Humoral Immunity and Antibody Responses against Diphtheria, Tetanus, and Pneumococcus after Immune Effector Cell Therapies: A Prospective Study.

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.

High activity of the new myeloablative regimen of gemcitabine/clofarabine/busulfan for allogeneic transplant for aggressive lymphomas.

Refractory aggressive lymphomas can be treated with allo-SCT, pursuing a graft-vs-lymphoma effect. While reduced intensity conditioning is safe, tumors often progress rapidly, indicating the need for more active conditioning regimens. The preclinical synergy we saw between gemcitabine (Gem), clofarabine (Clo) and busulfan (Bu) against lymphoma cell lines led us to study Gem/Clo/Bu clinically. Eligibility: age 12-65, refractory aggressive B-NHL, T-NHL or Hodgkin, with a matched donor. Infusional Gem was dose-escalated on days (d) -6 and -4 (475-975 mg/m2/day), followed by Clo (40 mg/m2/day) and Bu (target AUC, 4000 µMol min/day) (d -6 to -3). CD20+ tumors received rituximab. GVHD prophylaxis included ATG (MUD), tacrolimus and MMF. We compared their outcomes to matched-pair concurrent controls receiving Flu/Mel + matched allo-SCT. We enrolled 64 patients, median age 46 (17-63), 31 B-NHL/22 T-NHL/11 Hodgkin, 36 MSD/28 MUD (all PBPC), median 4 (2-10) prior therapies; 18 prior auto-SCT, 42 active diseases at allo-SCT (12 PD). Toxicities (mucositis and transaminitis) were manageable. Gem/Clo/Bu was myeloablative yielding early full donor chimerism. Grades II-IV/III-IV acute GVHD rates of 37% and 18%; chronic GVHD of 33% (13% severe); NRM at D100/1 year was 7% and 18%. ORR/CR rates: 78%/71% (B-NHL), 93%/93% (T-NHL), 67%/67% (Hodgkin). At a median follow-up of 60 (12-110) months, EFS/OS rates: 36%/47%. Gem/Clo/Bu patients had better median EFS (12 vs. 3 months, P = 0.001) and OS (25 vs. 7 months, P = 0.003) than 113 Flu/Mel matched-pair controls. The new myeloablative regimen Gem/Clo/Bu has limited toxicity and high activity in allo-SCT for aggressive lymphomas, yielding better outcomes than concurrent matched-pair controls receiving Flu/Mel.

On the Way to Curing Advanced-Stage Mycosis Fungoides/Sézary Syndrome.

INTRODUCTION/BACKGROUND: Advanced-stage mycosis fungoides (MF) and Sézary syndrome (SS) have poor prognosis with median survivals of less than 5 years. Although a variety of treatments are approved for MF/SS patients, durable complete remissions (CR) are rare. PATIENTS AND METHODS: Advanced-stage MF or SS patients who achieved CR and maintained in CR or stage IA for more than 10 years were identified by a retrospective search of the principal investigator's database. RESULTS: Of 2266 patients diagnosed with MF or SS, 23 patients with advanced-stage MF/SS (6 IIB, 1 IIIB, 5 IVA1, 3 IVA2, 8 IVB) who achieved CR and maintained in CR or stage IA for ≥ 10 years were identified. As final/curative treatment, 11 patients underwent allogeneic stem cell transplantation (SCT). Most patients presented at young age, underwent SCT with reduced intensity conditioning regimen, had matched related donors, and controllable post-transplant graft versus host disease. Eleven patients were treated with TSEB as part of combined modality protocol in 2 patients and debulking therapy before allogeneic SCT in 9 patients. Five stage IIB patients achieved CR with radiotherapy. Four patients with blood involvement were treated with extracorporeal photopheresis (ECP) in combination with long-term antibiotics and immunomodulatory agents. Long-term antibiotics were given to 14 patients. CONCLUSION: TSEB followed by allogeneic SCT, radiotherapy, ECP plus long-term antibiotics and immunomodulatory agents were the most common curative/final treatments found in our patients. We are reporting the details of our long-term complete responders' treatment course in the hopes of obtaining more cure responses in the future.

Gastrointestinal involvement refines prognosis in minnesota standard risk acute graft-vs.-host disease.

Minnesota acute graft versus host disease (AGVHD) risk score is a validated tool to stratify newly-diagnosed patients into standard-risk (SR) and high-risk (HR) groups with ~85% having SR AGVHD. We aimed to identify factors for further risk-stratification within Minnesota SR patients. A single-center, retrospective analysis of consecutive patients between 1/2010 and 12/2014 was performed. Patients who developed AGVHD within 100 days and treated with systemic corticosteroids were included (N = 416), 356 (86%) of which were Minnesota SR and 60 (14%) had HR AGVHD. Isolated upper gastrointestinal (GI) AGVHD patients had significantly better day 28 and 56 CR/PR rates (90% vs. 72%, p = 0.004) and (83% vs 66%, p = 0.01), respectively, and lower 1-year non-relapse mortality (NRM; 10% vs. 22%; HR 0.4, p = 0.03). Lower GI AGVHD had less favorable outcomes with 1-year NRM of 40% (HR 2.1, p = 0.001), although CR/PR rates were not statistically different. In multivariate analysis, lower GI involvement (HR 2.6, p < 0.001), age ≥ 50 (HR 2.9, p < 0.001) and HCT-CI > 3 (HR 2.1, p = 0.002) predicted for 1-year NRM. Heterogeneity within Minnesota SR patients requires consideration in clinical trials, as distinct outcomes are observed in those with isolated upper GI and lower GI AGVHD, highlighting the importance of stratification in clinical trial design.

Brentuximab vedotin plus cyclophosphamide, doxorubicin, etoposide, and prednisone followed by brentuximab vedotin consolidation in CD30-positive peripheral T-cell lymphomas: a multicentre, single-arm, phase 2 study.

BACKGROUND: CD30 expression is universal in anaplastic large-cell lymphoma and is expressed in some other peripheral T-cell lymphoma subtypes. Incorporation of brentuximab vedotin into initial therapy for people with CD30-positive peripheral T-cell lymphomas prolonged progression-free survival, but there is room for improvement, especially for people with non-anaplastic large-cell lymphoma subtypes. METHODS: We conducted a multicentre, international, single-arm, phase 2 trial to evaluate the safety and activity of CHEP-BV (cyclophosphamide, doxorubicin, prednisone, brentuximab vedotin, and etoposide) followed by brentuximab vedotin consolidation in patients with CD30-expressing peripheral T-cell lymphomas across five academic centres in the USA and Canada. Adults aged 18 years or older with newly diagnosed, untreated CD30-positive peripheral T-cell lymphomas, Eastern Cooperative Oncology Group score of 0-2, and adequate organ function were eligible to receive six planned cycles of CHEP-BV (ie, 1·8 mg/kg brentuximab vedotin intravenously on day 1, cyclophosphamide 750 mg/m2 intravenously on day 1, doxorubicin 50 mg/m2 intravenously on day 1, etoposide 100 mg/m2 daily intravenously on days 1-3, and prednisone 100 mg daily orally on days 1-5) with prophylactic G-CSF. Patients who responded to the treatment could receive brentuximab vedotin consolidation for up to ten additional cycles either after autologous haematopoietic stem-cell transplantation (HSCT) or directly after CHEP-BV. The primary endpoints were unacceptable toxicity during a 3-plus-3 safety lead-in in participants who received study treatment and completed the safety evaluation period (to confirm the recommended phase 2 dose of brentuximab vedotin in CHEP-BV) and the complete response rate after CHEP-BV induction therapy in participants who received study treatment and had response evaluation. The study was registered at ClinicalTrials.gov (NCT03113500), and this cohort completed the trial. The trial is ongoing with the enrolment of a new cohort. FINDINGS: 54 patients were screened for eligibility and 48 were eligible for the study. The participants (18 [38%] women and 30 [63%] men; 34 [71%] White, four [8%] Black, five [10%] Asian, ten [21%] Hispanic, and 37 [77%] non-Hispanic people) were recruited and enrolled between Dec 4, 2017, and June 14, 2021, and followed up until Aug 25, 2023, when the database was locked for analysis. 48 participants were evaluable for toxicity, and 47 were evaluable for response (one participant died from COVID-19 before response assessment). During the safety lead-in, one of six participants had an unacceptable toxicity (ie, platelet count <10 000 per mm3 in a participant with extensive bone marrow involvement), and the proposed phase 2 dose of 1·8 mg/kg brentuximab vedotin in CHEP-BV was confirmed. At completion of CHEP-BV, 37 of 47 participants had complete response, yielding a complete response rate of 79% (95% CI 64-89). The most common CHEP-BV-related toxicities of grade 3 or higher were neutropenia (14 [29%] of 48), leukopenia (11 [23%]), anaemia (ten [21%]), febrile neutropenia (ten [21%]), lymphopenia (nine [19%]), and thrombocytopenia (nine [19%]). There were no treatment-related deaths. INTERPRETATION: In patients with mostly CD30-expressing peripheral T-cell lymphomas other than non-anaplastic large-cell lymphoma, CHEP-BV (with or without autologous HSCT) followed by brentuximab vedotin consolidation was safe and active. FUNDING: SeaGen, Leukemia and Lymphoma Society, Lymphoma Research Foundation, and the National Cancer Institute of the National Institutes of Health.

Long-term outcomes after haploidentical stem cell transplantation for hematologic malignancies.

ABSTRACT: The introduction of posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis lead to significant improvements in haploidentical stem cell transplantation (haplo-SCT) outcomes over the past decade. We retrospectively assessed long-term outcomes of patients who had their first haplo-SCT between February 2009 and March 2019. Long-term survivors were defined as patients who were alive and disease-free at 2 years after transplant. Three hundred thirty-five patients with a median age of 48 years (range, 18-72) were identified. Of these, 142 patients were disease-free and alive at 2 years after transplant. The 4-year progression-free survival (PFS) and overall survival (OS) for all study patients were 42% and 47%, respectively. With a median follow-up of 52 months for the long-term survivor group, the 4-year PFS and OS were 94% and 96%, respectively. The 4-year cumulative incidence of relapse and non-relapse mortality (NRM) were 2.9% and 3.3%, respectively. Age ≥55 years was the only predictive factor in multivariate analysis for inferior PFS (hazard ratio [HR], 3.41; 95% confidence interval [CI], 1.21-9.60; P = .020) and OS (HR, 3.31; 95% CI, 1.08-10.18; P = .037). Thirteen patients (9%) died in the long-term survivor group, only 2 of whom died of relapsed disease. Secondary primary malignancy was the most frequent cause of NRM (n = 4), followed by infection (n = 2). For haplo-SCT with PTCy-based GVHD prophylaxis, our findings suggest an excellent long-term survival for patients who were disease-free and alive at 2 years after transplant. Late relapses were rare, and age was the only predictive factor for long-term outcomes.

Eltrombopag improves platelet engraftment after haploidentical bone marrow transplantation: Results of a Phase II study.

Slow platelet recovery frequently occurs after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with bone marrow graft and post-transplant cyclophosphamide (PCy)-based graft-versus-host disease (GVHD) prophylaxis. Improved platelet recovery may reduce the need for transfusions and improve outcomes. We investigated the safety and efficacy of eltrombopag, a thrombopoietin receptor agonist, at enhancing platelet recovery post-haplo-HSCT. The prospective study included patients ≥18 years of age who received haplo-HSCT with bone marrow graft and PCy. Patients received eltrombopag 300 mg/day starting on Day +5. The primary objective was to estimate platelet engraftment (>50 000/µL by Day 60). In a post hoc analysis, they were compared to a contemporary matched control group who did not receive eltrombopag. One hundred ten patients were included in the analysis (30 eltrombopag and 80 control). Seventy-three percent and 50% of patients in the eltrombopag group and control group, respectively, attained >50 000/µL platelet count by Day 60 (p = .043). No eltrombopag-related grade ≥4 adverse events were observed. Median time to platelet recovery (>20 000/µL) was 29 days with eltrombopag and 31 days for controls (p = .022), while its cumulative incidence was 90% (95% confidence interval [CI]: 78%-100%) with eltrombopag versus 67.5% (95% CI: 57%-78%) for controls (p = .014). Number of platelet transfusions received, overall survival, progression-free survival, GVHD rate, relapse rate, and non-relapse mortality were similar between groups. Overall, eltrombopag is safe and improves platelet recovery in patients undergoing haplo-HSCT with bone marrow graft and PCy.

Incidence and risk factors of early onset VOD/SOS differ in younger vs older adults after stem cell transplantation.

ABSTRACT: Veno-occlusive disease (VOD) is a rare but potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-SCT). Although increasing awareness and modern transplant techniques have mitigated risk, the interaction of historic risk factors in the current era with posttransplant cyclophosphamide (PTCy) is unknown. We performed a retrospective single-center analysis of adult patients aged ≥18 years undergoing allo-SCT (N = 1561) using predominately PTCy as graft-versus-host disease (GVHD) prophylaxis (72%). We found a higher rate of VOD at 16.8% (20 of 119) in those aged ≤25 years compared with 3.8% (55 of 1442) in those aged >25 years, with unique predictors of VOD within each cohort. Multivariate classification and regression tree (CART) analysis confirmed age as the primary independent determinant of the rate of VOD. Among patients aged 18 to 25 years, disease risk index (DRI; 31% with high/very high DRI vs 12% low/intermediate DRI; P = .03) and prior lines of chemotherapy (24% with >1 vs 6% with ≤1; P = .03) were the strongest predictors of VOD. Incidence of VOD in patients aged >25 years of age consistently ranged between 3% and 5% across most risk factors evaluated, with only hepatic factors (baseline elevation of bilirubin, aspartate transferase, alanine aminotransferase) or gemtuzumab exposure associated with increased rates of VOD. There was no significant difference in rates of VOD in those receiving PTCy compared with those receiving alternate GVHD prophylaxis. Our data highlight the differences in incidence and predictors of VOD between younger (≤25) and older (>25) adults undergoing allo-SCT.

Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial.

There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19+ B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 107 and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339 .

Characteristics and Outcomes of Patients With Multiple Myeloma Who Developed Therapy-Related Acute Myeloid Leukemia and Myelodysplastic Syndrome After Autologous Cell Transplantation.

Patients with multiple myeloma (MM) who undergo high-dose chemotherapy and autologous hematopoietic cell transplantation (Auto-HCT) have an increased risk of developing therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML). We retrospectively reviewed the medical records of all MM patients who underwent an Auto-HCT at our institution between 1 January and 31 December 2018 and later developed t-MDS/AML. Among the 2982 patients who underwent at least 1 Auto-HCT, 55 (2%) developed t-MDS/AML (MDS, n = 52; AML, n = 3). The median age at t-MDS/AML diagnosis was 66 years (range 43-83 years), and the median time from Auto-HCT to t-MDS/AML diagnosis was 58.5 months (range 6-206 months). At diagnosis, all 3 patients with tAML and 65% of those with therapy-related myelodysplastic syndrome (tMDS) had high-risk disease, per 2022 European LeukemiaNet and R-IPSS, respectively, and 62% had TP53 gene mutations. Patients who developed tMDS/AML were older at MM diagnosis (median 61 versus 59 years; P = .06), more often were male (73% versus 58%; P = .029), received more than 2 years of lenalidomide maintenance (57% versus 39%; P = .014), and experienced complete remission more frequently after Auto-HCT compared to those who did not develop t-MDS/AML (56% versus 40%; P = .012). In a multivariable model, male gender, advanced age at MM diagnosis, experiencing complete remission after Auto-HCT, and lenalidomide maintenance were independent predictors of developing t-MDS/AML. Among the patients who developed t-MDS/AML, 14 (25%) underwent allogeneic hematopoietic stem transplantation (Allo-HCT). After a median follow-up of 9.9 months from t-MDS/AML diagnosis, the median overall survival (OS) after t-MDS/AML diagnosis was 11.8 months for all patients, and 18.2 months versus 11.1 months for Allo-HCT recipients versus nonrecipients, respectively (P = .25). On univariate analysis, receiving an alkylator as induction for MM (hazard ratio [95% confidence interval]: 2.9 [1.3-6.3]; P = .009), age > 60 years (3.1 [1.2-8.2]; P = .025), and higher-risk R-IPSS (2.7 [1.3-6.0]; P=0.011) predicted worse OS after t-MDS/AML diagnosis. None of these retained significance in the multivariable analysis. T-MDS/AML after Auto-HCT for MM is associated with aggressive disease characteristics, including high-risk cytogenetics and TP53 mutations. The outcomes of patients remain poor, even with Allo-HCT. A better understanding of disease biology and novel therapeutic approaches is warranted.

Ex Vivo Expanded Cord Blood Natural Killer Cells Combined with Rituximab and High-Dose Chemotherapy and Autologous Stem Cell Transplantation for B Cell Non-Hodgkin Lymphoma.

Relapse is the major cause of failure of high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) for B cell non-Hodgkin lymphomas (B-NHL). Improvement strategies include use in combination with effective immunotherapies. We hypothesized that the combination of rituximab/HDC/ASCT with expanded cord blood (CB)-derived natural killer (NK) cells is safe and active in B-NHL. Patients with B-NHL age 15 to 70 years and appropriate ASCT candidates were eligible for the study. The CB units were selected without considering HLA match with the recipient. The CB NK cells were expanded from day -19 to day -5. Treatment included rituximab on days -13 and -7, BEAM (carmustine/etoposide/cytarabine/melphalan) on days -13 to -7, lenalidomide on days -7 to -2, CB NK infusion (108/kg) on day -5, and ASCT (day 0). The primary endpoint was 30-day treatment-related mortality (TRM); secondary endpoints included relapse-free survival (RFS), overall survival (OS), and persistence of CB NK cells. We enrolled 20 patients. CB NK cells were expanded a median of 1552-fold with >98% purity and >96% viability. We saw no adverse events attributable to the CB NK cells and 0% 30-day TRM. At median follow-up of 47 months, the RFS and OS rates were 53% and 74%, respectively. CB NK cells were detectable in blood for 2 weeks, independent of HLA-mismatch status. CD16 expression in donor NK cells was correlated favorably with outcome, and homozygosity for the high-affinity CD16 variant (158 V/V) in CB, but not recipient, NK cells was correlated with better outcomes. Our data indicate that the combination of expanded and highly purified CB-derived NK cells with HDC/ASCT for B-NHL is safe. CD16 expression in donor NK cells, particularly if homozygous for the high-affinity CD16 variant, was correlated with better outcomes.

Characteristics and outcomes of children, adolescents and young adults with relapsed/refractory non-hodgkin lymphoma undergoing autologous stem cell transplant.

BACKGROUND: 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). METHODS: Patients aged 0-39 years undergoing first ASCT for NHL at MD Anderson Cancer Center between 2000 and 2020 were analyzed. RESULTS: 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. CONCLUSIONS: 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.

Transplantation Outcomes of Myelofibrosis with Busulfan and Fludarabine Myeloablative Conditioning.

Outcomes of myelofibrosis (MF) with allogeneic stem cell transplantation (allo-SCT) have improved over the past decade, related in part to advances in supportive treatments and conditioning regimens. Several factors are known to predict transplantation outcomes. However, most studies lack homogeneity in conditioning regimens used, limiting their ability to assess prognostic factors on transplantation outcomes. We aimed to identify the risk factors that predict transplantation outcomes in patients with MF who underwent matched or mismatched allo-SCT using a uniform myeloablative conditioning regimen consisting of busulfan and fludarabine with tacrolimus and methotrexate-based graft-versus-host disease prophylaxis. This single-center study included patients with MF who underwent allo-SCT with a matched unrelated donor (MUD), matched related donor (MRD), or mismatched unrelated donor (MMUD) and received busulfan and fludarabine conditioning with methotrexate/tacrolimus-based GVHD prophylaxis. Sixty-five patients with MF met the study criteria and were included in our analysis. At a median follow-up of 35.6 months, the 3-year cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), and overall survival (OS) for all study patients were 27%, 20%, and 65%, respectively. In a multivariable analysis for CIR, prior use of JAK inhibitors was significantly associated with a decreased risk of relapse (hazard ratio [HR], .33; 95% confidence interval [CI], .11 to .99; P = .048). For NRM, Hematopoietic Cell Transplantation Comorbidity Index (≥3 versus <3; HR, 10.09; 95% CI, 2.09 to 48.76; P = .004) and donor type (MUD versus MRD: HR, 5.38; 95% CI, 1.14 to 25.30; P = .033; MMUD versus MRD: HR, 10.73; 95% CI, 1.05 to 109.4; P = .045) were associated with an increased risk of mortality. Likewise for OS, HCT-CI (≥3 versus <3; HR, 3.31; 95% CI, 1.22 to 8.99; P = .019) and donor type (MMUD versus MRD: HR, 5.20; 95% CI, 1.35 to 19.98; P = .016) were significantly associated with inferior survival. Longer time from diagnosis to allo-SCT seemed to confer worse survival, but the difference did not reach statistical significance (>12 months versus ≤12 months: NRM: HR, 7.20; 95% CI, .96 to 53.94; P = .055; OS: HR, 2.60; 95% CI, .95 to 7.14; P = .06). In a homogenous cohort of MF patients uniformly treated with busulfan/fludarabine myeloablative conditioning and methotrexate-based GVHD prophylaxis, we show that donor choice and HCT-CI are the 2 strongest predictors for improved survival after allo-SCT.

Radiation Therapy Can Be Safely Incorporated into Pretransplantation Treatment Regimens for Patients with Multiple Myeloma.

Primary treatment of multiple myeloma (MM) often involves systemic induction therapy (SIT) followed by autologous stem cell transplantation (ASCT). Radiation therapy (RT) is sometimes used for palliation; however, many practitioners avoid RT out of concern that future peripheral blood progenitor cell (PBPC) collection required for ASCT may be compromised. In this study, we retrospectively examined the possible effect of RT on PBPC collection. We reviewed the charts of 732 patients with MM treated with RT at our institution from 1999 to 2017, including patients who received RT prior to PBPC collection for planned ASCT. RT plans (both MM and non-MM RT) were reviewed to estimate the percentage of bone marrow (BM) treated using published estimates of skeletal BM distribution. Statistics were performed using Pearson correlation and the t-test. The 732 MM patients included 485 planned for ASCT; of these, 223 received RT prior to PBPC collection and were included in the final cohort. The median age at PBPC collection was 59 years (range, 33 to 80 years). For SIT, patients received combination regimens including the following agents: bortezomib (142 patients; 64%), lenalidomide (111 patients; 50%), and alkylators (46 patients; 21%). Nine patients (4%) received dexamethasone alone. The median cumulative %BM treated per patient was 6.7 (range .0 to 47.4). The median RT dose was 24 Gy (range, 10.0 to 75.6 Gy). Mobilization was performed using granulocyte-colony stimulating factor (G-CSF) alone (189 patients; 85%), G-CSF with plerixafor (15 patients; 7%), or chemotherapy (19 patients; 9%). A median of 7.8 × 106 CD34+/kg PBPCs (range, .5 to 54.8× 106 CD34+/kg) were collected in a median of 3 (range, 1 to 9) apheresis procedures. One hundred ninety-six patients (99%) collected ≥2.0 × 106 CD34+/kg PBPCs, and 166 (83%) collected >5.0 × 106 CD34+/kg PBPCs. The number of PBPCs collected was not associated with %BM treated (P = .15) or RT dose (P = .56). The number of apheresis procedures performed was not associated with %BM treated (P = .54) or RT dose (P = .85). The amount of PBPCs collected did not differ significantly between patients receiving RT to the pelvis/sacrum (P = .20) and those receiving RT to the spine (P = .13). The time to platelet engraftment was longer for patients with higher %BM treated (P = .02). Eleven patients did not undergo a confirmed ASCT, owing to patient preference (3 patients), trial therapy (1 patient), comorbidities (1 patient), election for hospice (1 patient), inadequate collection (4 patients), or inadequate follow-up (1 patient). In our study cohort, RT prior to ASCT did not impair successful ASCT. RT must be carefully planned and delivered to ensure safe incorporation into pre-ASCT treatment regimens.

Myeloablative fractionated busulfan for allogeneic stem cell transplant in older patients or patients with comorbidities.

Traditional conditioning regimens for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) provide suboptimal outcomes, especially for older patients and those with comorbidities. We hypothesized that a fractionated myeloablative busulfan dose delivered over an extended period would reduce nonrelapse mortality (NRM) while retaining antileukemic effects. Here, we performed a phase 2 trial for adults with hematological malignancies receiving matched related or unrelated allo-HCT. Participants received busulfan 80 mg/m2 as outpatients on days -20 and -13 before transplant. Fludarabine 40 mg/m2 was administered on days -6 to -3, followed by busulfan dosed to achieve a target area under the curve of 20 000 mol/min for the whole course. The primary end point was day-100 NRM. Seventy-eight patients were included, with a median age of 61 years (range, 39-70 years), who received transplantation for acute leukemia (24%), myelodysplastic syndrome (27%), or myeloproliferative disease/chronic myeloid leukemia (44%). HCT-specific comorbidity index (HCT-CI) was ≥3 in 34 (44%). With a median follow-up of 36.4 months (range, 2.9-51.5), the 100-day, 1-year, and 3-year NRM rates were 3.8%, 8%, and 9.3%, respectively, without a significant difference in age or HCT-CI score. The 1-year and 3-year relapse incidence was 10% and 18%, respectively. The 3-year overall survival was 80%, without a significant difference in age or HCT-CI score and was similar for patients aged >60 years and those aged <60 years as well as for those with HCT-CI ≥3 and HCT-CI <3. Overall, a myeloablative fractionated busulfan regimen has low NRM without an increase in relapse rate, resulting in promising survival, even in older patients or in patients with comorbidities. This trial was registered at www.clinicaltrials.gov as #NCT02861417.

High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma.

Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon, aggressive type of non-Hodgkin lymphoma. Rituximab-containing chemoimmunotherapy with or without radiation therapy (RT) is standard first-line treatment. Relapsed or refractory (R/R) disease has long been treated with salvage chemotherapy followed by high-dose chemotherapy (HDC), with autologous stem cell transplantation (ASCT) in appropriate patients. We retrospectively analyzed all patients with R/R PMBCL treated with HDC/ASCT at our center between January 2000 and August 2022. The 60 study patients received either rituximab-BEAM (n = 37) or rituximab-gemcitabine/busulfan/melphalan (R-GemBuMel) with or without vorinostat (n = 23), followed by ASCT. Forty-six patients received mediastinal RT, either as prior consolidation of frontline therapy or following ASCT. At median follow-up of 6 years (range, .3 to 21 years), the 5-year progression-free survival (PFS) and overall survival (OS) rates of the whole group were 58% and 77%, respectively, for the entire cohort, 51% and 65% for the R-BEAM recipients, and 69% and 82% for R-vorinostat/GemBuMel recipients. Multivariable analyses showed that a negative positron emission tomography scan at ASCT (hazard ratio [HR], .28) and involvement of only 1 organ (HR, .33) were independently associated with improved PFS. In addition, receipt of R-vorinostat/GemBuMel (HR, .23) was an independent favorable predictor of OS. Our data indicate that HDC/ASCT is effective in R/R PMBCL, with improved outcomes in patients receiving R-vorinostat/GemBuMel.

Classical Hodgkin Lymphoma: From Past to Future-A Comprehensive Review of Pathophysiology and Therapeutic Advances.

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.

A Nasal Inflammatory Cytokine Signature Is Associated with Early Graft-versus-Host Disease of the Lung after Allogeneic Hematopoietic Cell Transplantation: Proof of Concept.

Respiratory inflammation in bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplantation (HCT) is poorly understood. Clinical criteria for early-stage BOS (stage 0p) often capture HCT recipients without BOS. Measuring respiratory tract inflammation may help identify BOS, particularly early BOS. We conducted a prospective observational study in HCT recipients with new-onset BOS (n = 14), BOS stage 0p (n = 10), and recipients without lung impairment with (n = 3) or without (n = 8) chronic graft-versus-host disease and measured nasal inflammation using nasosorption at enrollment and then every 3 mo for 1 y. We divided BOS stage 0p into impairment that did not return to baseline values (preBOS, n = 6), or transient impairment (n = 4). We tested eluted nasal mucosal lining fluid from nasosorption matrices for inflammatory chemokines and cytokines using multiplex magnetic bead immunoassays. We analyzed between-group differences using the Kruskal-Wallis method, adjusting for multiple comparisons. We found increased nasal inflammation in preBOS and therefore directly compared patients with preBOS to those with transient impairment, as this would be of greatest diagnostic relevance. After adjusting for multiple corrections, we found significant increases in growth factors (FGF2, TGF-α, GM-CSF, VEGF), macrophage activation (CCL4, TNF-α, IL-6), neutrophil activation (CXCL2, IL-8), T cell activation (CD40 ligand, IL-2, IL-12p70, IL-15), type 2 inflammation (eotaxin, IL-4, IL-13), type 17 inflammation (IL-17A), dendritic maturation (FLT3 ligand, IL-7), and counterregulatory molecules (PD-L1, IL-1 receptor antagonist, IL-10) in preBOS patients compared to transient impairment. These differences waned over time. In conclusion, a transient multifaceted nasal inflammatory response is associated with preBOS. Our findings require validation in larger longitudinal cohorts.

Characteristics and Outcomes of Children, Adolescents and Young Adults with Relapsed/Refractory Non-Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplant.

There is paucity of data regarding outcomes of children, adolescents and young adults (CAYA) patients with non-Hodgkin lymphoma (NHL) undergoing autologous hematopoietic stem cell transplantation (ASCT). We analyzed 222 patients aged 0-39 years undergoing first ASCT for NHL between 2000 and 2020. The most common histological subtypes were DLBCL (44%), T-NHL (19%) and PMBCL (19%). Younger patients (age ≤ 25) had lower incidence of DLBCL and higher incidence of PMBCL and T-NHL compared to older patients (> 25 years) (P = 0.02). None of the younger patients had DH)/DE DLBCL, as compared to 14 patients in the older group (18%, P = 0.07). Younger patients had numerically better 15-year post-transplant PFS (67% vs. 54%) and OS (71% vs. 62%) compared to older patients, without statistically significant differences (P = 0.19 and P = 0.24, respectively). In MVA, not achieving a CR prior to ASCT was independently predictive of worse PFS (P < 0.0001). DH/DE status was an independent adverse predictor of PFS in MVA (HR 5.8, p = 0.03). 10 patients(4.5%) (all aged > 25 years) developed SPM Patients aged ≤ 25 years presented a distinct NHL histology as compared to older CAYA patients. Disease status at ASCT was predictive of both PFS and OS. DH/DE status was an adverse predictor of PFS.