Search

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Primary mediastinal B-cell lymphoma (PMBL) is an uncommon entity of aggressive B-cell lymphoma with an unusually good prognosis, except for 10-15% of chemotherapy-refractory cases. To identify earlier these higher risk patients, we performed molecular characterization of a retrospective multicenter cohort of patients treated with firstline immunochemotherapy. The traits of the patients with gene-expression profiling data (n = 120) were as follows: median age of 34 years (range, 18-67 years); female sex, 58.3%; elevated lactate dehydrogenase, 82.5%; Eastern Cooperative Oncology Group performance status score of 0 to 1, 85.7%; Ann Arbor stage I/II, 55%; International Prognostic Index score of 1 to 2, 64.4%; and median metabolic tumor volume, 290.4 cm3 (range, 15.7-1147.5 cm3). Among all 137 markers tested for correlation with survival data, only programmed death-ligand (PDL) 1 and PDL2 expression showed a prognostic impact. Overall, both PDL1 and PDL2 genes were highly expressed in 37 patients (30.8%; PDL1high/PDL2high). The baseline clinical characteristics of patients with PDL1high/PDL2high were similar to those of other patients. In univariate analysis, PDL1high/PDL2high status was associated with poor progression-free survival (PFS) (hazard ratio [HR], 4.292) and overall survival (OS; HR, 8.24). In multivariate analysis, PDL1high/PDL2high status was an independent prognostic factor of adverse outcomes (PFS: HR, 5.22; OS: HR, 10.368). We validated these results in an independent cohort of 40 patients and confirmed the significant association between PDL1high/PDL2high status and inferior PFS (HR, 6.11). High PDL1/PDL2 gene expression defines a population with strong immune privilege and poorer outcomes from standard chemotherapy who might benefit from firstline checkpoint inhibitor therapy., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Investigating prognostic factors in patients with relapsed or primary refractory classical Hodgkin lymphoma (R/R cHL) is essential to optimize risk-adapted treatment strategies. We built a prognostic model using baseline quantitative 18F-fluorodeoxyglucose positron emission tomography (PET) radiomics features and clinical characteristics to predict the progression-free survival (PFS) among patients with R/R cHL treated with salvage chemotherapy followed by autologous stem cell transplantation. Metabolic tumor volume and several novel radiomics dissemination features, representing interlesional differences in distance, volume, and standard uptake value, were extracted from the baseline PET. Machine learning using backward selection and logistic regression were applied to develop and train the model on a total of 113 patients from 2 clinical trials. The model was validated on an independent external cohort of 69 patients. In addition, we validated 4 different PET segmentation methods to calculate radiomics features. We identified a subset of patients at high risk for progression with significant inferior 3-year PFS outcomes of 38.1% vs 88.4% for patients in the low-risk group in the training cohort (P < .001) and 38.5% vs 75.0% in the validation cohort (P = .015), respectively. The overall survival was also significantly better in the low-risk group (P = .022 and P < .001). We provide a formula to calculate a risk score for individual patients based on the model. In conclusion, we developed a prognostic model for PFS combining radiomics and clinical features in a large cohort of patients with R/R cHL. This model calculates a PET-based risk profile and can be applied to develop risk-stratified treatment strategies for patients with R/R cHL. These trials were registered at www.clinicaltrials.gov as #NCT02280993, #NCT00255723, and #NCT01508312., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P 5 .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P 5 .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma. [ABSTRACT FROM AUTHOR]

To study the prognostic relevance of rare genetic aberrations in acute myeloid leukemia (AML), such as t(16;21), international collaboration is required. Two different types of t(16;21) translocations can be distinguished: t(16;21)(p11;q22), resulting in the FUS-ERG fusion gene; and t(16;21)(q24;q22), resulting in RUNX1-core binding factor (CBFA2T3). We collected data on clinical and biological characteristics of 54 pediatric AML cases with t(16;21) rearrangements from 14 international collaborative study groups participating in the international Berlin-Frankfurt-Münster (I-BFM) AML study group. The AML-BFM cohort diagnosed between 1997 and 2013 was used as a reference cohort. RUNX1-CBFA2T3 (n = 23) had significantly lower median white blood cell count (12.5 3 109/L, P = .03) compared with the reference cohort. FUS-ERG rearranged AML (n = 31) had no predominant French-American- British (FAB) type, whereas 76% of RUNX1-CBFA2T3 had an M1/M2 FAB type (M1, M2), significantly different from the reference cohort (P = .004). Four-year event-free survival (EFS) of patients with FUS-ERG was 7% (standard error [SE] = 5%), significantly lower compared with the reference cohort (51%, SE = 1%, P < .001). Four-year EFS of RUNX1-CBFA2T3 was 77% (SE = 8%, P = .06), significantly higher compared with the reference cohort. Cumulative incidence of relapse was 74% (SE = 8%) in FUS- ERG, 0% (SE = 0%) in RUNX1-CBFA2T3, compared with 32% (SE = 1%) in the reference cohort (P < .001). Multivariate analysis identified both FUS-ERG and RUNX1-CBFA2T3 as independent risk factors with hazard ratios of 1.9 (P < .0001 ) and 0.3 (P = .025), respectively. These results describe 2 clinically relevant distinct subtypes of pediatric AML. Similarly to other core-binding factor AMLs, patients with RUNX1-CBFA2T3 rearranged AML may benefit from stratification in the standard risk treatment, whereas patients with FUS-ERG rearranged AML should be considered high-risk. [ABSTRACT FROM AUTHOR]

We previously reported durable responses and manageable safety of ibrutinib from a 3-year follow-up of treatment-naïve (TN) older patients (≥65 years of age) and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We now report on long-term efficacy and safety with median follow-up of 5 years in this patient population with TN (N = 31) and R/R (N = 101) CLL/SLL. With the current 5-year follow-up, ibrutinib continues to yield a high overall response rate of 89%, with complete response rates increasing over time to 29% in TN patients and 10% in R/R patients. The median progression-free survival (PFS) was not reached in TN patients. The 5-year PFS rate was 92% in TN patients and 44% in R/R patients. Median PFS in R/R patients was 51 months; in those with del(11q), del(17p), and unmutated IGHV, it was 51, 26, and 43 months, respectively, demonstrating long-term efficacy of ibrutinib in some high-risk subgroups. Survival outcomes were less robust for R/R patients with del(17p) and those who received more prior therapies. The onset of grade ≥3 cytopenias, such as neutropenia and thrombocytopenia, decreased over time. Treatment--limiting adverse events were more frequent during the first year compared with subsequent periods. These results demonstrate sustained efficacy and acceptable tolerability of ibrutinib over an extended time, providing the longest experience for Bruton tyrosine kinase inhibitor treatment in patients with CLL/SLL. These trials were registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01109069. [ABSTRACT FROM AUTHOR]

Approximately 30% to 50% of adults with acute lymphoblastic leukemia (ALL) in hematologic complete remission after multiagent therapy exhibit minimal residual disease (MRD) by reverse transcriptase-polymerase chain reaction or flow cytometry. MRD is the strongest predictor of relapse in ALL. In this open-label, single-arm study, adults with B-cell precursor ALL in hematologic complete remission with MRD (≥10-3) received blinatumomab 15 μg/m2 per day by continuous IV infusion for up to 4 cycles. Patients could undergo allogeneic hematopoietic stem-cell transplantation any time after cycle 1. The primary end point was complete MRD response status after 1 cycle of blinatumomab. One hundred sixteen patients received blinatumomab. Eighty-eight (78%) of 113 evaluable patients achieved a complete MRD response. In the subgroup of 110 patients with Ph-negative ALL in hematologic remission, the Kaplan-Meier estimate of relapse-free survival (RFS) at 18 months was 54%. Median overall survival (OS) was 36.5 months. In landmark analyses, complete MRD responders had longer RFS (23.6 vs 5.7 months; P = .002) and OS (38.9 vs 12.5 months; P = .002) compared with MRD nonresponders. Adverse events were consistent with previous studies of blinatumomab. Twelve (10%) and 3 patients (3%) had grade 3 or 4 neurologic events, respectively. Four patients (3%) had cytokine release syndrome grade 1, n = 2; grade 3, n = 2), all during cycle 1. After treatment with blinatumomab in a population of patients with MRD-positive B-cell precursor ALL, a majority achieved a complete MRD response, which was associated with significantly longer RFS and OS compared with MRD nonresponders. [ABSTRACT FROM AUTHOR]

Mycosis fungoides (MF) is the most frequent form of cutaneous T-cell lymphoma. The disease often takes an indolent course, but in approximately one-third of the patients, the disease progresses to an aggressive malignancy with a poor prognosis. At the time of diagnosis, it is impossible to predict which patients develop severe disease and are in need of aggressive treatment. Accordingly, we investigated the prognostic potential of microRNAs (miRNAs) at the time of diagnosis in MF. Using a quantitative reverse transcription polymerase chain reaction platform, we analyzed miRNA expression in diagnostic skin biopsies from 154 Danish patients with early-stage MF. The patients were subdivided into a discovery cohort (n = 82) and an independent validation cohort (n = 72). The miRNA classifier was built using a LASSO (least absolute shrinkage and selection operator) Cox regression to predict progression-free survival (PFS). We developed a 3-miRNA classifier, based on miR-106b-5p, miR-148a-3p, and miR-338-3p, which successfully separated patients into high-risk and low-risk groups of disease progression. PFS was significantly different between these groups in both the discovery cohort and the validation cohort. The classifier was stronger than existing clinical prognostic factors and remained a strong independent prognostic tool after stratification and adjustment for these factors. Importantly, patients in the high-risk group had a significantly reduced overall survival. The 3-miRNA classifier is an effective tool to predict disease progression of early-stage MF at the time of diagnosis. The classifier adds significant prognostic value to existing clinical prognostic factors and may facilitate more individualized treatment of these patients. [ABSTRACT FROM AUTHOR]

Currently, prediction of time to treatment failure (TTF) and overall survival (OS) in mantle cell lymphoma (MCL) is based on the clinical factors included in the Mantle Cell Lymphoma International Prognostic Index (MIPI), and proliferation is assessed by Ki67. However, TP53 and SOX11 immunohistochemistry might improve risk stratification. We performed SOX11 and TP53 immunohistochemistry on the so far largest published cohort of lymphoma specimens (n 5 365). All patients were treated in prospective trials of the European MCL Network. In multivariate analyses, including MIPI and Ki67, SOX11 expression was not associated with TTF, but patients with low SOX11 expression had shorter OS. On the contrary, high TP53 expression was a strong predictor of TTF and inferior OS compared with low TP53 expression in univariate and multivariate analyses adjusting for MIPI score and Ki-67 index (hazard ratio [HR], 2.0; P 5 .0054 for TTF, and HR, 2.1; P 5 .068 for OS). In particular, patients with high TP53 expression (>50% positive lymphoma cells) had a shorter TTF and poor OS independent of both MIPI score and Ki-67 index. Thus, TP53 immunohistochemistry is a suitable test for routine diagnostic practice to assess MCL prognosis. (Blood. 2018;131(4):417-420) [ABSTRACT FROM AUTHOR]

CD38 is highly and uniformly expressed on multiple myeloma (MM) cells, and at relatively low levels on normal lymphoid and myeloid cells, and in some tissues of nonhematopoietic origin. CD38 is a transmembrane glycoprotein with ectoenzymatic activity, and also functions as a receptor and adhesion molecule. Altogether, this has triggered the development of several CD38 antibodies including daratumumab (fully human), isatuximab (chimeric), and MOR202 (fully human). CD38 antibodies have pleiotropic mechanisms of action including Fc-dependent immune-effector mechanisms, direct apoptotic activity, and immunomodulatory effects by the elimination of CD381 immune-suppressor cells. CD38-targeting antibodies are generally well tolerated and induce partial response or better in ~30% of heavily pretreated MM patients as monotherapy. Based on their distinct mechanisms of action, favorable toxicity profile, and single-agent activity, CD38 antibodies are attractive partners in combination regimens. Indeed, deep responses and prolonged progression-free survival can be achieved in relapsed/refractory MM patients when CD38 antibodies are combined with immunomodulatory agents or proteasome inhibitors. Infusion-related reactions, which typically occur during the first infusion, are the most frequent adverse events. Attention should also be paid to the interference of CD38 antibodies with certain laboratory assays, which may complicate response evaluation and blood compatibility testing. Several studies are currently examining the role of CD38-based therapies in newly diagnosed and highrisk smoldering MM. Furthermore, CD38 antibodies are currently also under investigation in other hematologic malignancies, including acute lymphoblastic leukemia, natural killer/T-cell lymphoma, and acute myeloid leukemia, as well as in solid tumors. [ABSTRACT FROM AUTHOR]

Certain cytogenetic abnormalities are known to adversely impact outcomes in patients with multiple myeloma (MM). The phase 3 TOURMALINE-MM1 study demonstrated a significant improvement in progression-free survival (PFS) with ixazomib-lenalidomide-dexamethasone (IRd) compared with placebo-lenalidomide-dexamethasone (placebo-Rd). This preplanned analysis assessed the efficacy and safety of IRd vs placebo-Rd according to cytogenetic risk, as assessed using fluorescence in situ hybridization. High-risk cytogenetic abnormalities were defined as del(17p), t(4;14), and/or t(14;16); additionally, patients were assessed for 1q21 amplification. Of 722 randomized patients, 552 had cytogenetic results; 137 (25%) had high-risk cytogenetic abnormalities and 172 (32%) had 1q21 amplification alone. PFS was improved with IRd vs placebo-Rd in both high-risk and standard-risk cytogenetics subgroups: in high-risk patients, the hazard ratio (HR) was 0.543 (95% confidence interval [CI], 0.321-0.918; P = .021), with median PFS of 21.4 vs 9.7 months; in standard-risk patients, HR was 0.640 (95%CI, 0.462- 0.888; P = .007), with median PFS of 20.6 vs 15.6 months. This PFS benefit was consistent across subgroups with individual high-risk cytogenetic abnormalities, including patients with del(17p) (HR, 0.596; 95% CI, 0.286-1.243). PFS was also longer with IRd vs placebo-Rd in patients with 1q21 amplification (HR, 0.781; 95% CI, 0.492-1.240), and in the "expanded high-risk" group, defined as those with high-risk cytogenetic abnormalities and/or 1q21 amplification (HR, 0.664; 95% CI, 0.474-0.928). IRd demonstrated substantial benefit compared with placebo-Rd in relapsed and/or refractory MM (RRMM) patients with high-risk and standard-risk cytogenetics, and improves the poor PFS associated with high-risk cytogenetic abnormalities. This trial was registered at www.clinicaltrials.gov as #NCT01564537. [ABSTRACT FROM AUTHOR]

Clonal chromosomal abnormalities in Philadelphia chromosome-negative metaphases (CCA/Ph-) emerge as patients with chronic phase chronic myeloid leukemia (CP-CML) are treated with tyrosine kinase inhibitors (TKI). We assessed the characteristics and prognostic impact of 598 patients with CP-CML treated on clinical trials with various TKIs. CCA/Ph- occurred in 58 patients (10%) and the most common were - Y in 25 (43%) and trisomy 8 in 7 patients (12%). Response to TKI therapy was similar for patients with CCA/Ph- and those without additional chromosomal abnormalities (ACAs). We further categorized CCA/Ph- into those where - Y was the only clonal abnormality, and all others. We found that patients with non -Y CCA/Ph- had worse failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS) and overall survival (OS) compared to those without ACAs with the following 5-year rates: FFS (52% vs 70%, P=0.02), EFS (68% vs 86%, P=0.02), TFS (76% vs 94%, P <0.01) and OS (79% vs 94%, P=0.03). In a multivariate analysis, non -Y CCA/Ph- increased the risk of transformation or death when baseline characteristics were considered with a hazard ratio (HR) of 2.81 (95% CI 1.15-6.89, P=0.02). However, this prognostic impact was not statistically significant when achieving BCR-ABL <10% at 3 months was included in the analysis. In conclusion, non -Y CCA/Ph- are associated with decreased survival when emerging in patients with chronic phase CML across various TKIs. [ABSTRACT FROM AUTHOR]

Daratumumab plus pomalidomide and dexamethasone (pom-dex) was evaluated in patients with relapsed/refractory multiple myeloma with ≥2 prior lines of therapy who were refractory to their last treatment. Patients received daratumumab 16 mg/kg at the recommended dosing schedule, pomalidomide 4 mg daily for 21 days of each 28-day cycle, and dexamethasone 40 mg weekly. Safety was the primary end point. Overall response rate (ORR) and minimal residual disease (MRD) by next-generation sequencing were secondary end points. Patients (N 5 103) received a median (range) of 4 (1-13) prior therapies; 76% received ≥3 prior therapies. The safety profile of daratumumab plus pomdex was similar to that of pom-dex alone, with the exception of daratumumab-specific infusion-related reactions (50%) and a higher incidence of neutropenia, although without an increase in infection rate. Common grade ≥3 adverse events were neutropenia (78%), anemia (28%), and leukopenia (24%). ORR was 60% and was generally consistent across subgroups (58% in double-refractory patients). Amongpatients with a complete response or better, 29% were MRD negative at a threshold of 1025. Among the 62 responders, median duration of response was not estimable (NE; 95% confidence interval [CI], 13.6-NE). At a median follow-up of 13.1 months, the median progression-free survival was 8.8 (95% CI, 4.6-15.4) months andmedian overall survivalwas17.5 (95% CI, 13.3-NE) months. The estimated 12-month survival ratewas 66% (95% CI, 55.6-74.8). Aside from increased neutropenia, the safety profile of daratumumab plus pom-dex was consistent with that of the individual therapies. Deep, durable responses were observed in heavily treated patients. The study was registered at www.clinicaltrials.gov as #NCT01998971. [ABSTRACT FROM AUTHOR]

The standard treatment of relapsed multiple myeloma has been either lenalidomide-dexamethasone (RD) or bortezomib-dexamethasone (VD) but it is changing rapidly for 2 reasons. First, lenalidomide and bortezomib are currently used in frontline treatment and many patients become resistant to these agents early in the course of their disease. Second, 6 second-line newagents have beenrecently developed and offer new possibilities (pomalidomide, carfilzomib and ixazomib, panobinostat, elotuzumab, and daratumumab). Recent randomized studies have shown that triple combinations adding 1 of these new agents (except pomalidomide) to the RD or VD regimens were superior to the double combinations in terms of response rate and progressionfree survival (PFS). Their place in the treatment of first relapse is discussed here. Among these agents, daratumumab is clearly a breakthrough and daratumumabbased combinations might become the preferred option in the near future. However, all of these drugs are expensive and are not available or affordable in all countries. We propose a decision algorithm for first relapse in fit patients with the objective of achieving the best PFS. The choice of salvage regimen is based on lenalidomide/bortezomib resistance, daratumumabavailability, andcost. Autologous transplantation should be considered in youngerpatientsif notusedupfront. [ABSTRACT FROM AUTHOR]

Patients with myeloid leukemia of Down syndrome (ML-DS) have favorable event-free survival (EFS), but experience significant treatment-related morbidity and mortality. ML-DS blast cells ex vivo have increased sensitivity to cytarabine (araC) and daunorubicin, suggesting that optimizing drug dosing may improve outcomes while reducing toxicity. The Children's Oncology Group (COG) AAML0431 trial consisted of 4 cycles of induction and 2 cycles of intensification therapy based on the treatment schema of the previous COG A2971 trial with several modifications. High-dose araC (HD-araC) was used in the second induction cycle instead of the intensification cycle, and 1 of 4 daunorubicin-containing induction cycles was eliminated. For 204 eligible patients, 5-year EFS was 89.9% and overall survival (OS) was 93.0%. The 5-year OS for 17 patients with refractory/relapsed leukemia was 34.3%. We determined the clinical significance of minimal residual disease (MRD) levels as measured by flow cytometry on day 28 of induction I. MRD measurements, available for 146 of the 204 patients, were highly predictive of treatment outcome; 5-year disease-free survival for MRD-negative patients (n = 125) was 92.7% vs 76.2% for MRD-positive patients (n = 21) (log-rank P = .011). Our results indicated that earlier use of HD-araC led to better EFS and OS in AAML0431 than in past COG studies. A 25% reduction in the cumulative daunorubicin dose did not impact outcome. MRD, identified as a new prognostic factor for ML-DS patients, can be used for risk stratification in future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT00369317. [ABSTRACT FROM AUTHOR]

High variability in patient outcome after rituximab-based treatment is partly explained by rituximab concentrations, and pharmacokinetic (PK) variability could be influenced by tumor burden. We aimed at quantifying the influence of baseline total metabolic tumor volume (TMTV0) on rituximab PK and of TMTV0 and rituximab exposure on outcome in patients with diffuse large B-cell lymphoma (DLBCL). TMTV0 was measured by 18F-fluorodeoxyglucosepositron emission tomography-computed tomography in 108 previously untreated DLBCL patients who received four 375mg/m² rituximab infusions every 2 weeks in combinationwith chemotherapy in 2 prospective trials. A 2-compartment populationmodel allowed describing rituximab PK and calculating rituximab exposure (area under the concentration-time curve; AUC). The association of TMTV0 and AUC with metabolic response after 4 cycles, as well as progression-free survival (PFS) and overall survival (OS), was assessed using logistic regression and Coxmodels, respectively. Cutoff values for patient outcomewere determined using receiver operating characteristic curve analysis. Exposure to rituximab decreased as TMTV0 increased (R² 5 0.41, P < .0001). A high AUC in cycle 1 (≥ 9400 mg x h per liter) was associated withbetter response (oddsratio, 5.56;P5.0006) and longerPFS(hazard ratio [HR], 0.38;P5.011) and OS(HR, 0.17; P = 5.001). A nomogram for rituximab dose needed to obtain optimal AUC according to TMTV0 was constructed, and the 375 mg/m² classical dose would be suitable for patients with TMTV0 <281 cm³. In summary, rituximab exposure is influenced by TMTV0 and correlates with response and outcome of DLBCL patients. Dose individualization according to TMTV0 should be evaluated in prospective studies. [ABSTRACT FROM AUTHOR]

Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by chromosomal fragility, progressive marrow failure, and cancer predisposition. Hematopoietic cell transplantation (HCT) is curative for FA-related marrow failure or leukemia, but both radiation exposure during transplant and graft-versus-host disease (GVHD) may increase risk of later malignancies of the head and neck and anogenital area. In this study, we tested a radiation-free conditioning regimen with a T-cell--depleted graft to eliminate radiation exposure and minimize early and late toxicities of transplant. Forty-five patients (median age, 8.2 years; range 4.3-44) with FA underwent HCT between June 2009 and May 2014. The preparative regimen included busulfan, cyclophosphamide, fludarabine, and rabbit anti-thymocyte globulin. Busulfan levels were monitored to avoid excess toxicity. All grafts were CD34-selected/T-cell--depleted using the CliniMacs CD34 columns (Miltenyi). Thirty-four patients (75.6%) with marrow failure and 11 (24.4%) with myelodysplastic syndrome underwent HCT using matched unrelated (n = 25, 55.5%), mismatched unrelated (n = 14, 31.1%), or mismatched related donors (n = 6, 13.4%). One year probabilities of overall and disease-free survival for the entire cohort, including patients with myeloid malignancy and those receiving mismatched related/haploidentical grafts, were 80% (±6%) and 77.7% (±6.2%), respectively (median follow-up 41 months). All young children (<10 years of age) undergoing HCT for marrow failure using low-dose busulfan-containing regimen survived. No patients developed acute grade 3-4 GVHD. Sequential reduction of busulfan dose was successfully achieved per study design. Our results show excellent outcomes in patients with FA undergoing alternative donor HCT without radiation exposure. The study is registered to www.clinicaltrials.gov as #NCT01082133. [ABSTRACT FROM AUTHOR]

Up to 50% of patients with Hodgkin lymphoma and diffuse large B-cell lymphoma will relapse, requiring additional therapy. Although surveillance imaging is commonly performed in clinical practice, its ability to identify asymptomatic relapses and improve survival for patients is not well defined. We evaluated the surveillance imaging role in relapse detection and reviewed its impact on survival for relapsed patients, and found that current imaging approaches do not detect most relapses prior to clinical signs and symptoms or improve survival. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) is clinically heterogeneous, with select patients tolerating extended watch-and-wait, whereas others require prompt treatment, suffer progression of disease within 24 months of treatment (POD24), and/or experience aggressive histologic transformation (t-FL). Because our understanding of the relationship between genetic alterations in FL and patient outcomes remains limited, we conducted a clinicogenomic analysis of 370 patients with FL or t-FL (from Cancer and Leukemia Group B/Alliance trials 50402/50701/50803, or real-world cohorts from Washington University School of Medicine, Cleveland Clinic, or University of Miami). FL subsets by grade, stage, watch-and-wait, or POD24 status did not differ by mutation burden, whereas mutation burden was significantly higher in relapsed/refractory (rel/ref) FL and t-FL than in newly diagnosed (dx) FL. Nonetheless, mutation burden in dx FL was not associated with frontline progression-free survival (PFS). CREBBP was the only gene more commonly mutated in FL than in t-FL yet mutated CREBBP was associated with shorter frontline PFS in FL. Mutations in 20 genes were more common in rel/ref FL or t-FL than in dx FL, including 6 significantly mutated genes (SMGs): STAT6, TP53, IGLL5, B2M, SOCS1, and MYD88. We defined a mutations associated with progression (MAP) signature as ≥2 mutations in these 7 genes (6 rel/ref FL or t-FL SMGs plus CREBBP). Patients with dx FL possessing a MAP signature had shorter frontline PFS, revealing a 7-gene set offering insight into FL progression risk potentially more generalizable than the m7-Follicular Lymphoma International Prognostic Index (m7-FLIPI), which had modest prognostic value in our cohort. Future studies are warranted to validate the poor prognosis associated with a MAP signature in dx FL, potentially facilitating novel trials specifically in this high-risk subset of patients., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

CD19 chimeric antigen receptor (CAR) T-cell therapy represents a breakthrough for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), inducing sustained remissions in these patients. However, CAR T cells can result in significant toxicities. Preinfusion disease burden is associated with toxicities and outcomes after CAR T-cell therapy. We identified 33 patients with R/R DLBCL treated at 8 academic centers who had no detectable disease at the time of CAR T-cell therapy. The median time from leukapheresis to CAR T-cell infusion was 48 (19-193) days. Nine patients received axicabtagene ciloleucel, and 24 received tisagenlecleucel. There was no severe (grade ≥3) cytokine release syndrome, and only 1 patient developed severe neurotoxicity (grade 4). After a median follow-up of 16 months, 13 patients relapsed (39.4%) and 6 died (18.1%). One-year event-free survival and overall survival were 59.6% and 81.3%, respectively. Our findings suggest that, in patients with R/R DLBCL who have an indication for CAR T-cell therapy, treating patients in complete remission at the time of infusion is feasible, safe, and associated with favorable disease control. Further exploration in a larger clinical trial setting is warranted., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Lenalidomide is an effective component of induction and maintenance therapy for multiple myeloma, though with a risk of secondary malignancies, including acute lymphoblastic leukemia (ALL). In contrast to therapy-related myeloid neoplasia, lenalidomide-associated lymphoblastic neoplasia remains poorly characterized. We conducted a dual institution retrospective study of 32 ALL cases that arose after lenalidomide maintenance (all B-lineage, 31/32 BCR::ABL-negative). B-cell ALL (B-ALL) was diagnosed at median 54 months (range, 5-119) after first exposure to lenalidomide and after median 42 months of cumulative lenalidomide exposure (range, 2-114). High incidence of TP53 mutations (9/19 evaluable cases) and low hypodiploidy (8/26 patients) were identified. Despite median age of 65 years and poor-risk B-ALL features observed in the cohort, rates of complete response (CR) or CR with incomplete hematologic recovery were high (25/28 patients receiving treatment). Median event-free survival was 35.4 months among treated patients (not reached among those undergoing allogeneic hematopoietic cell transplantation [HCT]). Sixteen patients remain alive without evidence of B-ALL after HCT or extended maintenance therapy. We also describe regression of B-ALL or immature B-cell populations with B-ALL immunophenotype after lenalidomide discontinuation in 5 patients, suggesting lenalidomide may drive leukemic progression even after initiation of lymphoblastic neoplasia and that lenalidomide withdrawal alone may be an appropriate first-line intervention in selected patients. Monitoring for early B-ALL-like proliferations may offer opportunities for lenalidomide withdrawal to prevent progression. Established combination chemotherapy regimens, newer surface antigen-targeted approaches, and allogeneic HCT are effective in many patients with lenalidomide-associated B-ALL and should be offered to medically fit patients., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Most patients receiving chimeric antigen receptor T-cell therapy (CAR-T) for aggressive B-cell non-Hodgkin lymphoma (B-NHL) do not experience a durable remission. Several novel agents are approved to treat relapsed, refractory aggressive B-NHL; however, it remains unclear how to sequence these therapies pre- and post-CAR-T. We conducted a multicenter retrospective analysis to describe peri-CAR-T practice patterns and survival predictors for patients receiving CD19-directed CAR-T. Patients (n = 514) from 13 centers treated with CAR-T for B-NHL between 2015-2021 were included in the study. Survival curves were constructed using Kaplan-Meier method. Multivariate Cox regression analysis was used to determine the impact of the variables on survival outcomes. For all patients receiving CAR-T, a greater number of lines of therapy pre-CAR-T apheresis and bridging therapy were predictive of inferior progression-free survival (PFS) and overall survival (OS). The median PFS and OS from the time of CAR-T cell infusion were 7.6 and 25.6 months, respectively. From the time of progression post-CAR-T, the median OS was 5.5 months. The median PFS of treatments administered in the first-line post-CAR-T failure was 2.8 months. Patients with refractory disease on day 30 had inferior OS and were less likely to receive subsequent treatment(s) than other patients with CAR-T failure. Allogeneic hematopoietic cell transplantation for selected patients at any time following CAR-T failure led to durable responses in over half of patients at 1 year. These data provide a benchmark for future clinical trials in patients with post-CAR-T cell progression, which remains an unmet clinical need., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Minimal residual disease (MRD) negativity, defined as <1 chronic lymphocytic leukemia (CLL) cell detectable per 10 000 leukocytes, has been shown to independently predict for clinical outcome in patients receiving combination chemoimmunotherapy in the frontline setting. However, the long-term prognostic value of MRD status in other therapeutic settings remains unclear. Here,weretrospectively analyzed, withupto 18 years follow-up, all patients at our institution who achieved at least a partial response (PR) with various therapies between 1996 and 2007, and received a bone marrow MRD assessment at the end of treatment according to the international harmonized approach. MRD negativity correlated with both progression-free survival (PFS) and overall survival (OS) independent of the type and line of treatment, as well as known prognostic factors including adverse cytogenetics. The greatest impact of achieving MRD negativity was seen in patients receiving frontline treatment, with 10-year PFS of 65% vs 10% and 10-year OS of 70% vs 30% for MRD-negative vs MRD-positive patients, respectively. Our results demonstrate the long-term benefit of achieving MRD negativity, regardless of the therapeutic setting and treatment modality, and support its use as a prognostic marker for long-term PFS and as a potential therapeutic goal in CLL. [ABSTRACT FROM AUTHOR]

Children with sickle cell disease experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplant from an HLA-matched sibling can halt disease progression but is limited by donor availability. A Blood and Marrow Transplant Clinical Trials Network (BMT CTN) phase 2 trial conducted from 2008 to 2014 enrolled 30 children aged 4 to 19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C, and -DRB1 loci) unrelated donor transplant. The conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, short-course methotrexate, and methylprednisolone. Transplant indications included stroke (n = 12), transcranial Doppler velocity >200 cm/s (n = 2), ≥3 vaso-occlusive pain crises per year (n = 12), or ≥2 acute chest syndrome episodes (n = 4) in the 2 years preceding enrollment. Median follow-up was 26 months (range, 12-62 months); graft rejection was 10%. The 1- and 2-year EFS rates were 76% and 69%, respectively. The corresponding rates for overall survival were 86% and 79%. The day 100 incidence rate of grade II-IV acute GVHD was 28%, and the 1-year incidence rate of chronic GVHD was 62%; 38% classified as extensive. There were 7 GVHD-related deaths. A 34% incidence of posterior reversible encephalopathy syndrome was noted in the first 6 months. Although the 1-year EFS met the prespecified target of ≥75%, this regimen cannot be considered sufficiently safe for widespread adoption without modifications to achieve more effective GVHD prophylaxis. [ABSTRACT FROM AUTHOR]

The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is frequently activated inappropriately in a wide range of hematological and solid cancers, but clinically available therapies targeting STAT3 are lacking. Using a computational strategy to identify compounds opposing the gene expression signature of STAT3, we discovered atovaquone (Mepron), an antimicrobial approved by the US Food and Drug Administration, to be a potent STAT3 inhibitor. We show that, at drug concentrations routinely achieved clinically in human plasma, atovaquone inhibits STAT3 phosphorylation, the expression of STAT3 target genes, and the viability of STAT3-dependent hematological cancer cells. These effects were also observed with atovaquone treatment of primary blasts isolated from patients with acute myelogenous leukemia or acute lymphocytic leukemia. Atovaquone is not a kinase inhibitor but instead rapidly and specifically downregulates cell-surface expression of glycoprotein 130, which is required for STAT3 activation in multiple contexts. The administration of oral atovaquone to mice inhibited tumor growth and prolonged survival in a murine model of multiple myeloma. Finally, in patients with acute myelogenous leukemia treated with hematopoietic stem cell transplantation, extended use of atovaquone for Pneumocystis prophylaxis was associated with improved relapse-free survival. These findings establish atovaquone as a novel, clinically accessible STAT3 inhibitor with evidence of anticancer efficacy in both animal models and humans. [ABSTRACT FROM AUTHOR]

For elderly patients with mantle cell lymphoma (MCL), there is no defined standard therapy. In this multicenter, open-label phase 1/2 trial, we evaluated the addition of lenalidomide (LEN) to rituximab-bendamustine (R-B) as first-line treatment for elderly patients with MCL. Patients >65 years with untreated MCL, stages II-IV were eligible for inclusion. Primary end points were maximally tolerable dose (MTD) of LEN and progression-free survival (PFS). Patients received 6 cycles every four weeks of L-B-R (L D1-14, B 90 mg/m2 IV, days 1-2 and R 375 mg/m2 IV, day 1) followed by single LEN (days 1-21, every four weeks, cycles 7-13). Fifty-one patients (median age 71 years) were enrolled from 2009 to 2013. In phase 1, the MTD of LEN was defined as 10 mg in cycles 2 through 6, and omitted in cycle 1. After 6 cycles, the complete remission rate (CRR) was 64%, and 36% were MRD negative. At a median follow-up time of 31 months, median PFS was 42 months and 3-year overall survival was 73%. Infection was the most common nonhematologic grade 3 to 5 event and occurred in 21 (42%) patients. Opportunistic infections occurred in 3 patients: 2 Pneumocystis carinii pneumonia and 1 cytomegalovirus retinitis. Second primary malignancies (SPM) were observed in 8 patients (16%). LEN could safely be combined with R-B when added from the second cycle in patients with MCL, and was associated with a high rate of CR and molecular remission. However, we observed a high degree of severe infections and an unexpected high number of SPMs, which may limit its use. [ABSTRACT FROM AUTHOR]

This multicenter pilot study assessed the safety and efficacy of brentuximab vedotin (BV) and AVD (adriamycin, vinblastine, and dacarbazine) followed by 30 Gy involved site radiation therapy (ISRT). Patients with newly diagnosed, early stage classical Hodgkin lymphoma (HL) with unfavorable-risk features were treated with 4 cycles of BV and AVD. Patients who achieved a negative positron emission tomography (PET) scan (Deauville score of 1-3) received 30 Gy ISRT. Thirty patients received treatment and were assessable for toxicity. Twenty-nine patients completed 4 cycles of BV 1 AVD, and 25 patients BV 1 AVD 1 30 Gy ISRT. No clinically significant noninfectious pneumonitis was observed. Serious adverseevents(≥grade 3)werereportedin4patients, includingfebrileneutropenia, peripheral neuropathy, and hypertension. After 2 and 4 cycles of BV 1 AVD, 90% (26 of 29) and 93% (27 or 29) of patients achieved a negative PET scan, respectively. Twopatientswith biopsy-proven primary refractory HL were treated off-study. All 25 patients who completed BV 1 AVD 1 ISRT achieved a complete response. With a median follow-up of 18.8 months, by intent to treat, the 1-year progression-free survival is 93.3% (95% confidence interval, 84-102). Overall, the treatment was well-tolerated with no evidence of significant pulmonary toxicity. The majority of patients (≥90%) achieved negative interim PET scans after 2 and 4 cycles of BV1AVD. Excludingthe 2 primary refractory patients, all patients are disease free, suggesting that this is a highly active treatment program even in patients with substantial disease bulk. [ABSTRACT FROM AUTHOR]

The efficacy and favorable safety profile of daratumumab monotherapy in multiple myeloma (MM) was previously reported. An updated pooled analysis of 148 patients treated with daratumumab 16 mg/kg is presented. Data were combined from part 2 of a "first-in-human," phase 1/2 study of patients who relapsed after or were refractory to ⩾2 prior therapies and a phase 2 study of patients previously treated with ⩾3 prior lines of therapy (including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double refractory. Among the pooled population, patients received a median (range) of 5 (2-14) prior lines of therapy, and 86.5% were double refractory to a PI and IMID. Overall response rate was 31.1%, including 13 very good partial responses, 4 complete responses, and 3 stringent complete responses. The median duration of response was 7.6 months (95% confidence interval [CI], 5.6-not evaluable [NE]). The median progression-free survival (PFS) and overall survival (OS) was 4.0 months (95% CI, 2.8-5.6) and 20.1 months (95% CI, 16.6-NE), respectively. When stratified by responders versus stable disease/minimal response versus progressive disease/NE, median PFS was 15.0 months (95% CI, 7.4-NE) versus 3.0 months (95% CI, 2.8-3.7) versus 0.9 months (95% CI, 0.9-1.0), respectively, and median OS was NE (95% CI, NE-NE) versus 18.5 months (95% CI, 15.1-22.4) versus 3.7 months (95% CI, 1.7-7.6), respectively. No new safety signals were identified. In this pooled dataset, daratumumab 16 mg/kg monotherapy demonstrated rapid, deep, and durable responses, with a clinical benefit that extended to patients with stable disease or better. [ABSTRACT FROM AUTHOR]

Carfilzomib, a proteasome inhibitor, is approved in the United States as a single agent, and in combination with dexamethasone or lenalidomide/dexamethasone (KRd) for relapsed or refractory multiple myeloma (MM). Under the single-agent and KRd approvals, carfilzomib is administered as a 10-minute IV infusion on days 1, 2, 8, 9, 15, and 16 of 28- day cycles (20mg/m2 [cycle 1, days 1-2]; 27mg/m2 thereafter).Thismulticenter, single-arm, phase 1/2 study, Community Harmonized Assessment of Myeloma Patients via an Integrated Oncology Network-1 (CHAMPION-1), evaluated once-weekly carfilzomib with dexamethasone in relapsed, or relapsed and refractory MM (1-3 prior therapies). Patients received carfilzomib (30-minute IVinfusion) on days 1, 8, and15 of 28-day cycles. Thephase 1 portion used a 3 1 3 dose-escalation scheme to determine the maximum tolerated dose (MTD) of carfilzomib. During phase 2, patients received carfilzomib on the same schedule at theMTD. Patients received dexamethasone (40mg) on days 1, 8, 15, and 22; dexamethasone was omitted on day 22 for cycles 91. A total of 116 patients were enrolled. The MTD was 70 mg/m2, and 104 patients (phase 1/2) received carfilzomib 70 mg/m2. At 70 mg/m2, the median number of prior regimens was 1; and 52% were bortezomib-refractory. At 70 mg/m2, the most common grade ≥3 adverse events were fatigue (11%) and hypertension (7%). Overall response rate at 70 mg/m2 was 77%. Median progression-free survival was 12.6 months. These findings merit additional evaluation of the once-weekly dosing regimen. This trial was registered at www.clinicaltrials. gov as #NCT01677858. [ABSTRACT FROM AUTHOR]

Induction therapy for childhood acute lymphoblastic leukemia (ALL) traditionally includes prednisone; yet, dexamethasone may have higher antileukemic potency, leading to fewer relapses and improved survival. After a 7-day prednisone prephase, 3720 patients enrolled on trial Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Münster (AIEOP-BFM) ALL 2000 were randomly selected to receive either dexamethasone (10 mg/m2 per day) or prednisone (60 mg/m2 per day) for 3 weeks plus tapering in induction. The 5-year cumulative incidence of relapse (± standard error) was 10.8 ± 0.7% in the dexamethasone and 15.6 ± 0.8% in the prednisone group (P < .0001), showing the largest effect on extramedullary relapses. The benefit of dexamethasone was partially counterbalanced by a significantly higher induction-related death rate (2.5% vs 0.9%, P = .00013), resulting in 5-year event-free survival rates of 83.9 ± 0.9% for dexamethasone and 80.8 ± 0.9% for prednisone (P = .024). No difference was seen in 5-year overall survival (OS) in the total cohort (dexamethasone, 90.3 ± 0.7%; prednisone, 90.5 ± 0.7%). Retrospective analyses of predefined subgroups revealed a significant survival benefit from dexamethasone only for patients with T-cell ALL and good response to the prednisone prephase (prednisone good-response [PGR]) (dexamethasone, 91.4 ± 2.4%; prednisone, 82.6 ± 3.2%; P = .036). In patients with precursor B-cell ALL and PGR, survival after relapse was found to be significantly worse if patients were previously assigned to the dexamethasone arm. We conclude that, for patients with PGR in the large subgroup of precursor B-cell ALL, dexamethasone especially reduced the incidence of better salvageable relapses, resulting in inferior survival after relapse. This explains the lack of benefit from dexamethasone in overall survival that we observed in the total cohort except in the subset of T-cell ALL patients with PGR. This trial was registered at www.clinicaltrials.gov (BFM: NCT00430118, AIEOP: NCT00613457). [ABSTRACT FROM AUTHOR]