The original version of this article contained a mistake. The name of Tanja Nicole Hartman should have been Tanja Nicole Hartmann. The original article has been corrected.
Lenalidomide has shown encouraging activity in monotherapy trials in CLL, but tumor lysis and tumor flare presented obstacles in development. We and others previously presented first data on ...combinations of lenalidomide with standard treatment regimens in CLL. As reported at ASH 2011 we combined Lenalidomide safely and efficaciously with the combination of Fludarabine and Rituximab, achieving early reduction of tumor load without tumor lysis or tumor flare and with high response rates. We also uncovered a patient population unable to tolerate higher Lenalidomide doses and marked by an exhausted T cell subset, measured pre-treatment. We now report final results of this trial, including the maintenance phase.
In induction Lenalidomide was combined with Fludarabine (40mg/m2 po d1-3 q28d) and Rituximab (375mg/m2 iv d4 cycle 1; 500mg/m2 iv d1 cycles 2-6, q28d). In cycle 1 Lenalidomide was added day 7-21 at 2.5 mg. Toxicity permitting, Lenalidomide dose was escalated to 5, 10, 15, 20 and 25mg day 1-21 over cycles 2-6. Subsequent maintenance treatment was two-monthly Rituximab at 375mg/m2 and Lenalidomide at the last dose tolerated in combination in a 28 day cycle without interruption for 6 months. The main goal of this treatment phase was to establish safety and efficacy as a secondary endpoint to the study.
Patient characteristics of 45 recruited patients were previously reported: median age was 66 years and at least one molecular high risk feature was present in 64% of patients. No systematic toxicity determining an MTD in induction, the primary study endpoint, was found. The median daily dose in cycle 6 was 15mg in 40 evaluable patients, with 3 patients receiving the last cycle without lenalidomide. Toxicity and efficacy of the induction regimen were reported previously. Maintenance treatment was started in all 40 patients finishing induction. Three patients that finished without lenalidomide received only Rituximab. The median starting dose for all 40 patients was 15mg daily and 70% started with 10mg upwards. In total, 46% needed dose reductions, with prolonged neutropenia being the main reason, but 47% received doses above 10mg up to cycle 6 of maintenance. Interestingly, 9/13 patients receiving 25mg as maintenance were able to receive the treatment uninterrupted for 6 months, suggesting that a biologically select group may tolerate very high doses. As alluded to the major toxicity was neutropenia with 45% and 27% reaching G3 and G4, respectively. Surprisingly this did not translate into a relevant signal for infections. Grade 3, but no G4 infections, were observed in 5% of patients and all other G3/4 toxicities remained below 5%. Compared to the reported incidence of skin reactions in induction, we did not observe a significant signal in the maintenance phase. Improvement of response from PR after induction to CR at the end of maintenance was observed in 25%. The overall best response in ITT to the regimen during induction and maintenance was CR in 67% and PR in 29%. Median follow up of the study is now 35 months, at which point PFS is 89% and observed median PFS is currently 46 months. Exploratory analyses show no significant influences of age>65, mutation state or CD38 risk on PFS, but undetectable MRD after induction and high risk cytogenetics showed borderline effects (both p=0.08), the latter (2 cases with del17p and 9 with del11q) being driven by relapses in patients with del11q with a median PFS of 42 months in this group.
A combination of Lenalidomide with FR followed my maintenance with Lenalidomide and Rituximab proved clinically feasible. While initial dose-finding was complicated by highly individual levels of tolerance to lenalidomide in the combination (with skin toxicity being a major problem), the main toxicity in maintenance was neutropenia. Although the important myelotoxicity did not translate into a rate of infection above that expected after induction treatment, our judgment is, that a more moderate approach to dosing may be warranted in maintenance, since a majority of patients had to be dose-adjusted. Finally, the PFS observed with this induction and maintenance regimen seems encouraging by comparison with other first line regimens. While the exploratory nature of the trial clearly limits this conclusion, we further explore combination approaches with lenalidomide.
Egle:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Research Funding. Off Label Use: Lenalidomide in CLL. Pleyer:Celgene: Honoraria, Research Funding. Fridrik:Roche: Honoraria. Thaler:Roche: Honoraria, Research Funding. Greil:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding.
The development of vaccines against H5N1 influenza A viruses is a cornerstone of pandemic preparedness. Clinical trials of H5N1 vaccines have been undertaken in healthy subjects, but studies in risk ...groups have been lacking. In this study, the immunogenicity and safety of a nonadjuvanted cell culture-derived whole-virus H5N1 vaccine were assessed in chronically ill and immunocompromised adults. Subjects received two priming immunizations with a clade 1 A/Vietnam H5N1 influenza vaccine, and a subset also received a booster immunization with a clade 2.1 A/Indonesia H5N1 vaccine 12 to 24 months later. The antibody responses in the two populations were assessed by virus neutralization and single radial hemolysis assays. The T-cell responses in a subset of immunocompromised patients were assessed by enzyme-linked immunosorbent spot assay (ELISPOT). The priming and the booster vaccinations were safe and well tolerated in the two risk populations, and adverse reactions were predominantly mild and transient. The priming immunizations induced neutralizing antibody titers of ≥1:20 against the A/Vietnam strain in 64.2% of the chronically ill and 41.5% of the immunocompromised subjects. After the booster vaccination, neutralizing antibody titers of ≥1:20 against the A/Vietnam and A/Indonesia strains were achieved in 77.5% and 70.8%, respectively, of chronically ill subjects and in 71.6% and 67.5%, respectively, of immunocompromised subjects. The T-cell responses against the two H5N1 strains increased significantly over the baseline values. Substantial heterosubtypic T-cell responses were elicited against the 2009 pandemic H1N1 virus and seasonal A(H1N1), A(H3N2), and B subtypes. There was a significant correlation between T-cell responses and neutralizing antibody titers. These data indicate that nonadjuvanted whole-virus cell culture-derived H5N1 influenza vaccines are suitable for immunizing chronically ill and immunocompromised populations. (This study is registered at ClinicalTrials.gov under registration no. NCT00711295.).
Abstract 292
CLL cells derive essential cues from their microenvironment, that may be targets for therapy. To this end the immunomodulatory drug Lenalidomide has shown remarkable clinical activity in ...monotherapy trials in CLL. However, tumor lysis and tumor flare have been major obstacles in development and marked and unexplained differences in the individual tolerance of the substance remains an unsolved problem. Furthermore, the potential for interaction with standard treatment for CLL is unknown. We employed the combination of Fludarabine and Rituximab for early reduction of tumorload and used it as a backbone to establish a tolerable Lenalidomide dose in combination.
In the induction phase a maximal tolerated dose (MTD) of Lenalidomide in combination with FR was to be determined during 6 cycles of Fludarabine (40mg/m2 po d1-3 q28d) and Rituximab (375mg/m2 iv d4 cycle 1; 500mg/m2 iv d1 cycles 2–6, q28d). In cycle 1 Lenalidomide was added day 7–21 at 2,5 mg. Toxicity permitting, Lenalidomide dose was escalated to 5, 10, 15, 20 and 25mg d1-21 over cycles 2–6. Data from this phase are presented in this planned analysis. Data from a 6 month Lenalidomide/Rituximab maintenance phase will be presented later.
The median age of the 45 recruited patients was 66 years (range 43–79). Half of the patients were in stages Rai III/IV and the median β2-MG was 4.4 mg/l. At least one high risk feature from CD38, FISH analysis and mutation status was present in 64% of patients. Five patients stopped treatment during induction (Two due to rashes, two as patient’s choice and one due to early Richter’s transformation). No systematic toxicity determining an MTD, the primary study endpoint, was found. In striking contrast to a small previous report, 34% of our patients proceeded through dose escalation steps as planned to receive a dose of 25mg of Lenalidomide with their last cycle of FR. The individual MTD was equal or higher than 10mg in 73% of ITT patients and 71% in this group were dose-limited due to individual differences in myelotoxicity. In ITT analysis 27% of patients had an MTD of less than 10mg. Grade 3 and 4 neutropenia was expected in this combination and observed in 88% of patients in any cycle. While it was not used as a dose limiting toxicity per se, 42% of patients were dose-limited due to myelotoxicity at some level. Infectious episodes of grade 3 severity were observed in 5 patients (11%), resulting in a relatively mild rate given the observed myelotoxicity and the phase I/II design. Surprisingly, 1/3 of the patients experienced greater than G2 skin toxicity and this was deemed dose-limiting in nine patients. No tumor lysis or greater than G2 flare reactions were observed. Full response assessment for induction treatment is available for 39 patients. Complete responses were observed in 49% and partial responses in 38% of the ITT population. In 35 patients flow MRD is available and 10 patients have reached MRD negativity. Response quality was not associated with risk factors, age or with lenalidomide dose in those receiving 6 cycles of treatment. Remarkably, one of three patients with deletion 17 achieved an MRD negative CR. Since we could not define a clinical predictor for the patients’ tolerance of lenalidomide, we performed extensive immunophenotyping of T cells in pretreatment samples, using markers for functional T cells subsets, their Th polarity and for suppressive or exhausted T cell subsets. Employing a combined endpoint including non-hematological dose-limiting events or MTD < 10mg as a comparator, we identified a fraction of non-exhausted memory CD4 cells as highly significant predictor of dose-limiting non-hematologic events (p<0,005). Using a cut-off the T cell fraction has an 85% NPV for such events, possibly allowing for future identification of patients that will have difficulty with higher lenalidomide doses.
A combination of Lenalidomide with FR seems clinically feasible. While no clear dose dependent limiting toxicity has uniformly emerged in this combination, more than a third of patients had to be dose-limited due to not clearly dose-dependent non-hematologic toxicities (mostly skin-related). Novel biomarkers may be efficient in identifying those patients. In addition, the regimen shows encouraging clinical efficacy with limited clinical complication, particularly in the patients tolerating doses above 5mg. A follow-up study with higher starting dose is planned.
Egle:Celgene: Consultancy, Research Funding, Speakers Bureau; Roche: Speakers Bureau. Off Label Use: Use of Lenalidomide in CLL. Steurer:Roche: Speakers Bureau. Fridrik:Roche: Speakers Bureau. Thaler:Roche: Speakers Bureau. Lang:Roche: Speakers Bureau. Greil:Roche: Speakers Bureau.
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