Opportunistic Infections Are Uncommon with Dasatinib in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP).

Abstract Abstract 1120 Poster Board I-142 BACKGROUND Dasatinib is a tyrosine kinase inhibitor that can achieve rapid and durable hematological, cytogenetic, and molecular responses in patients with CML-CP after resistance or intolerance to imatinib. Three years of follow-up data have been accumulated, with progression-free survival rates of 73% reported for second-line dasatinib 100 mg once daily (the currently approved dose for CML-CP). In addition to BCR-ABL, dasatinib inhibits Src family kinases (SFKs) and thereby mitigates T-cell receptor-mediated signaling. Dasatinib may have unique immunomodulatory properties. Modulation of CD8+ T-cell intracellular signal transduction, cellular proliferation, and cytokine production by dasatinib has been previously reported in vitro (Fei F. Exp Hematol. 2008;36(10):1297-308). Also, dasatinib has been shown to induce expansion of T-cells and NK cells in the clinic, an effect that was associated with achieving a complete molecular response (Mustjoki S. Leukemia. 2009;23(8):1398-405). Opportunistic infections (OI) like herpes zoster infections (HZV) have been previously reported with imatinib, albeit at a low rate (Mattiuzzi GN. Clin Cancer Res. 2003;9(3):976-80). AIM To determine the frequency of OI in clinical trials of dasatinib in CML-CP. METHODS Data from phase II CA180-013 and CA180-017, and phase III CA180-034 trial databases of 1150 CML-CP patients, collectively, were reviewed. A search for infection adverse events was conducted, and entries related to opportunistic pathogens were identified and tabulated. The follow-up time is ≥3 years for all patients in the phase III study and 2 years in the phase II studies. The median time on dasatinib treatment for patients treated with 100 mg once daily is 31 months, and for other doses is 25 months. RESULTS Of the 165 patients treated with dasatinib 100 mg once daily, only one grade 3–4 OI was identified (incidence <1%): a grade 3 HZV infection. In addition, there were 18 cases (11%) of grade 1–2 herpes simplex (HSV), 3 HZV, and one mycobacterial infection. Thirteen of the HSV cases were reported as not related to dasatinib treatment. Among 985 patients treated with other dosing schedules (50 mg twice daily, 70 mg twice daily, or 140 mg once daily), 7 cases (<1%) of grade 3–4 OIs were identified: 1 cytomegalovirus, 2 HSV, 1 HZV, 2 pneumocystis, and 1 unspecified fungal infection. There were 87 (9%) grade 1–2 HSV cases reported in the other dosing arms, but 62 were deemed not associated with dasatinib. There were 23 reports (2%) of grade 1–2 HZV infection with other doses, and one case of a grade 2 cytomegalovirus infection. CONCLUSION Our analysis indicates that OIs are rare in patients with CML-CP treated with dasatinib. Most of the infections associated with opportunistic pathogens were grade 1–2. Thus, despite in vitro data suggesting immunosuppressive properties of dasatinib, there do not seem to be adverse clinical consequences with this agent. Disclosures Kantarjian: Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Borthakur:Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau. Bahceci:Bristol-Myers Squibb: Employment. Szatrowski:Bristol-Myers Squibb: Employment. Damokosh:Bristol-Myers Squibb: Employment. Cortes:Bristol-Myers Squibb: Research Funding.

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Occurrence, Management, and Outcomes In Patients with Pleural Effusion During Dasatinib Treatment for Chronic-Phase Chronic Myeloid Leukemia (CML-CP) In the First-Line Setting: Analysis of the DASISION Trial

Blood ◽

10.1182/blood.v116.21.2282.2282 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2282-2282 ◽

Cited By ~ 2

Author(s):

Kimmo Porkka ◽

Michele Baccarani ◽

Andreas Hochhaus ◽

Hagop Kantarjian ◽

Satu Mustjoki ◽

...

Keyword(s):

Pleural Effusion ◽

Research Funding ◽

Chronic Phase ◽

Risk Scores ◽

Molecular Response ◽

Newly Diagnosed ◽

Once Daily ◽

Management Interventions ◽

Grade 3

Abstract Abstract 2282 Background: The Phase 3 DASISION trial comparing dasatinib 100 mg once daily with imatinib 400 mg once daily as initial treatment in patients (pts) with newly diagnosed CML-CP has demonstrated superior efficacy and favorable safety of dasatinib after a minimum of 12 months of follow-up (Kantarjian, H, et al. N Engl J Med 2010;362:2260). While fluid retention was more frequent with imatinib than with dasatinib, pleural effusion was seen only with dasatinib. Here, we provide a detailed analysis of pts experiencing pleural effusion, a clinically relevant adverse drug reaction. Methods: 519 pts with newly diagnosed, treatment-naive CML-CP (median disease duration of 1 month) were randomly assigned to either dasatinib 100 mg once daily (259 pts) or imatinib 400 mg one daily (260 pts). Key endpoints included complete cytogenetic response (CCyR), major molecular response (MMR) and safety. All pts were assessed by chest x-ray at baseline and at 6 months after randomization, or more frequently, if indicated clinically. Pts with pleural effusion at baseline were excluded. Pleural effusion was graded according to CTCAE version 3 (grade 1, asymptomatic; grade 2, symptomatic, up to 2 therapeutic thoracenteses; grade 3, symptomatic requiring supplemental oxygen, < 2 therapeutic thoracenteses; grade 4, life-threatening, hemodynamic instability). Results: After a minimum follow-up of 12 months with median treatment duration of 14.3 months (range, 0.3–25.8), 26 (10%, median age, 60 years) of the 258 dasatinib-treated pts (median age, 46 years) experienced pleural effusion. Of the pts with pleural effusion, 6 (23%) had low, 17 (65%) had intermediate and 3 (12%) had high Hasford risk scores. There were no grade 3 or 4 pleural effusion events. All events were grade 1(2%) or grade 2 (8%). Most events (n = 22, 85%) occurred more than 8 weeks after the start of study drug. In pts who had a pleural effusion, the median time to the event was 28 weeks (range, 4–88). Lymphocytosis (defined as peripheral blood lymphocyte count > 3.6 × 109/L) was noted in 11 (42%) of the 26 pts with pleural effusion, as compared to 46 (20%) of 232 pts with no pleural effusion. Pleural effusion was managed by dose modification and/or medical intervention. Therapy was interrupted in 19 pts, and the dose of dasatinib was reduced in 8 pts (4 pts, to 80 mg; 1 pt, to 70 mg; 3 pts, to 50 mg). Twelve pts received diuretics, 7 received corticosteroids, and only 1 pt underwent therapeutic thoracentesis. Only 3 pts (1.2%) discontinued therapy due to pleural effusion (grade 2). Eleven pts who continued dasatinib had resolution of their pleural effusion. Five pts had recurrent effusions. Of the 26 pts with pleural effusion, 24 (92%) achieved a CCyR and 17 (65%) achieved a MMR by 12 months of treatment; the corresponding CCyR and MMR rates in the total pt population were 83% and 46%, respectively Seven of the 8 pts with pleural effusion who reduced their dose achieved CCyR and MMR. Conclusion: In pts with newly diagnosed CML-CP treated with dasatinib as initial therapy, pleural effusion was mild to moderate in severity, and was manageable with dose interruption and/reduction and/or a short course of diuretics and/or corticosteroids. The occurrence of pleural effusion and management interventions did not negatively affect the achievement of CCyR or MMR. These findings are in line with data reported previously for second-line dasatinib in CML pts resistant or intolerant to imatinib (Porkka, K, et al. Cancer 2010;116:377). Furthermore, pleural effusion and peripheral lymphocytosis may be indicative of immune-mediated antitumor activity of dasatinib. Disclosures: Porkka: BMS, Novartis: Consultancy, Honoraria, Research Funding. Baccarani: Novartis, Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Brostol-Myers Squibb, Novartis: Consultancy, Research Funding. Kantarjian: BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Mustjoki: BMS, Novartis: Honoraria. Bradley-Garelik: Bristol-Myers Squibb: Employment, Equity Ownership. Zhu: Bristol-Myers Squibb: Employment. Cortes: Brostol-Myers Squibb, Novartis and Wyeth: Consultancy, Honoraria.

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A Phase III Study Of ASCT Vs Cyclophosphamide-Lenalidomide-Dexamethasone and Lenalidomide-Prednisone Maintenance Vs Lenalidomide Alone In Newly Diagnosed Myeloma Patients

Blood ◽

10.1182/blood.v122.21.763.763 ◽

2013 ◽

Vol 122 (21) ◽

pp. 763-763 ◽

Cited By ~ 16

Author(s):

Antonio Palumbo ◽

Francesca Gay ◽

Andrew Spencer ◽

Francesco Di Raimondo ◽

Adam Zdenek ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Study Endpoint ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3 ◽

To Receive

Abstract Background High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). The introduction of novel agents challenged the role of ASCT at diagnosis. We conducted a multicenter 2X2 randomized trial comparing conventional chemotherapy plus lenalidomide with ASCT followed by maintenance with lenalidomide-prednisone (RP) or lenalidomide (R) alone in newly diagnosed young MM (NDMM) patients. Methods Eligible patients with NDMM ≤ 65 years were enrolled. All patients received Rd induction (four 28-day cycles of lenalidomide 25 mg day 1–21 and low-dose dexamethasone 40 mg day 1,8,15,22) followed by stem cell mobilization. Patients were randomized to receive consolidation with CRD [six 28-day cycles of cyclophosphamide (300 mg/m2 day 1,8,15), dexamethasone (40 mg days 1,8,15,22) and lenalidomide (25 mg days 1–21)] or MEL200-ASCT (melphalan 200 mg/m2 with stem-cell support). Patients were randomly assigned to receive subsequent maintenance with RP (28-day cycles of lenalidomide 25 mg days 1–21 plus prednisone 50 mg every other day) or R alone (28-day cycles of lenalidomide 25 mg days 1–21). Primary study endpoint was progression-free survival (PFS); secondary endpoints included safety, responses and overall survival (OS). Data cut off was May 30th, 2013. Results Three-hundred and eighty-nine patients were enrolled in the trial. Patient characteristics were well balanced between CRD (n=194) and MEL200-ASCT (n=195), and between R (n=195) and RP (n=194) arms. Median follow-up was 31 months. In the intent to treat (ITT) analysis, the median PFS was not reached with MEL200-ASCT and 28 months with CRD (the respective 3-year PFS was 60% vs. 38%, HR=0.62, 95%CI: 0.49-0.85, P=0.003). Median time from enrolment to maintenance was 14 months. In the population of patients eligible for maintenance, 2-year PFS from the start of maintenance was 73% for RP and 56% for R patients (HR= 0.57, 95%CI: 0.34-0.93; P=0.03). In the subgroup of patients who received MEL200-ASCT, 2-year PFS from the start of maintenance was 83% for patients who received RP and 64% for those who received R alone (HR=0.36 95%CI: 0.15-0.87, P=0.02). In the subgroup of patients who received CRD, 2-year PFS from the start of maintenance was 64% for patients who received RP and 47% for those who received R alone (HR=0.75, 95%CI: 0.40-1.39, P=0.36). At present, no differences in OS were noticed between patients randomised to received CRD or MEL200-ASCT, and between patients who received RP or R maintenance. As expected, the rates of grade 3-4 hematologic (85% vs. 26%, P<0.001) and non-hematologic (35% vs. 19%, P=0.003) adverse events (AEs) were higher in the MEL200-ASCT arm compared with the CRD arm. The main non-hematologic AEs were infections (18% vs. 5%, P=0.001) and gastrointestinal AEs (18% vs. 3%, P<0.001). Rates of grade 3-4 hematologic (8% vs. 7%, P=0.85) and non-hematologic (12% vs. 13%, P=0.88). AEs were similar in the RP and R arms. The main non-hematologic AEs in both RP and R groups were infections (3% vs. 3%). At present, 6 second primary malignancies and 3 cases of cutaneous basalioma have been reported. Conclusions MEL200-ASCT significantly prolonged PFS in comparison with CRD. At present no difference in OS was reported, this may be due to the low number of events and to the length of follow-up. The increase in toxicity with MEL200-ASCT did not adversely impact on efficacy. The addition of prednisone to lenalidomide maintenance significantly reduced the risk of progression in comparison with lenalidomide alone, without increasing the toxicity. Updated data with longer follow-up will be presented at the meeting. Disclosures: Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Gay:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Spencer:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Larocca:Celgene: Honoraria. Caravita:Celgene: Honoraria, Research Funding. Petrucci:Celgene: Honoraria. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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A Phase Ib/II Study of Combined Obinutuzumab (Gazyva) and High-Dose Methylprednisolone (HDMP) As Treatment for Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v128.22.2051.2051 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2051-2051 ◽

Cited By ~ 1

Author(s):

Januario E. Castro ◽

Michael Y. Choi ◽

Carlos I. Amaya-Chanaga ◽

Natalie Nguyen ◽

Colin MacCarthy ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Phase Iii ◽

High Dose ◽

Free Survival ◽

Phase Ib ◽

High Dose Methylprednisolone ◽

Grade 3

Abstract High-dose methylprednisolone (HDMP) and rituximab (R) is an effective non-myelosuppressive treatment regimen for patients (pts) with chronic lymphocytic leukemia (CLL). Also, this combination has shown activity even in pts who have adverse leukemia-cytogenetics, such as del17p. Phase III studies have demonstrated that CLL pts treated with chlorambucil and obinutuzumab-Gazyva (G), another anti-CD20 mAb, had a superior outcome than comparable pts treated with R-chlorambucil. We hypothesized that G-HDMP is well-tolerated and effective in the treatment of pts with CLL. Accordingly, we initiated an open-label phase Ib/II clinical study. A total of 40 pts were enrolled in two cohorts of 20 pts each (previously untreated (PU) and relapsed/refractory (RR) CLL) and treated with HDMP 1 g/m2on Day 1-3 of cycles 1-4 (28 days/cycle) and G administered based on FDA dosing recommendations for 6 cycles. The pts had a median age of 67 years + 9.1 in the RR cohort and 63 years + 8.3 in the PU cohort. The median baseline absolute lymphocyte count was 30.7 + 7.3 x1,000/mm3 for pts in the RR cohort and 47.6 + 19.7 x1,000/mm3for pts in the PU cohort. Pts showed the following cytogenetic abnormalities: del(17p) in 30% RR vs. 0% PU, del(13q) in 60% RR vs. 70% PU, del(11q) in 20% RR vs. 35% PU, and trisomy 12 in 15% RR vs. 20% PU. Most AEs were grade 1-2 (RR=87%; PU=93%) without development of dose-limiting toxicities. Only two pts needed therapy discontinuation. One pt due to pulmonary embolism and the second pt due to asymptomatic gastrointestinal bleeding that required blood transfusion and resolved spontaneously. Grade 1-2 G-infusion-related reactions (IRR) were observed in 40% and 80% of pts in the RR and PU cohorts, respectively. Grade 3-4 IRR were observed in 10% of pts in the PU cohort only. We observed cytopenias (neutropenia grade 3-4: RR=55%, PU=40%; thrombocytopenia grade 3-4: RR=35%, PU=20%; and anemia grade 3-4: RR=0%, PU=0%). There were no cases of febrile neutropenia. Two pts (10%) in the RR cohort and one pt (5%) in the PU cohort developed infection grade 1-2 that was treated with oral antibiotics but did not require study treatment discontinuation. The most frequent non-hematological adverse events (AEs) were transaminitis, hyperglycemia, and electrolyte alterations (grade 1-2). There were no treatment related deaths in either cohort. The response assessment was performed in all 40 pts by iwCLL criteria. The ORR was 100% in the PU cohort and 95% in the RR cohort. 70% of the pts in the PU cohort and 85% of the pts in the RR cohort achieved a PR. CR was observed in 30% and 10% of the pts in the PU and RR cohorts, respectively. One pt (5%) in the RR cohort and four pts (20%) in the PU cohort achieved MRDneg status (<0.01% CLL in the bone marrow by multiparameter flow cytometry). Only one pt in the RR cohort achieved SD. At a median follow-up of 12.2 months, the RR cohort had a median Progression Free Survival (PFS) of 13.6 months and median Treatment Free Survival (TFS) of 14.7 months; the median Overall Survival (OS) has not been reached. In the PU cohort, the median PFS, TFS and OS have not been reached. One pt from the RR cohort and one pt from the PU cohort died during the follow-up period due to disease progression. G-HDMP was well tolerated and all 40 pts showed hematological and clinical responses during the study treatment without development of unexpected AEs. In both cohorts, most of IRR were grade 1-2 and severe IRR (grade 3-4) were much less compared with previously published data (G-chlorambucil / CLL-11 study). Compared to pts in the CLL-11 study, cytopenias appeared to be more frequent, however, the rate of infection and need for IV antibiotics or hospitalizations was lower. Of note, the eligibility criteria allowed pts with severe cytopenias and transfusion requirement to participate in our study. Response in PU pts were higher in terms of ORR, CR and CR-MRDnegativecompared with the data from the CLL-11 study and suggests a possible synergistic activity between G and HDMP. Overall, G-HDMP was well tolerated in the PU and RR CLL pts with a lower rate of IRR making this regimen more manageable in the outpatient setting. Responses were higher than previously reported in PU pts. Responses in RR pts appear to be comparable to our previous studies using R-HDMP. Our data supports G-HDMP as an alternative combination regimen for the treatment of CLL pts. Disclosures Kipps: Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria.

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Real-World Efficacy of Venetoclax-Based Regimens in Patients with Chronic Lymphocytic Leukemia in Israel: A Multicenter Prospective Study

Blood ◽

10.1182/blood-2021-146504 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3727-3727

Author(s):

Yair Herishanu ◽

Neta Goldschmidt ◽

Gilad Itchaki ◽

Itai Levi ◽

Ariel Aviv ◽

...

Keyword(s):

Real World ◽

Interim Analysis ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Phase Iii ◽

Publicly Traded ◽

Phase Iii Clinical Trials ◽

Medical Centers ◽

Grade 3

Abstract Background: The BCL-2 inhibitor venetoclax in combination with an anti-CD20 monoclonal antibody (rituximab or obinutuzumab) has demonstrated superior outcomes and manageable safety as compared to chemo-immunotherapy in phase III clinical trials for chronic lymphocytic leukemia (CLL). Moreover, venetoclax-based regimens induced high rates of undetectable minimal residual disease (uMRD). Prospective data on the effectiveness of venetoclax-based regimens specifically with regard to achieving uMRD in a real-world setting are still lacking. Here we report the first interim analysis for efficacy and safety of an ongoing nationwide real-world study of venetoclax based therapy for CLL/small lymphocytic lymphoma (SLL). Method: A prospective observational nationwide multicenter study. Treatment-naïve (TN) and relapsed/refractory (R/R) CLL/SLL patients were enrolled in 13 medical centers in Israel. The primary endpoint was clinical response, per physician assessment 12-months after the initiation of venetoclax treatment. Key secondary endpoints included progression free survival (PFS), overall survival (OS) and uMRD as assessed at a central laboratory by 8-color flow-cytometry. Results: Between February 10, 2019, and Jun 17, 2021 (data cut), 199 CLL/SLL patients were enrolled from 13 medical centers in Israel to receive venetoclax based therapy. The study included 83 TN and 116 R/R evaluable CLL/SLL patients with a median age of 69 years (range, 34-85) and 70.5 years (range, 25-91), respectively (Table 1). R/R patients had received a median of one prior therapy with a range up to 8, of these patients 60 (51.7%) were previously treated with a B-cell receptor inhibitor (BCRi) including ibrutinib in 52 (44.8%) and idelalisib in combination with rituximab in 6 (5.2%). TN patients had been treated with venetoclax in combination with obinutuzumab (92.8%) or rituximab (4.8%) and R/R patients received either venetoclax with rituximab (60.3%) or obinutuzumab (9.5%), venetoclax monotherapy (25.8%) or triple therapy with venetoclax, rituximab and ibrutinib in 5 (4.3%). Dose escalation of venetoclax to the recommended dose of 400 mg daily was achieved in 80.7% (n=67) of TN and 81% (n=94) of R/R patients. The median duration of ramp-up was 38 and 42 days in TN and R\R patients, respectively. Prior to therapy, tumor lysis syndrome (TLS) risk was considered high in 12% and 29.3% of TN and R/R patients, respectively (Table 1). Laboratory TLS occurred in one TN patient and 4 R/R patients, whereas 3 of the R/R patients experienced clinical TLS. Nineteen TN and 75 R/R patients had a follow-up of at least 12 months or discontinued study prematurely. The 12-month overall response rate (ORR) for TN and R/R patients was 89.5% [complete response (CR) 13 (68.4%), partial response (PR) 4 (21.1%)] and 73.3% [CR 37 (49.3%), PR 18 (24%)], respectively. In the R/R cohort, the 12-month ORR among assessed patients was 67.6% (25/37) in BCRi-exposed versus 85.7% (30/35) in BCRi-naïve patients. At 12 months, peripheral blood uMRD (<0.01%) was achieved in 12 out of 14 (85.7%) TN and 26 out of 38 (68.4%) R/R evaluated patients. At a median follow-up of 5.1 months (range, 0.5-15.6) for TN and 10.1 months (range, 0-25.7) for R/R patients, the median PFS and OS, for both cohorts have not been reached. The estimated 12-month PFS was 90.9% for TN and 81.1% for R/R patients. For R/R patients with prior exposure to BCRi, the estimated 12-month PFS was 69.6% versus 94.8% in BCRi-naïve patients (figure 1). Grade ≥3 adverse events (AEs) were reported in 34.9% of TN patients and 43.9% R/R patients. The most frequent grade ≥3 AEs documented were neutropenia (TN: 19.2% and R/R 17.2%), infections (TN: 4.8% and R/R: 21.5%) and febrile neutropenia (TN: 2.4% and in R/R: 2.6%). COVID-19 occurred in 7 patients including one death. At the time of data cut, 10 deaths occurred, one TN and 9 R/R patients. Causes for death included infections (5 patients), disease progression (2 patients), acute myeloid leukemia/ myelodysplastic syndrome (2 patients) and a soft-tissue sarcoma (1 patient). Conclusions: This first interim analysis of our ongoing prospective real-world study of venetoclax-based treatment for TN and R/R CLL/SLL, demonstrates high efficacy together with a high proportion of undetectable MRD levels and a favorable toxicity profile. These efficacy results are comparable to those reported in previous Phase III clinical trials for CLL, with no new safety signals. Figure 1 Figure 1. Disclosures Herishanu: AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; AstraZeneca: Honoraria. Goldschmidt: AbbVie: Consultancy, Research Funding. Itchaki: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Levi: AbbVie: Consultancy, Research Funding. Aviv: AbbVie: Honoraria, Research Funding. Fineman: AbbVie: Research Funding. Dally: AbbVie: Honoraria, Research Funding. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Ruchlemer: AbbVie: Consultancy, Honoraria, Research Funding. Abadi: AbbVie: Honoraria, Research Funding. Shvidel: AbbVie: Honoraria, Research Funding. Braester: AbbVie: Honoraria, Research Funding. Cohen: AbbVie: Current Employment, Current equity holder in publicly-traded company. Frankel: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ofek: AbbVie: Current Employment, Current equity holder in publicly-traded company. Berelovich: AbbVie: Current Employment, Current equity holder in publicly-traded company. Grunspan: AbbVie: Current Employment, Other: May hold equity. Benjamini: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding.

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Safety of everolimus for women over age 65 with advanced breast cancer (BC): 12.5-month follow-up of BOLERO-2.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.27_suppl.104 ◽

2012 ◽

Vol 30 (27_suppl) ◽

pp. 104-104 ◽

Cited By ~ 3

Author(s):

Hope S. Rugo ◽

Howard A. Burris ◽

Michael Gnant ◽

José Baselga ◽

Martine J. Piccart-Gebhart ◽

...

Keyword(s):

Elderly Patients ◽

Postmenopausal Women ◽

Mammalian Target Of Rapamycin ◽

Safety Data ◽

Progression Free Survival ◽

Phase Iii ◽

Tolerability Profile ◽

Once Daily ◽

Grade 3

104 Background: Postmenopausal women with estrogen-receptor–positive (ER+) BC who relapse/progress on a nonsteroidal aromatase inhibitor (NSAI) are usually treated with the steroidal AI exemestane (EXE), but there is no currently approved treatment for this indication. The BOLERO-2 trial showed that adding everolimus (EVE), an oral inhibitor of mammalian target of rapamycin (mTOR), to EXE significantly improved clinical benefit beyond that of EXE alone (Hortobagyi et al, SABCS 2011, Abstract S3-7). As many women with advanced BC are elderly, the tolerability profile of EVE + EXE in this population is of interest. Methods: BOLERO-2 is a phase III, randomized trial comparing EVE (10 mg once daily) vs placebo (PBO), both plus EXE (25 mg once daily), in postmenopausal women with advanced ER+ BC progressing or recurring after NSAIs. Safety data with a focus on elderly patients are reported at 12.5 months’ median follow-up. Results: Baseline disease characteristics, age, and prior cancer therapy were well balanced between treatment arms (N = 724). At 12.5 months’ median follow-up, the addition of EVE to EXE significantly improved progression-free survival in patients <65 (HR, 0.37; p < .05) or ≥65 years of age (HR, 0.56; p < .05). Adverse events (AEs) of special interest (all grades) occurring more frequently with EVE vs PBO (overall study population) included stomatitis (66.6% vs 11.3%), infection (50.4% vs 25.2%), rash (44.0% vs 8.4%), pneumonitis (18.7% vs 0.4%), and hyperglycemia (15.4% vs 2.5%). Elderly EVE-treated patients (≥65 years) had similar or marginally lower incidence of stomatitis (52.1%), rash (32.3%), pneumonitis (14.6%), and hyperglycemia (12.5%) compared with the overall population. Grade 3-4 AEs in patients ≥70 years of age (n = 161) reported only among patients receiving EVE (n = 118) included fatigue (10.2%), anemia (10.2%), hyperglycemia (8.5%), stomatitis (7.6%), dyspnea (6.8%), pneumonitis (5.1%), neutropenia (3.4%), and hypertension (3.4%). Conclusions: Adding EVE to EXE was well tolerated in the overall population and in elderly patients with advanced BC; grade 3-4 AEs were uncommon and manageable. Overall, AEs were consistent with the known safety profile of EVE.

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Neurotoxicity of Axicabtagene Ciloleucel and Long-Term Outcomes - in a Minority Rich, Ethnically Diverse Real World Cohort

Blood ◽

10.1182/blood-2021-153917 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4842-4842

Author(s):

Ryann Quinn ◽

Astha Thakkar ◽

Sumaira Zareef ◽

Richard Elkind ◽

Karen Wright ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Research Funding ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Grade 3

Abstract Introduction Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of B- cell malignancies leading to durable responses in patients with relapsed/refractory disease. 1,2 One of the most severe toxicities associated with this treatment is immune effector cell-associated neurotoxicity syndrome (ICANS), which was seen in 65-75% of patients treated with axicabtagene ciloleucel (axi-cel) in initial clinical trials. ICANS can range from mild headache to coma, and can occur with or without cytokine release syndrome (CRS). Due to the recent development of CAR T-cell therapy, the long-term effects of ICANS are unknown. This study sought to determine the long-term outcomes in patients with neurotoxicity from axi-cel. Methods We conducted a retrospective chart review of patients who received CAR T-cell therapy with axi-cel between June 2018 and June 2021. Neurotoxicity was graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) ICANS grading system. 3 The primary outcome was percentage of patients who had neurotoxicity defined as ICANS grade ≥ 1 as well as the percentage of patients with neurotoxicity lasting ≥ 1 month. We captured descriptive data such as age, sex, ethnicity, comorbidities, IPI score, stage, baseline neurologic dysfunction, performance status, and number of prior treatments. Secondary outcomes included progression free survival (PFS) and overall survival (OS). Results Thirty-four patients received axi-cel between June 2018 and June 2021 at our institution. Median age of patients was 65. Twenty patients (59%) were male and 14 (41%) were female. The majority of patients received axi-cel for diffuse large B-cell lymphoma (97%). Study population was predominantly hispanic (35%), white (32%), African american (29%) and asian (3%). (Sixteen patients (47%) developed neurotoxicity of any grade, with 7 patients (21%) ≥ grade 3. Of note, 4 patients (12%) died during admission for CAR T-cell therapy and 3/4 deaths were in patients with ICANS ≥ grade 3. Median follow up time was 8 months. Of the 12 patients with neurotoxicity who survived initial admission for CAR-T, 9 (75%) patients recovered from neurotoxicity and mental status was at baseline at discharge without recurrence during follow up. Three (25%) of patients had prolonged neurotoxicity lasting > 1 month. Long-term neurotoxicity included confusion, disorientation, and mild cognitive impairment in the three patients. One patient recovered 15 months after CAR T-cell infusion. 2 patients had prolonged neurotoxicity resulting in deterioration of functional status and death in 1 patient, and 1 patient transitioning to hospice and being lost to follow up. Conclusions Neurotoxicity from axicabtagene ciloleucel is a common adverse event, with half of patients in our cohort having neurotoxicity of some degree, and 20% ≥ grade 3. Twenty-five percent of patients that developed neurotoxicity had long-term effects lasting > 1 month, which resulted in deterioration of functional status in 2 patients. Long-term neurotoxicity included disorientation, confusion, and memory impairment. Our study is limited by a small sample size. Larger studies with longer follow-up times are needed to further characterize the long-term outcomes of neurotoxicity associated with CAR T-cell therapy. Neurotoxicity can be confounded by other causes of neurological dysfunction in these patients such as hospital delirium, chemotherapy toxicity, encephalopathy from infection, and subtle baseline neurologic dysfunction that may not be apparent at presentation. Next steps include prospective evaluation of patients with formal neurology evaluation prior to CAR T-cell therapy and periodically after treatment, in order to objectively monitor late neurologic effects of CAR T-cell therapy. 1. Fl, L. et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 20, (2019). 2. Jacobson, C. Primary Analysis of Zuma-5: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL). in (ASH, 2020). 3. Dw, L. et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant. 25, (2019). Disclosures Gritsman: iOnctura: Research Funding. Shastri: Onclive: Honoraria; Guidepoint: Consultancy; GLC: Consultancy; Kymera Therapeutics: Research Funding. Verma: Celgene: Consultancy; BMS: Research Funding; Stelexis: Current equity holder in publicly-traded company; Curis: Research Funding; Eli Lilly: Research Funding; Medpacto: Research Funding; Novartis: Consultancy; Acceleron: Consultancy; Stelexis: Consultancy, Current equity holder in publicly-traded company; Incyte: Research Funding; GSK: Research Funding; Throws Exception: Current equity holder in publicly-traded company.

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Dasatinib 140 Mg Once Daily (QD) Has Equivalent Efficacy and Improved Safety Compared with 70 Mg Twice Daily (BID) in Patients with Imatinib-Resistant or -Intolerant Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL): 2-Year Data from CA180- 035

Blood ◽

10.1182/blood.v112.11.2926.2926 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2926-2926 ◽

Cited By ~ 2

Author(s):

Richard A. Larson ◽

Oliver G. Ottmann ◽

Neil P. Shah ◽

Michael B. Lilly ◽

Josy M. Reiffers ◽

...

Keyword(s):

Lymphoblastic Leukemia ◽

Chromosome Rearrangement ◽

Philadelphia Chromosome ◽

Phase Iii ◽

Cell Transplant ◽

Once Daily ◽

Imatinib Resistant ◽

Equivalent Efficacy ◽

Grade 3

Abstract Patients with ALL who have the Ph chromosome rearrangement and the resulting BCR-ABL oncogene represent 20–40% of cases of adult ALL and have an adverse prognosis. Even with current standard therapies, which comprise aggressive multi-agent chemotherapy, imatinib, and allogeneic stem cell transplant, there is a high risk of relapse. Dasatinib (SPRYCEL®) is a potent BCR-ABL inhibitor, and has 325-fold greater potency than imatinib against unmutated BCR-ABL in vitro. Dasatinib is also active against SRCfamily kinases, which may have a role in Ph+ ALL pathogenesis. Following a phase II trial, dasatinib was approved for the treatment of imatinib-resistant or -intolerant Ph+ ALL. CA180-035 is a randomized, phase III, open-label trial comparing dasatinib 140 mg QD with 70 mg BID in patients with advanced CML (accelerated or blast phase) or Ph+ ALL. The primary trial objective was to compare the major hematologic response (MaHR) rates of QD and BID dosing schedules. Secondary objectives included comparison of major cytogenetic response (MCyR) rates, time to and duration of response, progressionfree survival (PFS), overall survival (OS), and safety profiles between the two schedules. Preliminary analyses from this study have demonstrated that QD treatment is associated with equivalent efficacy and less frequent key adverse events (AEs) compared with BID treatment. Here, results are reported in 84 patients with Ph+ ALL randomized to QD (n=40) or BID (n=44) schedules with a minimum of 2 years of follow-up. MaHR rates were similar with dasatinib administered QD (38%) or BID (32%), and all MaHRs were achieved within 4 months. Of the 15 patients (QD) and 14 patients (BID) who achieved a MaHR, median durations were 4.6 and 11.5 months, respectively. A MCyR was achieved by 70% (QD) and 52% (BID) of patients, with median durations of 4.1 and 4.4 months, respectively. Excluding patients that were BCR-ABL positive, Ph negative (n=11), rates of MCyR were nearly identical (QD 69% vs BID 51%). Estimated 24-month rates of OS were similar in QD and BID groups (11% vs 20%; hazard ratio 1.26, 95% CI 0.78–2.04). Dasatinib was generally well tolerated. The most common grade 3/4 nonhematologic AEs in both groups included diarrhea (5% in both groups) and nausea (QD 3% vs BID 5%). Fewer patients experienced a pleural effusion when dasatinib was administered QD (all grades, 18%; grade 3–5, 5%) vs BID (all grades, 32%; grade 3–5, 14%). The incidence of grade 3/4 cytopenia was similar in both groups, including neutropenia (QD 67% vs BID 72%) and thrombocytopenia (QD 72% vs BID 61%). Fewer patients required dose reductions for toxicity with QD (10%) vs BID (23%) treatment. Median durations of dasatinib therapy were 3.4 months in the QD group and 2.5 months in the BID group, although these were longer in patients who achieved a MaHR (4.6 and 5.9 months, respectively). Median average daily doses were 140 mg (QD) and 138 mg (BID). At last follow-up, most patients had discontinued therapy, with disease progression (QD 70% vs BID 75%) the most common cause. In conclusion, findings from the CA180-035 trial in patients with Ph+ ALL are consistent with previous data and demonstrate that dasatinib is associated with durable treatment responses in a proportion of patients with a poor prognosis who are resistant or intolerant to imatinib. Compared with the approved BID dosing schedule, dasatinib administered as a once-daily dose has equivalent efficacy, provides greater convenience, and may have improved safety in this patient group.

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A Phase III PETHEMA/GEM Study of Induction Therapy Prior Autologous Stem Cell Transplantation (ASCT) In Multiple Myeloma: Superiority of VTD (Bortezomib/Thalidomide/Dexamethasone) Over TD and VBMCP/VBAD Plus Bortezomib

Blood ◽

10.1182/blood.v116.21.307.307 ◽

2010 ◽

Vol 116 (21) ◽

pp. 307-307 ◽

Cited By ~ 12

Author(s):

Laura Rosiñol ◽

María Teresa Cibeira ◽

Maria Victoria Mateos ◽

Joaquin Martinez ◽

Albert Oriol ◽

...

Keyword(s):

High Risk ◽

Induction Therapy ◽

Research Funding ◽

Progression Free Survival ◽

Phase Iii ◽

Eligibility Criteria ◽

Advisory Committees ◽

Intention To Treat ◽

Grade 3

Abstract Abstract 307 Introduction: In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) activated a randomized phase III trial comparing TD vs. VTD vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM followed by ASCT with MEL-200. Primary end points: response rate after induction and after ASCT and time to progression. Patients and Method: TD consisted of thalidomide 200 mg daily (escalating doses in the first cycle) and dexamethasone 40 mg on days 1–4 and 9–12 at 4-week intervals for 6 cycles. The VTD regimen was identical to TD plus bortezomib 1.3 mg/m2 on days 1,4,8,11 of each cycle. Combination chemotherapy plus bortezomib consisted of 4 cycles of VBMCP/VBAD on an alternating basis followed by 2 cycles of bortezomib (1.3 mg/m2 on days 1,4,8, and 11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. From April 6, 2006 to August 5, 2009 the 390 planned patients entered the study. Four patients failed the eligibility criteria. 386 patients (median age: 56 yrs; M: 207, F: 179; IgG: 233, IgA: 85, light chain: 57, IgD: 9, Ig M: 2) were analyzed. The stage according to the ISS was I in 147 patients, II in 160, III in 75 and unknown in 4 and 66 patients (17%) had extramedullary soft-tissue plasmacytomas (EMP). Seventy out of the 330 patients (21%) with cytogenetic studies had high-risk cytogenetics (t(4;14), t(14;16), and/or 17p deletion). One-hundred and thirty patients were allocated to VTD, 127 to TD and 129 to VBMCP/VBAD/B. Prognostic factors, including cytogenetics, were similar in the 3 arms. Response, survival and toxicity were evaluated on an intention-to-treat basis. Responses reported by investigators were centrally reassessed. Result: The IFE negative CR rate was significantly higher with VTD (35%) compared to TD (14%) and VBMCP/VBAD/B (22%) (p=0.0001 and p=0.01, respectively). The progressive disease (PD) rate during induction was significantly lower with VTD than with TD (7% vs. 23%, p=0.001). In patiens with high-risk cytogenetics, the CR rate was significantly greater with VTD when compared with TD (35% vs. 0%, p=0.002) and with VBMCP/VBAD/B (35% vs. 22%, p=0.02). The CR rate to VTD in patients with 17p deletion was 58% while none of the patients with this cytogenetic abnormality responded to TD or to VBMVP/VBAD/B (p=0.03 and p=0.02, respectively). Of interest, the CR rate in patients with t(11;14) was significantly lower than in patients lacking this abnormality (11% vs. 27%, p=0.01). This low CR rate in patients with t(11;14) was similar in the 3 arms. In the overall series, PD was significantly higher in patients with EMP (24% vs. 11%, p=0.01) with a significantly higher PD rate for TD as compared to VTD (40% vs. 12%, p=0.02). The incidence of thrombotic events was 2%, 6% and 5% for VTD, TD and VBMCP/VBAD/B, respectively (p=NS). The frequency of grade ≥ 3 peripheral neuropathy was 12% with VTD compared to 1% in both the TD and the VBMCP/VBAD/B arms (p= 0.0002). Treatment was discontinued due to toxicity en 16 patients (VTD:9, TD:4, VBMCP/VBAD/B:3). Nine patients died during the induction period (3 in each arm). On an intention to treat basis, the post-ASCT CR rate was higher in the VTD arm compared with TD (46% vs. 24%, p=0.004) and VBMCP/VBAD/B (46% vs. 38%, p=0.1). The estimated overall survival (OS) at 4 years was 76% with no significant differences among the 3 arms. After a median follow-up of 27 months, the progression-free survival (PFS) was not reached with VTD while it was 27 and 38 months with TD and VBMCP/VBAD/B, respectively (p=0.006). In the overall series, patients with high-risk cytogenetics had a significantly shorter OS (p=0.00007) and PFS (p=0.004). In addition, when compared with the good-risk group, patients with high-risk cytogenetics showed a trend towards a shorter PFS either after induction with VTD (median not reached vs. 17 months, p=0.05) and with TD (median 28 vs. 15 months, p=0.09). Conclusion: Induction with VTD resulted in a significantly higher CR rate in both the overall series and in patients with high-risk cytogenetics. The post-ASCT CR rate was also significantly higher with VTD than with TD and there was a trend when compared with VBMCP/VBAD/B. Finally, VTD resulted in a significantly longer PFS. However, longer follow-up is required to establish whether or not VTD will overcome the poor prognosis of patients with high-risk cytogenetics. Disclosures: Rosiñol: Janssen-Cilag: Honoraria; Celgene: Honoraria. Off Label Use: Bortezomib and Thalidomide are not approve for first line in Spain. Cibeira:Janssen-Cilag: Honoraria; Celgene: Honoraria. Mateos:Janssen-Cilag: Honoraria; Celgene: Honoraria. Oriol:Janssen-Cilag: Honoraria; Celgene: Honoraria. García-Laraña:Janssen-Cilag: Honoraria; Celgene: Honoraria. De La Rubia:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sureda:Janssen-Cilag: Honoraria; Celgene: Honoraria. Díaz-Mediavilla:Janssen-Cilag: Honoraria. Alegre:Janssen-Cilag: Honoraria; Celgene: Honoraria. Lahuerta:Janssen-Cilag: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria, Speakers Bureau. Blade:Janssen-Cilag: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

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Dasatinib Dose-Optimization in Chronic Phase Chronic Myeloid Leukemia (CML-CP): Two-Year Data from CA180-034 Show Equivalent Long-Term Efficacy and Improved Safety with 100 Mg Once Daily Dose

Blood ◽

10.1182/blood.v112.11.3225.3225 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3225-3225 ◽

Cited By ~ 13

Author(s):

Neil P. Shah ◽

Dong-Wook Kim ◽

Hagop M. Kantarjian ◽

Philippe Rousselot ◽

Pedro Dorlhiac-Llacer ◽

...

Keyword(s):

Pleural Effusion ◽

Median Time ◽

Chronic Phase ◽

Phase Iii ◽

Dose Optimization ◽

Once Daily ◽

Term Efficacy ◽

Grade 3

Abstract Dasatinib (SPRYCEL®) is an effective BCR-ABL inhibitor and is 325-fold more potent than imatinib in vitro against unmutated BCR-ABL. CA180-034 is a randomized, phase III, open-label study in patients with CML-CP (N=670) who have resistance, suboptimal response, or intolerance to prior imatinib 400–800 mg/d. Patients were randomized using a 2×2 factorial design to one of four treatment arms: 100 mg once daily (QD), 70 mg twice daily (BID), 140 mg QD, or 50 mg BID. Time to and duration of response, progressionfree survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis. Earlier reports demonstrated that dasatinib 100 mg QD (the currently approved dose in CML-CP) maintains efficacy while significantly minimizing adverse events (AEs). This finding was supported by pharmacokinetic analyses, which have demonstrated a correlation between low dasatinib steady-state trough plasma concentration (achieved with 100 mg QD dosing) and less frequent key toxicities and fewer dose interruptions. With a minimum of 2 years of follow-up in all patients, dasatinib 100 mg QD treatment resulted in a MCyR rate of 63% and a CCyR rate of 50%, and rates were similar in the other 3 arms (MCyR: 61%–63%; CCyR 50%–54%) (Table). Rates were similar when 14 patients with Ph-negative BCR-ABL-positive disease were excluded. Among responding patients in the 100 mg QD arm, median time to MCyR was 12.4 weeks and to CCyR was 13.0 weeks, and after 24 months, 87% of patients had maintained their MCyR and 89% had maintained their CCyR, with similar results in other arms. The 24-month PFS rate with 100 mg QD was 80% (vs 75%–76% in other arms) and OS rate was 91% (vs 88%–94%). In all arms, high response rates were achieved in patients with or without a baseline BCR-ABL mutation (CCyR rates for 100 mg QD: 40% vs 54%, respectively). Dasatinib was well tolerated and the incidence of treatment-related AEs after a minimum of 2 years of follow-up was similar to rates after a minimum of 1 year. In the 100 mg QD arm, overall 2-year rates (vs 1 year) were 2% (vs 2%) for grade 3 pleural effusion (grade 4: 0%), 23% (vs 22%) for grade 3/4 thrombocytopenia, and 35% (vs 34%) for grade 3/4 neutropenia. Among the 4 treatment arms, significant differences were observed in the overall incidences of drug-related pleural effusions (all grades: p=0.049) and cytopenias (p=0.003 for grade 3/4 thrombocytopenia), with lowest rates observed for 100 mg QD. After a minimum of 2 years of 100 mg QD treatment, 12% of patients discontinued therapy following drug toxicity (vs 6% after 1 year), compared with 2-year rates of 16%–21% in other arms. Overall, 2-year data from CA180-034 extend previous findings and demonstrate that dasatinib dose optimization at 100 mg QD is associated with minimal incidence of key grade 3/4 toxicities in Year 2, and maintains long-term efficacy, in patients with CML-CP following resistance, suboptimal response, or intolerance to prior imatinib. Response duration and PFS with dasatinib 100 mg QD are similar to other dose schedules. Table 100 mg QD 70 mg BID 140 mg QD 50 mg BID All randomized patients n=167 n=168 n=167 n=168 CHR (%) 92 88 87 92 MCyR (%) 63 61 63 61 Median time to MCyR (wks) 12.4 12.3 12.3 12.3 MCyR maintained at 24 mos (%) 87 88 68 88 CCyR (%) 50 54 50 50 Median time to CCyR (wks) 13.0 12.9 13.8 12.9 CCyR maintained at 24 mos (%) 89 85 78 93 24-month PFS (%) 80 76 75 76 24-month OS (%) 91 88 94 90 Excluding Ph(−) BCR-ABL(+) n=164 n=163 n=163 n=166 MCyR (%) 63 61 63 61 CCyR (%) 49 53 50 50 All treated patients n=165 n=167 n=163 n=167 Pleural effusion (drug-related), grade 3/4 (%) 2 5 5 4 Neutropenia, grade 3/4 (%) 35 45 44 47 Thrombocytopenia, grade 3/4 (%) 23 38 41 36 Dose interruption (%) 62 77 79 72 Dose reduction (%) 39 62 62 46

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Alemtuzumab can be Incorporated Into Front-Line Therapy of Adult Acute Lymphoblastic Leukemia (ALL): Final Phase I Results of a Cancer and Leukemia Group B Study (CALGB 10102).

Blood ◽

10.1182/blood.v114.22.838.838 ◽

2009 ◽

Vol 114 (22) ◽

pp. 838-838 ◽

Cited By ~ 30

Author(s):

Wendy Stock ◽

Ben Sanford ◽

Gerard Lozanski ◽

Ravi Vij ◽

John C. Byrd ◽

...

Keyword(s):

T Cell ◽

Phase I ◽

B Cell ◽

Phase Ii ◽

Dose Escalation ◽

Research Funding ◽

Front Line ◽

Line Therapy ◽

Grade 3

Abstract Abstract 838 Eradication of minimal residual disease (MRD) during the first months of ALL treatment is associated with improved disease-free survival (DFS). We hypothesized that alemtuzumab, a humanized anti-CD52 monoclonal antibody, might be an effective, novel agent for eradication of MRD. In CALGB 10102, we tested dose escalation of alemtuzumab in sequential cohorts of CD52+ cases to a target dose of 30 mg administered SC 3 times/week for 4 weeks (12 doses) during post-remission therapy. Dose limiting toxicity (DLT) was defined as the inability to proceed with protocol treatment within 6 weeks after the last dose of alemtuzumab. Eligible patients (pts) had ≥10% lymphoblast CD52 expression at diagnosis determined in a CALGB reference laboratory. Antimicrobial prophylaxis for cytomegalovirus (CMV) and Pneumocystis carinii was mandated. The 10102 therapy consisted of 6 monthly chemotherapy modules followed by maintenance therapy for a total of 2 years (Stock et al. ASH 2005, abstr 145); 299 untreated ALL pts were eligible and enrolled from 2003–2007. We previously reported (Lozanski et al. ASH 2007, abstr 2386) that 70% were CD52+ and eligible to receive Alemtuzumab (70% of B-cell ALL; 53% of T-cell ALL; 100% of Ph+ cases). Results: Twenty-four pts in remission (CR1) received Alemtuzumab as their fourth treatment module during the Phase I portion of the study. The median age was 37 years (18-77 years); 18 (80%) had B-cell ALL; 5 (19%) had T-cell ALL. 17/24 cases had evaluable cytogenetics after central review: 5 had favorable, 8 intermediate-risk, 2 poor-risk cytogenetics (neither were Ph+), and 2 were not classifiable (miscellaneous abnormalities). Non-hematologic toxicities were mild. SC alemtuzumab was well tolerated. Grade 3-4 myelosuppression was reported during 4 weeks of alemtuzumab treatment in 4 pts; 2 pts had Grade 3-4 lymphopenia. 4 pts had DLT: subsequent treatment was delayed in 2 due to transient CMV viremia; 1 developed Staph aureus empyema; and 1 had prolonged myelosuppression but did not receive G-CSF support as recommended by the protocol. 3 pts relapsed with ALL immediately following completion of the alemtuzumab module. Serial assessment of MRD using quantitative clone-specific PCR was possible in 11/24 cases. There was a median 1-log decrease in MRD during alemtuzumab therapy in the 20 and 30 mg cohorts. However, there was a 2-log rise during alemtuzumab therapy in one pt who relapsed 6 weeks later. Pharmacokinetic analysis revealed rising alemtuzumab serum levels during treatment in all dose cohorts, and levels were still detectable in some pts 10 weeks after completing alemtuzumab. During subsequent post-remission therapy, 8 pts developed CMV viremia, 2 had Herpes simplex infections, and 3 had Herpes zoster reactivation. There was not a significant correlation between serum alemtuzumab level and change in MRD or risk of viral infection. The median follow-up time for the 14 surviving pts is 51 months (49-54 months). Median DFS is 53 months (95% CI, 39 – not reached); median overall survival is 55 months (95% CI, 42- not reached). Conclusions: CD52 is expressed in the majority of adult ALL cases. Addition of alemtuzumab to front-line therapy is feasible and provides reduction in MRD, but is associated with viral infections. Dose escalation of alemtuzmab was not associated with DLT. Based on these results, the 30 mg dose of alemtuzumab was explored in an additional 70 patients in the Phase II portion of the study. The encouraging DFS results reported here require confirmation from longer follow-up of the larger Phase II cohort of patients. Disclosures: Stock: Genzyme: Research Funding. Off Label Use: The testing of alemtuzumab for treatment of ALL in adults. Lozanski:Genzyme: Research Funding. Vij:CELGENE: Honoraria, Research Funding, Speakers Bureau. Powell:Antisoma: Research Funding. Sher:invivoscribe: Employment. Richards:Genzyme: Employment. Sung:genzyme: Employment.

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