Autologous Transplantation Research Articles

Comparison of Maintenance Therapy Regimens of Patients Treated for Multiple Myeloma

Background: Despite significant progress in treatment modalities and improved survival and response rates in patients diagnosed with multiple myeloma (MM), it remains an incurable disease with a poor outcome, especially in high-risk groups. Though not all patients are eligible, autologous stem-cell transplantation (ASCT) remains an integral part of the treatment of patients with both newly diagnosed and relapsed MM. Regardless of whether patients receive a transplant, they do receive maintenance therapy, and recent evidence has demonstrated that maintenance therapies offer an advantage in progression free and overall survival. While Revlimid is the standard of care, data regarding the specifics of maintenance therapy in high-risk patients is limited and the overall impact of various regimens on survival needs to be further investigated. In our retrospective chart review we reviewed all adult patients with advanced MM within Henry Ford Cancer Institute in the last 10 years to determine the impact of maintenance therapy on progression free survival (PFS) and overall survival (OS). Methods: We conducted a retrospective chart review of adult patients with MM who underwent ASCT between January 1, 2012 to December 31, 2022. Those who received maintenance chemotherapy after transplant were included in the study. Patients who were lost to follow-up or who had largely incomplete records were excluded. Data points including age, ethnicity, cytogenetic analysis, risk category, maintenance regimen after transplant, last chemotherapy regimen, last follow-up, and date of death (if applicable) were recorded. Maintenance chemotherapy regimens were recorded as Revlimid versus other. Patients were split into 2 categories based on risk - high risk and standard risk. Kaplan-Meier plots were used to illustrate overall survival and time to relapse between groups for various variables. Statistical significance was set at p<0.05 Results: 158 patients were included in the study of which 44 were considered high-risk based on cytogenetics, 106 were standard-risk and 8 were missing. Most of the patients (n=137, 87.3%) received Revlimid, while 20 (12.7%) received maintenance therapy other than Revlimid, and for 1 patient, the type of maintenance therapy was unknown. Within the high-risk group, no statistical significance in OS or PFS was found between patients that received Revlimid versus those that did not. Furthermore, there was no statistical significance in OS and PFS within high risk versus standard cytogenetic risk groups. Conclusions: We did not see a difference in outcome based on risk and believe all patients would derive equal benefit from maintenance therapy We also did not see a difference in outcome between high and standard risk patients, and for the high-risk subgroup, there was a separation in curves suggesting that maintenance therapy has benefit compared to no maintenance.

Cryopreservation Impacts Allogenic Stem Cell Engraftment: Relation between Graft Quality Control and Post-Transplant Clinical Outcome

Introduction: Freezing hematopoietic stem cells (HSC) has been a standard procedure in cellular therapy, either for allogenic, autologous, or cord blood transplantation. While cryopreservation is generally reported in the literature as a safe procedure with little impact on graft quality, some reports suggest significant effects of cryopreserved HSC as compared to fresh cells in the outcome of Hematopoietic Stem Cell Transplantation (HSCT). Recently, the COVID-19 pandemic enforced cryopreservation of HSC to secure allograft transplantation from related and unrelated donors. Modifying our standard practices was a unique opportunity to analyze the impact of this additional procedure on cell quality and HSC engraftment. Method: This study compared the HSCT engraftment from fresh versus cryopreserved allogeneic HSC performed in Necker Hospital (n = 236) between January 2020 to December 2022. We retrospectively collected clinical data on patients from our unicentric PROMISE database and extracted the graft characteristics (cell phenotypes, viability, and clonogenicity) from the quality assurance database. Delayed platelets or neutrophils recoveries, early graft loss, and the need for CD34+ selected stem cell boost were used to define post-transplant graft dysfunctions. Results: 107 pediatric patients with a median age of 3.9 years old and 129 Adult patients underwent primary HSCT in our center during the COVID-19 pandemic. Indications were hematological malignancies (n= 97: Acute leukemia, myelodysplastic syndrome, lymphoma, plasma cell disorders), inborn error diseases (n= 131: primary immune deficiency, hemoglobin disorder, histiocytic disorder), and bone marrow failure (n= 8). Sixty six (28.0%) graft of hematopoietic stem cells were cryopreserved from Bone Marrow (BM) (n = 18, 14.8%) and Peripheral Blood Stem Cells (PBSC) (n = 48, 42.1%). Cryopreservation significantly affects the viability (98.2% fresh vs. 84.4% cryopreserved HSC, p<0.0001) and the clonogenicity (18.7% fresh vs. 8.75% cryopreserved HSC, p<0.0001), whatever the source of stem cells. While cell viability and clonogenicity complied with the international standard before graft infusion, graft dysfunctions were a significant concern for cryopreserved allogeneic transplant (n= 22; 33.3%). Graft dysfunctions in cryopreserved HSC groups occurred with both bone marrow and PBSC. Significantly, dysfunctions increased to 38.5% for cryopreserved BM despite a higher median dose of CD34+/kg infused 15.5 (range, 10.2-20.7). No quality control parameter was predictive of engraftment dysfunction. Discussion conclusion: Cryopreservation of HSC was critical during the SARS-CoV-2 pandemic; however, in our experience, the procedure could impact graft function. Considering the development and worldwide distribution of cell therapy drug products, accurately evaluating the pretransplant graft quality is an issue in predicting the engraftment of HSC.

Efficacy of CD19-Directed CAR T Cell Therapy in Patients with Primary or Secondary CNS Lymphoma - an Analysis of the EBMT Lymphoma WP and the Gocart Coalition

Introduction: The prognosis of patients (pts) with relapsed or refractory (r/r) large B cell lymphoma (LBCL) and central nervous system (CNS) involvement is dismal. Standard treatment for pts with r/r LBCL are anti-CD19 chimeric antigen receptor T-cells (CART). Several reports with limited numbers of patients suggest that CART might also be an effective treatment for pts with CNS lymphoma. This EBMT registry study aimed at compiling data to investigate the potential of CART in pts with primary (PCNSL) or secondary CNS lymphoma (SCNCL). Methods: Centers contributing to the EBMT database were asked for cases of PCNSL and SCNSL, treated with CART between 01/ 2018 and 07/ 2022. Reported pts were identified in the database, patient characteristics and pre-treatment retrieved, and major clinical endpoints analyzed. To calculate overall survival (OS) and progression-free survival (PFS) from date of CART infusion Kaplan Meier estimates were used, whereas cumulative incidence was used for relapse incidence (RI) and non-relapse mortality (NRM). Results: 88 pts with PCNSL (n=10) or SCNSL (n=78) with complete information on major endpoints were analyzed. Median follow-up was 20.3 months [95% CI: 16-27]. Median age was 63 years (range 31-80), 52 pts (59%) were male. ECOG was ≥ 2 in 19 of 86 pts (22%). 41 of 65 pts (63%) had undergone ≥3 prior treatment lines, 56 of 82 pts (68%) were refractory to at least one previous line of chemotherapy. 29 of 86 pts (34%) had received autologous stem-cell transplantation (ASCT). Of 84 patients 68% were not in remission at time of CART, 8% were in complete remission (CR) and 24% in partial remission (PR). Information on disease status was missing for four patients. 49 pts were treated with axicabtagene ciloleucel, 39 pts received tisagenlecleucel. OS- and PFS-rates at 24 months were 47% [95% CI: 37-61] and 32% [CI: 23-45] for the whole cohort (figure 1). RI at 24 months was 58% [CI: 47-68], NRM 10% [CI: 4-19]. OS and PFS for pts in CR/PR were 58% [CI 40-85] and 51% [CI: 33-77]. For 57 pts not in remission at CART infusion OS and PFS were 42% [CI: 30-59] and 24% [CI: 14-39], respectively. Conclusion: With a 47% OS rate at 24 months CART seem to be a very effective therapeutic option in heavily pre-treated r/r LBCL with CNS manifestation. These results compare favorably with those reported for conventional treatment including pts treated with ASCT. Indeed, these results are similar to those reported by real-world analyses of CART in LBCL without CNS manifestation (Bethge et al., 2021, Le Gouill et al., 2021). Based on these promising early results, we consider treatment with CART for pts with CNS involvement and r/r LBCL as the preferred treatment option.

Daratumumab, Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) Alone in Transplant-Ineligible Asian Patients with Newly Diagnosed Multiple Myeloma: Final Analysis of the Phase 3 Octans Study

Introduction: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action and has shown clinical efficacy for the treatment of multiple myeloma (MM). In an updated analysis of the global phase 3 ALCYONE study, D-VMP demonstrated a significant progression-free survival (PFS) benefit compared to VMP in transplant-ineligible patients with newly diagnosed MM (NDMM). A prior analysis of the phase 3 OCTANS study (median follow-up, 12.3 months) also showed a favorable clinical benefit/risk profile for D-VMP versus VMP in transplant-ineligible Asian patients with NDMM. Here, we report results from the final analysis of OCTANS, with a median follow-up of >3 years. Methods: The randomized, phase 3 OCTANS study (NCT03217812) enrolled Asian patients with NDMM who were ineligible for autologous stem-cell transplant due to age or presence of comorbidities. Patients were randomized 1:2 (VMP:D-VMP) to receive up to nine 42-day cycles of VMP (bortezomib 1.3 mg/m 2 SC twice weekly in Cycle 1 and weekly in Cycles 2-9, and melphalan 9 mg/m 2 and prednisone 60 mg/m 2 orally on Days 1-4 of each cycle) or D-VMP (VMP + daratumumab 16 mg/kg IV weekly in Cycle 1, every 3 weeks in Cycles 2-9, and every 4 weeks thereafter until disease progression). Per a protocol amendment, patients receiving daratumumab IV were permitted to switch to daratumumab SC 1,800 mg (same schedule as IV) on Day 1 of any cycle. The primary endpoint was achievement of a very good partial response (VGPR) or better. Results: A total of 220 patients were randomized to D-VMP (n = 146) or VMP (n = 74). At the time of the final analysis, with a median follow-up of 41.2 months, the rate of VGPR or better was significantly higher with D-VMP versus VMP (80.1% vs 47.3%; P <0.0001; Table). The rate of measurable residual disease negativity (10 -5) was also higher with D-VMP versus VMP (40.4% vs 10.8%; P <0.0001). D-VMP continued to show a significant improvement in PFS versus VMP (median, 38.7 vs 19.2 months; HR, 0.35; 95% CI, 0.23-0.52; P <0.0001; Table, Figure), as well as a longer time to subsequent antimyeloma therapy (median, 46.8 vs 20.6 months; HR, 0.31; 95% CI, 0.20-0.47; P <0.0001). However, median overall survival was not yet reached for either group. The overall safety profile of D-VMP was consistent with that observed for the primary analysis. Grade 3/4 treatment-emergent adverse events (TEAEs) were reported for 133 (92.4%) patients who received D-VMP and 60 (84.5%) patients who received VMP and were primarily hematologic events; nonhematologic grade 3/4 TEAEs in ≥10% of patients included pneumonia (D-VMP, 31.3% vs VMP, 18.3%), hypokalemia (15.3% vs 4.2%), and hypertension (13.2% vs 8.5%). Grade 3/4 infection TEAEs were reported for 67 (46.5%) and 22 (31.0%) patients who received D-VMP or VMP, respectively. Serious TEAEs were reported for 75 (52.1%) and 28 (39.4%) patients in the D-VMP and VMP groups, respectively, and TEAEs led to treatment discontinuation in 6 (4.2%) and 4 (5.6%) patients, respectively. The incidence of infusion-related reaction TEAEs in the D-VMP group was 33.3%, which is consistent with that previously reported for daratumumab; most events were of grade 1 or 2 severity. The risk of immunogenicity to daratumumab was low, with 1 of 130 evaluable patients testing positive for daratumumab antibodies. Within the D-VMP group, 76 patients switched from daratumumab IV to SC administration. Among these patients, 64 (84.2%) patients preferred SC administration, 7 (9.2%) preferred IV administration, and 15 (19.7%) had no preference on ≥1 of 2 surveys. Of the 64 patients who preferred SC administration, primary reasons included treatment administration time (84.4%), more comfortable administration process (57.8%), less caregiver burden (31.2%), and fewer administration-related reactions (26.6%). Conclusions: With a median follow-up of >3 years, this final analysis of OCTANS demonstrated a continued clinical benefit with D-VMP versus VMP in Asian patients, with PFS improvement comparable to that observed in the global ALCYONE study (HR, 0.35 vs 0.42, respectively). No new safety concerns were identified for D-VMP with extended follow-up. In addition, daratumumab SC administration was preferred by the majority of patients who switched from daratumumab IV. These results further support the use of daratumumab IV or SC in combination with VMP in transplant-ineligible Asian patients with NDMM.

A New Machine Learning-Based Prognostic Prediction Strategy for Patients with Diffuse-Large B-Cell Lymphoma

Introduction - Diffuse large B-cell lymphoma (DLBCL) is a frequent and aggressive lymphoma. First line of treatment associates an anti-CD20 immunotherapy with an anthracycline-based chemotherapy (R-CHOP). After this treatment, 30% of patients present primary refractory disease or early relapse within two years (R/R DLBCL). At date, CAR-T cells improve the prognosis of patients with R/R DLBCL compared with high-dose chemotherapy followed by autologous stem-cell transplant. However, predicting this failure remains a challenge at time of diagnosis. Current standard tools as the R-IPI score have many weaknesses, particularly for patients most at risk. A multitude of clinical, biological and PET data are available and could help to precise R/R DLBCL probability. In this study, we propose a new strategy based on machine learning and exploitation of a large dataset to early detect patients with high risk of R/R DLBCL at diagnosis. Material and methods - Between August 2012 and November 2021, we retrospectively collected a cohort of 218 patients with DLBCL receiving first-line treatment R-CHOP. Twenty-two parameters were evaluated for each patient, including well-known predictive factors such as R-IPI components, but also advanced metabolic parameters (SUVmax, total metabolic tumor volume (TMTV), total lesion glycolysis (TLG) and Dmax), as well as pathological and biological features. We used supervised machine learning (ML) to build a multidimensional model to predict POD24, which is defined by primary refractory disease or relapse within two years. Conventional binomial logistic regression was also performed to create a conventional predictive model. In parallel, a group of three hematologists was asked to generate a consensus about POD24 occurrence using Delphi method. Results - Median age was 70 years. With a median follow up of 46 months, complete response rate was 87% and overall response rate was 89%. Overall survival and progression-free survival were respectively 81.6 % (95%CI 76.6 - 86.9) and 70.6 % (95%CI 64.8 - 76.9) at 24 months. POD24 event occurred in 23,5 % of patients. Performance status, Ann-Arbor staging, number of extranodal sites, medullar infiltration, TMTV, TLG, Dmax, lymphocytes and LDH showed significant predictability of POD24 when considered in univariate analysis. We used forward selection of variables to build a conventional predictive model including LDH, lymphocytes and Dmax. Area under the ROC curve was 0,72. Secondly, a ML model was trained on 147 patients and was applied on a test cohort with 49 remaining patients. Prediction accuracy was 89.7% and area under the ROC curve was 0,91. Decision threshold was raised to 0.75 cut-off, allowing to predict 60% of POD24 with 100% specificity. The four predominant variables in the model were Dmax, hepatic SUV, LDH and monocytes. Additionally, experts were confronted to 55 patients randomly sampled from the cohort, 14 (25%) of whom showed POD24. Prediction accuracy was 71% and area under the ROC curve was 0,73. Seventy-nine percents of POD24 was predicted by experts, with 68% specificity. Conclusion - We present a ML model that was built to predict POD24 and then R/R situations in DLBCL patients. It showed great accuracy with high specificity rate. In new immunotherapies and CAR-T cells era, this proof-of-concept study highlights the fact that ML models could be a helpful to decide on first-line strategies for DLBCL patients. Larger multicentric study is necessary to confirm and validate this model for clinical use.

Patient Recorded Outcomes from a Randomized, Controlled Phase 2 Trial of E-Selectin Inhibition with Uproleselan Vs Placebo to Reduce GI Toxicity during Melphalan-Conditioned Autologous Hematopoietic Cell Transplantation for Multiple Myeloma

Background: The use of high-dose melphalan conditioning followed by autologous hematopoietic cell transplant (AHCT) continues to be a key component in the treatment of patients with multiple myeloma (MM). However, high-dose melphalan is associated with a high rate of GI toxicity (>90%), which adversely impacts clinical outcomes and negatively influences patient quality of life (QoL). Indeed, it has been reported that AHCT leads to short-term deterioration of health-related QoL in patients with MM, and QoL typically improves by 2-3 months post-AHCT. Pre-clinical and clinical data suggest that E-selectin inhibition may play a role in reducing immune-mediated GI epithelial injury following cytotoxic chemotherapy. We hypothesized that uproleselan (upro), a synthetic, competitive E-selectin antagonist, may improve health-related QoL by reducing risk of chemotherapy-induced diarrhea in patients undergoing AHCT. Methods: We conducted a Phase 2, single-center, randomized, double-blind, placebo-controlled trial in patients with MM receiving high-dose melphalan (200 mg/m2) as conditioning for AHCT for MM. Patients were randomized 1:1 to receive prophylactic upro+standard of care (SoC) vs placebo+SoC. Uproleselan was given in 6 doses of 800 mg IV starting on day-3 through day 0. The primary endpoint was diarrhea severity as assessed by CTCAE v5.0 (secondary endpoint - Bristol Stool Scale). In addition, a key secondary endpoint was patient reported outcomes (PRO) of GI-related QoL using the National Cancer Institute (NCI) PRO-CTCAE Measurement System, a validated PRO tool developed to evaluate symptomatic toxicities in patients with cancer in clinical trials. Significance level of p<0.2 was pre-specified for all endpoints, per protocol. Patients were surveyed during the peri-transplant period at day-3 (baseline), day+8, and day+14 or day of discharge (DoD). Responses were graded on a scale of 1-5, with 1 indicating absence of symptoms or zero interference with daily activities and 5 indicating very severe symptoms or very significant interference with daily activities. GI-specific domains assessed included swallowing, mouth sores, appetite, nausea, vomiting, heartburn, bloating, abdominal pain, flatulence, and incontinence. Results: Fifty adult patients with MM were enrolled from 5/2021-10/2022. Baseline PRO symptoms were similar between the upro+SoC and placebo+SoC arms at baseline (day-3). By day+8 post-AHCT patients in the upro+SoC arm reported a significant improvement in severity of GI-related symptoms across 30% (6/20) of domains surveyed vs placebo+SoC (p=0.07-0.14). Furthermore, improvement in mouth sore-related symptoms continued to day+14 post-AHCT in the upro+SoC arm vs placebo+SoC (p=0.17). The remaining GI-related symptoms returned to baseline by D+14 or DoD (p>0.20). Also of note, a numerically lower mean diarrhea severity score and lower incidence of Grade 3 diarrhea (by CTCAE v5.0) was observed favoring upro+SOC which did not meet the pre-specified significance threshold (p=0.34, p=0.26, respectively). However, a significant reduction in severe diarrhea (by Bristol Stool Scale) was observed favoring upro+SoC (p=0.10) vs placebo+SoC, with improvement in the upro+SoC arm to mild diarrhea (p=0.02). Conclusions: Upro+SoC resulted in a clinically significant improvement in GI-toxicity related symptoms as assessed via PRO-CTCAE in patients with MM undergoing melphalan-conditioned AHCT, when compared to placebo+SoC. These improvements in patient reported outcomes are further supported by data from the primary and additional secondary endpoints of the study. Taken together, these results suggest prophylactic E-selectin inhibition may represent a promising strategy to mitigate chemotherapy-associated GI-toxicity. Further studies are needed to verify these findings and to further define the optimal dosing of upro in the peri-AHCT period.

Characteristics and Outcomes of Adolescent, Young Adults, and Adults 40-50 Years Old with Multiple Myeloma: A Single Center Experience

Background Multiple myeloma (MM) is a malignant tumor with abnormal proliferation of plasma cells. Adolescent and Young Adult (AYA) patients are defined as patients between 15-39 years of age. Multiple myeloma is uncommon in non-elderly populations. Its prevalence is only 2% in AYA age group and only 10% in patients 40-50 years old. The feature of MM is not well known or understood in those two age groups. In this retrospective study we describe the clinical characteristics, cytogenetics, prognostic markers, treatments given and outcomes of MM in AYA and 40-50 years old patients. Methods We retrospectively analyzed data from the clinical database of our single tertiary hematology center, The National Center for Cancer Care and Research, Doha, Qatar. This center serves a country's population of about 2,8 million people. All patients diagnosed with MM between the age 50 or less during the period of January 2007 to December 2022 were included. Results Seventy-four patients were diagnosed at our centre with MM before the age of 50 years, total of all MM cases 222 (33%) Males was predominant 55/74 (74.3 %) with a median age of 41 years (range, 15-49). Most of the patients were from Asian 55%. At diagnosis patients had a median hemoglobin of 10.2 g/dl, creatinine 294 umol/L, total protein 90 gm/L, albumin 34.75 gm/L, calcium 2.7 mmol/L, LDH 255 U/L, IgG 2289.75 mg/dl, IgA 424.15 mg/dl, IgM 34.2 mg/dl, FLC-Kappa 1993 mg/L and FLC-Lambda 1177 mg/L. Median of bone marrow filtration by plasma cell was 51 %. Most of the patients presented at advance stages with 44 patient (59%) presented as IIIA Durie Salmon or stage III and IV by ISS 70 %. IgG Kappa most frequent type of MM 18 patients (24%), followed by Free light chain kappa (23%), IgG Lambda (18%) and others including two cases of plasmacytoma (Most recurrent cytogenetics were diploid cytogenetics in 42 patients (57%), while 7 patients (9%) had complex cytogenetics. Twenty-eight patients had spinal cord compression at single or multiple levels ( thoracic were most common site 20%) while 3 patients had pathological fractures. Bortezomib based regimen is most one used to treat our patients. Daratumumab- Velcade, Revlimid, and dexamethasone (D-VRD) was used for 35 patients (74%) and Velcade,Cyclophosphamide and Dexamethasone VCD in 20 patients (27%). The first response to treatment showed completed remission (CR) in 35 patients, very good partial remission in 10 patients, partial response in 9 patients, four patients either refractory or primary refractory disease and one patient with stable disease. Thirty -five patients (48%) underwent their first autologous bone marrow transplant ASCT. A total of 8 patients underwent second ASCT and one patient underwent third ASCT. After a median duration of follow up of 6.25 years and 72 % of the patients were still alive. We compared the characteristics and outcome for the AYA group (18-39) with patient age group 40 to 49 years. Although there was no statistical significance difference between the two groups regarding overall survival (p=0.21) , the older group had more cases of spinal cord compressions and more cases of refractory disease. Patient characteristics are described in Table 1. Conclusion One third of MM patients in our center are younger than 50 years. These patients tend to present with advanced stage and serious manifestation such as spinal cord compression. IgG kappa and free light chain are the most common myeloma type in this cohort. D-VRD is the most used protocol with a good response rate. Patient characteristics and treatment outcomes are the same for AYA patients compared with patients 40-49 years old (p=0.21). Patients who received first transplant had better OS compare the those who didn't (p0.01)

Impact of Prior Lines of Therapy before Autologous Hematopoietic Cell Transplant on Survival in Standard Risk Multiple Myeloma

Introduction: Patients with standard risk (SR) multiple myeloma (MM), as defined by the absence of high risk cytogenetic abnormalities including immunoglobulin heavy chain (IGH) gene translocations such as t(4;14), t(14;16), t(14;20), deletion of (17p), or gain/amplification(1q), have favorable prognosis and respond well to standard of care induction with plasma-cell directed therapy followed by AHCT consolida-tion and lenalidomide (LEN)-based maintenance. Despite this, it has been noted that a significant proportion of SRMM patients may suffer from early relapse after AHCT, and could potentially benefit form mitigation strategies. The aims of this study were to assess the impact of prior lines of therapy on post-AHCT outcomes in SR MM patients, and then evaluate the role of an augmented LEN-based maintenance regimen in those who did not achieve a complete response (CR) post transplant. Methods: All MM patients who underwent AHCT at our institutions between January 2011 and January 2021 were retrospectively reviewed. Electronic medical charts were searched to collect data on baseline demographic characteristics, disease status, fluorescent in situ hybridization (FISH) cytogenetic studies, blood and bone marrow studies, number of lines of treatments pre-AHCT, as well as maintenance therapy post-transplant. Responses were according to the International Myeloma Working Group (IMWG) criteria. Kaplan Meier method was used for event free survival (EFS) assessment. Results: A total of 293 SR MM patients were included in this analysis, of whom 188, 63, 32 and 10 received 1, 2, 3, and ≥4 lines of therapy pre-AHCT. Despite having comparable CR rates pre-AHCT (28% vs 19% vs 22% vs 10%, respectively; p=0.3), patients with ≥4 prior lines of therapy experienced significantly worse outcomes as determined by shorter mediant EFS of 8.4 months vs 54.5, 55.9 and 21.7 months (P<0.0001) for the 1, 2, and 3 pre-AHCT lines of therapy groups, respectively ( Figure 1A). We then focused on the subgroup of SR MM patients (n=100) who did not achieve a hematologic CR at day-100 post-AHCT. Among them 87 were placed on LEN-monotherapy, and 13 on LEN-based combination maintenance therapy post-AHCT. Of note, none was LEN-refractory. Both the LEN-monotherapy and combination groups had comparable baseline patients and disease characteristics including age (60.5 vs 56 years, p=0.07), time from diagnosis to transplant (≥12 months in 24% vs 30.8%, p=0.7), hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score ( ≥3 in 44% vs 30.8%, p=0.5), male representation (59% vs 69%, p=0.6), white ethnicity (82 vs 77%, p=0.7), international scoring system stages (p=0.9), pre-AHCT number of lines of therapy (p=0.8), and pre-AHCT bone marrow plasma cell percentage (≥10% in 9.5% vs 7.7%, p=0.9), respectively. Kaplan-Meier survival analysis showed a significantly shorter median estimated EFS for the LEN monotherapy group at 38.1 months vs 68.6 months (p=0.03) for the LEN combination maintenance group ( Figure 1B). Conclusion: SR MM constitute heterogenous group of patients with variable outcomes post-AHCT. Those with heavily pretreated disease, that have received four or more lines or therapy, tend to have worse outcomes post transplant, therefore, should be considered for alternative approaches such as chimeric antigen receptor T cell therapies or bispecific agents. For patients who undergo AHCT but do not achieve a CR, LEN-combination maintenance should be strongly considered especially in the setting of relapsed-refractory disease.

Belantamab Mafodotin in Relapse/Refractory AL Amyloidosis- Real-Life Multi-Center Experience

Introduction: Bortezomib and daratumumab revolutionized the therapy for AL amyloidosis (AL). However, relapsed/refractory AL resistant to both drugs is an unmet clinical need, with limited options due to the frailty of these patients and paucity of prospective data. The safety profile and efficacy of belantamab mafodotin (BLM) in multiple myeloma (MM) are well known. In contrast, published data for AL are currently limited to case series of 6 (Zhang, Ann Hematol. 2022) and 12 patients only (Khwaga, Blood Cancer J. 2022). Here, we report a multicenter real-world data on 12 AL patients treated with BLM and compare these to the prior reports. Methods: We retrospectively identified all AL amyloidosis patients who received BLM outside a clinical trial, between Feb 2020-Sep 2022. The diagnosis, staging, hematologic and organ responses and progression of AL were evaluated according to consensus criteria. Event-free survival (EFS) was defined as the time from the first day of BLM administration to hematologic progression or therapy change for inadequate response or death. Results: Twelve AL patients from 5 centers in Israel and Italy were included. The median age at BLM initiation was 66 y (range 54-70). The most common FISH aberrations were 1q gain in 8 patients (67%) and t(11;14) in 5 (42%). All patients except one had cardiac involvement (92%) and 9 (75%) had renal involvement. The median number of prior lines of therapy was 3 (range 2-9). All patients previously received bortezomib, an alkylator and daratumumab, 11 (92%) received lenalidomide, 10 (83%) received pomalidomide and 9 (75%) underwent prior autologous transplant. Seven patients (58%) had Eastern cooperative oncology group performance status (ECOG-PS) of at least 2 at BLM initiation and half of the patients had AL Mayo stage of at least 3a. Most patients (10/12) received BLM as a single agent at 2.5mg/kg q3 weeks. The overall hematological response rate (ORR) to BLM was 75% (9/12), including 5 patients with complete response, 3 with very good partial response, and 1 with partial response (Figure 1). Detailed biomarker-based evaluation of organ responses was missing in many patients, yet, of 4 evaluable patients, 3 cardiac responses were observed. An additional patient had marked clinical improvement of heart failure. Four renal responses (out of 5 evaluable patients) and 2 hepatic responses (out of 2 evaluable) were also observed. With a median follow-up of 13.0 months (m) from initiation of BLM therapy (range 1.1-33.8m), the median EFS was 22.3m and the median OS was 28.8m. At data cutoff 6/12 (50%) were still on therapy, 9/12 patients (75%) were alive, all 3 deaths were due to heart disease. Seven patients (58%) had at least one grade 3 toxicity, included mostly infections/corneal toxicity. Apart from one event of grade 3 thrombocytopenia, there were no grade ≥3 hematological toxicities. No grade 4/5 toxicities were observed. Most patients (10/12, 83%) had corneal toxicity (6 patients- grade 1-2; 4 patients- grade 3), and dose reductions/delays were frequent (4/12 and 6/12, respectively). However, 7/10 patients with corneal toxicity improved overtime, no permanent visual disabilities were observed and only one patient stopped BLM due to keratopathy. Discussion: While BLM provides an ORR of 30-45% in triple-refractory MM patients, it might have a greater efficacy in AL patients. The ORR in our heavily pre-treated AL patients, as well as in other studies (2 small, retrospective + preliminary results of the EMN27 prospective study (Kastritis, EHA conference 2023) approached 60-83%, and the EFS was also encouraging. This difference may be attributed to the lower burden of disease in AL compared to MM. Alternatively, AL plasma cells may be more sensitive to BLM, in a mechanism that still merits further exploration. Corneal toxicity was similar to what was seen in MM, and overall manageable. Hematological toxicity was significantly milder than that observed in MM, probably related to the better marrow reserve in AL. Conclusions: BLM, being an off-the shelf immune therapy, with acceptable toxicity even in frail patients, can be a valuable option in AL, with a high ORR, and a signal for durable responses and high-quality organ responses in these patients.

Prephase Cyclophosphamide: An Advantageous Bridge to Definitive Therapy

Background Classic Hodgkin lymphoma (cHL) and aggressive non-Hodgkin lymphoma (NHL) account for an estimated 0.5% and 4.1% of all new cancer diagnosis in the US in 2023, respectively. At time of diagnosis, approximately 43% of cHL and 53% of NHL are staged as advanced disease (stage III-IV). While these diseases are considered curable, standard treatments involve intensive combination chemotherapy that may preclude certain patients from receiving optimal therapy. One option to minimize risks is to use prephase cyclophosphamide (pCy) as an initial treatment in aggressive lymphomas. There is however limited data on the utility, adverse effects, and outcomes of this approach. Here we present data on our institutional experience of employing pCy for patients ineligible for intensive chemotherapy. Methods We performed a single institution, retrospective chart review of patients with history of cHL and NHL that received cyclophosphamide (Cy) as an initial chemotherapy during hospitalization. Lymphoma subtype, medical history, baseline bloodwork at time of treatment initiation, outcomes including transplant, relapse data and overall survival were collected. Fifty patients received pCy at 200 mg/m2 with the remaining four receiving 100 mg/m2, 150 mg/m2, or 300 mg/m2 based on provider preference. Corticosteroids, including prednisone, dexamethasone or methylprednisolone, were administered simultaneously with varying duration and dosage. We analyzed hepatic and kidney injury at the time of diagnosis, after initiation of pCy and time to recovery. Acute kidney injury (AKI) was defined as an increase in creatine more than 30% from baseline and hepatic injury was defined based on Common Terminology Criteria for Adverse Events (CTCEA) version 5. Charlson scores for all patients were collected. Results Fifty-four patients received pCy as a bridge to possible definitive therapy. The most common diagnosis was diffuse large B-cell lymphoma (DLBCL) and cHL, with 29 (53.7%) and seven (13%) patients, respectively (Figure 1). The median age was 56 years (18-84) with 21 (39%) patients >65 years. Advanced stage was observed in 49 (90.7%) patients. Four patients required treatment for tumor lysis syndrome (TLS) prior to initiation of pCy. Nineteen (35%) patients had AKI and 15 (28%) patients had hepatic injury at the time of initial presentation. Five patients experienced AKI from pCy with an average time to recovery of 11.2 days. Six patients, with only two having concurrent AKI, had hepatic injury from pCy with an average time to recovery of 8.5 days. PCy allowed 42 (78%) patients to undergo definitive treatment in respect to their lymphoma subtype. Eight (14.8%) patients went on to receive a consolidative autologous transplantation (HSCT) after reaching a remission from definitive therapy. At the time of our analysis, 30 (55%) patients are deceased which includes four patients that underwent HSCT. Of the 30 deceased, 10 patients were transitioned to comfort care during the admission after receiving pCy. Median overall survival is 370.5 days. Conclusion Based on our institutional experience, pCy is a reliable method to salvage patients with aggressive lymphomas that are not candidates for intensive chemotherapy. In our analysis, pCy allowed 78% of patients to receive definitive therapy for their respective lymphoma. In general, patients receiving pCy required hospitalization related to disease burden and pCy represents an effective and cost-efficient bridging strategy to outpatient treatment. Cyclophosphamide has a broad indication across hematologic malignancies and is a well-tolerated chemotherapy with a limited side effect profile. The modest dosing in combination with corticosteroids allows initial disease control and provides the ability to start definitive therapy in a timely manner. Additionally, we feel that pCy should be considered when designing clinical trials in an effort to promote enrollment of the “real-world” patient.

Roginolisib a Highly Selective Allosteric Modulator of the Phosphoinositide 3-Kinase Delta (PI3Kδ) in Patients with Refractory/Relapsed Follicular Lymphoma

Introduction PI3Kδ inhibitors are active in patients (pts) with lymphomas, but their clinical development has been hampered by toxicity (Brown et al, Lancet Oncol 2022). Roginolisib (IOA-244) exerts an allosteric modulation of the PI3Kδ C-terminus and functions as a non-ATP competitive PI3Kδ inhibitor, delivering a selective inhibition without off-target effects typically seen with other PI3K inhibitors (Johnson et al, Cancer Res Commun 2023). Using the recommended phase 2 dose (RP2D) of 80 mg QD established in solid tumors patients, patients with refractory/relapsed (r/r) follicular lymphoma (FL) were treated to investigate its safety profile in pts with hematologic malignancies (NCT04328844). Methods In Part A of the FiH dose escalation study, roginolisib was investigated at 20 and 80 mg QD in pts with r/r FL. Primary objective: safety of the RP2D established in solid tumor pts. Secondary objectives: PK; PD (e.g., changes in immune cell subsets in peripheral blood); Lugano-based responses; PFS and OS. Results In Part A for pts with r/r FL, there were two cohorts: (a) Cohort 1: 20 mg QD daily (4/4; 2 female, 2 male); (b) Cohort 2: 80 mg QD (4/4; 3 female, 1 male). There were no DLT observed and no dose modifications were needed. The mean time on treatment was 1.9 months (20 mg QD) and 4.3 months (80 mg QD), with one patient at the 80 mg receiving Roginolisib for 9 mo. More than 4 prior lines of treatment were in 3/8 pts. Transient (lasting less than 48 hrs) platelet reduction (G3) and AST/ALT elevation (G3) were observed in 2/8 pts, which improved while pts continued without a treatment intervention, such as dose modification or medical treatment with steroids. Lugano-based PRs were observed in 2/4 pts at the 80 mg QD dose and none at the 20 mg QD. At the 80 mg QD dose a third pt had a clinical response manifested by improvement in night sweats and fever, reduction in cervical palpable lymph nodes and relief from chronic pleural effusion. This clinical improvement lasted less than 5 weeks. While Overall Survival (OS) is still ongoing, the median has not been reached in this study and is currently at 14.3 mo. Subsequent to ending Roginolisib treatment, patients received at least one additional therapy (6/8), one patient was able to undergo autologous transplant with a complete metabolic response (CMR). Biomarker evaluation using flow cytometry showed low counts of T regulatory cells (Treg) in peripheral blood in all 8 r/r FL patients compared to solid tumor patients at baseline and throughout the treatment. Myeloid derived suppressor cells in peripheral blood remained unchanged during the course of treatment with Roginolisib. Conclusions The safety profile of roginolisib in pts with r/r FL appears to match that in pts with solid malignancies. In contrast to other PI3Kδ inhibitors, roginolisib is highly selective for binding to PI3Kδ, favoring an inactive confirmation of PI3Kd and functions as a non-ATP competitive inhibitor.

CD19-Directed CAR T-Cells (CD19-CAR) Combined with Acalabrutinib Achieves Durable Remissions in Patients with Relapsed or Refractory (r/r) Mantle Cell Lymphoma (MCL)

Background: MCL is an aggressive non-Hodgkin lymphoma (NHL) subtype which remains incurable despite improvements in progression free survival with consolidative autologous transplant and the introduction of novel targeted therapies [Dreyling et al. Blood 2012]. CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CD19-CAR) has shown durable disease control in r/r MCL, but current standard of care products are limited by high rates of grade 3+ immune-related toxicities [Wang et al. NEJM 2020]. We hypothesized that combining a naïve/stem-memory (T N/SCM) phenotype-enriched CD19-CAR T-cell product with the selective BTK inhibitor (BTKi) acalabrutinib would attenuate the rates of severe toxicities, improve durable remission rates, and obviate the need for indefinite use of acalabrutinib in r/r MCL. Methods: We conducted a phase 1 single center, prospective clinical trial (NCT04484012) evaluating a single infusion of T N/SCM-enriched CD19.28.z.EGFRt-CAR at a target dose of either 2x10 8 (DL1) or 5x10 8 (DL2) CAR+ cells (≤20% lower dose allowed) in combination with ongoing acalabrutinib 100 mg twice daily for patients with r/r MCL after at least 1 prior line of therapy. Patients were required to undergo at least 3 months but less than 7 months of treatment with a BTKi prior to enrollment without evidence of progression and with measurable disease per Lugano criteria. All patients were switched to acalabrutinib for protocol therapy prior to lymphodepletion, and planned to continue until day 180 post CD19-CAR infusion at which time all therapy would be discontinued. We report outcomes from the dose finding portion of the study. Descriptive statistics were utilized for baseline characteristics and survival analyses were calculated utilizing the Kaplan-Meier method. Investigator-assessed response rates were based on Lugano criteria. Minimal residual disease (MRD) status was determined using either multiparameter flow cytometry (FCM) or next-generation sequencing (NGS). Results: To date, 8 patients enrolled and have received CD19-CAR (n=4 at DL1; n=4 at DL2). Manufacturing was successful in 100% of patients. Median time from leukapheresis to product infusion was 53 days (range, 41-114). Treated patients were 75% male; with a median age of 63 years (range, 38-70); and median number of prior therapies of 2 (range, 2-3). All patients had bone marrow involvement, and had high risk features including progression of disease within 24 months (n=6), relapse after autologous HCT (n=2), TP53 mutations (n=6), Ki-67 ≥30% (n=4), and/or complex karyotype (n=1). Prior to enrollment, all patients had received BTKi (n=8 acalabrutinib) for a median of 6.1 months (range, 4.5-7.3). No BTK and PLC-γ mutations were detected in patients with available samples. The combination of acalabrutinib and CD19-CAR was well tolerated; 5 patients (63%; n=1 grade 2; n=4 grade 1) had cytokine release syndrome (CRS), with no severe cases. No patients (0%) had immune effector cell associated neurotoxicity syndrome (ICANS) [Figure 1A]. No patient required corticosteroids for toxicity management, and only 2 patients (n=2/5, 40%) required tocilizumab for CRS. There were no serious adverse events (SAEs), and no treatment discontinuations due to AEs observed. The best ORR was 88% [n=6 CR (75%); n=1 PR (13%)], with median time to best response of 28 days. In those 6 patients who achieved CR, 2 patients were FCM-MRD negative (<10 -4) and 2 were NGS-MRD negative (<10 -6) (n=4/6, 67%) [Figure 1B]. After a median follow-up of 18.5 months (range, 8.3-28.9), 5 of 6 patients remain in CR, while1 patient who achieved an initial CR relapsed at 9.2 months. At 1-year post-infusion, the cumulative incidence of relapse and NRM were 30% (95% CI, 3%-67%) and 0%, respectively. The 1-year PFS and OS were 70% (95% CI: 22%-92%) and 100%, respectively. Conclusion: The combination of CD19-CAR with acalabrutinib was well tolerated and effective, yielding an ORR 88% and MRD- rate 50% in a cohort of patients with high-risk MCL. Notably, CRS events were manageable and low grade, and no ICANS was observed. Enrollment is ongoing in the expansion cohort (DL2), and additional clinical and correlative analyses will be presented at the meeting.

Fat transplant: Amazing growth and regeneration of cells and rebirth with the miracle of fat cells.

During fat transplantation, adipose tissue is removed from the body and injected into different areas under the skin. The goal of this review article is to look into the efficacy and applicability of fat transplantation in regenerative medicine and rejuvenation, including Nanofat, Microfat, and Millifat. As a search strategy and study selection, we searched the PubMed and Medline databases until 2023 using related keywords (e.g., Nanofat, Microfat and Millifat, Regenerative Medicine, and Rejuvenation). Autologous fat transplantation has no risk of an allergic reaction or rejection of the transplant by the individual. Autologous adipose tissue is considered an ideal filler for facial rejuvenation and is suggested as the most biocompatible and non-immunogenic skin filler. Adipose tissue transplant may have semi-permanent to permanent effects. According to recent reports, adipose tissues possess a high percentage of mature stem cells. The effect of regenerating adipose tissue and its intrinsic cells can be described as an obvious process. Variations in the sizes of adipose tissues can result in different results depending on the surgical site. Based on topographic assessment, graft fats are assigned depending on the anatomical locations and the size such as Millifat (2-2.5 mm), Microfat (1 mm), and Nanofat (500 μm or less). Some characteristics of fat tissue increase its effectiveness, such as increasing stem cells, growth factors, cytokines, and compounds effective in repair, regeneration, and rejuvenation.

Implanting mechanically reprogrammed fibroblasts for aged tissue regeneration and wound healing.

Cell-based therapies are essential for tissue regeneration and wound healing during aging. Autologous transplantation of aging cells is ineffective due to their increased senescence and reduced tissue remodeling capabilities. Alternatively, implanting reprogrammed aged cells provides unique opportunities. In this paper, we demonstrate the implantation of partially reprogrammed aged human dermal fibroblasts into invitro aged skin models for tissue regeneration and wound healing. The partially reprogrammed cells were obtained using our previously reported, highly efficient mechanical approach. Implanted cells showed enhanced expression of extracellular matrix proteins in the large area of aged tissue. In addition, the implanted cells at wound sites showed increased extracellular matrix protein synthesis and matrix alignment. Transcriptome analysis, combined with chromatin biomarkers, revealed these implanted cells upregulated tissue regeneration and wound healing pathways. Collectively our results provide a novel, nongenetic, partial reprogramming of aged cells for cell-based therapies in regenerative medicine.

Artificial dermis combined with skin grafting for the treatment of hand skin and soft tissue defects and exposure of bone and tendon

BACKGROUND The recovery time of hand wounds is long, which can easily result in chronic and refractory wounds, making the wounds unable to be properly repaired. The treatment cycle is long, the cost is high, and it is prone to recurrence and disability. Double layer artificial dermis combined with autologous skin transplantation has been used to repair hypertrophic scars, deep burn wounds, exposed bone and tendon wounds, and post tumor wounds. AIM To investigate the therapeutic efficacy of autologous skin graft transplantation in conjunction with double-layer artificial dermis in treating finger skin wounds that are chronically refractory and soft tissue defects that expose bone and tendon METHODS Sixty-eight chronic refractory patients with finger skin and soft tissue defects accompanied by bone and tendon exposure who were admitted from July 2021 to June 2022 were included in this study. The observation group was treated with double layer artificial dermis combined with autologous skin graft transplantation (n = 49), while the control group was treated with pedicle skin flap transplantation (n = 17). The treatment status of the two groups of patients was compared, including the time between surgeries and hospital stay. The survival rate of skin grafts/flaps and postoperative wound infections were evaluated using the Vancouver Scar Scale (VSS) for scar scoring at 6 mo after surgery, as well as the sensory injury grading method and two-point resolution test to assess the recovery of skin sensation at 6 mo. The satisfaction of the two groups of patients was also compared. RESULTS Wound healing time in the observation group was significantly longer than that in the control group (P < 0.05, 27.92 ± 3.25 d vs 19.68 ± 6.91 d); there was no significant difference in the survival rate of skin grafts/flaps between the two patient groups (P > 0.05, 95.1 ± 5.0 vs 96.3 ± 5.6). The interval between two surgeries (20.0 ± 4.3 d) and hospital stay (21.0 ± 10.1 d) in the observation group were both significantly shorter than those in the control group (27.5 ± 9.3 d) and (28.4 ± 17.7 d), respectively (P < 0.05). In comparison to postoperative infection (23.5%) and subcutaneous hematoma (11.8%) in the control group, these were considerably lower at (10.2%) and (6.1%) in the observation group. When comparing the two patient groups at six months post-surgery, the excellent and good rate of sensory recovery (91.8%) was significantly higher in the observation group than in the control group (76.5%) (P < 0.05). There was also no statistically significant difference in two point resolution (P > 0.05). The VSS score in the observation group (2.91 ± 1.36) was significantly lower than that in the control group (5.96 ± 1.51), and group satisfaction was significantly higher (P < 0.05, 90.1 ± 6.3 vs 76.3 ± 5.2). CONCLUSION The combination of artificial dermis and autologous skin grafting for the treatment of hand tendon exposure wounds has a satisfactory therapeutic effect. It is a safe, effective, and easy to operate treatment method, which is worthy of clinical promotion.

Acute interstitial nephritis secondary to sarcoid-like reaction after autologous bone marrow transplantation: Case report

Sarcoid-Like Reaction is a systemic inflammatory granulomatous condition that does not meet the criteria for systemic Sarcoidosis—it is triggered by a known underlying factor, such as immunosuppression. Here we report a case of acute interstitial nephritis without granuloma in the context of a Sarcoid-Like systemic disease in the three-year period after an autologous stem cell transplant. The patient presented with a suspected relapse, associated with hemolytic anemia and an increase of serum creatinine. The investigation showed non-caseating epithelioid cell granuloma in a chest lymph node and in bone marrow, associated with combined hypogammaglobulinemia. Evaluation of the kidney tissue demonstrated acute interstitial nephritis.

Effects of SU5416 on angiogenesis and the ERK-VEGF/MMP-9 pathway in rat endometriosis.

SU5416 is a small molecule vascular endothelial growth factor (VEGF) receptor signal transduction inhibitor, which can block the VEGF re-ceptor autophosphorylation and inhibit receptor tyrosine kinase signal trans-duction, thereby reducing VEGF activity. However, there are few reports about the correlation of SU5416 to the occurrence and angiogenesis in endometrio-sis. In this study, we observed the effects of VEGF receptor inhibitor SU5416 on angiogenesis in endometriosis in rats. Thirty femalespecific-pathogen-free Sprague-Dawley rats were randomly divided into sham operation group (SOG), model group (MG), and SU5416 group (n=10 for each group). In the SOG, only the uterus was cut and sutured, and endometriosis models were established in the MG and SU5416 group by autologous transplantation. The SU5416 group was injected with 15 mg/kg SU5416 intraperitoneally, and the SOG and MG were intraperitoneally injected with an equal volume of normal saline for 6 weeks. The volume of ectopic lesions was lower in the SU5416 group at 42 d postoperatively thanin the MG (p<0.05). The proportion of CD31-positive cells in the endometrial tissue of the SU5416 group was lower than that of the MG (p<0.05); angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), laminin-5γ2 (LN-5γ2) and phosphorylation of ERK (P-ERK), VEGF, matrix metalloproteinase (MMP)-2, and MMP-9 protein expressions were lower in the SU5416 groupthan in the MG (p<0.05).VEGFreceptor inhibitor SU5416 can inhibit endometrio-sis angiogenesis and reduce inflammatory response in rats, and its mechanism of action may be related to the down-regulation of the ERK-VEGF/MMP-9 path-way expression.

High-dose chemotherapy with autologous stem-cell transplantation for relapsed metastatic germ cell tumors The Alberta experience.

High-dose chemotherapy with autologous stem-cell transplantation (HDC-ASCT) is standard therapy for metastatic germ cell tumors (mGCTs) in patients whose disease progresses during or after conventional chemotherapy. We conducted a retrospective review of HDC-ASCT in relapsed mGCT patients in the province of Alberta, Canada, over the past two decades. Patients with mGCTs who received HDC-ASCT at two provincial cancer referral centers from 2000-2018 were identified from institutional databases. Baseline clinical and treatment characteristics were collected, as well as overall survival (OS ) and disease-free survival (DFS). Relevant prognostic variables were analyzed. Forty-three patients were identified. The median age was 28 years (range 19-56). A majority (95%) had non-seminoma histology and testis/retroperitoneal primary (84%). Twenty patients (47%) had poor-risk disease, as per The International Germ Cell Consensus Classification (IGCCC), at start of first-line chemotherapy. HDC-ASCT was used as second-line therapy in 65% of patients, and 58% of ASCT patients received tandem transplants. Median followup after ASCT was 22 months (range 2-181). At last followup, 42% of patients were alive without disease, including 3/7 (43%) of patients with primary mediastinal disease. Two-year and five-year DFS/OS ratios were 44%/65% and 38%/45%, respectively. Median OS and DFS for all patients were 30.0 months (13.3-46.6) and 8.0 months (0.9-15.1), respectively. We found that HDC-ASCT is an effective salvage therapy in mGCT, consistent with existing literature. Patients appeared to benefit regardless of primary site. Although limited by small sample size, we found a numerical difference in DFS and OS between second- and third-line HDC-ASCT and single vs. tandem ASCT.

Clinical Outcomes of Human Rhinovirus Infections in Pediatric Hemopoietic Stem Cell Transplant Patients

Abstract Background Respiratory viral infections (RVIs) are common among pediatric transplant patients, with Human rhinovirus (HRV) being most frequently. In pediatric patients undergoing hematopoietic cell transplant (HCT), HRV infection prior to, or early post-transplant has been associated with progression to lower respiratory tract infection (LRTI) and adverse outcomes. The primary objective is to describe the clinical presentation and outcomes of HRV infections in patients undergoing HCT at St. Jude Children’s Research Hospital. Methods This is a single-center retrospective cohort study. HCT recipients who had a respiratory sample positive for HRV (HRV positive) or negative for any respiratory virus (virus negative) between October 1, 2014, and December 31, 2017, were included. Testing was performed using BioFire® Respiratory Panel. Primary outcomes were progression to LRTI, ICU admission, all-cause mortality rate, and respiratory event-related mortality rate. Results A total of 227 patients (166 allogeneic and 61 autologous transplants) were included in the analysis. Of these, 108 (47.5%) were HRV positive and 119 (52.4%) were virus negative. Of the HRV patients, 63.6% were diagnosed pretransplant. All samples were nasopharyngeal, except for 1 tracheal aspirate. There were no significant differences in sex, race, type of transplant, underlying malignancy, and conditioning regimen between patients with and without HRV infection. However, patients who had HRV were significantly younger compared with virus negative (Table 1). Cough and rhinorrhea were more frequently observed in patients with HRV (53.7% vs 19.8%, and 60.2% vs 22.8%, respectively). Almost 1 in 4 patients with HRV had LRTI. No significant association was found between the severity of respiratory disease and the type of conditioning regimen, type of transplant, or absolute lymphocyte count (ALC) within a week of infection. HRV positive patients were more likely to be tested due to symptoms, have URTI, and present with co-infections compared to the virus negative group. There were no differences in the proportion of abnormal radiological findings, and no differences in outcomes between groups (Table 1). Clearance of HRV infection was confirmed with a negative PCR in 45 patients. Of these, 60% remained positive by week 4. Conclusion HRV infection is frequently detected in symptomatic patients undergoing transplant. Despite presenting respiratory symptoms more frequently, there was not a significant association with progression to LRTI, need for intensive care unit, mechanical ventilation or mortality.

Treatment of dermal ulcer with autologous fibrin glue: Two case reports of an exploratory prospective pilot study.

The healing of recurrent and refractory skin ulcers requires a long time, during which there is risk of infection, and hospital admission is occasionally required for surgical or daily conservative treatment. Therefore, the development of promising treatments that promote faster, uneventful healing is a must. Composed of cryoprecipitate and thrombin, fibrin glue has a history of surgical use for preventing bleeding and spinal fluid leakage. Moreover, in-house cryoprecipitates contain higher concentrations of coagulation factors and cytokines that may enhance wound healing than commercially available products. However, the efficacy of completely autologous fibrin glue (AFG) in tissue repair has not yet been fully demonstrated. This study aimed to evaluate the efficacy of AFG in the treatment of refractory skin ulcers in comparison with the conventional treatment. Two patients with skin ulcer on their lower extremities due to trauma or scleroderma who showed resistance to conventional treatment were included in the study. Both study participants were diagnosed with refractory skin ulcer and were ineligible for autologous skin transplantation. AFG was prepared following autologous blood donation using a Cryoseal® system. Subsequently, AFG was administered to 50% of the area of each ulcer and observed for 4 weeks in comparison with recombinant basic fibroblast growth factor with bucladesine sodium treatment that was administered to the rest of the ulcer. The skin ulcer after trauma in participant 1 showed better improvement in the AFG-treated area. Although AFG did not show superiority regarding the ulcer area of a patient with scleroderma, it guarded the continuous exudation from the edge of the swollen skin surrounding the ulcer. AFG showed effective and beneficial results for wound healing of refractory skin ulcer and prevented exudation without any severe adverse events.