Wiernik, Peter H.

Abstract Background: Population registries and the Alliance co-operative group database have highlighted racial disparities in AML survival attributed to differential prevalence and impact of oncogenic drivers on disease biology. However, the small number of Black patients with well-annotated genomic profiles limits the validity of these findings. The current study leverages ECOG-ACRIN cytogenetic and outcomes data from newly diagnosed adult AML patients treated on intensive chemotherapy-based clinical trials over three decades. Methods: Self-reported race was categorized as White, Black or Other. Descriptive statistics were used to summarize baseline characteristics using the Wilcoxon rank-sum and Fisher's exact tests. Multivariable Cox proportional hazards regression models evaluated the association between race and survival outcomes adjusting for age, hemoglobin, platelet count, white blood cell count, blast percentage, performance status and ELN cytogenetic risk score (RS). All Cox models were stratified by protocol. Subgroup analyses of overall survival (OS) and disease-free survival (DFS) were performed using Kaplan-Meier curves stratified by race using log-rank tests. All statistical tests were two-sided. Analyses included only patients with complete data for the variables of interest. Results: Data was collected across 10 phase II and III interventional trials for newly diagnosed adult AML that accrued patients between 1984 and 2019. The study population included 3469 White, 184 Black, and 156 Other patients with a Black representation of 1.1-11% across trials. Blacks were significantly younger at diagnosis with a median age of 47.9 years compared to 53.5 years in Whites (p<0.001). Racial groups were well matched for gender and performance status. Black race was an independent prognostic factor for inferior OS (HR 1.212, CI 1.01 – 1.453; p = 0.0383) and DFS (HR 1.313, CI 1.05-1.641; p = 0.017). Complete cytogenetic results were available for 117 Black and 2162 White patients and revealed no significant racial differences in the distribution of ELN 2017 cytogenetic RS, although core binding factor AML was non-significantly enriched in Black patients (12.8% vs 8.3%). No difference was observed between Blacks and Whites in the prevalence of complex karyotype (CK), CK with -5/del(5q), -7/del(7q), or -17/del(17p), and AML-MRC including +8 and del(20q). Notably, the ELN 2017 cytogenetic RS effectively predicted OS in Black (57.8 vs 14.2 vs 5.8 months in favorable, intermediate and adverse RS, p = 0.018), and White patients (60.1 vs 15.2 vs 7.1 months, p < 0.0004 for Whites) but only predicted DFS for White AML patients (p < 0.0001 for Whites, p=0.48 for Blacks). In patients with molecular data for FLT3-ITD (n=1218), CEBPA (n=576), TP53 (n=572), or NPM1(n=683), no racial difference in the prevalence of these mutations was observed. However, NPM1 mutations were associated with inferior OS in Blacks compared to Whites (19.1 vs 8.9 months; p = 0.0095). Black and White AML patients had similar responses with complete remission rates of 58.2% vs 57.5%, p=0.55, and treatment tolerability with 30-day mortality of 7.1% vs 8.9%, p=0.50. However, consolidation approaches differed significantly. Among patients that underwent stem cell transplant (SCT), a significantly higher percentage of White patients received allogenic SCT compared to Blacks (48.5% versus 37.1%, p <0.01). Conclusions: This study represents one of the largest race-based comparisons of cytogenetic abnormalities and clinical outcomes in prospective trials of intensive chemotherapy in AML . Our data confirms the independent prognostic relevance of race in AML survival and validates the predictive ability of the ELN 2017 cytogenetic RS for OS across racial groups. There is ancestry-based attenuation of the survival benefit of NPM1 mutations as previously reported, underscoring the need to tailor the current treatment approach to NPM1 mutated AML based on race. The availability of NGS data limited the genomic analysis to a subset of patients. Future studies should examine the depth of treatment response incorporating MRD biomarkers and explore the effect of race on co-occurring mutations and the leukemic stem cell transcriptome to better explain the observed disparities. Finally, persistent disparities in access to allo-SCT even within the context of clinical trials reinforces the need to address diversity in the stem cell donor pool and social barriers to transplant.

Abstract Introduction Several studies reported that AML patients who remain in long-term remission after allogeneic transplant (allo-HCT) or autologous transplant (auto-HCT) have a shorter life expectancy, compared to the general population. However, little is known about the life expectancy of adult long-term survivors of AML who were treated with chemotherapy without HCT and, there have been no comparisons with survival among the general population. The current study reports on the life expectancy of AML patients who survived 3 years in complete remission (CR) after treatment without HCT, and compared this to the gender- and age-matched normal population. At 3 years in CR, the incidence of recurrence is exceedingly low (3%; Watts JM, Leuk Res 2014) minimizing the impact of relapse on the long-term survival. Methods Between 1984 and 2008, 3,012 patients, aged 15 years and older, with untreated AML entered 9 consecutive, phase II and III, ECOG-ACRIN trials (E3483, PC486, E3489, E1490, E3993, E4995, E3997, E3999, E1900). Patients in CR and relapse-free at 3 years are included in the analysis . Minimal cytogenetic information was available in the early protocols (E1490, E3483, PC486). A Kaplan-Meier plot was generated for the three groups, allo, auto and no HCT, censoring for patients alive at last contact. Univariate and multivariate cox proportional hazard regression models were generated, considering death as an event. For comparison of long-term outcomes, patients were grouped together by age and matched to a normative population mortality rate. Subjects were also grouped by gender and treatment allowing for separate analysis of these groups with the no HCT group as the main group of interest. The normative population comparator of expected deaths was derived using mortality rates from United State CDC life table data. The median year was derived by calculating the person-years for each calendar year that patients were followed. To calculate the expected deaths for each age group, person-years was calculated by tabulating the years lived in each age group for all subjects. Each year of follow-up for AML patient was counted as one person year, and the tabulated bin corresponded with their age at the time. Person-years was then multiplied by the matching mortality rate. Chi-square statistics were derived using expected and observed deaths and then summed for each gender and treatment. The final comparison was of mortality rates since diagnosis in the 3-year alive and relapse-free AML patient population vs the normative population. To produce plots of mortality from diagnosis, person-years was tabulated for every year since diagnosis by treatment. The person-years were tabulated into 2-year bins. The US life tables from the CDC were used to generate a population mortality rate from diagnosis. Results A total of 503 adult AML patients in 3 year CR with a mean age of 42.9 years (15-79) were identified; 78 underwent allo, 110 auto and 315 did not undergo transplantation. The patients in the groups differed in age (p<.001) and cytogenetics (p=.01). The multivariate model showed equivalent hazards of death to the 3 groups. Observed deaths and person-years were given by age group, gender, and treatment group and each were matched to a mortality rate from the United State CDC life table data that matched the median year of each treatment group. A chi square test for each group compared the derived expected to observed deaths. In every treatment group, patients had a shorter survival compared to their age- and gender- matched general population (p-value of 0.004 for the auto-HCT and <0.001 for both allo-HSCT and no transplant groups). Table 1, selected only for the no HCT group, demonstrates the mortality rates by age and gender. Figure 1 indicates that AML patients who have survived relapse-free for at least 3 years continue to have higher mortality rates compared to the normative population for up to 14 years. This finding is not altered even if the very small number of patients who die from late relapse (>3 years from diagnosis) are removed from the analysis (data not shown) Conclusions Patients with AML who remain in CR at 3 years, do not have a normal life expectancy, even if they do not undergo HCT. The shorter life expectancy observed following an HCT may, at least in part, be related to the prior intensive therapy or other predisposing factors (e.g. CHIP) of the leukemia, rather than the transplant procedure itself. Figure 1 Figure 1. Disclosures Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Lazarus: Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees. Douer: Amgen: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Adaptive: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Speakers Bureau; Jazz: Consultancy. Tallman: Syros: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; NYU Grand Rounds: Honoraria; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. Litzow: Pluristem: Research Funding; Biosight: Other: Data monitoring committee; AbbVie: Research Funding; Actinium: Research Funding; Astellas: Research Funding; Omeros: Other: Advisory Board; Jazz: Other: Advisory Board; Amgen: Research Funding.

Abstract Central nervous system (CNS) involvement in patients with newly diagnosed acute myeloid leukemia (AML) is rare, and systematic data regarding outcome are scarce. This retrospective study summarized data from 11 consecutive Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) clinical trials for patients with newly diagnosed AML. In all, 3240 patients with AML were analyzed, and 36 (1.11%) were found to have CNS involvement at diagnosis. The incidence of CNS disease among the 5 studies with per protocol mandatory lumbar puncture (LP) was similar to the incidence among studies in which LP was performed at the discretion of the investigator (0.86% vs 1.41%; P = .18). There was no significant difference in the rate of complete remission (CR) among patients with CNS involvement and those with other extramedullary disease (EMD) sites or those with no EMD (52.8% vs 59.3%-60%). The median overall survival (OS) for patients who were CNS positive, who had other EMD, or who had no EMD was 11.4, 11.3, and 12.7 months, respectively. There was no difference in OS among patients with CNS involvement, those with other EMD (hazard ratio [HR], 0.96; adjusted P = .84), and those with no EMD (HR, 1.19; adjusted P = .44). In conclusion, the reported incidence of CNS involvement in patients with newly diagnosed AML is low (1.1%), irrespective of whether an LP is mandatory or not. The presence of CNS disease at diagnosis in and of itself does not seem to portend a poor prognosis for achieving an initial CR or for OS.

SummaryThere are conflicting reports in the literature suggesting that one gender or the other has a better survival with acute myeloid leukaemia (AML). The present study was done in an attempt to resolve the issue. The effect of gender was examined on 3546 newly diagnosed patients with AML, including 548 patients with acute promyelocytic leukaemia (APL) enrolled in 10 multi‐institutional treatment studies from March 1984 to November 2008. Kaplan–Meier estimates were used to estimate event‐time distributions for survival and multivariate models were used to examine the gender effect after adjusting for multiple risk factors. P values were based on two‐sided tests. Non‐APL female patients had a significantly better overall (OS) but not disease‐free survival (DFS) than males, irrespective of age, initial white blood cell count, or dose of daunorubicin. No differences were observed for obese or FMS‐like tyrosine kinase 3‐internal tandem duplication (FLT3‐ITD)‐positive patients. Female patients with APL had a significantly better OS and DFS than male patients with APL, and differences in survival were greater for patients with t(15;17) + other cytogenetic abnormalities compared with those with t(15;17) only. Gender is an independent prognostic variable in patients with AML. Whether these survival differences are due to hormonal, genetic or pharmacokinetic differences between the sexes or differential toxin exposure such as smoking is unknown. However, the former seems less likely as patient age did not influence the survival advantage for female patients.

Abstract Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1− B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome data, 29.5% with favorable outcomes (5-year OS 65% to 80%) were deemed standard risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5-year OS of 0% to 27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); 20.3% had intermediate-risk genotypes with 5-year OS of 33% to 45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like, and TP53 mutations in patients who were low-hypodiploid (54%) and BCL2/MYC-rearranged (33%) but were not independently associated with outcome. Of patients considered high risk based on presenting age and white blood cell count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non–risk-adapted approach on a single trial show the prognostic importance of genomic analyses, which may translate into future therapeutic benefits.

Abstract On intergroup phase III trial, MRC UKALLXII/ECOG2993, 25% of 613 ECOG patients were positive for Ph or its molecular equivalent, BCR/ABL; all were B-lineage ALLs (B-ALL). When compared to Ph(−) B-ALL, Ph(+) ALL had more blasts expressing CD25 (α-chain of interleukin-2 [IL-2] receptor) (p=3E-31), CD34 (p=4E-10), CD13 (p=3.9E-16) and CD33 (p=3.5E-09), and blasts with higher density of CD10 (p=9.6E-12). There was no difference in antigen expression profiles between pts with e1a2 (N=107) and b2a2/b3a2 (N=48) BCR/ABL transcripts. Complete remission (CR) rate was lower (p= 7.4E-6) and overall survival (OS) was shorter in Ph(+) compared with Ph(−) B-ALL (p=6.5E-5). There was no difference in outcome between e1a2 and b2a2/b3a2 pts (p=0.65). CD25 was the most powerful prognostic indicator in Ph(+) cases, both for CR (p=0.004) and OS (p=1.3E-05). Strikingly, CD25 negatively affected OS in a continuous fashion; 1% increase in CD25 was related to a 1% increase in the hazard of death. On the other hand, CD25 expression was not associated with OS in Ph(−) pts (p=0.66). Among 152 Ph(+) pts, 30 lacked CD25 expression, 24 with e1a2 and 6 with b2a2/b3a2 transcripts. When analyzed separately, CD25(−)Ph(+) pts had outcome indistinguishable from that of Ph(−) pts (p=0.89). Compared to CD25(+)Ph(+) pts, CD25(−) Ph(+) pts had lower WBC counts at presentation (p=4.1E-05). Both CD25(+) and CD25(−) Ph(+) blasts expressed the γ-chain but not the β-chain of the IL-2 receptor, arguing against the presence of a functional IL-2 receptor. There was no association between CD25 expression or outcome and the presence of additional cytogenetic abnormalities seen in 52% of Ph(+) pts. To further examine the prognostic impact of CD25, BCR/ABL levels were quantitated by real-time PCR in 136 Ph(+) pts at presentation. There was no correlation between presenting BCR/ABL levels and blast count (p=0.98), achievement of CR (p=0.73), or OS (p=0.67). However, higher blast counts at diagnosis were associated with shorter survival (p=0.003). BCR/ABL levels were measured in 43 pts 1 month after induction therapy. Changes in BCR/ABL after therapy were classified as undetectable, >90% reduction, >50% reduction, or no change. While CR status did not correlate with BCR/ABL reduction (p=0.97), the chance of survival ranked in the order of undetectable (p=0.01), >90% reduction (p=0.05), >50% reduction (p=0.37), or no change (p=0.87). CD25 expression at presentation correlated with that order (p=0.002). CD25(−)Ph(+) pts fell into the group with undetectable BCR/ABL levels after treatment, whereas pts with highest initial CD25 expression fell into the group with no change. In conclusion, CD25(−)Ph(+) blasts are more sensitive to non-TKI therapy than CD25(+) Ph(+) blasts. Outcome in Ph(+) ALL is thus determined by CD25 expression rather than the presence of Ph per se. RESPONSE CD25(+)Ph(+) CD25(−)Ph(+) Ph(−) B-Lin ALL n 122 30 308 % CR Rate 57% 71% 81% MedianOS (months) 12.2 30.2 27.7

Abstract Over the past decade several prospective studies of post-remission therapy in AML have compared allogeneic hematopoietic stem cell transplantation (HSCT), autologous HSCT and chemotherapy. The data are appropriately presented by intention-to-treat analyses. However, such analyses do not provide information to the clinician or patient as to outcome from the initiation of post-remission therapy, be it HSCT or chemotherapy. Furthermore, such analyses are impossible to interpret when a significant percentage of patients do not receive their intended therapies (for example, only 54% of patients randomized to autologous HSCT; Cassileth, NEJM, 1998). Finally, such studies present survival data that may not be relevant to current practice where the mortality from autologous HSCT has decreased sharply (for example, 14% non-relapse mortality from autologous HSCT; Cassileth, NEJM, 1998). In the current analysis, results from 4 consecutive ECOG studies that included autologous HSCT were analyzed and the data collated. In PC486 patients received standard induction followed by allogeneic HSCT if they had a compatible sibling; otherwise they were to undergo an autologous HSCT without any prior consolidation (Cassileth, JCO, 1993). E4995 studied standard induction with added high-dose cytarabine (HiDAC) intensification on D 8–10, followed by 2 courses of HiDAC consolidation. All patients were to undergo an autologous HSCT after induction and consolidation (Cassileth, Leuk Lymph, 2005). E3489 was a US Intergroup study in which patients received standard induction (3 + 7). If in CR, all patients received an attenuated course of induction (2 + 5). Patients who had a histocompatible sibling were assigned to allogeneic HSCT; those without a donor were randomized to an autologous HSCT or chemotherapy (Cassileth, NEJM, 1998). E1900 is an ongoing phase III study in which patients receive standard induction followed by allogeneic HSCT or two courses of HiDAC followed by autologous HSCT. The latter study is ongoing; therefore, only data describing transplant-related mortality (TRM) are presented. The relapse rate from start of each post-remission regimen in these studies, based on therapy actually received and not on intention-to-treat analysis, is presented in table 1 and the TRM is presented in table 2. Table 1. Relapse Rate from Start of Post-Remission Therapy Cytogenetics Allogeneic HSCT (n=85) Autologous HSCT (n=113) Chemotherapy (n=109) Favorable 11.8% (2/17) 10.5% (2/19) 60% (12/20) Intermediate 20.5% (8/39) 32.3% (10/31) 53.7% (22/41) Unfavorable 16.7% (2/12) 41.7% (5/12) 83.3% (15/18) Unknown 23.5% (4/17) 33.3% (17/51) 56.7% (17/30) Table 2. Treatment-Related Mortality after Post-Remission Therapy Allogeneic HSCT Autologous HSCT – Marrow Autologous HSCT – Blood Chemotherapy Study E3489, E4995, E1900 E3489, PC 486 E4995, E1900 E3489 Treatment-related mortality 15.3% (18/117) 11% (16/85) 1.5% (2/135) 2.7% (3/109) In conclusion: The TRM after autologous HSCT using mobilized peripheral blood has decreased substantially in recent years. As shown in table 2, in PC486 and E3489 where bone marrow was harvested and treated with perfosfamide (4-HC) prior to cryo-preservation, the TRM was significantly greater than in the later studies, E4995 and E1900, where peripheral blood was harvested after priming with chemotherapy and/or cytokines. The lower relapse rate post autologous transplant, together with the lower procedural mortality with current practice, may confer a survival advantage in future prospective studies of autologous HSCT versus chemotherapy. While absolute comparisons cannot be made, as the timing of each therapy may not be identical, these data provide crucial information for informed and patient/physician discussions prior to initiation of postremission therapy.

Abstract Background: Patients with diffuse large B-cell lymphoma (DLBCL) not cured by first line R-CHOP chemotherapy or second line high-dose chemotherapy with autologous stem cell rescue have a poor prognosis and represent a clear unmet medical need. Lenalidomide (Revlimid®), an immunomodulatory drug, has activity in hematological malignancies including relapsed/refractory multiple myeloma, chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Aim: To determine the activity and safety of lenalidomide monotherapy in relapsed/refractory DLBCL. Methods: Patients with relapsed/refractory DLBCL with measurable disease after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Univariate analyses using Fisher’s exact test was conducted to investigate and characterize associations of prognostic variables with response. Results: Twenty-six patients with DLBCL lymphoma were enrolled. The median age was 66 (45–86) and 13 were female. Median time from diagnosis to lenalidomide was 2.4 (0.5–12) years and median number of prior treatment regimens was 3 (1–6). Three patients (12%) exhibited an objective complete response (1 complete response (CR) and 2 complete responses unconfirmed (CRu)). Two patients had a partial response (PR) for an overall response rate of 19% and 7 had stable disease (SD). Response to lenalidomide was associated with low disease burden (33% for < 50 cm2v 0% for ≥ 50 cm2, P=0.06) and longer time from rituximab to lenalidomide treatment (33% for ≥ 230 days v 0% for < 230 days, P=0.05). Patients with favorable values for both these prognostic factors (N = 10) had a 50% response rate [RR] (30% CR/CRu RR) compared with a 0% RR for patients with unfavorable values (N = 16; P < 0.004) and a progression free survival (ongoing) of 7.4 months v 1.9 months. Although there were no responses in the poor prognosis group, 4 patients exhibited stable disease with an ongoing median PFS of > 4.2 months (> 3.6 - > 6.2). Eight patients (31%) required at least one dose reduction with a median time to first dose reduction of 1.8 months (0.4–2.9). One patient each (4%) had Grade 4 anemia, cauda equinine syndrome, febrile neutropenia, intermittent rash, lymphopenia, neutropenia, pneumonitis and thrombocytopenia. Most common Grade 3 adverse events were neutropenia (19%), thrombocytopenia (15%) and leukopenia (12%). Conclusion: The prognostic factors of tumor burden and time from last dose of rituximab appear to identify relapsed/refractory DLBCL patients with a high likelihood of response to lenalidomide oral monotherapy.

Abstract Background: Indolent non-Hodgkin’s lymphoma (NHL) has a median survival as long as 10 years but is rarely cured. Lenalidomide (Revlimid®), an immunomodulatory drug, is approved in the US for treatment of myelodysplastic syndromes associated with a del[q5] cytogenetic abnormality and is approved both in the US and the EU for the treatment of relapsed/refractory multiple myeloma. Lenalidomide also has activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Aim: This study was designed to assess the safety and efficacy of lenalidomide monotherapy in patients with relapsed/refractory indolent NHL. Methods: Patients with relapsed/refractory indolent NHL with measurable disease ≥ 2cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: Forty-three patients were enrolled in the study and included in this analysis. The median age was 63 (43–89) and 17 were female. Histology was small lymphocytic lymphoma [SLL] (n=18), follicular center lymphoma grades 1, 2 [FCL] (n=22), nodal marginal B-cell lymphoma (n=2) and extranodal marginal zone B-cell lymphoma of MALT type (n=1). Median time from diagnosis to lenalidomide treatment was 4.5 (0.4–24) years and median number of prior treatment regimens was 3 (1–15). Eleven of the 43 patients (26%) exhibited an objective response (2 complete responses (CR), 1 complete response unconfirmed (CRu), 8 partial responses (PR)), 15 had stable disease (SD), 13 had progressive disease (PD) and 4 were not evaluated. Responses included 4/18 SLL (22%) and 7/22 FCL (32%). Median time to response was 3.6 months (range 1.7–4.1). Progression free survival is 4.6 months for all patients, > 7.7 months (range 4.4 - > 13.5) for responding patients and ongoing. Sixteen patients (37%) required at least one dose reduction with a median time to first dose reduction of 2 months (0.5–9.6). The most common Grade 4 adverse event was neutropenia (14%) and the most common Grade 3 adverse events were neutropenia (21%) and thrombocytopenia (12%). Conclusion: Lenalidomide oral monotherapy is active with manageable side effects in relapsed/refractory indolent NHL.

Abstract Background: Lenalidomide (Revlimid®) has demonstrated activity with manageable side effects in relapsed/refractory aggressive non-Hodgkin’s lymphoma (NHL). In the initial pilot study, response to lenalidomide was associated with low tumor burden, long duration from prior rituximab and high absolute lymphocyte count. Aims: To confirm the activity and safety of lenalidomide monotherapy in patients with relapsed/refractory aggressive NHL in an international setting and Determine whether predictors of response identified in the previous study were valid. Methods: Patients with relapsed/refractory aggressive NHL with measurable disease ≥ 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Univariate analyses using Fisher’s exact test were conducted to investigate and characterize associations of prognostic variables with response. Results: Eighteen patients who received lenalidomide were eligible for response assessment as of May 15, 2007. The median age was 66 (43–81) and 17 were male. Histology was diffuse large B-cell lymphoma [DLBCL] (n=11), mantle cell lymphoma [MCL] (n=5) and transformed (n=2). Median time from diagnosis was 2 (0.4–12) years and median number of prior treatment regimens was 3 (1–13). Four patients (22%) exhibited an objective partial response including 2/11(18%) DLBCL and 2/5 (40%) MCL. Five patients had stable disease. Lenalidomide response was associated with low disease burden (29% for < 50 cm2v 0% for ≥ 50 cm2), time from last rituximab to lenalidomide treatment (36% for ≥ 230 days v 0% for < 230 days) and absolute lymphocyte count [ALC] (33% for ≥ 0.6×109/L v 0% < 0.6×109/L). Patients with favorable values for these three prognostic factors (N = 7) had a 57% response rate (compared with a 0% response rate for patients with unfavorable values (N = 11; P = 0.01). Grade 4 adverse events were neutropenia (22%) and thrombocytopenia (11%). Most common Grade 3 adverse events were fatigue (17%), thrombocytopenia (11%) and leukopenia (11%). Conclusion: Lenalidomide has activity in relapsed/refractory aggressive NHL with a favorable safety profile. Initial results from this ongoing study are confirming that patients with low tumor burden, long duration from prior rituximab, and high ALC are more likely to respond.