100-day Mortality Research Articles

Outcomes of patients who received CAR T cell therapy and developed IEC-HS treated with cytokine directed therapy.

7516 Background: Immune effector cell hemophagocytic lymphohistiocytosis IEC-HS is a complication of CAR T cell therapy (CART). This study aims to look at the outcomes of CART patients who develop IEC-HS. Methods: Patients who developed IEC-HS after receiving CART and patients who developed IEC-HS without (nonCART) between December 2020 and March 2022 were included. Results: The 20 CART patients were older than the 25 nonCART patients. Peak ferritin, fibrinogen, CRP, serum creatinine and transaminases were similar between the 2 group. CART patients had lower white blood cell count and platelets and bilirubin than the nonCART patients. CART patients were more like to have markedly elevated IL-6 levels (> 315 mg/ml), higher IL-18, higher MCP-1, and suppressed IL-1β and GMCSF than nonCART patients (Table). Treatment of IEC-HS included tocilizumab (n = 19), anakinra (n = 18) siltuximab (n = 4) and basiliximab (n = 4), dexamethasone (n = 18) methylprednisolone (n = 6), etoposide (n = 1) and ruxolitinib (n = 1). A significant response defined by a 90% reduction or normalization of the cytokine was observed with IL-10 and IFN-ϒ in 92.3% and 84.6% of the CART patients respectively. An intermediate response was noted with TNF, IL-6, MCP-1 and MIP-1 in 38.4%, 30.8% and 61.6% and 38.5% of the patients respectively. No patient had a significant response in IL-2Rα or IL-1β and only 7.7% had a significant response in IL-18. Of the 5 patients who had a MIP-1 response, 4 were on basiliximab +/- high flow continuous venovenous hemofiltration and the only patient that had an IL-18 response was on both modalities. The 100-day mortality after IEC-HS in the CART patients was 40% and was associated with higher peak and lower best ferritin but not the percentage reduction (Table). Higher TNF (90.3 pg/ml vs 37.2 pg/ml, p = 0.05), markedly elevated levels of IL-6 (92% vs 50%, p = 0.03) and IL-10 (33% vs 0%) and an IL-6 response (44.4% vs 0%) were associated with survival at day 100. IL-6 responders had lower peak ferritin vs IL-6 nonresponders (14066 mcg/L vs 45051 mcg/L, p = 0.08). Enterococcus faecium bacteremia developed in 75% of the nonsurvivors vs 16.6% of the 100-day survivors (p = 0.009). Survivors cleared the enterococcus bacteremia within days while nonsurvivors had protracted bacteremia. Conclusions: IEC-HS is devastating complication of CART. Anti-cytokine therapy can reduce some cytokines and ferritin but overimmunosuppression may lead infectious complication, in particular with E. faecium. Better biomarkers are needed to finetune immunosuppressive therapy in order to avoid over-immunosuppression. [Table: see text]

Letermovir Primary Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients: Real-Life Data from a University Hospital in Argentina.

Cytomegalovirus (CMV) infection remains the most common clinically significant infection after allogeneic hematopoietic stem cell transplantation (allo-HCT) and is associated with considerable morbidity and mortality. The present study was designed to describe and compare the incidence of untreated CMV reactivation (uCMVr), clinically significant infection (cs-CMVi) and disease (CMVd), as well as CMV-related hospitalization and outcome of allo-HCT patients, either treated with letermovir (LET) primary prophylaxis or managed with preemptive therapy (PET). This is a prospective observational cohort study of adult CMV seropositive allo-HCT patients who either received primary prophylaxis with LET within the first 100 days after HCT or were managed with PET. The study population comprised 105 patients (28 in the LET group and 77 in the PET group). Compared to the PET group, patients in the LET group received more allo-HCT from alternative donors (54.5% vs. 82.14%, P=0.012). More than half of the patients in both groups were classified as high risk for CMVd. In the LET vs. PET group, cs-CMVi and CMVd developed respectively in 0 vs. 50 (64.94%), P=<0.0001, and 0 vs. 6 (7.79%), P=0.18. In the LET group, uCMVr occurred in 5 (17.8%) and were all considered blips. Hospital admissions related to cs-CMVi or CMVd in the PET group vs. LET group were 47 (61.04%) vs. 0, respectively, P=<0.0001. No differences were observed in 100-day mortality. LET primary prophylaxis proved effective in preventing cs-CMVi and CMVd and reducing hospitalizations in allo-HCT adults. Blips can occur during prophylaxis and do not require LET discontinuation.

A Deeper Depth of Response After Salvage Therapy Improves Outcomes of Autologous Stem Cell Transplantation in Relapsed Lymphoma and the Feasibility of Non-controlled Rate Freezing of Peripheral Blood Stem Cells.

Background High-dose chemotherapy followed by autologous stem cell transplantation is considered a standard treatment approach for patients with relapsed Hodgkin's lymphoma (HL) and non-Hodgkin lymphoma (NHL). The goal of autologous stem cell transplant in relapsed lymphoma is to achieve long-term disease control, i.e., cure, in contrast to disorders like multiple myeloma, where it only prolongs the duration of remission, progression-free survival, and improves the quality of life. Published outcomes of high-dose therapy and ASCT and the impact of different factors affecting survival in low- to middle-income countries are very limited. Our study analyzed all the autologous stem cell transplants performed in our center over a six-year period to ascertain engraftment, responses, outcomes, and variables that may have impacted transplant outcomes. Methods We conducted a retrospective study including 76 patients from January 2015 to December 2020. Data were retrieved from electronic medical records at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan. Results Out of a total of 82 autologous transplant patients, 76 were eligible for the study, out of which 50 (66%) had HLand 26 (34%) had NHL. The median age was 29 years (range 18-53) and 29 years (range 20-45) for HL and NHL, respectively. The male-to-female ratio was 5:2 and 4:1 for HL and NHL, respectively. The majority had advanced-stage disease, 85% in HL and 75% in NHL. The minimum cell dose infused was 2.5 million CD34+ cells/kg. Median days to platelets and ANC engraftment were 14 and 11 days, respectively. The 30-day transplant-related mortality was 8.9% and 7.4% in HL and NHL, respectively. The 100-day mortality was 15.2% and 11% in HL and NHL, respectively. The two-year disease-free survival (DFS) and overall survival (OS) were 83% and 83%, respectively, in HL patients. The two-year DFS and OS were 78% and 85%, respectively, in NHL patients. Conclusion High-dose therapy and autologous stem cell transplantation in low- to middle-income countries are limited to relatively younger patients, potentially curative conditions such as lymphoma, and predominantly after achieving a complete response to salvage therapy due to limited resources. Due to these factors, our study shows excellent response rates and survival outcomes compared to internationally published data. Engraftment was also excellent and comparable to published data despite the non-controlled rate freezing of peripheral blood stem cells.

Efficacy and Reliability of T-Cell–Depleted Haploidentical Stem Cell Transplantation in Hematologic Disorders: A Retrospective Study

A promising recent strategy for haploidentical transplantation is the depletion of T lymphocytes based on the selective elimination of T cells by manipulation, which enables a very low incidence of nonrelapse mortality and graft-vs-host disease. It is more expensive than conventional unmanipulated methods and requires dedicated transplant centers and sufficient stem cell processing facilities. This retrospective study aimed to evaluate the relapse, survival, and clinical data of the patients and to analyze the outcomes of the technique. The study included 56 adult patients who underwent haploidentical stem cell transplantation via αβ T-cell depletion. The median age of the patients at the time of hematopoietic stem cell transplantation was 41.5 years (range, 20-70 years); 22 patients (39.3%) were women. After the transplantation, half of the patients (50.0%) needed immunosuppressive drugs, and 17.9% of the patients experienced a post-transplant relapse. The mortality rate was 55.4%, and nonrelapse mortality was 25.0%. The 100-day mortality rate was 19.6%. The median overall days was 1101 days (142-3813 days), whereas the median progression-free overall was 302.5 days (11-2479 days). Being older (age >40), having hypertension, having acute liver graft-vs-host disease, and having systemic fungal infection were found as risk factors that significantly increased mortality (with 3.5-, 2.8-, 3.7-, and 2.7-fold increases, respectively). To conclude, T-cell-depleted hematopoietic stem cell transplantation is an effective and reliable technique that has the potential to decrease morbidity and improve relapse-free survival, especially for young patients requiring haploidentical donor transplantation for hematologic malignancy.

Allogeneic Hematopoietic Stem Cell Transplantation in Advanced Systemic Mastocytosis

Purpose Advanced systemic mastocytosis (AdvSM) is driven by the KIT D816V mutation in &amp;gt;90% of patients (pts.). Depending on subtype, median survival is between 1.5 and 4 years. Despite recent advances on responses and survival due to the availability of effective KIT inhibitors, allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only curative treatment option. Data on optimal timing, conditioning regimens, and pre- as well as post-alloHSCT treatments for maintenance or relapse are however scarce. Current recommendations mainly refer to a retrospective analysis published almost 10 years ago (Ustun et al., JCO 32, 2014). With the advent of new therapies and improved transplant procedures, more recently collected data on alloHSCT in AdvSM are needed for actual assessment of optimal treatment strategies. Patients &amp; Methods This retrospective analysis identified 71 pts. with AdvSM who underwent alloHSCT at 20 German centers between 1999 and 2021. Data were collected via the 'German Stem Cell Transplantation Registry (DRST)' and the 'German Registry on Disorders of Eosinophils and Mast Cells (GREM)'. Additional baseline characteristics and response status prior to, during and post alloHSCT were provided by the participating centers. Results At time of alloHSCT, median age was 59 years (range 21-84); 55/71 (77%) pts. were male. Median time between diagnosis of AdvSM and alloHSCT was 1.2 years (range 0.1-16.7). Pts. were grouped into (i) aggressive systemic mastocytosis (ASM, n=6) and SM with an associated hematological neoplasm (SM-AHN, n=24), totaling 30/71 (42%) ASM/SM-AHN pts., (ii) SM with an associated acute myeloid leukemia (SM-AML; 28/71, 39%) and (iii) mast cell leukemia ± AHN (MCL±AHN; 13/71, 18%). The median follow-up time after alloHSCT was 1.4 years (range 0-20.4). PFS and OS were 52% (SD ± 6.1%) and 62% (SD ± 5.9%) at 1 year, and 39% (SD ± 6.3%) and 50% (SD ± 6.2%) at 3 years. Discrimination between the three cohorts allowed a three-tier risk stratification (median PFS, 4.5 vs. 0.7 vs. 0.3 years, P&amp;lt;0.001; median OS, 9.0 vs. 3.3 vs. 0.9 years, P=0.007, Figure 1). Overall non-relapse mortality rate was 30% (21/71) including infectious complications in 8/21 (38%), GvHD in 1/21 (5%), cardiotoxicity in 1/21 (5%) and ‘combinations/not further specified’ in 11/21 (52%) pts. The 100-day non-relapse mortality was 8% (6/71; ASM/SM-AHN, 0/30; SM-AML, 4/28, 14%; MCL±AHN, 2/13, 15%). OS was associated with response status of SM (17/41, 41%; median OS 4.6 vs. 1.1 years, P=0.029) or AHN (26/43, 60%, median OS not reached vs. 0.4 years, P=0.003) prior to alloHSCT ( Figure 2). Univariable analyses revealed absence of a KIT D816V mutation (HR 2.9 [1.2-6.5], P&amp;lt;0.001) and a complex karyotype (HR 4.2 [1.8-10.0], P=0.016) as adverse prognostic factors regarding OS. PFS was significantly impacted by diagnosis of MCL±AHN (HR 3.5 [1.7-7.5], P&amp;lt;0.001), absence of a KIT D816V mutation (HR 2.5 [1.2-5.4], presence of a complex karyotype (HR 4.2 [1.8-10.0], P=0.016), P=0.021) and absence of the use of tyrosine kinase inhibitors prior to alloHSCT (HR 0.461 [0.249-0.854], P=0.014). In contrast, HLA match (complete vs. incomplete), type of conditioning (myeloablative vs. dose-reduced intensity), use of total body irradiation (≥8 Gy yes vs. no) or the transplantation at high volume centers (≥7 patients yes vs. no) were not associated with significant differences in PFS or OS. During or after alloHSCT, 30/71 (42%) pts. showed either refractory (9/71, 13%) or relapsed (21/71, 29%) disease (R/R), being highest among MCL±AHN pts. (11/13, 85%; ASM/SM-AHN, 9/30, 30%; SM-AML, 10/28, 36%; P=0.002). R/R SM was predominantly observed in MCL±AHN (10/11, 91%) while R/R AHN was higher in SM-AML patients (6/10, 60%) and ASM/SM-AHN (5/9, 56%). The median time to relapse was 0.6 years (range 0.1-4.5). Post alloHSCT, a response to various treatment regimens was achieved in 13/30 (43%) pts. (ASM/SM-AHN, 3/9, 33%; SM-AML, 5/10, 50%; MCL±AHN, 5/11, 45%) with highest response rates in 9 pts. receiving midostaurin and/or avapritinib (7/9, 78%). Conclusions In pts. with AdvSM eligible for alloHSCT, i) baseline characteristics affect outcome of alloHSCT more than specific transplant procedures, ii) alloHSCT should not be performed in pts. without response prior to alloHSCT and iii) post-alloHSCT strategies such as preemptive or residual disease guided maintenance therapy should be considered to improve post-alloHSCT outcome.

Salvage hematopoietic stem cell transplantation for patients with higher leukemia burden in relapsed or refractory acute myeloid leukemia: a ten-year study.

Patients with relapsed and refractory acute myeloid leukemia (R-R AML), especially those in non-remission (NR) have a poor prognosis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to optimize the entire allo-HSCT process for R-R AML patients and identify potential factors affecting clinical outcomes after HSCT, we retrospectively analyzed 44 adult patients with R-R AML who underwent salvage allo-HSCT while in NR or with concomitant extramedullary leukemia at the Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from 2013 to 2022. The 1-year and 2-year overall survival (OS) of the 44 patients were 55.3% (95% confidence interval [CI], 41.1%-74.3%) and 44.4% (95%CI, 30.2%-65.4%), respectively. The 1-year and 2-year cumulative incidence of relapse (CIR) were 39.4% (95%CI, 38.0%-40.7%) and 53.0% (95%CI, 51.0%-55.1%), respectively, and the 1-year and 2-year leukemia-free survival (LFS) were 37.8% (95%CI, 24.8%-57.7%) and 20.3% (95%CI, 9.1%-45.3%), respectively. The 100-day, 1-year and 2-year treatment-related mortality (TRM) was 13.8% (95%CI, 13.3%-14.4%), 22.8% (95%CI, 21.9%-23.7%) and 26.7% (95%CI, 25.5%-27.8%), respectively. Multivariate analysis revealed that patients who developed chronic graft-versus-host disease (cGVHD) after transplantation had lower relapse rate. Our analysis also indicated that patients with blast counts in bone marrow (BM) <20% and those with ≥20% had comparable clinical outcomes after allo-HSCT. In conclusion, our study demonstrated that R-R AML patients in NR or with concomitant extramedullary leukemia can benefit from allo-HSCT, regardless of leukemia burden at the time of transplantation. Patients who experience cGVHD after allo-HSCT may have lower relapse rate due to enhanced graft-versus-leukemia (GVL) effects, but cGVHD should be controlled at mild to moderate level to avoid life-threatening complications.

Substitution of calcineurin inhibitors with corticosteroids after allogeneic hematopoietic cell transplantation.

Combination of calcineurin inhibitors (CIs) with short-term methotrexate is a standard prophylactic regimen for graft-versus-host disease (GVHD). However, it is sometimes difficult to continue CIs due to adverse effects, such as renal impairment and fluid overload. In such cases, we replace CIs with corticosteroids, considering that full dose of CIs is equivalent to prednisolone (PSL) at 1mg/kg. We retrospectively evaluated the clinical significance of replacement of CIs with corticosteroids after allogeneic hematopoietic cell transplantation (HCT). We evaluated 42 patients switched from CIs to corticosteroids within 90days among the 479 patients who underwent allogeneic HCT at our center between 2007 and 2019. Renal impairment (n = 33), fluid overload (n = 13), and thrombotic microangiopathy (n = 3) were the main reasons for switching. Although creatinine and body weight returned to baseline at 4weeks after switching, 100-day non-relapse mortality was high (57.1%). Grade II-IV acute GVHD was seen in 10 (24.4%) patients who did not have it before switching treatment (n = 41). In conclusion, CIs were switched to corticosteroids in patients with severe clinical conditions. The incidence of acute GVHD was acceptable. Although the short-term mortality rate was high, improvement of renal function or fluid overload was observed in a certain proportion of the patients.

Patient Blood Management after Hematopoietic Stem Cell Transplantation in a Pediatric Setting: Starting Low and Going Lower.

Despite the substantial transfusion requirements, there are few studies on the optimal transfusion strategy in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). Our study aimed to retrospectively analyze red blood cell (RBC) and platelet (PLT) transfusion practices during the first 100 days after HSCT at the pediatric hematology/oncology unit of our hospital between 2016 and 2019, due to a more restrictive approach adopted after 2016. We also evaluated the impact on patient outcomes. A total of 146 consecutive HSCT patients were analyzed. In patients without hemorrhagic complications, the Hb threshold for RBC transfusions decreased significantly from 2016 to 2017 (from 7.8 g/dL to 7.3 g/dL; p = 0.010), whereas it remained the same in 2017, 2018, and 2019 (7.3, 7.2, and 7.2 g/dL, respectively). Similarly, the PLT threshold decreased significantly from 2016 to 2017 (from 18,000 to 16,000/μL; p = 0.026) and further decreased in 2019 (15,000/μL). In patients without severe hemorrhagic complications, the number of RBC and PLT transfusions remained very low over time. No increase in 100-day and 180-day non-relapse mortality or adverse events was observed during the study period. No patient died due to hemorrhagic complications. Our preliminary observations support robust studies enrolling HSCT patients in patient blood management programs.

Lower Body Mass Index and Prognostic Nutritional Index Are Associated with Poor Posttransplant Outcomes in Lymphoma Patients Undergoing Autologous Stem Cell Transplantation

Introduction: Pretransplant inflammatory and nutritional status has not been widely explored in terms of its impact on autologous hematopoietic stem cell transplantation (auto-HSCT) outcomes in lymphoma patients. We aimed to evaluate the impact of body mass index (BMI), prognostic nutritional index (PNI), and C-reactive protein to albumin ratio (CAR) on auto-HSCT outcomes. Methods: We retrospectively analyzed 87 consecutive lymphoma patients who underwent their first auto-HSCT at the Adult Hematopoietic Stem Cell Transplantation Unit at Akdeniz University Hospital. Results: The CAR had no impact on posttransplant outcomes. PNI ≤50 was an independent prognostic factor for both shorter progression-free survival (PFS) (hazard ratio [HR] = 2.43, p = 0.025) and worse overall survival (OS) (HR = 2.93, p = 0.021), respectively. The 5-year PFS rate was significantly lower in patients with PNI ≤50 than in patients with PNI >50 (37.3% vs. 59.9%, p = 0.003). The 5-year OS rate in patients with PNI ≤50 was significantly low when compared with patients who had PNI >50 as well (45.5% vs. 67.2%, p = 0.011). Patients with BMI <25 had higher 100-day transplant-related mortality compared with patients with BMI ≥25 (14.7% vs. 1.9%, p = 0.020). BMI <25 was an independent prognostic factor associated with shorter PFS and OS (HR = 2.98 [p = 0.003], HR = 5.06 [p < 0.001], respectively). The 5-year PFS rate was significantly lower in patients with BMI <25 than patients with BMI ≥25 (40.2% vs. 53.7%, p = 0.037). Similarly, the 5-year OS rate in patients with BMI <25 was significantly inferior compared to patients with BMI ≥25 (42.7% vs. 64.7%, p = 0.002). Conclusion: Our study confirms that lower BMI and CAR have negative impacts on auto-HSCT outcomes in lymphoma patients. Furthermore, higher BMI should not be considered an obstacle for lymphoma patients who need auto-HSCT; conversely, it could be an advantage for posttransplant outcomes.

Breakthrough invasive fungal infection among patients with haematologic malignancies: A national, prospective, and multicentre study

We describe the current epidemiology, causes, and outcomes of breakthrough invasive fungal infections (BtIFI) in patients with haematologic malignancies. BtIFI in patients with ≥7 days of prior antifungals were prospectively diagnosed (36 months across 13 Spanish hospitals) according to revised EORTC/MSG definitions. 121 episodes of BtIFI were documented, of which 41 (33.9%) were proven; 53 (43.8%), probable; and 27 (22.3%), possible. The most frequent prior antifungals included posaconazole (32.2%), echinocandins (28.9%) and fluconazole (24.8%)-mainly for primary prophylaxis (81%). The most common haematologic malignancy was acute leukaemia (64.5%), and 59 (48.8%) patients had undergone a hematopoietic stem-cell transplantation. Invasive aspergillosis, principally caused by non-fumigatus Aspergillus, was the most frequent BtIFI with 55 (45.5%) episodes recorded, followed by candidemia (23, 19%), mucormycosis (7, 5.8%), other moulds (6, 5%) and other yeasts (5, 4.1%). Azole resistance/non-susceptibility was commonly found. Prior antifungal therapy widely determined BtIFI epidemiology. The most common cause of BtIFI in proven and probable cases was the lack of activity of the prior antifungal (63, 67.0%). At diagnosis, antifungal therapy was mostly changed (90.9%), mainly to liposomal amphotericin-B (48.8%). Overall, 100-day mortality was 47.1%; BtIFI was either the cause or an essential contributing factor to death in 61.4% of cases. BtIFI are mainly caused by non-fumigatus Aspergillus, non-albicans Candida, Mucorales and other rare species of mould and yeast. Prior antifungals determine the epidemiology of BtIFI. The exceedingly high mortality due to BtIFI warrants an aggressive diagnostic approach and early initiation of broad-spectrum antifungals different than those previously used.

Association between different MAP levels and 30-day mortality in sepsis patients: a propensity-score-matched, retrospective cohort study

BackgroundSepsis is a life-threatening organ dysfunction caused by the infection-related host response disorder. Adequate mean arterial pressure is an important prerequisite of tissue and organ perfusion, which runs through the treatment of sepsis patients, and an appropriate mean arterial pressure titration in the early-stage correlates to the positive outcome of the treatment. Therefore, in the present study, we aimed to elucidate the relationship between early mean arterial pressure levels and short-term mortality in sepsis patients.MethodsWe included all suspected sepsis patients from MIMIC-III database with average mean arterial pressure ≥ 60 mmHg on the first day of intensive care unit stay. Those patients were then divided into a permissive low-mean arterial pressure group (60–65 mmHg) and a high-mean arterial pressure group (> 65 mmHg). Multivariate Cox regression analysis was conducted to analyze the relationship between MAP level and 30-day, 60-day, and 100-day mortality of suspected sepsis patients in the two groups. Propensity score matching, inverse probability of treatment weighing, standardized mortality ratio weighting, PA weighting, overlap weighting, and doubly robust analysis were used to verify our results.ResultsA total of 14,031 suspected sepsis patients were eligible for inclusion in our study, among which 1305 (9.3%) had an average first-day mean arterial pressure of 60–65 mmHg, and the remaining 12,726 patients had an average first-day mean arterial pressure of more than 65 mmHg. The risk of 30-day mortality was reduced in the high mean arterial pressure group compared with the permissive low-mean arterial pressure group (HR 0.67 (95% CI 0.60–0.75; p < 0.001)). The higher mean arterial pressure was also associated with lower 60-day and 100-day in-hospital mortality as well as with shorter duration of intensive care unit stay. Patients in the high-mean arterial pressure group also had more urine output on the first and second days of intensive care unit admission.ConclusionsAfter risk adjustment, the initial mean arterial pressure of above 65 mmHg was associated with reduced short-term mortality, shorter intensive care unit stay, and higher urine volume in the first two days among patients with sepsis.

High-titer post-vaccine COVID-19 convalescent plasma for immunocompromised patients during the first omicron surge.

Transplant and hematologic malignancy patients have high Coronavirus disease 2019 (COVID-19) mortality and impaired vaccination responses. Omicron variant evades several monoclonal antibodies previously used in immunocompromised patients. Polyclonal COVID-19 convalescent plasma (CCP) may provide broader neutralizing capacity against new variants at high titers. Vaccination increases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) titer in convalescent donors. We conducted a retrospective chart review of hospitalized immunocompromised patients with COVID-19 who received high-titer CCP during the first omicron surge, collected from vaccinated donors within 6 months of pre-omicron COVID-19. Data on safety and outcomes were extracted. A total of 44 immunocompromised patients were included, 59.1% with solid organ transplant, 22.7% with hematopoietic cell transplant, 11.4% with hematologic malignancy, and 6.8% with autoimmune disease. Overall, 95% of CCP units transfused were from recently recovered and vaccinated donors and had SARS-CoV-2 antibody results 8- to 37-fold higher than the Food and Drug Administration's cutoff for high-titer CCP. There were two mild transfusion reactions. A total of 30-day mortality was 4.5%. There were no differences in 100-day mortality by underlying diagnosis, levels of immunosuppression, and timing of CCP administration. Patients with higher immunosuppression had significantly higher mean World Health Organization clinical progression scores at 30-day post-CCP compared to those with lower immunosuppression. CCP is a safe, globally available treatment for immunocompromised patients with COVID-19. Mortality was lower in our cohort than that of COVID-19 patients with similar immunocompromising conditions. Post-vaccine CCP with very high titers should be prioritized for study in immunocompromised patients. Post-vaccine CCP has the potential to keep pace with new variants by overcoming mutations at sufficiently high titer.

Post-Transplantation Sinusoidal Obstruction Syndrome in Adult Patients with B Cell Acute Lymphoblastic Leukemia Treated with Pretransplantation Inotuzumab

Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication that can be observed after allogeneic hematopoietic cell transplantation (HCT). Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody-drug conjugate that has demonstrated high efficacy in relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) but is associated with an increased risk of SOS in HCT recipients. Here we aimed to examine the incidence and outcomes of SOS in 47 adult patients with R/R ALL who received inotuzumab therapy and subsequently underwent HCT at our institution. All patients received prophylactic therapy with ursodiol, and continuous low-dose heparin also was administered to patients receiving myeloablative conditioning (MAC). SOS occurred in 12 patients (26%) post-HCT, at a median onset of 11 days (range, 3 to 41 days). SOS was graded as very severe in 50% (n=6), severe in 25% (n=3), and mild in 25% (n=3). All patients diagnosed with SOS received treatment with defibrotide for a median of 21 days (range, 3 to 34 days), with resolution of SOS occurring in 8 patients (67%). Mortality from SOS was 33% (n=4) and occurred at a median of 10 days from diagnosis (range, 3 to 31 days) in patients graded as very severe (n=3) or severe (n=1). There were no significant differences between patients who developed SOS and those who did not develop SOS in the median time from the last dose of inotuzumab to transplantation (46 days versus 53 days; P = .37), use of an MAC regimen (42% versus 49%; P=.75), number of lines of therapy prior to inotuzumab (P=.79), median number of administered cycles of inotuzumab (2 versus 2; P=.14), or receipt of inotuzumab as the last therapy prior to HCT (67% versus 66%; P=1.0). Sirolimus-based graft-versus-host disease (GVHD) prophylaxis was used more frequently in the SOS group (75% versus 29%; P < .01), but there was no between-group difference in the peak sirolimus level (P=.81) or the median time to peak sirolimus level (7 days versus 3.5 days; P=.39). In univariable analysis, only the use of sirolimus-based GVHD prophylaxis was significantly associated with an increased risk of SOS (hazard ratio [HR], 7.50; 95% confidence interval [CI], 1.7 to 33.6; P < .01). In the SOS group, the 100-day mortality rate was 33% (n=4), and median overall survival (OS) post-HCT was 4.3 months (range, 0.2 to 57.2 months). In the group without SOS, the 100-day mortality rate was 14% (n=5) and the median OS post-HCT was 10.7 months (range, .52 to 39.6 months). In this study cohort, SOS was prevalent in HCT recipients who had been treated with inotuzumab prior to transplantation, and sirolimus-based GVHD prophylaxis was a risk factor for SOS in inotuzumab recipients.

Preconditioning Modified-Easix as a Predictor of Prognosis in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

Allogeneic hematopoietic stem cell transplantation (alloHCT) is associated with severe complications, most of which share a common physiopathological background characterized by endothelial dysfunction. A novel risk assessment model, endothelial activation and stress index (EASIX), has been introduced as a predictor of endothelial activation. This retrospective study was performed to evaluate the predictive impact of EASIX/modified-EASIX (mEASIX) on transplant outcome. Medical records of 398 alloHCT recipients [median age: 43(17-71) years; M/F: 243/155] were examined. EASIX/mEASIX were calculated at specific time points before and after transplantation. EASIX/mEASIX were significantly associated with transplant complications including engraftment syndrome, sinusoidal obstruction syndrome, febrile neutropenia and transplant associated thrombotic microangiopathy. The probability of overall survival was significantly higher in low-preconditioning mEASIX (day -7) group (37% vs 25.2%; p = 0.008; HR: 2.057; 95% CI: 1.208-3.504). The probabilities of day30 mortality (2.9% vs 19.4%; p = 0.017; HR: 7.028; 95% CI: 1.418-34.836), day100 mortality (9% vs 33%; p = 0.004; HR: 4.469; 95% CI: 1.619-12.336) and non relapse mortality (44.8% vs 61.4%; p = 0.005; HR: 2.551; 95% CI: 1.318-4.941) were lower in low-preconditioning mEASIX (day -7) group. This retrospective cohort analysis demonstrates the significant impact of EASIX/mEASIX on transplant complications and survival. Prospective analyses are mandatory to assess the predictive role of EASIX/mEASIX in clinical practice.

Allogeneic Hematopoietic Stem Cell Transplantation in Transformed Follicular Lymphoma (tFL): Results of a Retrospective Multicenter Study from GELTAMO/GETH-TC Spanish Groups.

Transformation of follicular lymphoma into an aggressive lymphoma (tFL) worsens the prognosis and the standard treatment is not completely defined. Allogeneic hematopoietic stem cell transplantation (alloSCT) could be a potentially curative option for these patients, but it has not been widely explored. We designed a retrospective multicenter study to analyze the efficacy and toxicity of alloSCT in tFL patients and potential prognostic factors of survival. A total of 43 patients diagnosed with tFL who underwent alloSCT in 14 Spanish centers between January 2000 and January 2019 were included. Median age was 44 (31-67) years. After a median follow-up of 58 months, estimated 5-year overall survival (OS) and progression-free survival (PFS) were both 35%. Estimated 100-day and 1-year non-relapse mortality (NRM) were 20% and 34%, respectively. The type of conditioning regimen (3-year OS of 52% vs. 20%, respectively, for reduced-intensity vs. myeloablative conditioning) and development of chronic graft versus host disease (cGVHD) (3-year OS of 75% vs. 40%) were the only factors significantly associated with OS. The only variable with an independent association with OS was cGVHD (HR, 3.4; 95% CI, 1.2-9.6). Our results indicate that alloSCT continues to be a potentially curative option for patients with tFL.

Long-Term Outcomes of Acute Myeloid Leukemia Following Allogeneic Stem-Cell Transplantation after Decitabine and Venetoclax: Subgroup Analysis of a Phase II Trial

Introduction: Venetoclax (VEN)-based lower intensity regimens are the current standard for older/unfit patients with newly diagnosed acute myeloid (AML). Such regimens are increasingly used in the salvage setting as well. Allogeneic stem-cell transplantation (SCT) following VEN-based regimens has been shown to be safe and feasible in pts with AML (Mukherjee et al. J Clin Oncol 2019; Pratz et al. Blood 2019). We herein describe long-term outcomes after SCT following treatment on a prospective clinical trial of 10-day decitabine and venetoclax (DEC10-VEN) for treatment-naïve and previously treated AML (NCT03404193). Methods: In this phase II trial, pts received decitabine 20 mg/m2 for 10 days during induction and 5 days during consolidation. VEN was administered 400 mg daily on D1-28 during cycle 1 but was held on day 21 if bone marrow evaluation showed blasts ≤5%. During subsequent cycles VEN duration could be reduced in pts with myelosuppression. This trial enrolled pts with ECOG PS ≤3 with adequate organ function. Pts with favorable risk cytogenetics were excluded. Pts with newly diagnosed AML were either unfit for intensive therapy, or older than 60 yrs. Pts in relapsed/refractory cohort were ineligible if they had received prior BCL2 inhibitor. Eligible pts with an available donor could proceed to SCT at any time following achievement of response. Response, overall survival (OS) and relapse-free survival were defined per ELN2017. Survival outcomes were not censored at SCT. Data cut-off date was July 26, 2022. Results: Between January 2018 and June 2022 we enrolled 230 pts with AML, high-risk or relapsed/refractory myelodysplastic syndrome or chronic myelomonocytic leukemia, and blastic plasmacytoid dendritic cell neoplasm. Among 201 pts with AML, CR/CRi/MLFS response was achieved in 146 pts (73%) and 40 pts (20%) were able to proceed to SCT; including 21 pts with treatment-naïve AML and 19 pts with either R/R AML or AML following treatment for antecedent hematological disorder (AHD) including MDS-EB (n=2) and CMML (n=1), considered "previously treated AML". The median age of pts undergoing SCT was 66 yrs (range 18-77); 10 pts (25%) were older than 70 yrs, 16 pts (40%) pts had R/R AML, 19 pts (45%) had ELN adverse risk disease and 4 pts had received prior SCT (Table 1). Fourteen pts in each group received additional concomitant therapy with FLT3 inhibitors including gilteritinib and sorafenib (Table 1). All pts proceeding to SCT were in CR/CRi except in the previously treated group where 4 pts had non-CR/CRi responses including MLFS/aplasia. 28 pts (70%) had achieved negative measurable residual disease (MRD) by flow cytometry (sensitivity 0.1-0.01%) prior to proceeding to SCT while 8/40 pts (20%) had persistent MRD. Remaining 4 pts either had inadequate sample or were not evaluated for MRD. Conditioning regimens and donor types are summarized in Table 1. Median no. of cycles of DEC10-VEN administered was 2 (range 1-12) and the median time to SCT was 3.5 mo from start of DEC10-VEN (range 1.1-16.2). The median follow-up duration was 29.1 mo. Among pts with AML who proceeded to SCT, the 100-day post-SCT mortality was 8% (n=3). The median OS for treatment-naïve pts was 35.1 mo and for previously treated pts was 16.7 mo. Median RFS for treatment naïve pts was 23.5 mo and for previously treated pts was 12.9 mo. Landmark analysis of pts achieving CR/CRi/MLFS and alive at 3.5 mo showed that pts with treatment-naïve AML who were eligible to proceed to SCT (n=21) derived significant benefit in OS with median OS 35.1 vs 15.7 mo in pts who did not / were ineligible (n=60) (HR 0.47, 95% CI 0.24, 0.76, p=.01, Fig. 1). Similarly, pts with previously treated AML who proceeded to SCT in CR/CRi/MLFS (n=18) had median OS of 19.3 vs 12.0 mo for pts who could not (n=36) (HR 0.53, 95% CI 0.28, 1.01, p=.07). Both analyses were limited by confounding factors. At data cut-off, 19 pts (48%) are alive, 8 pts (20%) died in remission, and 13 pts (33%) pts died after disease progression (Table 1). Conclusion: In this prospective trial of DEC10-VEN enrolling older/unfit pts with newly diagnosed AML, secondary AML, and younger or older pts with R/R AML, 20% of pts were able to proceed to SCT. DEC10-VEN served as bridge to SCT for responding pts with newly diagnosed as well as previously treated AML, with low 100-day post-SCT mortality. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic Hematopoietic Stem Cell Transplantation in Older Patients with Acute Myeloid Leukemia: Analysis of Outcomes and Contemporary Trends Spanning 10 Years

Background: Allogeneic hematopoietic stem cell transplantation (SCT) is a highly effective consolidation strategy in acute myeloid leukemia (AML). Non-myeloablative and reduced-intensity (NMA/RIC) conditioning regimens have expanded the use of SCT to older patients (pts) (age ≥ 60 years). Age alone no longer appears to be a barrier for successful SCT, with reported 3-year overall survival (OS) rates in the 45-50% range (Maakaron 2022). Methods: We conducted a retrospective study spanning 10 years to evaluate SCT-related outcomes in older AML. All pts ≥ 60 years presenting to our institution with newly-diagnosed (ND) AML were included. Acute promyelocytic leukemia (APL) was excluded. Median OS and relapse-free survival (RFS) were calculated using the Kaplan Meier method. A landmark analysis was performed to evaluate time-to-event endpoints in pts who underwent SCT in first response compared to those who did not. Results: Between 7/19/2012 and 11/17/2021, we identified 1073 pts ≥ 60 years with ND-AML. The median age at diagnosis was 71 years (range 60-94), 622 (58%) were male, 189 (18%) had prior myelodysplastic/myeloproliferative neoplasm, and 220 (21%) had therapy-related AML. ELN 2017 risk was favorable in 215 (20%), intermediate in 234 (22%), and adverse in 538 (50%) pts (86 with data missing). Most pts (84%) were treated with low-intensity (LOW) regimens. Only 16% were treated with intensive (INT) chemotherapy (intermediate or higher dose cytarabine). Venetoclax (VEN) was included in 34% of the regimens. The CR/CRi rate was 60% in the overall cohort. The CR/CRi rate was 74%, 48%, and 72% in pts treated with INT, LOW, and LOW + VEN therapies, respectively. The median OS and RFS were 11.2 and 10.6 months for the full cohort, respectively. The rate of referral to the SCT service was 38% (413/1073) and increased over time (31% in 2012-2013, 52% by 2020-2021). This occurred in parallel to increasing rates of CR/CRi (53% in 2012-2013, 66% by 2020-2021), likely reflecting increased efficacy of VEN-containing regimens in the later years. We identified 198/1073 pts (18%) who underwent SCT at some point during therapy, 152/198 (77%) in first response (CR/CRi/MLFS) after frontline therapy, and 46/198 (23%) following one or more salvage regimens. Of all ND-AML pts, the SCT rate was 37%, 10%, and 22% in pts treated with INT, LOW, and LOW + VEN, respectively. The rate of undergoing SCT increased over time (15% in 2012-2013, 27% by 2020-2021). Clinical/SCT characteristics for the pts who underwent SCT are shown in table 1. The rate of grade 3/4 acute graft-vs-host disease (GVHD) was 11% and 19% of pts experienced chronic GVHD of any grade. Following SCT, 24% of pts experienced relapse of AML and 21% died without disease relapse. The 100-day mortality following SCT was 13%. We then performed a landmark analysis (using median time to SCT [4.3 months] as the landmark) comparing pts undergoing SCT in first response following frontline therapy at our institution (n=139) to responding pts who did not receive SCT in first response and who were alive and without relapse at the landmark (n=353). Both the median OS (31.0 vs 18.9 months, p=0.0208, figure 1) and median RFS (23.2 vs 10.0 months, p<0.0001) were superior in the pts who underwent SCT compared to those who did not. Pts undergoing SCT in first response were younger (median age 66 vs 72 yrs) and had better performance status (PS 2-4 in 10% vs 22%) compared to no-SCT pts. Distribution of ELN risk categories and best response (CR/CRi/MLFS) were similar in the SCT and no-SCT groups. In pts who responded to initial therapy and were referred for SCT, but ultimately did not undergo SCT in first response (n=161), the most common documented reasons for forgoing SCT were social reasons (pt preference, financial/insurance/caregiver issues) in 29%, disease relapse in 29%, being deemed unfit due to comorbidities in 22%, active uncontrolled infections in 11%, and other reasons in 11%. An adequate donor was documented in 66% of these pts. Conclusions: Our results support the use of SCT as a consolidative strategy in older AML pts. Pts who undergo SCT have superior OS and RFS compared to those who do not. However, fewer than 20% of pts undergo the procedure mostly due to inadequate disease control, comorbidities, and a variety of social reasons. Recent trends indicate higher rates of SCT referral and completion as more effective anti-leukemic therapies are allowing a greater proportion of older AML pts to undergo SCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comorbidities Associated with Early Mortality after CD19 CAR-T Cell Therapy

Objective: CD19 chimeric antigen receptor (CAR) T-cell therapy has changed the standard for treatment of relapsed and/or refractory (r/r) large b-cell lymphoma (LBCL). Currently, pre-treatment evaluation of patients and disease factors do not accurately predict outcomes. This study aims to identify risk factors associated with early mortality prior to day 100 after CAR-T infusion. Methods: We performed a single-centered retrospective adult patients (pts) with r/r LBCL who received CAR-T cell therapy between 2018-2021. CAR-T cell toxicities graded according to either CAR T-Cell Therapy-Associated Toxicity (CARTOX) grading system prior to May, 2019 or American Society of Transplantation and Cellular Therapy (ASTCT) consensus grading thereafter for cytokine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS). Comorbidities defined as per Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI). (Sorror et al., 2009). Hepatic dysfunction defined as infection with hepatitis B or C or history of liver cirrhosis or elevated total bilirubin, AST, or ALT on at least two values on two different days from day -24 till day -10 prior to CAR-T. Cardiovascular (CV) comorbidity determined by presence of coronary heart disease, congestive heart failure or reduced ejection fraction detected by echocardiogram. Psychiatric disturbance defined as presence of depression and/or anxiety requiring treatment or consultation. Patient demographics, disease characteristics and clinical outcomes summarized through descriptive statistics. Wilcoxon rank sum test used to evaluate difference in a continuous variable between patient groups. Kaplan-Meier method used to estimate time-to-event endpoints including progression free survival (PFS), and overall survival (OS). Results: Two hundred and fifty patients included in analysis. Median age of 61years (range: 18-89) and 30.8% of patients were female (n=77). Histology was categorized as LBCL (65.9%) and included diffuse LBCL or high grade LBCL, transformed follicular lymphoma (26.9%), primary mediastinal b-cell lymphoma (6.4%) or follicular lymphoma (0.8%). Majority of pts received axicabtagene ciloleucel 95.6% (n=239) while 4.4% (n=11) received tisagenlecleucel and 52% (n=130) of pts received bridging therapy. CRS of any grade was 90.4% ; ICANS any grade was 57.2% while grade 3 CRS/ICANS occurred 6.4% and 38.4% respectively. Median follow-up 24.7 months (mo) (95% CI: 20.7 ~ 26.4 mo). One-hundred twenty-eight pts died during follow-up, 48 pts died within 100 days, and most common cause of death was progression of lymphoma (29.2%; n=73). Early 30-day mortality occurred in 4.8% pts and causes of death due to CAR-T related toxicity in 6 pts, disease progression in 3 pts, and infection in 1 pts. 100-day mortality rate was 24.6% (n=32) for pts >60 years old vs 13.3% (n=16) for <60 (p-value=0.02). 100-day mortality rate was 36.5% for ECOG 2-4 vs 14.9% for ECOG 0-1 (p-value=0.0005). In terms of non-relapsed mortality (NRM), risk stratification according to cumulative HCT-CI score was not associated with higher 100-day NRM (p=0.24). Pts with cardiac score of 1 had a higher NRM (26.9% vs. 8.1%; p-value=0.005). The 100-day NRM rates for hepatic score of 0, 1, and 3 were 8.9%, 14.3%, and 50% (p-value=0.04). Pts with psychiatric disturbance score of 1 had higher 100-day NRM (19.6% vs. 7.8%; p-value=0.03). Conclusion: This single center retrospective study observed an increase in 100-day mortality in correlation with pre-treatment performance status, and older age. Pts with cardiac comorbidity, hepatic dysfunction or psychiatric disturbance had a higher 100-day NRM. Similar to other studies, the combined HCT-CI score was not predictive of NRM, but individual variables were associated with higher non-CART related toxicity. These findings require validation with further studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

IPSS-Molecular but Not Individual Mutations Predicts Outcomes of Patients with Myelodysplastic Syndrome (MDS) after Allogeneic Hematopoietic Cell Transplantation (Allo-HCT): A Mayo Clinic Cohort

The decision to offer Allo-HCT in MDS relies on prognostic scoring models which include clonal cytogenetic (CG) abnormalities, blood counts (cytopenias), and % of marrow blasts (i.e. revised international prognostic scoring system, IPSS-R). Recently, an updated clinical-molecular prognostic model combining genomic profiling with hematologic and CG parameters, namely IPSS-Molecular (IPSS-M), showed better prognostic discrimination across all clinical endpoints and re-stratified almost one-half of patients (pts) vs. IPSS-R. Hence, we evaluated the impact of IPSS-M, CG risk group and individual mutations on Allo-HCT outcomes. The analysis included 191 consecutive MDS pts undergoing Allo-HCT who had available next generation sequencing (NGS) analysis performed at Mayo Clinic (at diagnosis (Dx, n=164 or prior to Allo-HCT, n=162) between 11/2015 and 1/2022. Median age at Allo-HCT was 64 (18-75) yrs, and 112 (58.6%) were male. At Dx, 126 (77%) pts had at least one pathogenic genetic alteration, including (>5% incidence) ASXL1 (28.0%), TP53 (18.9%), TET2 (14.6%), SRSF2(12.2%), U2FA1 (12.2%), DNMT3A (8.5%), BCOR (7.9%), RUNX1 (6.7%), and SF3B1 5.5%; a similar mutational pattern was present at Allo-HCT: ASXL1 (28%),TET2 (15.2%) U2AF1 (13.4%), TP53 (12.2%), SRSF2 (11%), RUNX1(9.8%), DNMT3A (7.3%), SETBP1 (7.3%), SF3B1 (6.7%), BCOR (6.7%), STAG2 (5.5%), and JAK2 (5.5%). Most pts (156, 81.7%) received at least 1 line of therapy, and 45 (23.6%) had >5% marrow blasts at Allo-HCT. The majority (134, 70%) received reduced intensity conditioning. Graft versus host disease (GVHD) prophylaxis consisted of methotrexate/tacrolimus in 138 (77.5%) and post-transplant cyclophosphamide in 40 (22.5%). HCT comorbidity index was >3 in 113 (59%). IPSS-M risk group was calculated and reclassified from IPSS-R into very low (1, 0.6%), low (24, 14.7%), moderate low (34, 20.9%), moderate high (41, 25.2%), high (29, 17.8%), very high (34, 20.9%), mainly for IPSS-R intermediate and high-risk groups (Fig. 1). Median F/U after Allo-HCT was 18.8 (0.4-76.8) months. The 100-day and 1-year non-relapse mortality (NRM) were 7.9% and 18.1%, respectively. The 2-year incidence of death and relapse were 40.1% (95% confidence intervals (CI) 33.5-48%) and 21.6% (95%CI 16.4-28.4%), respectively. Cumulative incidences of grade III-IV acute GVHD was 10% and 1-year cumulative incidence of extensive chronic GVHD was 12%. In multivariable analysis, IPSS-M predicted mortality [Hazard ratio (HR) (per 1 risk category) 1.21, 95%CI 1.00-1.47, p=0.049] and relapse (HR=1.47, 95%CI 1.13-1.92, p=0.004), but not NRM (HR 0.95, 95%CI 0.74-1.22). The 1-year mortality rates for very low/low, moderate-low, moderate-high, high/very high risks were 21%, 24%, 32%, and 37%, respectively (Fig. 1). Individual mutations had minimal independent association with outcome in the multivariable model. For mortality, only ASXL1 at Dx (HR 0.48, 95%CI 0.26-0.91, p=0.024) and SF3B1 at Allo-HCT (HR 2.51, 95%CI= 1.06-5.96, p=0.037) were significant. TP53 at Dx had a borderline association (HR 0.46, 95% CI= 0.942.69, p=0.086). Also, there was no significant association of individual mutation with relapse (including TP53 at Allo-HCT, HR 1.77, p=0.085). Only SF3B1 at Allo-HCT correlated with NRM (HR 3.16, 95%CI= 1.22-8.17, p=0.018). Conversely, CG risk group remained strongly associated with mortality (p=0.007) and relapse (p=0.003), particularly poor/very poor (P/VP) risk CG (Mortality: HR 2.46, 95%CI 1.44-4.19, p=0.001; Relapse: HR 3.46, 95%CI 1.70-7.05, p=0.0006). There was no association of CG risk with NRM. We demonstrate value of IPSS-M risk stratification in predicting outcomes after Allo-HCT for MDS, re-stratifying pts into more discrete prognostic groups that predict mortality and relapse risk. Hence, IPSS-M could inform post allo-HCT decision including future maintenance strategies to prevent relapse in high/very high IPSS-M. CG risk group (esp. P/VP risk), a core component of IPSS-M, independently contributes to outcome prediction both within the model and individually. Disease risk does not predict NRM, and individual mutations have limited association with outcome, suggesting allo-HCT may mitigate the poor prognostic impact of high-risk oncogenic mutations present at Dx, including TP53 and ASXL1. An updated analysis on mutational complexity will be shown at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Consolidation with Allogeneic Hematopoietic Cell Transplant Improved Survival Outcomes of Adults with Relapsed / Refractory Acute Lymphoblastic Leukemia Following Response to Memory-Enriched CD19CAR T Cells

Background: CD19-directed chimeric antigen receptor (CD19CAR) T cell therapy produces excellent remission rates in children and adults with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL). While a small number of adult patients (pts) who respond to CD19CAR T cells have durable remission without additional therapy, most do not, and it remains debatable whether consolidation with allogeneic hematopoietic cell transplantation (alloHCT) after CD19CAR T cells should be offered to every adult responder with r/r ALL, especially in context of a second consolidative alloHCT in pts who relapsed following prior alloHCT. Here we report a subanalysis from our recently completed phase 1/2 prospective study (NCT02146924) using memory-enriched CD19CAR T cells in adults with r/r ALL to assess the role of alloHCT consolidation on outcome. Methods: This study assessed the safety and efficacy of naïve, stem and central memory (Tn/mem)-derived CAR T cells delivered at the recommended phase 2 dose (RP2D; 200x106 CAR T cells) in adults with r/r ALL. If pts achieved complete remission (CR)/CR with incomplete hematologic recovery (CRi) post CAR T cells, they could receive optional consolidation with alloHCT per the treating physician discretion anytime 4 weeks after infusion. We evaluated the adjusted association between relapse free survival (RFS) and time varying status for alloHCT consolidation, Philadelphia (Ph)-like status, bone marrow blasts at time of lymphodepletion (LD; <5% vs. ≥5%) and presence of extramedullary disease (EMD) at LD among the responders by performing a pre-specified Cox proportional hazards regression model. Results: We enrolled 58 pts at the RP2D who underwent leukapheresis; 46 pts received CD19CAR T cells. The median age for pts who received CD19CAR T cells was 38 years (range, 22-72), with 15 (33%) pts ≥ 50 years. The median number of prior lines of therapy was 3 (range, 1-9); 29 (63%) pts had prior alloHCT, and 29 (63%) and 15 (33%) pts failed blinatumomab and inotuzumab before enrollment, respectively. Eighteen (39%) had Ph-like genotype and 16 (35%) had EMD at LD. Forty (87%) patients achieved CR/CRi, 1 (2%) progressed and 5 (11%) were unevaluable for response. Twenty-one (53%) responders proceeded directly to alloHCT consolidation while in CR/CRi post CAR T cell therapy, including 10 pts who received their second alloHCT. Notably, 6/13 pts with EMD at LD who achieved CR/CRi after infusion underwent alloHCT consolidation. The median time to transplant was 79 days (range, 50-192) post CAR T cell infusion. For the 40 responders, with a median follow up of 11.4 months (range, 3.3-65.8) post CAR T cell infusion, median overall survival (OS) was not reached, and median RFS was 17.1 months (95%CI: 6.9 to NA). The 12-month OS and RFS were 63.2% and 52.6%, respectively. Among responders, 12-month RFS were 81% and 16% for those who did and those who did not undergo consolidation with alloHCT in CR/CRi, respectively. In the prespecified multivariable analysis, only consolidation with alloHCT post CAR T cells was independently associated with superior RFS [adjusted hazard ratio (HR)=0.16; 95% CI: 0.05-0.48; P= 0.001]. Of the 19 pts who responded to CAR T cells and did not have alloHCT consolidation, 11 relapsed with a median time of 3.4 months (range, 2.1-10.3) post CAR T cell infusion, 3 pts died in remission, and 5 pts remained alive and in remission at last contact or date of censoring, with a median follow up of 9.7 months (range, 3.3-51.8) including 1 pt who was censored at day 99 post infusion upon initiating ponatinib maintenance. Of the 21 pts who responded to CAR T cells and underwent alloHCT consolidation, 2 pts relapsed (6.9- and 12.4-months post-transplant) of whom 1 died after relapse and 1 received a second CAR T cell infusion and was censored for OS at the date of second infusion, 3 pts died in remission, and 16 pts remained alive and in remission. (Figure A) The 100-day non-relapse mortality rate post-transplant was 5% (n= 1). OS was comparable for responders who had their first or second alloHCT post CAR T cells (12-months OS= 82% vs 79%, p= 0.9; Figure B). Conclusion: Outcomes of alloHCT consolidation in adults with high-risk r/r ALL after achieving remission with Tn/mem CD19CAR T cells were promising, including for pts receiving their second alloHCT, and transplant led to improved survival outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal