Refractory B-cell Chronic Lymphocytic Leukemia Research Articles

GB261, an Fc-Function Enabled and CD3 Affinity De-Tuned CD20/CD3 Bispecific Antibody, Demonstrated a Highly Advantageous Safety/Efficacy Balance in an Ongoing First-in-Human Dose-Escalation Study in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Introduction: GB261 is a novel and highly differentiated CD20/CD3 bispecific T cell engager antibody computationally designed to maintain Fc effector function, i.e., antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC) to broaden the mechanisms of action (MOA) for tumor cell killing. Furthermore, the “imbalanced” design of GB261 integrates de-tuned CD3 binding to reduce CRS incidence and improve safety features of the Fc effector function. Extensive pre-clinical studies have shown that GB261 has a highly advantageous safety/efficacy balance.Here, we present the preliminary clinical safety and efficacy results of an ongoing phase I/II study for GB261 (NCT04923048). Methods: This is an open-label, multicenter (China and Australia), dose-escalation/expansion phase 1/2 study of GB261 to evaluate the safety, tolerability and efficacy in patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma(B-NHL) and Chronic Lymphocytic Leukemia (CLL). Adult patients were eligible when they have CD20+ r/r B-NHL or CLL with no available standard of care treatments, adequate organ function, and no CNS involvement or other CNS disease, infections or other active/serious medical issues that may affect compliance or interpretation of results. GB261 was administered in 21-day cycles, weekly (QW) for the first 6 doses followed by every 3 weeks (Q3W) until disease progression, or other situation defined in protocol. Response assessment was based on Lugano 2014 and LYRIC 2016 criteria. Results: As of June 17, 2023, 47 r/r B-NHL patients (DLBCL:76.6%; FL:23.4%) were enrolled at flat or step-up doses of GB261 ranging from 1mg to 300 mg. Median age was 60.0 years (range: 28, 81), 55.3% of patients were male. Median prior lines of therapy were 3 (range: 1, 10). 78.7% of patients were refractory to any anti-CD20 therapy, 70.2% refractory to their last systemic therapy. Median time since last prior therapy to first study treatment was 1.9 months. In efficacy evaluable patients (n=22) from 3mg to 100mg, with at least 75% dose exposure before the first radiographic assessment, the median duration of study follow-up was 4.5 months (95%CI: 4.0, 7.4). The overall response rate (ORR) was 73% (16/22), and complete response rate (CRR) was 45.5% (10/22). ORR and CRR were 100% and 100% in 3mg, 56% and 22% in 10mg, 67% and 33% in 30mg. At 100mg dose, there were 5 evaluable patients, with ORR 100% (5/5), CRR 80% (4/5) and PR (20%, 1/5; mosunetuzumab-refractory rrDLBCL patient). Median time to response (TTR) was 1.3 months (95%CI: 1.2, 1.5), the same as median time to CR. Median duration of response (DOR) was not reached. In safety evaluable patients (n=47), the median duration of study follow-up was 4.1 months (95%CI: 2.9, 5.3). Treatment-emergent adverse events (TEAEs) were 95.7%, treatment-related adverse events were 85.1%. The most common TEAEs were COVID-19 infection (40.4%; grade 1 or 2: 27.6%; grade >=3: 12.8%) and neutropenia (31.9%; grade 1or 2: 14.9%; grade >=3: 17.0%). AE related treatment discontinuation and death were reported in 2 patients, which were all due to COVID-19 pneumonia. CRS occurred in 12.8% (6/47) patients, was mild and transient. CRS in 100mg were 14.3% (2/14). All cases of CRS were grade 1 (8.5%, 4/47) or 2 (4.3%, 2/47), no grade 3 (Lee et al., ASTCT criteria), no interruptions of treatment, and no administration of Tocilizumab. The median duration of CRS was 7 hours. No ICANS were reported. The PK profile of GB261 appeared to be linear across dose ranges tested (1mg-100mg). Effective half-life appeared to be 2-3 weeks which supports every 3-4 weeks dosing. Conclusion: GB261, a novel and highly differentiated CD20/CD3 bispecific antibody, is the first clinical stage Fc+ CD20/CD3 T cell engager. In heavily pretreated B-NHL patients, GB261 showed a highly advantageous safety/efficacy balance, consistent with the MOA. The safety profile is excellent especially for the CRS which is very mild, transient and less frequent compare with other CD20/CD3 bispecific antibodies. The response after GB261 treatment was early, deep and durable. At the 100mg dose level, 80% of patients achieved CR and with favorable safety. Additionally, clinical benefit seen in other CD20/CD3 bispecific antibody failed patients provides clinical support to the unique and differentiated MOA of GB261.

Quality of Life, Tryptophan Metabolites, and Neurotoxicity Assessments of Patients with Relapsed or Refractory B Cell Malignancies Undergoing CAR 20/19 - T Cell Therapy

Introduction Chimeric antigen receptor (CAR) T cell immunotherapy represents a novel and increasingly used treatment modality for patients with relapsed and/or refractory B cell malignancies. Acute neurological toxicities of CAR-T cell therapy (e.g. immune effector cell-associated neurotoxicity syndrome) are well described, though delayed cognitive and emotional functioning and quality of life (QOL) are less well studied, with mechanisms of all incompletely understood. Given the known bidirectional relationship between neuroinflammation and depression, and the role of kynurenine (Kyn) metabolism in both, we studied QOL through patient-reported outcomes (PROs) and neurotoxicity and their relationship to Kyn metabolites. Methods Patients with relapsed refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia treated with CAR-20/19-T cells on our Phase I/Ib clinical trial (NCT03019055) (N=16) were included. Patients were excluded if they had a history of previous allogeneic hematopoietic stem cell transplantation. Study subjects provided serum and PROs through self-report surveys at the following time points: baseline/ apheresis, Day-14 (D14), D28, and D90 post-intervention. The following scales were used to assess QOL: Inventory of Depression and Anxiety Symptoms (IDAS), Brief Pain Inventory (BPI), Fatigue Severity Index (FSI), and Pittsburgh Sleep Quality Index (PSQI). Tryptophan and its metabolites (kynurenine (Kyn), 3-Hydroxy-anthranilic Acid (3-HAA), 3-Hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KA)) and neurotoxicity grades were measured for all 16 subjects. Patients were evaluated for neurotoxicity with the CTCAE 5.0. The measurements were log-transformed to stabilize the variances and allow modeling of the expected multiplicative effects. A mixed effects longitudinal model was used for all eligible patients to evaluate the impact of time on all PRO variables over the 4 timepoints through 90 days post CAR-T infusion. Neurotoxicity was evaluated two ways: as a categorical variable with 5 levels (0 to -4) and as a continuous variable. Results Depression symptoms improved over time with the lowest value at Day 90, though the changes were not statistically significant (P = .072). Remaining QOL PRO variables did not show statistically significant changes, tending to improve or remain stable over time (Table 1 & Figure 1). Mean Kyn levels significantly changed over time (P = .028; Table 2). This effect is most pronounced in patients with Grade 3/4 neurotoxicity where Kyn levels rise at Day 14 and Day 28 followed by a decrease by Day 90 (Figure 2). Among patients who exhibited neurotoxicities, baseline levels of 3-HAA and 3-HK before CAR-T therapy were elevated; though nonsignificant, similar trends were not observed in the other metabolites (Figure 2). These observations however were significant when neurotoxicity was evaluated as a continuous variable (Table 2) with 3-HAA and 3-HK higher in patients with higher grade neurotoxicities (P = .015 and .070). Conclusions Our findings suggest that CAR-T therapy does not impair QOL and may in fact result in improved mood in the early months following cell infusion, adding to recent literature about long-term QOL in CAR-T survivors. Here, we also identify elevated baseline 3-HAA and 3-HK levels as well as increased Kyn levels following CAR-T therapy, with the first two associated with worse neurotoxicity. Most interestingly, we find higher levels of 3-HAA and 3-HK in patients who experience neurotoxicities. Correlational studies will be needed to confirm potential relationships between PROs and metabolites. Disclosures Hari: Incyte Corporation: Consultancy; Takeda: Consultancy; BMS: Consultancy; Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy. Shah:Cell Vault: Research Funding; Miltenyi Biotec: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Incyte: Consultancy; TG Therapeutics: Consultancy; Verastim: Consultancy; Kite Pharma: Consultancy, Honoraria; Lily: Consultancy, Honoraria.

Phase I Dose-Escalation Trial of CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) T-Cells for the Treatment of Relapsed or Refractory B-Cell Lymphomas and Chronic Lymphocytic Leukemia

Background: Single-input anti-CD19 CAR T-cells have demonstrated clinical efficacy for relapsed or refractory (R/R) non-Hodgkin B-cell lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Despite excellent response rates, over 50% of CD19 CAR T-cell recipients relapse. Preclinical data show engineering of bispecific anti-CD19/CD20 CAR T-cells via lentiviral transduction effectively targets tumor cells and overcomes antigen escape (Zah E et al., Cancer Immunol Res, 2016). Based on these promising preclinical results and the limitations of single-input anti-CD19 CARs, we investigated the bispecific anti-CD19/CD20 CAR naïve/memory T-cells in a phase I dose-escalation clinical trial for patients with R/R NHL/CLL (NCT04007029). Methods: This trial includes patients who have measurable disease after 2 lines of therapy for diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL), and after 3 lines of therapy for mantle cell lymphoma (MCL), follicular lymphoma (FL), CLL and small lymphocytic leukemia (SLL). Eligible participants received lymphodepleting chemotherapy with fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 for three days, followed by anti-CD19/CD20 CAR T-cell infusion. The CAR T-cell infusion will be given with standard "3+3" dose escalation to determine the maximum tolerated dose (MTD), with a dose range of 5 x 107 to 6 x 108 CAR-positive cells per patient. Results: To date, three patients received treatment on cohort 1 with 5 x 107 CD19/CD20 CAR T-cells for R/R MCL, FL and PMBCL, with an average age of 49.3 (range, 29-60) and a mean of 3.7 prior regimens (range, 3-4). All 3 patients' lymphomas were CD19+/CD20+ on tissue biopsy prior to CAR infusion and all 3 received bridging chemotherapy. The infusion was well tolerated and no major infusion reactions occurred. Peak expansion was noted on day 14. No dose limiting toxicities were identified. The maximum grade CRS was 1 and there was no ICANS. At the 6.0-month cutoff date, 2 of the 3 patients remain in ongoing complete remission. Unfortunately, one patient developed progressive disease 0.5 months after CAR infusion, yet remains alive after treatment with immunotherapy. Both of the responders continue to demonstrate ongoing CAR T-cell persistence and B-cell aplasia by 3.0 and 6.0-month follow up, respectively. Conclusions: Here we demonstrate impressive responses in 2 of 3 patients at the 5 x 107 CD19/CD20 CAR T-cell dosages. Bispecific CD19/CD20 CAR T-cell therapy appears to be safe and effective in patients with R/R NHL and CLL and obviates the challenges with the single antigen directed CARs by decreasing risk of target antigen loss and expression downregulation. A longer follow up period is required to determine the impact of modifying naïve/memory T cells and the durability of response. The trial continues to enroll patients and additional clinical and translational data are being collected on the initial patient cohort. Disclosures Timmerman: Corvus: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; Bluebird Bio: Current equity holder in publicly-traded company; Immune Design: Honoraria; Celldex Therapeutics: Consultancy; Valor: Research Funding; Merck: Research Funding; Spectrum Pharmaceuticals: Research Funding; BMS: Other: Travel support, Research Funding; Kite, a Gilead Company: Consultancy, Other: Travel support, Research Funding; Genmab: Current equity holder in publicly-traded company. Chen:Kalthera Therapeutics: Other: Co-founder; Notch Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gritstone Oncology: Membership on an entity's Board of Directors or advisory committees. Larson:BMS, Bioline, Celgene, Juno, Janssen: Research Funding; TORL Biotherapeutics: Current equity holder in private company.

Safety and activity of the anti-CD79B antibody–drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study

Patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) have an unfavourable prognosis with few treatment options. Polatuzumab vedotin is an antibody-drug conjugate containing an anti-CD79B monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the safety and clinical activity of polatuzumab vedotin in relapsed or refractory B-cell NHL and chronic lymphocytic leukaemia (CLL). In this phase 1, multicentre, open-label study, we enrolled patients with documented NHL or CLL expected to express CD79B (confirmation of CD79B expression was not required) and for whom no suitable therapy of curative intent or higher priority existed from 13 centres. The primary endpoints of the study were to assess safety and tolerability, determine the maximum tolerated dose, and identify the recommended phase 2 dose of polatuzumab vedotin as a single agent and in combination with rituximab. A 3 + 3 dose-escalation design was used in which we treated patients with polatuzumab vedotin (0·1-2·4 mg/kg every 21 days) in separate dose-escalation cohorts for NHL and CLL. After determination of the recommended phase 2 dose, we enrolled patients with relapsed or refractory diffuse large B-cell lymphoma and relapsed or refractory indolent NHL into indication-specific cohorts. We also enrolled patients with relapsed or refractory NHL into an additional cohort to assess the feasibility of the combination of polatuzumab vedotin and rituximab 375 mg/m(2). Patients who received any dose of polatuzumab vedotin were available for safety analyses. This study is registered with ClinicalTrials.gov, number NCT01290549. Between March 21, 2011, and Nov 30, 2012, we enrolled 95 patients (34 to the NHL dose-escalation cohort, 18 to the CLL dose-escalation cohort, 34 with NHL to the expansion cohort at the recommended phase 2 dose, and nine with NHL to the rituximab combination cohort; no expansion cohort of CLL was started due to lack of activity in the dose-escalation cohort). The recommended phase 2 dose in NHL was 2·4 mg/kg as a single agent and in combination with rituximab; the maximum tolerated dose in CLL was 1·0 mg/kg as a result of dose-limiting toxic effects reported in two of five patients given 1·8 mg/kg. Grade 3-4 adverse events were reported in 26 (58%) of 45 patients with NHL treated at the single-agent recommended phase 2 dose, and the most common grade 3-4 adverse events were neutropenia (18 [40%] of 45), anaemia (five [11%]), and peripheral sensory neuropathy (four [9%]). Serious adverse events were reported in 17 (38%) of 45 patients, and included diarrhoea (two patients), lung infection (two patients), disease progression (two patients), and lung disorder (two patients). Seven (77%) of nine patients in the rituximab combination cohort had a grade 3-4 adverse event, with neutropenia (five [56%]), anaemia (two [22%]), and febrile neutropenia (two [22%]) reported in more than one patient. 11 (12%) of 95 patients died during the study: eight with relapsed or refractory diffuse large B-cell lymphoma (due to progressive disease in four patients, infections in three patients [two treatment related], and treatment-related worsening ascites in one patient) and three with relapsed or refractory CLL (due to progressive disease, pulmonary infection, and pneumonia; none thought to be treatment-related). At the recommended phase 2 dose, objective responses were noted in 23 of 42 activity-evaluable patients with NHL given single-agent polatuzumab vedotin (14 of 25 with diffuse large B-cell lymphoma, seven of 15 with indolent NHL, and two with mantle-cell lymphoma) and seven of nine patients treated with polatuzumab vedotin combined with rituximab. No objective responses were observed in patients with CLL. Polatuzumab vedotin has an acceptable safety and tolerability profile in patients with NHL but not in those with CLL. Its clinical activity should be further assessed in NHL. Genentech.

Erratum to: A phase I/II study of ofatumumab (GSK1841157) in Japanese and Korean patients with relapsed or refractory B-cell chronic lymphocytic leukemia

Erratum to: A phase I/II study of ofatumumab (GSK1841157) in Japanese and Korean patients with relapsed or refractory B-cell chronic lymphocytic leukemia

A phase I/II study of ofatumumab (GSK1841157) in Japanese and Korean patients with relapsed or refractory B-cell chronic lymphocytic leukemia

The tolerability, efficacy, safety and pharmacokinetic profile of a human anti-CD20 monoclonal antibody, ofatumumab, was evaluated in this phase I/II study in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL). This study consisted of two parts. Tolerability was assessed in phase I (Part A), while the overall response rate (ORR) was assessed in phase II (comprising Parts A and B). Three patients were enrolled in Part A, and another seven patients were enrolled in Part B. Ofatumumab 300mg was given at the first infusion, followed by seven weekly and four monthly infusions of 2000mg. No patients experienced dose-limiting toxicity, and tolerability was confirmed. The ORR was 70%. The most commonly reported adverse events (AEs) were leukopenia, neutropenia, and lymphopenia. No patients discontinued the study due to AEs. Plasma concentrations of ofatumumab prior to the next weekly dose increased steadily over the 8weeks and did not reach steady state; with monthly dosing, pre-dose ofatumumab concentrations decreased. Inter-patient variability of pharmacokinetic parameters was larger after the first dose than after the later dose. In conclusion, this phase I/II study suggests that ofatumumab provides favorable safety and efficacy in Japanese/Korean patients with relapsed or refractory B-CLL.

Postoperative Transplant Immunosuppression in the Critical Care Unit

Postoperative Transplant Immunosuppression in the Critical Care Unit

Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell Malignancies

Survival and progression of mature B-cell malignancies depend on signals from the B-cell antigen receptor, and Bruton tyrosine kinase (BTK) is a critical signaling kinase in this pathway. We evaluated ibrutinib (PCI-32765), a small-molecule irreversible inhibitor of BTK, in patients with B-cell malignancies. Patients with relapsed or refractory B-cell lymphoma and chronic lymphocytic leukemia received escalating oral doses of ibrutinib. Two schedules were evaluated: one, 28 days on, 7 days off; and two, once-daily continuous dosing. Occupancy of BTK by ibrutinib in peripheral blood was monitored using a fluorescent affinity probe. Dose escalation proceeded until either the maximum-tolerated dose (MTD) was achieved or, in the absence of MTD, until three dose levels above full BTK occupancy by ibrutinib. Response was evaluated every two cycles. Fifty-six patients with a variety of B-cell malignancies were treated over seven cohorts. Most adverse events were grade 1 and 2 in severity and self-limited. Dose-limiting events were not observed, even with prolonged dosing. Full occupancy of the BTK active site occurred at 2.5 mg/kg per day, and dose escalation continued to 12.5 mg/kg per day without reaching MTD. Pharmacokinetic data indicated rapid absorption and elimination, yet BTK occupancy was maintained for at least 24 hours, consistent with the irreversible mechanism. Objective response rate in 50 evaluable patients was 60%, including complete response of 16%. Median progression-free survival in all patients was 13.6 months. Ibrutinib, a novel BTK-targeting inhibitor, is well tolerated, with substantial activity across B-cell histologies.

Bendamustine plus mitoxantrone for relapsed/refractory chronic lymphocytic leukaemia (CLL): results of a multicentre phase II study of the German CLL Study Group (GCLLSG)

The efficacy of bendamustine (50 mg/m², days 1-3) plus mitoxantrone (10 mg/m², day 1), every 28 days for up to four courses, was evaluated in a Phase II multicentre trial enrolling 59 patients with relapsed or refractory B-cell chronic lymphocytic leukaemia (CLL). Major toxicities were grade 3/4 leucopenia, thrombocytopenia and infections in 42%, 12% and 12% of patients, respectively. Complete and partial response was achieved in 5/59 and 25/29 patients, respectively (overall response rate, 51%). Median time to progression was 22 months (range 1-49 + ) and median survival 27 months (range 0-49 + ). The combination of bendamustine and mitoxantrone is an active regime in relapsed or refractory CLL.

Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Phase I/II study of oxaliplatin, fludarabine, cytarabine, and rituximab in patients (OFAR2) with Richter's syndrome (RS), and relapsed or refractory B-cell chronic lymphocytic leukemia (CLL)

7031 Background: The first Phase I-II clinical trial of oxaliplatin, fluradabine, Ara-C, and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate with a decrease in myelosuppression, the dose of oxaliplatin was increased to 30 mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods: The OFAR2 regimen consisted of oxaliplatin 30mg/m2, D1–4; fludarabine 30mg/m2, Ara-C 0.5 g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg D6. Fludarabine and Ara-C were given on D2–3 (dose level 1) D2–4 (dose level 2) or D2–5 (dose level 3); courses were repeated every 4 wks. Prophylaxis for tumor lysis, DNA viruses, and PCP was given. Results: A total of 55 pts have been treated to date: 12 pts enrolled in phase I (dose level 1, n=3; dose level 2, n=6; and dose level 3, n=3). DLTs were noted in 2/3 pts in dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1), therefore level 2 was the MTD. Forty-three pts were treated in the Phase II portion of the study (relapsed CLL, 35; RS, 8). The median age was 64 yrs (range, 40- 81); 50 (91%) had β2-microglobulin > 3 mg/L; platelets were < 100 x109/L in 22 pts; and 44 pts had > 1 prior therapies. FISH results were: 17p deletion, n=15; 11q del, n=7; trisomy 12, n=12; 13q del, n=8; normal, n=2; unknown, n=11. Overall, 33 pts had unmutated and 7 mutated IgVH gene; ZAP70 was positive in 30, and negative in 14. Six (46%) of 13 pts with 17p del by FISH responded to OFAR2 (nPR, 2; PR, 4). Eleven pts underwent stem cell transplantation as postremission or salvage therapy. The most common toxicity was myelosuppression. Conclusions: Preliminary results demonstrated that OFAR2 resulted in an overall response rate of 63%, had antileukemic activity in pts with 17p del and clinical outcomes appeared to be superior to those of OFAR1. Accrual is ongoing. [Table: see text] [Table: see text]

Lenalidomide Associated Tumor Flare Reaction Correlates with Clinical Response in Patients with Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia

INTRODUCTION: We have previously reported that in patients with B-CLL, lenalidomide induces a tumor flare reaction (TFR) that is clinically characterized by painful, tender enlargement of disease involved lymph nodes, spleen and/or liver along with low grade fever. The underlying mechanism as well as the impact of TFR on treatment outcomes remains unknown. We analyzed data from our phase II clinical trial in which the clinical efficacy of lenalidomide alone was investigated in patients with relapsed or refractory B-CLL and correlated the severity of TFR with clinical efficacy.METHODS: Forty five patients with relapsed refractory CLL, enrolled in a phase II study were divided into two groups; group A consisted of first 29 patients who were treated with 25 mg of lenalidomide for 21 days of a 28 day cycle without any prophylaxis for tumor flare reaction, group B consisted of subsequent 16 patients who received 10 mg per day of lenalidomide initially with subsequent escalations of 5 mg every 1–2 weeks to a maximum dose of 25 mg along-prednisone prophylaxis (20 mg/day for 5 days followed by 10 mg/day for 5 days) was given to this group during cycle 1 only.RESULTS: Thirty of the 45 patients (67%) developed clinically significant TFR. Of these 20 (67%) were grade I, 7 (23%) grade II and 3 (10%) grade III. The median time to TFR was 6 days (range 0–56 days). The median time to resolution was 14 days (95% CI: 10–26 days). In over 90% of cases flare occurred only during first treatment cycle. Median age for those who either developed or did not develop flare reaction was 61 and 71 years respectively (p=0.004, 2-sided, Wilcoxon test). Nineteen patients (66%) in group A and 11 (69%) in group B developed TFR. Grade II/III flare was observed in 9 (47%) and 1 (9%) patients in group A and B, respectively (p=0.05). The median time to onset of TFR was 4 days in group A and 9 days in group B (p=0.01). The median duration of TFR was 13 and 28 days in groups A and B respectively (p=0.16). A total of 8 patients achieved molecular complete remission (mCR). All but 1 patient who achieved mCR had a flare reaction (p=0.24). The median progression free survival of patients with or without TFR was 19.9 and 19.4 months, respectively. There was a trend to improvement of progression free survival in group A patients compared to group B patients, 23 vs. 17.8 months, respectively (p=0.74, log rank test), however, this difference did not reach statistical significance. TFR reaction was managed by non-steroidal anti-inflammatory agent with or without oral morphine. Eleven of the 30 patients with TFR required treatment and only 3 patients received supplemental morphine. None of patient required discontinuation of lenalidomide for TFR.CONCLUSION: Although the mechanism of TFR remains to be determined clinically it appears to be an immunologically mediated phenomenon that is uniquely seen in CLL patients. We observe that the occurrence and severity of TFR appears to correlate with clinical response to lenalidomide. Steroid prophylaxis decreases the severity but not the incidence of TFR. The effect on overall efficacy of steroid pre-treatment for prevention of TFR remains to be determined in larger cohort of patients.

Pharmacokinetics of alemtuzumab in combination with fludarabine in patients with relapsed or refractory B-cell chronic lymphocytic leukemia

In recent years, chemoimmunotherapies that combine cytotoxic agents and monoclonal antibodies have been studied intensively for the treatment of B-cell chronic lymphocytic leukemia (CLL). Of particular interest are fludarabine-based combination regimens such as FluCam (fludarabine and alemtuzumab),

Mycobacterium haemophilumInfection after Alemtuzumab Treatment

To the Editor: The immunosuppressive agent alemtuzumab is a DNA-derived, humanized monoclonal antibody directed against the panlymphocyte, cell-surface antigen CD52 (1). The drug is approved for the treatment of refractory B-cell chronic lymphocytic leukemia (2) and also has been used after stem cell (3) and organ transplantations (4). Alemtuzumab causes profound and prolonged lymphocyte depletion, which results in a variety of complications involving infections (5). However, mycobacteria have rarely been reported to cause infection after alemtuzumab treatment. We describe infections with Mycobacterium haemophilum, a fastidious nontuberculous mycobacterium, in 2 patients who experienced cutaneous lesions while they received alemtuzumab.

Alemtuzumab in the treatment of fludarabine refractory B-cell chronic lymphocytic leukemia (CLL).

The introduction of immunotherapeutic agents has provided renewed hope for Chronic lymphocytic leukemia fludarabine-refractory patients. Several clinical trials have shown that alemtuzumab is a more effective option compared to combination chemotherapy for treatment of patients who have relapsed or who are refractory to fludarabine, including those with poor prognostic factors. Although there are significant potential toxicities associated with alemtuzumab, such as infusional reactions and the risk of cytomegalovirus (CMV) reactivation, most are manageable. Pre-treatment anti-pyretics and anti-histamines are recommended to prevent or mitigate the acute infusional reactions associated with intravenous infusion. Recent use of alemtuzumab via the subcutaneous route has been shown to be well tolerated and has yielded similar response rates to the infusional method of administration. Prophylaxis with thrimethoprim/sulphamethoxazole (TMP/SMZ) as well as valacyclovir or a similar anti-viral can prevent many of the opportunistic infections seen in early trials. Reactivation of CMV infection can be effectively managed with monitoring and early treatment. Chemo-immunotherapy combination with alemtuzumab has been tested and demonstrated unprecedented clinical results in relapsed and refractory patients. The use of this agent earlier in the algorithm of patients with these characteristics should be considered. Future areas of research will include the use of alemtuzumab in combination with other monoclonal antibodies and other targeted therapies.

Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study

AbstractSafety and efficacy of the fully human anti-CD20 monoclonal antibody, ofatumumab, was analyzed in a multicenter dose-escalating study including 33 patients with relapsed or refractory chronic lymphocytic leukemia. Three cohorts of 3 (A), 3 (B), and 27 (C) patients received 4, once weekly, infusions of ofatumumab at the following doses: (A) one 100 mg and three 500 mg; (B) one 300 mg and three 1000 mg; (C) one 500 mg and three 2000 mg. Sixty-seven percent of the patients were Binet stage B, and the median number of previous treatments was 3. The maximum tolerated dose was not reached. The majority of related adverse events occurred at first infusion, and the number of adverse events decreased at each subsequent infusion. Seventeen (51%) of 33 patients experienced infections, 88% of them of grade 1-2. One event of interstitial pneumonia was fatal; all other cases resolved within one month. The response rate of cohort C was 50% (13/26), one patient having a nodular partial remission and 12 patients partial remission. In conclusion, ofatumumab was found to be well tolerated in patients with chronic lymphocytic leukemia (CLL) in doses up to 2000 mg. Preliminary data on safety and objective response are encouraging and support further studies on the role of ofatumumab in CLL patients. This trial was registered at www.clinicaltrials.gov as no. NCT00093314.

Ofatumumab,* a novel antiCD20 monoclonal antibody, is active in patients with relapsed or refractory B-cell chronic lymphocytic leukaemia

Ofatumumab,* a novel antiCD20 monoclonal antibody, is active in patients with relapsed or refractory B-cell chronic lymphocytic leukaemia

A phase Ib trial of atacicept (TACI-Ig) to neutralize APRIL and BLyS in patients with refractory or relapsed B-cell chronic lymphocytic leukemia (B-CLL)

3029 Background: B-CLL cells are resistant to apoptosis and thus exhibit prolonged survival and accumulation in vivo. Exogenously added soluble BLyS (B-Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand) have been shown to protect B-CLL cells from apoptosis in vitro. Nurse-like cells derived in vitro from CLL patients express high levels of APRIL and BLyS and thereby support CLL cell survival. Inhibition of APRIL significantly reduces CLL viability in vitro, indicating an important role for APRIL in this setting. Methods: This is an open-label, dose-escalation phase I trial to assess the safety, pharmacokinetics and biological effects of atacicept administered intravenously once weekly for 5 weeks to patients with refractory or relapsed B-CLL. Eligible patients are being enrolled in sequential cohorts of 3 to receive atacicept at 1, 4, 10, 15, 20 or 27 mg/kg. Evaluation of response is being assessed using NCI-WG criteria. Results: Preliminary results of the first 4 cohorts of the dose-escalation study are reported. Twelve CLL patients have entered the trial. No dose limiting toxicity has been observed and no SAE related to study drug has been reported to date. One case of mild nausea is the only drug-related toxicity reported to date. Three of six patients treated with 10 mg/kg and 15 mg/kg experienced a stabilization of their disease during the treatment period; prior to start of atacicept treatment, all had rapidly increasing leukocyte counts. One of these patients (10 mg/kg cohort), who was refractory to fludarabine therapy, has had stable disease according to NCI-WG criteria for over six months and is still receiving atacicept treatment. This same patient had a slight decrease (approximately 14% change from baseline) in absolute CLL cell concentration by Day 29 before final dosing. At lower dose levels all patients demonstrated progressive disease. Conclusions: Treatment with atacicept was well tolerated at the dose levels tested so far. The multiple cases of disease stabilization at higher dose levels in this heavily pre-treated patient population are promising, and support further study with atacicept in CLL. Accrual of patients at higher dose levels is ongoing. No significant financial relationships to disclose.

Lenalidomide is active in the treatment of patients with relapsed or refractory B-cell chronic lymphocytic leukaemia

Lenalidomide is active in the treatment of patients with relapsed or refractory B-cell chronic lymphocytic leukaemia

Clinical Efficacy of Lenalidomide in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia: Results of a Phase II Study

Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) have profound immune defects and limited treatment options. Given the dramatic activity of lenalidomide in other B-cell malignancies and its pleotropic immunomodulatory effects, we conducted a phase II trial of this agent in CLL. Patients with relapsed or refractory B-cell CLL (B-CLL) were eligible if they required treatment as per the National Cancer Institute Working Group 1996 guidelines. Lenalidomide was administered orally at 25 mg on days 1 through 21 of a 28-day cycle. Response was assessed after each cycle. Patients were to continue treatment until disease progression, unacceptable toxicity, or complete remission. Rituximab was added to lenalidomide on disease progression. Forty-five patients were enrolled, with a median age of 64 years. Sixty-four percent of the patients had Rai stage III or IV disease, and 51% were refractory to fludarabine. The overall response rate was 47%, with 9% of the patients attaining a complete remission. Fatigue, thrombocytopenia, and neutropenia were the most common adverse effects noted in 83%, 78%, and 78% of the patients, respectively. Lenalidomide is clinically active in patients with relapsed or refractory B-CLL. These findings are encouraging and warrant further investigation of this agent in the treatment of this disorder.