early autologous hemopoietic stem cell transplant is the best option for treatment of relapsed or refractory Hodgkin lymphoma (HL), which is the standard of care at the time being. The aim of this study was to evaluate the outcome of patients with relapsed/refractory (R/R) HL who received autologous hemopoietic stem cell transplant.METHODS: This is a cohort study with data obtained from the patient's sheets and then with follow-up from January/2014 to May/2017. Analysis involved 48 patients with R/R HL. Those patients received high-dose chemotherapy followed by autologous hemopoietic stem cell transplantation (ASCT). Disease status before ASCT, chemo-mobilization protocols, and stem cell collection and ASCT procedure were recorded. The posttransplantation complications and 30-day mortality were also recorded. Re-evaluation of disease status was done at day 100 post transplantation and the patients were followed up for any evidence of relapse or progression till the end of the study. Comparison of various predictors affecting overall survival (OS) and progression-free survival (PFS) was also performed.RESULTS: The 3-year PFS and OS for the patients with R/R Hodgkin disease who received ASCT were 80% and 70.2%, respectively, with various predictors affecting them. Patients with disease status before ASCT as partial remission and resistant have shorter mean OS and PFS that are not statistically significant (P = 0.325 for OS and 0.45 for PFS). Patients with the number of pretransplant treatment regimens more than 2 have a statistically significant shorter mean PFS and statistically nonsignificant OS (P = 0.4 for OS and 0.06 for PFS). The first 30-day posttransplantation mortality (procedure-related death) was 6.3% due to sepsis.CONCLUSION: The mean PFS was inversely affected by the number of treatment lines received prior to ASCT.

Excellent Outcomes of Patients of Middle Eastern Ethnic Origin with Autologous Haemopoietic Stem Cell Transplantation and COVID-19: Does a Dampened Immune System Protect Against Severe COVID-19?

IntroductionOutcomes of patients with hematological cancers and coronavirus disease 2019 (COVID-19) have been reported to be poor with high rates of hospitalization, mechanical ventilation with high case fatality rates, mortality being around 10% or higher. The mortality had been particularly higher among blacks and ethnic minority individuals. There is paucity of data on the outcomes of patients with autologous stem cell transplant and concurrent COVID-19 infections, especially from eastern mediterranean region, no similar studies have been reported so far.MethodsHere we describe outcomes of five consecutive patients of middle eastern ethnic origin who had a history of autologous stem cell transplant and developed COVID-19 infection, who were admitted at our tertiary care center between April and June 2020 with a minimum of 10 days follow-up.ResultsA total of five patients were identified who had undergone autologous stem cell transplantation and had developed COVID-19 infection. There were 3 males and 2 females and the median age was 43 years (range 18-59). Indications for transplant were myeloma (n=3), relapsed Hodgkin lymphoma (n=1), and relapsed diffuse large b cell lymphoma (n=1). Three of five patients had other comorbidities. Median time from transplant was 9 months (range 3-33 months). Four of five patients were on active treatment or maintenance at the time of infection. One patient was on brentuximab, and three were on lenalidomide based therapy. Only one of the five patients had active disease at the time of infection while the rest were in remission. None of the patients had severe disease and four were discharged to home isolation and made full recovery, and one needed admission requiring minimal oxygen and eventually made full recovery. At a median follow up of 70 days (range 12-90) all patients were doing well with no sequelae.ConclusionOur study, albeit small, shows excellent outcomes among patients of middle eastern ethnic origin with hematological cancers who had undergone autologous stem cell transplantation and had developed COVID-19 infection, unlike other studies that have shown high mortality among patients with hematological cancers. However, our cohort is relatively younger, most of them were in remission at the time of infection which may have had a protective effect. At the same time, the majority had transplant within the last nine months and four-fifths of the patients were on some sort of immunosuppressive therapy whilst developing COVID-19 infection. It is possible that a dampened immune system due to transplant and recent therapy might have had a protective effect against cytokine storm or severe COVID-19, in our view. More studies are needed to examine this aspect further, however, these results are encouraging.DisclosuresNo relevant conflicts of interest to declare.

Clinical and biological characteristics of neuroblastoma in adolescents and young adults. Case study and literature review

Introduction. Neuroblastoma (NB) is the most common extracranial solid tumor in infants, but it is more rarely found in older children. Only 1–2 % of cases are registered in adolescents and young adults. The long-term prognosis in these patients is highly unfavorable due to indolent clinical course formed by peculiar biological characteristics of tumors. We publish a case study of 11 patients with NB older than 10 years at the time of diagnosis.Case series description. In 2008 to 2020 a total of 11 adolescent and young adults patients with median age of 14 (10–28) years were treated in Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg. Seven of 11 patients had mediastinal neuroblastoma, in other cases the primary lesion was abdominal (n = 2), pelvic (n = 1), and in one case no primary lesion was defined. Ten of 11 patients had primary disseminated disease with lymph nodes (n = 5), bone (n = 5), bone marrow (n = 3), or hepatic (n = 1) metastases. Tumor morphology and cytogenetics were assessed in all patients, in 4 cases additional targeted sequencing of potentially pathogenic genes was performed. All patients received chemotherapy and local control measures according to high-risk NB guidelines, in 7 of 11 cases additional chemotherapy regimens were used. Seven of 11 patients also received dose-intensive consolidation with autologous hemopoietic stem cell transplantation (auto-HSCT). In case of primary resistance MIBG-therapy, targeted or immunotherapy were used. In 6 cases tumor morphology corresponded to undifferentiated neuroblastoma, in 5 cases to ganglioneuroblastoma. Although all cases were high-risk, they mostly lacked high-risk biological features seen in younger patients. None had MYCN amplification, the cytogenetic assay yielded the following aberrations: +2 (n = 2), del1p (n = 1), g17q (n = 1). All patients, in whom the targeted sequencing was performed had pathogenic mutations: ATRX (in two patients 19 and 28 years at diagnosis), TP53 and PIK3CA, FBXW7. Nine of 11 patients had primary resistant disease, in 7 cases response was obtained on second or subsequent therapy lines. Two patients responded two chemoand targeted therapy combination, in 3 cases monoor combined immunotherapy yielded prolonged (16–32 months) response. Six of 7 auto-HSCT recipients developed a relapse. 6 out of 11 patients are currently alive. In 2 cases, a complete response is maintained according to scintigraphy with 123I-MIBG, lasting 86 and 14 months after completion of therapy.Conclusions. NB is biologically different in adolescents and young adults. It is characterized by indolent clinical course with very high risk of late relapse. As most patients in this group are chemoresistant, the standard dose-intensive tactics may be less effective and perhaps more attention should be given to targeted and immunotherapy-based approaches.