Chitra Hosing

Purpose:More active high-dose chemotherapy (HDC) regimens are needed for autologous stem cell transplantation (ASCT) for refractory lymphomas. Seeking HDC enhancement with a PARP inhibitor, we observed marked synergy between olaparib and vorinostat/gemcitabine/busulfan/melphalan (GemBuMel) against lymphoma cell lines, mediated by the inhibition of DNA damage repair. Our preclinical work led us to clinically study olaparib/vorinostat/GemBuMel with ASCT.Patients and Methods:Patients ages 15 to 65 years with refractory lymphoma and adequate end-organ function were eligible for this phase I trial. The olaparib dosage was escalated from 25 mg orally twice a day on days −11 to −3, plus vorinostat (1,000 mg orally/day, days −10 to −3), gemcitabine (2,475 mg/m2/day i.v., days −8 and −3), busulfan (target AUC 4,000 µmol/L.minute−1/day i.v., days −8 to −5), melphalan (60 mg/m2/day i.v., days −3 and −2), and rituximab (CD20+ tumors; 375 mg/m2, day −10), with ASCT.Results:Fifty patients were enrolled (23 with Hodgkin lymphoma, 18 with diffuse large B-cell lymphoma, and 9 with T-cell non–Hodgkin lymphoma); the median age was 35 years (range, 20–61); patients received a median of three prior lines of therapy (range, 2–7); 17 patients had previously relapsed after chimeric antigen receptor T-cell therapy or other cellular immunotherapies; 23 patients had PET-positive tumors at HDC (9 in progression). An olaparib dosage of 150 mg orally twice a day was identified as the recommended phase II dosage. The main extramedullary toxicity was mucositis. The overall response rate and complete response rate were 100% and 90%, respectively. At the median follow-up of 30 (range, 12–56) months, the event-free survival and overall survival rates were 72% and 82% in all patients and 71% and 88% in patients with prior CAR T-cell failure, respectively.Conclusions:In this first trial combining a PARP inhibitor with HDC, olaparib/vorinostat/GemBuMel was safe and showed promising activity in refractory lymphomas, including post–CAR-T relapses.

Purpose: More active high-dose chemotherapy (HDC) regimens are needed for autologous stem cell transplantation (ASCT) for refractory lymphomas. Seeking HDC enhancement with a PARP inhibitor, we observed marked synergy between olaparib and vorinostat/gemcitabine/busulfan/melphalan (GemBuMel) against lymphoma cell lines, mediated by the inhibition of DNA damage repair. Our preclinical work led us to clinically study olaparib/vorinostat/GemBuMel with ASCT. Patients and Methods: Patients ages 15 to 65 years with refractory lymphoma and adequate end-organ function were eligible for this phase I trial. The olaparib dosage was escalated from 25 mg orally twice a day on days −11 to −3, plus vorinostat (1,000 mg orally/day, days −10 to −3), gemcitabine (2,475 mg/m2/day i.v., days −8 and −3), busulfan (target AUC 4,000 µmol/L.minute−1/day i.v., days −8 to −5), melphalan (60 mg/m2/day i.v., days −3 and −2), and rituximab (CD20+ tumors; 375 mg/m2, day −10), with ASCT. Results: Fifty patients were enrolled (23 with Hodgkin lymphoma, 18 with diffuse large B-cell lymphoma, and 9 with T-cell non–Hodgkin lymphoma); the median age was 35 years (range, 20–61); patients received a median of three prior lines of therapy (range, 2–7); 17 patients had previously relapsed after chimeric antigen receptor T-cell therapy or other cellular immunotherapies; 23 patients had PET-positive tumors at HDC (9 in progression). An olaparib dosage of 150 mg orally twice a day was identified as the recommended phase II dosage. The main extramedullary toxicity was mucositis. The overall response rate and complete response rate were 100% and 90%, respectively. At the median follow-up of 30 (range, 12–56) months, the event-free survival and overall survival rates were 72% and 82% in all patients and 71% and 88% in patients with prior CAR T-cell failure, respectively. Conclusions: In this first trial combining a PARP inhibitor with HDC, olaparib/vorinostat/GemBuMel was safe and showed promising activity in refractory lymphomas, including post–CAR-T relapses.

Patients undergoing immune effector cell therapy (IECT) are at high risk for infections. We assessed seropositivity against pneumococcus, tetanus, and diphtheria in patients before and after IECT and the patients’ response to vaccination. We enrolled patients who underwent IECT from January 2020 to March 2022. Antibody levels for diphtheria, tetanus, and pneumococcus were measured before IECT, at 1 month, and 3–6 months after. Eligible patients were vaccinated after IECT. In non-seroprotected patients, we discontinued testing. Before IECT, most patients had seroprotective antibody levels against tetanus (68/69, 99%) and diphtheria (65/69, 94%), but fewer did against pneumococcus (24/67, 36%). After IECT, all patients had seroprotective antibody levels for tetanus at 1 month (68/68) and 3–6 months (56/56). For diphtheria, 65/65 patients (100%) had seroprotective antibody levels at 1 month, and 48/53 (91%) did at 3–6 months. For pneumococcus, seroprotective antibody levels were identified in 91% (21/23) of patients at 1 month and 79% (15/19) at 3–6 months following IECT. Fifteen patients received a pneumococcal vaccine after IECT, but none achieved seroprotective response. One patient received the tetanus-diphtheria vaccine and had a seroprotective antibody response. Because some patients experience loss of immunity after IECT, studies evaluating vaccination strategies post-IECT are needed.

There is paucity of data regarding outcomes of children, adolescents and young adults (CAYA) patients with non-Hodgkin lymphoma (NHL) undergoing autologous stem cell transplantation (ASCT). Patients aged 0–39 years undergoing first ASCT for NHL at MD Anderson Cancer Center between 2000 and 2020 were analyzed. Two hundred twenty-one patients were included in the analysis, 129 (58%) were male and the median age was 32 (range 6–39) years. The most common histological subtypes were diffuse large B cell lymphoma (DLBCL) (44%), T-NHL (19%) and primary mediastinal B-Cell lymphoma (PMBCL) (19%). Younger patients (age ≤ 25) had lower incidence of DLBCL and higher incidence of PMBCL and T-NHL compared to older patients (age > 25) (P = 0.02). None of the younger patients had double hit (DH)/double expressor (DE) DLBCL, compared to 14 patients in the older age group (18%, P = 0.07). Considering the three main aggressive NHL subtypes (DLBCL, PMBCL and T-NHL), younger patients had numerically better 15-year post-transplant progression free survival (PFS) (67% vs. 54%) and overall survival (OS) (71% vs. 62%) compared to older patients, yet these differences did not reach statistical significance (P = 0.19 and P = 0.24, respectively). In multivariate analysis, not achieving a CR prior to ASCT was independently predictive of worse PFS [partial remission (PR) (HR, 3.9); stable disease (SD) (HR, 18.0), P = 0.03] and of worse OS [PR (HR, 4.2), SD (HR, 6.5) and progressive disease (HR, 4.7), P < 0.0001]. DH/DE status was an independent adverse predictor of PFS in multivariate analysis (HR 5.8, p = 0.03). Ten patients (4.5%) (all aged > 25 years) developed second primary malignancies (SPM), at a median of 34.4 (range, 1.0–196.6) months after ASCT, and SPM was the cause of death in five (50%) of them. CAYA NHL patients aged ≤ 25 years who received ASCT presented a distinct NHL histology as compared to older CAYA patients, and none in this younger age group had DH/DE DLBCL. We observed a trend towards improved PFS and OS in younger patients. Disease status at ASCT was predictive of both PFS and OS. DH/DE status was an adverse predictor of PFS.

Background: Eligible patients with multiple myeloma (MM) are offered autologous hematopoietic cell transplantation (auto-HCT) in their first remission. The usual conditioning regimen consists of melphalan (Alkeran) 200 mg/m 2 infused over ~ 30 minutes due to its limited stability. Evomela is a newer formulation of melphalan, which is stable at room temperature for ~ 24 hours. The current trial studied the dose escalation and compared the short versus extended infusion time of evomela used as a conditioning regimen before auto-HCT. Methods: Patients with newly diagnosed MM, age ≤ 70, were eligible. Two dose levels, 200 and 225 mg/m 2 were studied. Patients were randomized between two infusion schedules: 30-60 minutes (short) and an extended infusion of 8-9 hours. Disease response was measured using IMWG criteria. Minimal residual disease (MRD) was measured by flow cytometry at 10 -5. Results: Sixty patients were enrolled. The first 3 patients in each arm were treated at evomela 200 mg/m 2. Since no dose-limiting toxicity (DLT) was observed, all subsequent patients (n=54; 27 in each arm) were treated at evomela 225 mg/m 2. The results are presented for patients treated at evomela 225 mg/m 2. Patient characteristics were evenly distributed (Table 1). The median age was 58.6 years (range: 42.6 -70.3). Twelve (22%) patients had high-risk cytogenetics (4 [15%] in the short infusion; 8 [30%] in the extended infusion arm), p-value 0.19. There were no deaths, and no patient experienced grade > 3 adverse events (AE). Grade 2-3 AEs were seen in 53 (98%) patients (26 [96%] in the short infusion; 27 [100%] in the extended infusion). Twenty-four (44%) patients experience grade 2-3 diarrhea (16 [60%] in the short infusion; 8 [30%] in the extended infusion). Grade 2-3 esophagitis was seen in 3 (6%) patients overall (0 in the short infusion; 3 [11%] in the extended infusion). Atrial fibrillation was seen in one patient (grade 2, extended infusion). Before transplant, six (22%) patients were in stringent complete remission (sCR) or CR in the short infusion arm vs. 4 (15%) patients in the extended infusion arm. At day-90 post-transplant, 13 (48%) patients in each arm were in sCR/CR, and 17 (63%) patients in each arm achieved MRD-negative status. Overall, 23 (43%) patients achieved MRD-negative plus sCR/CR status at day-90 (11 [41%] in short and 12 [50%] in the extended infusion arm). The median follow-up was 14.5 (range: 6-40) months (13.8 months in the short infusion and 14.8 months in the extended infusion arm). The median progression-free survival (PFS) was not reached in the overall trial population (Figure). The median PFS in the short infusion arm was not reached vs. 28.2 months in the extended infusion arm. The 2-year progression-free survival (PFS) was 91% in the short infusion arm vs. 77% in the extended infusion arm (hazard ratio (HR)=9.5 with 95% CI: 1- 91.2), p-value=0.022. On multivariate analysis, controlling for age and cytogenetic risk category, the extended infusion arm was associated with a shorter PFS (HR 10.96; 95% CI 1.18 - 102.02), p-value 0.0355, although the range for HR was notably wide, which could be attributed to a small number of events in each arm. Conclusions: Dose escalation of evomela to 225 mg/m 2 is safe and associated with an acceptable toxicity profile and a high response rate. Short and extended infusions of evomela are well-tolerated and associated with high response rates. The PFS is longer with the short infusion schedule, however, to affirm these preliminary observations, additional follow-up is needed.

Disclosures. Shpall:Axio: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: License agreement; Affimed: Other: License agreeme

Background: Veno-occlusive disease (VOD) is a rare but potentially life-threatening complication following allogeneic stem cell transplantation (allo-SCT). Improved transplant techniques and increased awareness of modifiable risk factors have reduced VOD incidence. However, the interaction of historic risk factors in the current era, particularly with the increasing use of calicheamicin-based therapies and post-transplant cyclophosphamide as GVHD prophylaxis, remains unclear. Methods: We conducted a retrospective, single center, chart-based study of consecutive adult patients (age ≥ 18 years) undergoing allo-SCT at MD Anderson Cancer Center between January 1 st, 2017 and December 31 st, 2021. VOD cases were defined using the classic VOD EBMT criteria or if patients received defibrotide treatment for VOD based on clinical judgment of the treating physician. Risk factors for VOD were evaluated in univariate analysis using Fine and Grey regression analysis. Multivariate analysis was performed using Classification and Regression Tree (CART) analysis to validate the findings of univariate analysis and evaluate independent effects accounting for potential interaction effects. Results: A total of 1561 patients were included in our analysis. Median age was 56 years and 60% were male. Patients primarily had acute myeloid leukemia/myelodysplastic syndrome (AML/MDS; 60%), acute lymphoblastic leukemia (ALL; 13%), or myeloproliferative neoplasms (13%). Most patients had matched related (28%) or unrelated donors (48%), and 21% underwent haploidentical transplantation. Forty-nine (3%) patients received inotuzumab ozogamicin (InO) containing regimens prior to allo-SCT, and 30 (2%) were exposed to gemtuzumab ozogamicin (GO). Post-transplant cyclophosphamide (PTCy) was used as GVHD prophylaxis in 72% of patients. Incidence of VOD in the entire study population was 4.8%. There was a significant difference in the median age of patients diagnosed with VOD compared to those without VOD (46 years vs 56 years, respectively, p=0.001). Further examination of the incidence of VOD within different age groups identified a VOD rate of 16.8% (20/119) in those aged ≤ 25 years compared to 3.8% (55/1442) in those > 25 years (Table 1). Multivariate classification and regression tree (CART) analysis confirmed age as the primary independent determinant of the rate of VOD (Figure 1). Given these findings, risk factor analysis was stratified according to age. In patients ≤25 years of age, disease risk index (DRI) (31% with high/very high DRI vs 12% low/intermediate DRI; p=0.03) and prior lines of chemotherapy (24% with >1 vs 6% with ≤1, p=0.03) were the strongest predictors of VOD. Within the younger cohort of patients with AML/MDS, 2 of 3 patients (67%) who received gemtuzumab ozogamicin (GO) developed VOD compared to 10% who did not receive GO (p=0.05). In patients aged >25 years, elevated baseline bilirubin, AST, ALT, and GO exposure were associated with increased VOD rates. VOD incidence based on baseline bilirubin levels (WNL, >ULN to 1.5x ULN, and >1.5x ULN) was 3%, 14%, and 16%, respectively (pULN to 2.5x ULN, and >2.5x ULN), VOD rates were 4%, 3%, and 8%, respectively (p=0.02). Similarly, VOD rates with baseline AST levels (WNL, >ULN to 2.5x ULN, and >2.5x ULN) were 3%, 4%, and 27%, respectively (p≤0.001). In patients aged >25 years with AML/MDS, those receiving GO had a higher incidence of VOD compared to AML/MDS patients not exposed to GO (15% vs. 3%; p=0.01). There was no significant difference in VOD rates between those receiving PTCy and those receiving alternate GVHD prophylaxis in either age cohort. Conclusion: In summary, our data highlight that young adults (age 18 - 25 years) represent a distinct adult population with increased rates of VOD compared to their older counterparts, which are exacerbated by disease and treatment related factors (DRI and number lines of therapy). In contrast, patients > 25 years of age had low rates of VOD even in the presence of historical predictors, with only hepatic risk factors identified as increasing baseline VOD risk. There was no observed increased incidence of VOD among those receiving PTCy as GVHD prophylaxis.

Hodgkin lymphoma, a hematological malignancy of lymphoid origin that typically arises from germinal-center B cells, has an excellent overall prognosis. However, the treatment of patients who relapse or develop resistant disease still poses a substantial clinical and research challenge, even though current risk-adapted and response-based treatment techniques produce overall survival rates of over 95%. The appearance of late malignancies after the successful cure of primary or relapsed disease continues to be a major concern, mostly because of high survival rates. Particularly in pediatric HL patients, the chance of developing secondary leukemia is manifold compared to that in the general pediatric population, and the prognosis for patients with secondary leukemia is much worse than that for patients with other hematological malignancies. Therefore, it is crucial to develop clinically useful biomarkers to stratify patients according to their risk of late malignancies and determine which require intense treatment regimens to maintain the ideal balance between maximizing survival rates and avoiding late consequences. In this article, we review HL’s epidemiology, risk factors, staging, molecular and genetic biomarkers, and treatments for children and adults, as well as treatment-related adverse events and the late development of secondary malignancies in patients with the disease.