High-dose Cyclophosphamide Research Articles

A Study on the Alteration of Endoplasmic Reticulum Stress-related Proteins in Cyclophosphamide-induced Damage to Urothelium

Background: Cyclophosphamide is widely prescribed as an anti-cancer drug and used as an immunosuppressant. Hemorrhagic cystitis is one of the common complications of cyclophosphamide intake. We hypothesized that endoplasmic reticulum stress-related proteins could be altered in urothelium treated with cyclophosphamide. Objectives: We checked the effect of cyclophosphamide on the expression of various endoplasmic reticulum stress-related proteins in Vero cells. Methods: We treated Vero cells with varying doses of cyclophosphamide and observed its viability in flow cytometry using propidium iodide staining. We looked for changes in the expression of endoplasmic reticulum stress-related proteins in Vero cells treated with cyclophosphamide by western blot technique. Results: Cyclophosphamide at higher doses caused more death in Vero cells that could be attributed to an increase in apoptosis as evidenced by the changes in the morphology of cells and increased expression of endoplasmic reticulum specific caspase-12 proteins. Growth arrest/DNA damage 153 (GADD 153), one of the key transcription factors involved in the mediation of endoplasmic reticulum stress and apoptosis, was upregulated in Vero cells treated with cyclophosphamide. The protective effect of glucose-regulated protein GRP 78 against apoptosis was lost in Vero cells treated with a higher dose of cyclophosphamide, which is corroborated by decreased expression of GRP 78 in Vero cells treated with higher doses compared to Vero cells treated with lower doses of cyclophosphamide. Expression of disulfide isomerase protein, which guides misfolded proteins to fold properly, was downregulated in Vero cells treated with cyclophosphamide. Conclusion: To summarize, our study showed an alteration in the expression of key endoplasmic reticulum stress-related proteins in Vero cells treated with cyclophosphamide.

RESULTS OF A COMPARATIVE PHRMACOECONOMICS ANALYSIS OF STRATEGIES FOR THE PREVENTION OF GRAFT-VERSUS-HOST DISEASE IN CHILDREN WITH HEMATOLOGICAL MALIGNANCES: A SINGLE CENTER EXPERIENCE

The discussion around the cost of allogeneic hematopoietic stem cell transplantation and follow-up of patients, methods of calculation and cost structure, despite the breadth of application of hematopoietic stem cell transplantation in oncohematological practice, remains an unresolved problem. The discussion is complicated using various modifications of therapeutic options regarding the preparation of the patient for surgery and the prevention of complications. The purpose of this article is a comparative assessment of the clinical and economic efficiency of the two most used technological platforms – TCRαβ/CD19 depletion and ‘’in vivo’’ depletion with high doses of cyclophosphamide, having studied the features of each of these methods in the real practice of one center. Materials and Methods. For evaluation, two “match paired” groups of children were selected, who underwent transplantation according to one of the methods for hemoblastosis in the period from May 2013 to January 2021 at the National Medical Research Center for Pediatric Hematology, oncology and immunology named after Dmitry Rogachev" of the Ministry of Health of Russia. Based on the obtained indicators of clinical effectiveness (significance of differences was made using the nonparametric Mann-Whitney test), pharmacoeconomic modeling was carried out on the basis of the Markov model, the cost structure was determined and the pharmacoeconomic analysis "cost-effectiveness" was performed, incremental analysis "cost-effectiveness" ”, as well as the calculation of indicators of the cost of the operation after 5 years, taking into account discounting. The results of overall and event-free survival, as well as survival without the development of graft-versus-host disease and relapse were used as endpoints. The costs are divided into 2 time periods: stage 1 – up to 30 days after HSCT and stage 2 – from 31 days after HSCT and up to 1 year. Costs are divided into direct and indirect. For indirect costs, the average figures of the available socio-economic data are taken. Results of the study: The total costs for the two stages were comparable for both platforms: TCRa/b/CD19 deletions – 6702.094 thousand rubles; PtCy – 7325.661 thousand rubles. The costs are unevenly distributed over the stages: the 1st stage is more expensive for the TCR platform, the second for PtCy. In cost-effectiveness analysis, each unit of efficiency (1% survival per 1 year of curation will cost more for the PtCy platform. Given the WHO recommended discount factor of 3% per year, over 5 years, the annual cost for the TCR method should decrease to 5933.316 thousand rubles, and for the PtСy platform up to 6,485.355 thousand rubles without considering macroeconomic indicators. Each additional unit of efficiency (1% survival rate) of TCR will cost: survival rate of 207 855.67 rubles, for survival without GVHD and recurrence of 51 963.92 rubles. Conclusions. Pharmacoeconomically less costly for a period of 1 year of curation is the preventive TCR platform compared to the depletion platform ''in vivo'' using high doses of cyclophosphamide, despite the higher cost of its use at the 1st stage of curation.

Immunostimulatory and Immunorestorative Effects of Leaf Extract and Fractions of Musanga cecropioides on Immunocompetent and Experimentally Immunocompromised Mice

• Musanga cecropioides boosted immune stimulation in immunocompetent animals • M. cecropioides brought about fast rate of restoration of immune status • M. cecropioides stimulated immune response to (sheep red blood cell) SRBC antigen Stimulation of the immune system against disease causing agents and restoration of immune functions in immunodeficiency disease state are essential for maintaining good health. Objective : This study investigated the immunomodulatory effects of the leaf extract and fractions of Musanga cecropioides in immunocompetent and induced immunocompromised animal models. Humoral immune stimulatory effect of the extract and its fractions at 200 and 400 mg∙kg −1 against sheep red blood cells (SRBCs) antigen was determined in both immunocompetent and cyclophosphamide (80 mg∙kg −1 ) immunosuppressed animals. The effect of the most active fraction on leucopoiesis was also determined following high dose cyclophosphamide (300 mg∙kg −1 ) suppression of the immune system. Levamisole at 2.5 mg∙kg −1 was used as the reference drug throughout the study. The extract dose dependently stimulated the humoral immune response to SRBC antigen in immunocompetent animals; however, its stimulatory effect was not significant ( P > 0.05). In the immunosuppressed model, the extract at 400 mg∙kg −1 evoked significant ( P < 0.05) increase in antibody titer value with a corresponding 67% immune-restorative effect. The ethyl acetate fraction (EAF) maintained the most active fraction with significant ( P < 0.05) antibody stimulatory effect in immunocompetent and immunosuppressed animals. Similarly, higher recovery rate was demonstrated by the EAF as shown by steep time recovery curve in high dose immunosuppressed animals. The EAF at 200 and 400 mg∙kg −1 showed above 50% leucopoiesis just like the reference drug (2.5 mg∙kg −1 levamisole) against 33.83% shown by the immune-suppressed control group. M. cecropioides boosted immune stimulation in immunocompetent animals and brought about fast rate of restoration of immune status in immunocompromised animals.

Prediction of Nonrelapse Mortality in Patients With Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia Receiving Allogeneic Stem Cell Transplantation With Posttransplantation Cyclophosphamide-based Graft Versus Host Disease Prophylaxis.

Graft versus host disease (GVHD) prophylaxis with posttransplantation cyclophosphamide (PTCY) has been established to reduce severe GVHD, and thereby potentially reducing nonrelapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). We evaluated the predictive capacity of established NRM-risk scores in patients receiving PTCY-based GVHD prophylaxis, and subsequently developed and validated a novel PTCY-specific NRM-risk model. Adult patients (n = 1861) with AML or ALL in first complete remission who received alloSCT with PTCY-based GVHD prophylaxis were included. The PTCY-risk score was developed using multivariable Fine and Gray regression, selecting parameters from the hematopoietic cell transplantation-comorbidity index (HCT-CI) and European Group for Blood and Marrow Transplantation (EBMT) score with a subdistribution hazard ratio (SHR) of ≥1.2 for 2-year NRM in the training set (70% split), which was validated in the test set (30%). The performance of the EBMT score, HCT-CI, and integrated EBMT score was relatively poor for discriminating 2-year NRM (c-statistic 51.7%, 56.6%, and 59.2%, respectively). The PTCY-risk score included 10 variables which were collapsed in 3 risk groups estimating 2-year NRM of 11% ± 2%, 19% ± 2%, and 36% ± 3% (training set, c-statistic 64%), and 11% ± 2%, 18% ± 3%, and 31% ± 5% (test set, c-statistic 63%), which also translated into different overall survival. Collectively, we developed an NRM-risk score for acute leukemia patients receiving PTCY that better predicted 2-year NRM compared with existing models, which might be applicable to the specific toxicities of high-dose cyclophosphamide.

Plasma Cytokine Levels and Cytokine Genetic Polymorphisms in Patients with Metastatic Breast Cancer Receiving High-Dose Chemotherapy

Differences in the baseline levels of serum cytokines or in single-nucleotide polymorphisms (SNPs) in cytokine genes may be useful to predict outcomes for patients being treated for metastatic breast cancer. We have measured the plasma levels and characterized individual SNPs for IL-1RA, IL-1β, IL-2, IL-6 and TNFα in 130 patients with metastatic breast cancer treated with high-dose chemotherapy. Patients were treated with high-dose cyclophosphamide (Group 1, 74 patients) or high-dose paclitaxel-containing regimens (Group 2, 56 patients). A high plasma level of IL-1RA and a SNP in the IL-1RA gene indicated a better prognosis for patients in Group 1 (but not Group 2). However, the level of plasma IL-1RA did not correlate with the SNP genotype. A high plasma level of IL-6 or TNFα indicated a poorer outcome for patients in Group 1 although the SNP genotypes for the IL-6 and TNFα SNPs were not associated with differences in outcome. The plasma levels of IL-1β and IL-2 and the genotype of the IL-1β SNPs did not indicate differences in outcome. Although, individually, plasma levels of cytokine or “risk” SNP genotypes may not indicate outcome, in combination there was an increased trend to predict outcome for patients treated with high-dose cyclophosphamide but not high-dose paclitaxel. These results suggest that the immune cytokines may be useful as prognostic biomarkers in the treatment of patients with metastatic breast cancer treated with different types of chemotherapy.

Low- Versus High-dose Cyclophosphamide in Class III/IV Lupus Nephritis: A Retrospective Study from South Asia.

The comparative efficacy of low-dose cyclophosphamide (LD-CYC) and high-dose cyclophosphamide (HD-CYC) for treatment of lupus in South Asians is not well established. We aimed to compare treatment outcomes in South Asian patients with class III and IV lupus nephritis treated with either regimen. This was a single-center, retrospective study conducted in Sri Lanka. Patients with biopsy-proven class III or IV lupus nephritis were recruited. The HD-CYC group was defined as having received ≥6 doses of 0.5-1 g/m2 cyclophosphamide (CYC) followed by quarterly doses. The LD-CYC group was defined as having received six doses of 500 mg CYC at two-weekly intervals. The primary outcome was treatment failure defined as persistent nephrotic range proteinuria or renal impairment at 6 months. Sixty-seven patients were recruited (HD-CYC 34, LD-CYC 33), all South Asian ethnicity. The HD-CYC group had received treatment between 2000 and 2013, and the LD-CYC group from 2013 onward. The HD-CYC and LD-CYC groups had 30/33 (90.9%) and 31/34 (91.2%) females, respectively. Nephrotic syndrome and nephrotic range proteinuria on presentation were seen in 22/33 (67%) and 20/32 (62%) in the HD-CYC and LD-CYC groups, respectively, and renal impairment was seen in 5/33 (15%) of the HD-CYC group and 7/32 (22%) of the LD-CYC group (P > 0.05). Treatment failure and complete or partial remission occurred in 7/34 (21%) and 28/34 (82%), respectively, of HD-CYC and 10/33 (30%) and 24/33 (73%), respectively, of LD-CYC (P > 0.05). Adverse events rates were similar. This study suggests that LD-CYC and HD-CYC induction is comparable in South Asian patients with class III and IV lupus nephritis.

Curing Systemic Lupus Erythematosus and Severe Aplastic Anemia with an Allogeneic Transplant: A Case Report and Brief Literature Review

Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs, including the bone marrow. Aplastic anemia (AA) is a rare but serious complication of this condition. Patients with AA secondary to SLE are usually treated with immunosuppression but less is known about hematopoietic stem cell transplantation (HSCT) as a therapeutic option. We present the case of a 22-year-old Latin-American woman with a known diagnosis of SLE referred to our center due to pancytopenia. She presented joint pain, fatigue, oral ulcers, a non-scarring alopecia, and anemic syndrome. A diagnostic workup revealed severe aplastic anemia (sAA). She received immunosuppressive therapy with corticosteroids, cyclosporine, danazol, and rituximab, which led to a transient partial response. An outpatient HLA-matched related allogeneic HSCT was performed. She received 5.9 x 106 CD34+ cells/kg after conditioning with high-dose cyclophosphamide plus fludarabine and anti-thymocyte globulin. She achieved a complete response and continues in remission with no signs of graft-versus-host disease (GVHD) or SLE activity at 38 months of follow-up. Even though allogeneic hematopoietic stem cell transplantation is not defined as a first-line treatment for severe AA in SLE, the procedure resulted in the complete remission of both related autoimmune diseases in this patient.

Allogeneic Blood or Marrow Transplantation with High-Dose Post-Transplantation Cyclophosphamide for Acute Lymphoblastic Leukemia in Patients Age ≥55 Years

Patients age ≥55 years with acute lymphoblastic leukemia (ALL) fare poorly with conventional chemotherapy, with a 5-year overall survival (OS) of ∼20%. Tyrosine kinase inhibitors and novel B cell-targeted therapies can improve outcomes, but rates of relapse and death in remission remain high. Allogeneic blood or marrow transplantation (alloBMT) provides an alternative consolidation strategy, and post-transplantation cyclophosphamide (PTCy) facilitates HLA-mismatched transplantations with low rates of nonrelapse mortality (NRM) and graft-versus-host disease (GVHD). The transplantation database at Johns Hopkins was queried for patients age ≥55 years who underwent alloBMT for ALL using PTCy. The database included 77 such patients. Most received reduced-intensity conditioning (RIC) (88.3%), were in first complete remission (CR1) (85.7%), and had B-lineage disease (90.9%). For the entire cohort, 5-year relapse-free survival (RFS) and overall survival (OS) were 46% (95% confidence interval [CI], 34% to 57%) and 49% (95% CI, 37% to 60%), respectively. Grade III-IV acute GVHD occurred in only 3% of patients, and chronic GVHD occurred in 13%. In multivariable analysis, myeloablative conditioning led to worse RFS (hazard ratio [HR], 4.65; P=.001), whereas transplantation in CR1 (HR, .30; P=.004) and transplantation for Philadelphia chromosome-positive (Ph+) ALL versus T-ALL (HR, .29; P=.03) were associated with improved RFS. Of the 54 patients who underwent RIC alloBMT in CR1 for B-ALL, the 5-year RFS and OS were 62% (95% CI, 47% to 74%) and 65% (95% CI, 51% to 77%), respectively, with a 5-year relapse incidence of 16% (95% CI, 7% to 27%) and an NRM of 24% (95% CI, 13% to 36%). RIC alloBMT with PTCy in CR1 represents a promising consolidation strategy for B-ALL patients age ≥55 years.

Effect of CD34+ Cell Dose on the Outcomes of Allogeneic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide

The impact of infused CD34+ cell dose on outcomes after allogeneic hematopoietic stem cell transplantation (alloHSCT) using standard graft-versus-host disease (GVHD) prophylaxis remains controversial. Information on this subject is scarce for alloHSCT using high-dose post-transplantation cyclophosphamide (PTCy). We aimed to assess the effect of CD34+ cell dose in peripheral blood stem cell (PBSC) grafts on the outcome of alloHSCT using PTCy-based GVHD prophylaxis. To do so, we conducted a single-center retrospective analysis of 221 consecutive adult patients who underwent PTCy alloHSCT from HLA-matched sibling donors (MSDs; n=22), HLA-matched unrelated donors (MUDs; n=83), mismatched unrelated donors (MMUDs; n=73), and haploidentical donors (n=43). Based on the binary partitioning method, 5×106/kg was used as the optimal cutoff for CD34+ cell dose. According to our institutional protocol, the maximum CD34+ cell dose was capped at 8×106/kg. The study cohort was divided into 2 groups based on CD34+ cell dose: high dose (>5 to 8×106/kg) and low dose (≤5×106/kg). Patients receiving high-dose CD34+-containing grafts had significantly shorter median times to neutrophil engraftment and platelet engraftment compared to those who received low-dose CD34+ (19 days versus 21 days [P=.002] and 16 days versus 22 days [P=.04], respectively). There were no differences between the high-dose and low-dose groups in the cumulative incidence of day +100 acute GVHD (grade II-IV: 25% versus 23% [P=.7]; grade III-IV: 5% versus 4% [P=.4], respectively) or 2-year chronic GVHD (moderate/severe GVHD: 9% versus 6%; P=.5). There was no impact of CD34+ cell dose on survival outcomes with the use of MSDs, MUDs, or MMUDs. Recipients of haploidentical alloHSCT using low-dose CD34+ cells had significantly worse overall survival (hazard ratio [HR], 6.01; P=.004) and relapse-free survival (HR, 4.57; P=.004). In recipients of PBSC PTCy alloHSCT, infused CD34+ cell doses>5 to 8×106/kg were associated with faster neutrophil and platelet engraftment, independent of donor type. Our study suggests an impact of CD34+ cell dose on survival outcomes only with haploidentical donors, for whom the administration of a CD34+ cell dose≤5×106/kg significantly decreased survival outcomes.

Impact of Early Intrapatient Variability of Tacrolimus Concentrations on the Risk of Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide.

Tacrolimus (Tac) is a pivotal immunosuppressant agent used to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloHSCT). Tac is characterized by a narrow therapeutic window and a high inter-patient and intra-patient pharmacokinetic variability (IPV). Although high IPV of Tac concentrations has been associated with adverse post-transplant outcomes following solid organ transplantation, the effects of Tac IPV on alloHSCT recipients have not been determined. Tac IPV was therefore retrospectively evaluated in 128 alloHSCT recipients receiving high-dose post-transplant cyclophosphamide (PTCy) and the effects of Tac IPV on the occurrence of acute GVHD (aGVHD) were analyzed. Tac IPV was calculated from pre-dose concentrations (C0) measured during the first month after Tac initiation. The cumulative rates of grades II-IV and grades III-IV aGVHD at day +100 were 22.7% and 7%, respectively. Higher Tac IPV was associated with a greater risk of developing GVHD, with patients having IPV > 50th percentile having significantly higher rates of grades II-IV (34.9% vs. 10.8%; hazard ratio [HR] 3.858, p < 0.001) and grades III-IV (12.7% vs. 1.5%; HR 9.69, p = 0.033) aGVHD than patients having IPV ≤ 50th percentile. Similarly, patients with IPV > 75th percentile had higher rates of grades II-IV (41.9% vs. 16.5%; HR 3.30, p < 0.001) and grades III-IV (16.1% vs. 4.1%; HR 4.99, p = 0.012) aGVHD than patients with IPV ≤ 75th percentile. Multivariate analyses showed that high Tac IPV (>50th percentile) was an independent risk factor for grades II-IV (HR 2.99, p = 0.018) and grades III-IV (HR 9.12, p = 0.047) aGVHD. Determination of Tac IPV soon after alloHSCT could be useful in identifying patients at greater risk of aGVHD.

Shrunken pore syndrome in childhood cancer survivors treated with potentially nephrotoxic therapy

Childhood cancer survivors (CCS) are at risk of kidney dysfunction. Recently, the shrunken pore syndrome (SPS) has been described, which is characterized by selectively impaired filtration of larger molecules like cystatin C, while filtration of smaller molecules like creatinine is unaltered. It has been associated with increased mortality, even in the presence of a normal estimated glomerular filtration rate (eGFR). The aim of this study was to evaluate the prevalence of SPS in CCS exposed to potentially nephrotoxic therapy. In the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER 2 Renal study, a nationwide cross-sectional cohort study, 1024 CCS ≥5 years after diagnosis, aged ≥18 years at study, treated between 1963-2001 with nephrectomy, abdominal radiotherapy, total body irradiation, cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide or hematopoietic stem cell transplantation participated, and 500 age- and sex-matched controls form Lifelines. SPS was defined as an eGFRcys/eGFRcr ratio <0.6 in the absence of non-GFR determinants of cystatin C and creatinine metabolism (i.e. hyperthyroidism, corticosteroids, underweight). Three pairs of eGFR-equations were used; CKD-EPIcys/CKD-EPIcr, CAPA/LMR, and FAScys/FASage. Median age was 32 years. Although an eGFRcys/eGFRcr ratio <0.6 was more common in CCS (1.0%) than controls (0%) based on the CKD-EPI equations, most cases were explained by non-GFR determinants. The prevalence of SPS in CCS was 0.3% (CKD-EPI equations), 0.2% (CAPA/LMR) and 0.1% (FAS equations), and not increased compared to controls. CCS treated with nephrotoxic therapy are not at increased risk for SPS compared to controls. Yet, non-GFR determinants are more common and should be taken into account when estimating GFR.

A case report of atypical anti-glomerular basement membrane disease

BackgroundAnti-glomerular basement membrane (anti-GBM) disease is characterized by crescentic necrotizing glomerulonephritis, with linear deposits of immunoglobulin G (IgG) in the GBM. Classic anti-GBM disease is clinically associated with rapidly progressive glomerulonephritis with or without pulmonary hemorrhage. Some patients have a better renal prognosis and milder symptoms than those with classic anti-GBM disease, which is termed atypical anti-GBM disease.Case presentationA 43-year-old Japanese woman was admitted to our hospital complaining of hematuria that had persisted for more than one month. Serological examination revealed negativity for anti-nuclear, anti-neutrophilic cytoplasmic, and anti-GBM antibodies. However, renal biopsy showed cellular crescents. Immunofluorescence revealed strong diffuse linear capillary loop staining for IgG. An indirect immunofluorescence antibody method was performed by applying the patient serum to normal kidney tissue to confirm the presence of autoantibodies binding to the GBM. Using this method, anti-GBM antibodies were detected. The patient was treated with high-dose steroids, cyclophosphamide, and plasma exchange. Aggressive treatment resolved proteinuria and hematuria and improved renal function.ConclusionsRenal biopsy is crucial in the diagnosis of anti-GBM disease, especially when serological tests are negative. Accurately identifying the presence of anti-GBM disease is important to initiate optimal treatment.

Allogeneic Blood or Marrow Transplantation (AlloBMT) with High-Dose Post-Transplantation Cyclophosphamide (PTCy) for Acute Lymphoblastic Leukemia (ALL) in Patients Aged ≥ 55: Best Results in B ALL in First Remission (CR1) with Reduced-Intensity Conditioning (RIC)

Background: Older patients with ALL fare poorly with conventional chemotherapy. Patients aged 55-65 on E2993 and ≥ 60 treated with Hyper-CVAD have 5-year overall survival (OS) of just 21% and 20%, respectively (Sive. BJH. 2012 and O'Brien. Cancer. 2008). Recently, HyperCVD with inotuzumab +/- blinatumomab in patients ≥ 60 years old with Ph- B ALL demonstrated an improved 5-year OS of 47% with 38% of patients dying in remission (Short. Blood. 2021). AlloBMT provides an alternative consolidation strategy. Registry studies in ALL patients ≥ 60 years old and B ALL patients ≥ 55 years old who underwent alloBMT with RIC in CR1 demonstrated 5 and 3-year OS of 42% and 45%, respectively (Roth-Guepin. Oncotarget. 2017 and Rosko. Am J Hematol. 2017). These studies utilized heterogenous conditioning and graft-versus-host disease (GVHD) prophylaxis regimens. The use of high-dose post-transplantation cyclophosphamide as GVHD prophylaxis facilitates transplants in older adults with low rates of non-relapse mortality, GVHD, and the use of HLA haploidentical donors (Kasamon. JCO. 2015). Methods: The bone marrow transplant database at Johns Hopkins was queried for patients ≥ 55 years old who received a first alloBMT using PTCy from January 2008-January 2021. Characteristics of patients were summarized and compared using Fisher's exact test for categorical variables. Estimators of OS and relapse-free survival (RFS) were reported using the Kaplan-Meier method. Differences in time-to-event outcomes were estimated using Cox proportional hazards model, or Fine and Gray's model for cumulative incidence of relapse (CIR)/nonrelapse mortality (NRM) considering competing risks. Results: A total of 77 patients aged ≥ 55 underwent a first alloBMT with PTCy for ALL. The vast majority were performed in CR1 (85.7%), utilized RIC (88.3%), and were performed for B ALL (90.9%). Demographics and transplant characteristics are presented in Table 1. RIC consisted of fludarabine, cyclophosphamide and total body irradiation followed by PTCy-based GVHD prophylaxis as previously described (Kasamon. BBMT. 2008). Relapse-free survival (RFS) and OS at 5 years for the entire cohort were 46% (95% CI 34-57) and 49% (95% CI 37-60), respectively, with a 5-year CIR of 27% (95% CI 18-38) and NRM of 28% (95% CI 18-39). The cumulative incidences of grade 3-4 acute GVHD at 1 year and chronic GVHD at 3 years were 3% (95% CI, 0% to 9%) and 13% (95% CI 5% to 21%), respectively. In univariate analysis, the use of myeloablative conditioning led to worse RFS (HR 0.25, p=0.0004); while the absence of MRD (HR 2.93, p=0.008), transplant in CR1 (HR 3.81, p=0.0004), and transplant for Ph+ ALL vs. T ALL (HR 3.15, p=0.03) led to improved RFS. Subsequent analysis focusing on the 54 patients receiving RIC alloBMT in CR1 for B ALL demonstrated RFS and OS at 5 years of 61% (95% CI 46-73) and 64% (95% CI 49-76), respectively, (see Figure 1) with a 5-year CIR of 16% (95% CI 7-27) and NRM 24% (95% CI 13-36), although just 7% at 1 year. For B ALL patients transplanted with RIC in CR1, 3-year NRM was higher among patients who received a peripheral blood stem cell transplant (55%, 95% CI 18% to 81%), those treated with rituximab pre-transplant (36%, 95% CI 16% to 57%), and those who received ≥100 mg/m2 of doxorubicin equivalent for ALL (67%, 95% CI 19% to 90%). Outcomes did not differ among the 20% of patients who received pre-transplant blinatumomab compared to those who did not. Among the 23 Ph+ B ALL patients transplanted with RIC in CR1 following treatment with a 2nd or 3rd generation tyrosine kinase inhibitor (TKI), the 5-year CIR was 5% (95% CI, 0% to 22%). Conclusions: RIC AlloBMT with PTCy in CR1 represents a promising consolidation strategy for B ALL patients ≥ 55 years old. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Addition of ATG to Clofarabine-Based Reduced Intensity Conditioning Regimen with PBSC and Ptcy in Adults with Myeloid Malignancies

INTRODUCTION In allogeneic hematopoietic stem cell transplantation (Allo-HSCT), the Clo-Baltimore (CloB) regimen is a variant of the Baltimore reduced-intensity conditioning (RIC) regimen that uses clofarabine in replacement of fludarabine and high-dose post-transplant cyclophosphamide (PTCY). This regimen provides good survivals for patients (pts) with myeloid malignancies (Chevallier et al., Oncotarget 2018). Yet, graft-versus host disease (GVHD) remains a major cause of morbidity and mortality in Allo-HSCT recipients. The administration of anti-thymocyte globulin (ATG) is a standard method to prevent GVHD in matched Allo-HSCT. Here, we retrospectively investigated whether the addition of ATG to CloB conditioning with PTCY was beneficial in terms of GVHD rates. METHODS This retrospective study included all consecutive Allo-HSCT adult recipients with myeloid malignancies transplanted between March 2014 and February 2022 in our hospital after CloB+/-ATG conditioning regimen. CloB consisted in clofarabine 30 mg/m²/day (d) from d-6 to d-2, cyclophosphamide 14.5 mg/kg/d on d-6 and d-5, and cyclophosphamide 50mg/kg/d on d+4 and d+5 after Allo-HSCT. In CloB+ATG, pts additionally received ATG 2.5mg/kg/d on d-2. GVHD prophylaxis consisted in the administration of cyclosporine A and mycophenolate mofetil to all patients. Graft source was exclusively peripheral blood stem cells. We determined overall (OS), disease-free (DFS) and GVHD relapse-free (GRFS) survivals, as well as non-relapse mortality (NRM) and relapse incidences. RESULTS Sixty-six pts (median age 61 years old, range 32-74) were included, with 36 pts treated with CloB conditioning between 2014 and 2017, and 30 with CloB+ATG between 2019 and 2022. Between the two periods other conditioning regimens were used in our Department. Diagnoses comprised acute myeloblastic leukemia (AML, n=32), myelodysplastic syndromes (MDS, n=18), myeloproliferative neoplasms (MPN, n=5), or MDS/MPN (n=10). The disease risk index (DRI) was low in 7 (11%) pts, intermediate in 43 (66%), and high in 15 (23%). The median HSCT-specific comorbidity index was 3 (range 0-7). Donors were haploidentical in 54 (82%) cases, and matched in 12. In the whole cohort, 18-months(m) OS, DFS and GRFS were 71±6%, 65±6%, and 55±6%, and 18-m NRM and relapse incidences were 14±4% and 21±5% respectively. A higher proportion of high DRI was observed in the CloB group (36 vs 10%, p=0.03). The median follow-up was 68 months (m) in the CloB cohort and 19.5 m in the CloB+ATG cohort. These two groups were otherwise comparable (Table 1). A lower proportion of acute GVHD was observed in the CloB+ATG group (23.3 vs 50%, p=0.05), with no statistical differences in terms of chronic GVHD (p=0.49). Of note, no extensive chronic GVHD was observed in the CloB+ATG group (vs 11% in CloB patients, p=0.17) In multivariate analysis, the addition of ATG to CloB conditioning was associated with a significant increase in 18-m GRFS (70±8% vs 43±8%, HR 0.38 [95%CI 0.17-0.85], p=0.02; Figure1). No differences were observed in terms of OS (HR 0.74, p=0.51), DFS (HR 0.58 p=0.22), NRM (HR 0.84, p=0.79), relapse rate (HR 0.51, p=0.25), median time of neutrophil (>1 109/L) and platelet (> 50 109/L) recovery (respectively 19d [range 12-27] vs 18d [8-32], p=0.69, and 36d [22-471] vs 31d [12-134], p=0.09). The results were similar when considering only patients with a haploidentical donor (n=54), with a benefit in terms of GRFS in the ATG group in multivariate analysis: HR 0.30 (95%CI 0.12-0.73; p=0.008). CONCLUSION Addition of ATG to the Clo-Baltimore RIC regimen with PTCY improved GRFS rates in this cohort without increasing infection-related mortality nor relapse rate in pts with myeloid malignancies and matched or haplo-donors. This strategy should be more widely implemented. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Intravenous Cyclophosphamide Therapy for Anti-IFN-γ Autoantibody-Associated Talaromyces marneffei Infection.

High titers of anti-interferon-γ autoantibodies (AIGAs) are an important factor leading to persistent, relapsed, and refractory infections in HIV-negative hosts infected with Talaromyces marneffei (TM). We report 5 patients treated with pulses of high-dose intravenous cyclophosphamide (IVCY) who were followed for 2 years. Before IVCY therapy, all patients had multiple relapses, with a median (interquartile range [IQR]) of 2 (1-3) instances of relapse. The median serum AIGA titers (IQR) were 58 753 (41 203-89 605) ng/mL at diagnosis, 48 189.4 (15 537-83 375) ng/mL before IVCY therapy, and 10 721.2 (5637-13 245) ng/mL at the end of IVCY therapy (P < .05). After 3 months of follow-up, the median AIGA titers (IQR) rose gradually to 21 232.6 (9896-45 626) ng/mL, and to 37 464.2 (19 872-58 321) ng/mL at 24 months (P < .05). Five patients discontinued antimicrobial therapy within 3-12 months after completion of IVCY therapy, but only 1 patient had a relapse. In conclusion, pulses of short-term and high-dose IVCY can effectively reduce AIGA titers.

Abstract 13093: Global Longitudinal Strain Prediction of Cardiac Dysfunction in Hematopoietic Stem Cell Transplant Patients

Introduction and Hypothesis: Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for hematological malignancies, but patients undergoing HSCT are at increased risk of cardiovascular events and death. Global longitudinal strain (GLS) is more sensitive than left ventricular ejection fraction (LVEF) to identify subclinical LV dysfunction. Early heart failure guideline-directed medical therapy (GDMT) may improve heart function and symptoms in these patients. Methods: Transthoracic echocardiography with speckle tracking was performed every 3 months for 9 months before and after BMT (Figure 1A), with GLS and LVEF as markers of systolic function and E/e' as markers of diastolic function, troponin I, NT-ProBNP and D-dimer as markers of cardiac insufficiency. Patients with a 10% reduction in GLS or a 15% reduction in LVEF from baseline were defined as LV dysfunction and GDMT were prescribed. Results: A total of 27acute myeloid leukemia and 5 acute lymphoblastic leukemia received high dose cyclophosphamide before HSCT, 2 patients developed minimal pericardial effusion without tamponade, 2 patients expired during transplantation. The mean GLS before HSCT was -16.8±0.75%, which was significantly reduced to -15.11±0.86% (p=0.026) after 3 months (Figure 1B). After GDMT, GLS improved to -18.86±1.6% 9 months after HSCT. No significant changes in LVEF, E/e' and serum biomarkers during follow-up Conclusions: Our results further support an increased risk of subclinical myocardial dysfunction in patients with hematological malignancies on HSCT. In these patients, GLS may be an earlier noninvasive marker than LVEF, ECG, or serum biomarkers. Early heart failure GDMT may improve heart function once GLS is reduced.

Comparison of short interval and low dose (SILD) with high dose of cyclophosphamide in the susceptibility to infection in SLE: a multicentrereal-world study

ObjectiveInfection is a major cause of death in patients with SLE. This study aimed to explore the infection rate in patients with SLE receiving a low dose of intravenous cyclophosphamide...

Predictors of mortality for dermatomyositis patients positive with anti-melanoma differentiation-related gene 5 and optimal treatment.

To explore the risk factors of early death in dermatomyositis patients positive with anti-melanoma differentiation-related gene 5 antibody (anti-MDA5-DM). To explore the optimal treatment regimen for patients with anti-MDA5-DM. Patients with newly onset anti-MDA5-DM from June 2018 to October 2021 in our centre were retrospectively reviewed for 6 months. Patients were divided into five groups based on initial treatments. The major outcome was mortality in 6 months. Secondary outcomes included remission and severe infection. A total of 214 patients were included in the study. During 6 month follow-up, 63 patients (30.14%) died, 112 patients (53.59%) achieved remission, 52 patients (24.88%) experienced serious infection and 5 patients (2.34%) were lost. Independent risk factors of mortality in the first 6 months after diagnosis were as follows: age> 53 years, skin ulcer, peripheral blood lymphocyte count (LYMP)≤ 0.6×109/L, lactate dehydrogenase (LDH) > 500 U/L, C reactive protein (CRP) > 5mg/L, anti-Ro52 antibody and ground-glass opacity (GGO) score> 2. On the contrary, prophylactic use of the compound sulfamethoxazole (SMZ Co) was independent protective factor. The five-category treatment was not an independent influencing factor of early death, but subgroup analysis found that patients with rapidly progressive interstitial lung disease (RPILD) responded better to a triple combination of high-dose glucocorticoids (GC), calcineurin inhibitors (CNI) and cyclophosphamide (CYC) or a triple combibation of GC, CNI and tofacitinib (TOF). Advanced age, skin ulcer, lymphopenia, anti-Ro52 antibody and higher levels of LDH, CRP and GGO score increase the risk of early death for MDA5-DM, while prophylactic use of SMZ Co is protective. Aggressive therapy with combined immunosuppressants may improve the short-term prognosis of anti-MDA5-DM with RPILD.

P.216 Two interesting and unique cases of acquired neuropathies in pediatrics

A 2-year-old boy known for an abdominal neuroblastoma was admitted after his fourth cycle of chemotherapy for generalized deterioration and pain when weight bearing. Multiple investigations and medication trials were made without finding the cause or relieving the patient's pain. While in hospital, the pain worsened and he developed gastroparesis, psychomotor regression and respiratory distress. A sensory polyneuropathy was confirmed by NCS, and the diagnosis of anti-Hu syndrome was subsequently made by CSF and serum paraneoplastic antibody panel. He received high-dose steroids, plasmapheresis, rituximab and cyclophosphamide, without clear improvement. After a few weeks, he underwent surgical resection of his neuroblastoma and was started on daratumumab bimonthly, mycophenolate mofetil and monthly IVIG after which he finally mildly improved. In summary, anti-Hu syndrome, while extremely rare in pediatrics, must be included in the differential diagnosis of refractory pain in children with a tumor diagnosis. A 15-year-old boy with no previous health issue presented with a subacute onset paraparesis. He had been recently diagnosed with diabetes of unknown type after a weight loss of 45 kg and started on insulin. He presented with progressive bilateral leg weakness, and the physical exam showed asymmetric weakness and decreased reflexes in the lower limbs, as well as sensory loss in a distal-to-proximal gradient. Investigations, such as a spine MRI and blood tests, showed no abnormality except for high HbA1c. The EMG and NCS confirmed involvement of multiple nerves and nerve roots with axonal loss. The final diagnosis was radiculo-plexo-neuropathy related to diabetes type II. The patient refused immunotherapy, and then completely recovered when his treatment was adjusted for diabetes type II.

CT-514 Acute Cardiac Tamponade Following Adult Allogeneic Hematopoietic Transplantation

Large pericardial effusions (LPEs) occur in <1% of the adult population. Early onset (<100 days from allogeneic hematopoietic transplantation (allo-SCT)) LPEs are related to cardiac toxicity of conditioning regimen while late LPEs (>100 from allo-SCT) are chronic GvHD related. The major determinant of acute pericardial tamponade (ACT) is the rapidity with which fluid accumulates. We herein document 4 adult patients with early LPEs that led to ACT. Interestingly, 3 of these also manifested idiopathic immune thrombocytopenia (ITP), an association that has not been previously described. Median age of 3 females and 1 male was 46 years (range 19-58). All patients received high-dose cyclophosphamide either as part of conditioning or post-transplant GvHD prevention (conditioning comprised: busulfan, fludarabine and tiotepa and post-transplantation cyclophosphamide =1, cyclophosphamide, total body irradiation and alemtuzumab =2 and cyclophosphamide and antithymocyte globulin =1). Donors comprised: matched unrelated donor =2, matched sibling donor =1 and haploidentical donor =1. Engraftment occurred on days +20, +30, +12, and +21. All four patients developed ACT at <100 days from allo-SCT on days +1, +16, + 22, and +60 after allo-SCT. ACT manifested as acute, new, or worsening shortness of breath. At ACT, all 4 were negative for CMV infection and acute GvHD (aGVHD). Pericardial fluid was serous in 2 and serosanguinous in 2 patients. Laboratory analysis did not support bacterial or viral infections and rheumatologic profile was negative. ACT was managed by cardiologist who performed either pericardiocentesis with pericardial drain or pericardial window. A cumulative total of 1700 ml, 1500 ml, 1500 ml and 300 ml pericardial fluid was removed. LPEs reoccurred in 2 patients; one with ACT physiology required pericardial window. Additionally, 3 patients developed ITP after development of ACT. The median time to ITP was day+30 (30, 30 and 75 days) from engraftment. Bone marrow biopsies in patients who developed ITP revealed adequate megakaryocytes. ITP responded promptly to steroids, thrombopoietin receptor agonists and IVIG. Prompt cardiac evaluation with doppler echocardiogram facilitates lifesaving management of ACT. Early onset LPEs in our patients was not associated with aGVHD; it is more likely to be associated with cardiac toxicity of cyclophosphamide. Association with ITP may reflect shared pathogenesis.