A Phase II Study of AT9283, an Aurora Kinase Inhibitor, in Patients with Relapased or Refractory Multiple Myloma; NCIC Clinical Trials Group IND.191

Abstract Background:Although outcomes for patients with multiple myeloma (MM) have improved, it remains an incurable malignancy for which new therapies are needed. Aurora kinases are overexpressed in MM. Inhibition of Aurora A kinase, a key component of the centrosome, in MM cell lines induces apoptotic cell death. Inhibition of Aurora B, a chromosome passenger protein, has therapeutic effects against myeloma lines, primary bone marrow plasma cells and murine xenografts. Histone H3 is a direct downstream substrate of Aurora B. The Aurora A and B kinase inhibitor AT9283 has shown anti-myeloma activity in pre-clinical studies. Based on an NCIC CTG phase I trial in patients with advanced malignancy the recommended phase 2 dose (RP2D) was 40 mg/m2 on days 1 and 8 of a 21 day cycle. This single arm phase II trial was designed to explore the efficacy of AT9283 in patients with relapsed and refractory multiple myeloma. Methods: Eligibility criteria included age ≥ 18, neutrophils ≥ 1 and platelets ≥ 70 x109/L. There was no upper limit on the number of prior regimens. The primary endpoint was response rate; secondary endpoints included toxicity and evaluation of potential biomarkers. According to the 2-stage design at least 1 response was required in the first 15 patients to proceed to a full sample size of 30, assuming an HA of ≥ 0.20. Initially AT9283 was administered by 24 hour continuous infusion at the RP2D. Hematological toxicity in the first 2 patients met protocol specified criteria for reduction of the starting dose to 30 mg/m2 for subsequent patients. Adverse events were graded according to CTCAE V4.0. Phosphorylated Histone H3 (Ser10), a marker of Aurora B activity, and total Histone H3 protein expression was measured by western blot analysis in baseline and day 21 bone marrow samples. Results:Over 18 months, eight eligible patients (3 male, 5 female) with MM (4 IgG, 2 IgA, 2 light chain) were accrued. All were evaluable for toxicity and 7 evaluable for response. Median age was 60 (range 48 – 75). The median number of prior regimens was 3 (range 1 - 5). Patients received between 1 – 4 cycles of AT9283 (median 1) with 25% of patients receiving ≥ 90% of the planned dose intensity. No responses were observed. The trial was closed due to slow accrual and toxicity, in particular myelosuppression. Transient neutropenia occurred in all patients (63% grade 3, 37% grade 4). Recovery from nadir to normal range was rapid in the majority (range 1 – 8 days, median 5) but prolonged in 2 patients who were neutropenic at baseline (11 and 13 weeks). Grade 3/4 thrombocytopenia occurred in 50% of patients. There were 3 infections ≥ grade 3 including 1 death. Grade 3 skin ulceration thought possibly related to AT9283 by the investigator occurred in 1 patient. The most common non-hematologic adverse events reported as possibly, probably or definitely related to AT9283 were grade 1-3 nausea (50%), grade 1 and 3 vomiting (38%), grade 4 febrile neutropenia (25%), grade 1/2 anorexia (25%), grade 1/2 diarrhea (25%) and grade 1/2 fatigue (25%). Paired baseline and day 21 bone marrow samples were provided from 4 patients; sufficient protein was extracted from both samples for western blot analysis from 3 patients. Of these, 2 showed a reduction in Histone 3 phosphorylation (H3-P) after the first cycle of treatment consistent with inhibition of Aurora B. Both of these patients had a best response of stable disease (SD). Abstract 5734. Table Patient Dose (mg/m2) Number of cycles Best response Non-hematological toxicity ≥ Grade 3* Reason off study H3-P/H3Baseline Day 21 1 40 1 PD Gr 3 skin ulceration Toxicity 0.3 0.5 2 40 1 SD Gr 3 lung infection Intercurrent illness 1.6 0.5 3 30 3 SD None PD 0.6 0.5 4 30 1 PD Gr 4 febrile neutropenia & gr 4 left ventricular systolic dysfunction Toxicity NE NE 5 30 1 NE Gr 4 febrile neutropenia & gr 5 sepsis** Death NE NE 6 30 4 PD Gr 3 nausea & vomiting PD NE NE 7 30 3 SD None PD NE NE 8 30 1 PD None Death NE NE * Reported as possibly, probably or definitely related to AT9283 by investigator ** Neutrophil count recovered to normal range prior to death PD progressive disease, NE not evaluable, Gr grade Conclusions: This study failed to reach full accrual. No objective responses were observed. Administration of AT9283 to patients with previously treated myeloma at this dose and schedule is associated with toxicity, particularly myelosuppression. Disclosures Sandhu: Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Reece:Otsuka: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Millenium: Honoraria, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria. Lyons:Astex: Employment. Seymour:Astex: Research Funding.

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A Phase I Dose Escalation Study of KW-2449, An Oral Multi-Kinase Inhibitor against FLT3, Abl, FGFR1 and Aurora in Patients with Relapsed/Refractory AML, ALL and MDS or Resistant/Intolerant CML

Blood ◽

10.1182/blood.v112.11.2967.2967 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2967-2967 ◽

Cited By ~ 9

Author(s):

Jorge Cortes ◽

Gail J. Roboz ◽

Hagop M. Kantarjian ◽

Eric J. Feldman ◽

Judith E. Karp ◽

...

Keyword(s):

Atrial Fibrillation ◽

Bone Marrow ◽

Febrile Neutropenia ◽

Kinase Inhibitor ◽

De Novo ◽

Recovery Period ◽

Post Dose ◽

Grade 3 ◽

Dose Levels ◽

Bone Marrow Blasts

Abstract Background: Activating mutations of FMS-like tyrosine kinase 3 (FLT3) occur in 30% of patients with de novo AML and confer a poor prognosis. KW-2449 is an oral multi-kinase inhibitor which is highly potent against mutant FLT3 (IC50=0 1–7 nmol/L) and other tyrosine kinases including FGFR1, TrkA, Abl (including T315I) and Aurora A serine threonine kinase. Based on the activity of KW-2449 and its metabolite (M1) in both in vitro and in vivo preclinical leukemia models, KW-2449 was evaluated in patients with leukemia and MDS in this first-in-man study. M1 is formed via monoamine oxidase-B and aldehyde oxidase mediated oxidation of KW-2449. Methods: The objectives were to assess the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic effects of KW-2449 in patients with refractory/relapsed AML, ALL and MDS, or resistant/intolerant CML. A range of daily doses of KW-2449 (12.5–250 mg twice daily, i.e. 25–500 mg/day) on 2 treatment schedules (14 or 28 days) with a recovery period of 7–28 days between cycles were evaluated. Dose limiting toxicity (DLT) and maximum tolerated dose (MTD) were assessed for the 1st cycle. The 28-day schedule was later eliminated. The plasma concentration of KW-2449 and M1 were analyzed by LC-MS/MS method. A plasma inhibitory activity (PIA) assay [Blood 108(10) 3477–83] for P-FLT3 and P-STAT5 was used to measure FLT3 inhibition. Results: 37 patients aged 26–88 years (16 male) were treated at 7 dose levels: 25, 50, 100, 200, 300, 400, and 500 mg daily. Thirty-one patients had AML, 5 CML and 1 ALL. The mean duration of therapy was 2 cycles in AML patients and 4 cycles in CML patients. KW-2449 was rapidly absorbed and metabolized to M1. The half-lives for KW-2449 and M1 were not dose-related and ranged from 2.4 to 4.9 hours and 2.6 to 6.6 hours, respectively. Administration of KW-2449 in a BID regimen led to minor accumulation and was consistent with the short half-life. The PIA assay demonstrated the near complete down-regulation of P-FLT3 and P-STAT5 2 hours post-dose at a dosing level of 400 mg daily. The extent of inhibition was lower at 8 hours and generally absent at 12 hours post-dose. The most frequently reported adverse events (AEs; any grade, regardless of causality) were nausea (70.3%), vomiting (48.6%), fatigue (45.9%), diarrhea (32.4%), dyspnea (29.7%), febrile neutropenia (29.7%), pain in extremity (29.7%), and arthralgia (27.0%). Febrile neutropenia (24.3%), pneumonia (10.8%), and thrombocytopenia (10.8%) were the most frequently reported Grade 3/4 AEs. DLTs occurred in 2 patients: Grade 3 atrial fibrillation (100 mg daily) and Grade 3 nausea and vomiting (500 mg daily). A total of 70 SAEs were reported in 27 patients including 11 on-study deaths; only atrial fibrillation and pleural effusion were considered possibly related to KW-2449. Eight of 31 patients with AML (26%) (FLT3 mutation: 5 positive and 3 negative) and 1 of 5 patients with CML (20%) exhibited a ³ 50% reduction in peripheral blasts and/or bone marrow blasts from baseline to the end of Cycle 1. One patient (500 mg daily) with AML exhibited a > 50% decrease in peripheral blasts, increased platelets, and ANC, and decreased WBC count. A patient with CML (Bcr-Abl T315I +) lost the mutant clone while on KW-2449 treatment. Conclusions: KW-2449 was safe and well tolerated at the dose levels evaluated. There were no complete or partial responses, but transient decreases in peripheral blood and bone marrow blasts were observed, justifying continued investigation of this agent. Sustained inhibition of P-STAT5 and P-FLT3 was not achieved at trough at the highest BID dose evaluated. TID and QID dosing schedules should be evaluated to accommodate the short t1/2 and to achieve sufficient target inhibition.

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Safety and Efficacy of Obinutuzumab Plus Bendamustine in Previously Untreated Patients with Chronic Lymphocytic Leukemia: Subgroup Analysis of the Green Study

Blood ◽

10.1182/blood.v126.23.493.493 ◽

2015 ◽

Vol 126 (23) ◽

pp. 493-493 ◽

Cited By ~ 9

Author(s):

Stephan Stilgenbauer ◽

Osman Ilhan ◽

Darius Woszczyk ◽

Christoph Renner ◽

Eva Mikuskova ◽

...

Keyword(s):

Bone Marrow ◽

Chronic Lymphocytic Leukemia ◽

Febrile Neutropenia ◽

Board Of Directors ◽

Safety Profile ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Safety And Efficacy ◽

Grade 3

Abstract Background The glycoengineered type II anti-CD20 monoclonal antibody obinutuzumab (GA101; GAZYVA/GAZYVARO; G) combined with chlorambucil (Clb) has superior efficacy to Clb monotherapy and to rituximab plus Clb with an acceptable safety profile in patients with chronic lymphocytic leukemia (CLL), as shown in the CLL11 study (Goede V, et al. NEJM 2014). GREEN is an ongoing, non-randomized, multi-cohort phase IIIb study (NCT01905943) investigating the safety (primary objective) and efficacy of G alone or in combination with chemotherapy in patients with previously untreated or relapsed/refractory CLL and assessing various strategies (cohorts 1-3) for reducing the rate of infusion-related reactions (IRRs) during the first infusion of G (Bosch F, et al. Blood 2014). We report safety and efficacy data from a subgroup of previously untreated patients in cohort 1 who received G-bendamustine (G-B). Methods Subjects were aged ≥18 years withdocumented CLL (except one case of SLL), an ECOG performance status of 0-2, and adequate hematologic function. Non-fit patients were those with a CrCl of <70 mL/min, and/or a CIRS score of >6. Fit patients comprised all others. Treatment was six 28-day cycles of G-B, where G was administered IV on D1/D2 of C1 (split dose: 25mg D1/975mg D2), and 1000mg on D8 and D15 of C1 and D1 C2-6. B was administered ≥30 minutes after G on D1 and D2 of each cycle at 90mg/m2 IV, or at 70mg/m2 in non-fit patients at the investigator's discretion. Safety endpoints included incidence, type and severity of AEs. Efficacy endpoints included ORR (investigator-assessed) and minimal residual disease (MRD) measured 3 months post-treatment. ORR was strictly assessed per International Workshop Group criteria (iwCLL 2008). Patients with missing response assessment components had their responses downgraded mandatorily. MRD negativity was defined as <1x10-4 malignant B cells in peripheral blood or bone marrow aspirate, measured in a central laboratory by 4-color flow cytometry. The population comprised all patients from cohort 1 of GREEN who received at least a partial dose of both G and B, and was based on a data cut-off of 26 March 2015. Results With a planned overall sample size of 950 patients in GREEN, the G-B subgroup in cohort 1 comprised 158 patients (157 CLL, 1 SLL; 74 fit, 84 non-fit). Median age was 67.6 years, 15.8% of patients had a CIRS score of >6, and 44.9% had a CrCl of <70 mL/min; 31.6% of patients had Binet stage A disease, 38% Binet B, and 30.4% Binet C. 7.0% of patients' disease displayed 17p deletion, 16.5% 11q deletion, and 58.2% unmutated IGHV. 91.1% of patients receiving B and 93.0% of those receiving G took ≥90% of the recommended total dose. The safety profile of G-B was as expected. 50% of patients developed grade 3-5 neutropenia and 12.7% developed a grade 3-5 infection. Other common grade 3-5 AEs included thrombocytopenia (12.7%) and tumor lysis syndrome (TLS; 10.1%). The most common serious AEs were neutropenia (10.8%), pyrexia (7.6%), febrile neutropenia (7.0%), and TLS (5.1%). There were nine deaths - one due to progression, and eight due to AEs (considered related to study drug by the investigator: 1 infection, 1 sudden death, 1 acute hepatic failure, and 1 febrile neutropenia combined with TLS; considered unrelated: 2 infections and 2 secondary neoplasms). IRRs occurred in 55.7% of patients (15.2% grade 3-5, none fatal). Overall, 26 patients (16.5%) prematurely discontinued treatment due to ≥1 adverse event. The ORR was 78.5% (124/158). The rate of CR (including incomplete CR [CRi]) was 32.3% (51/158), PR 46.2% (73/158), SD 10.8% (17/158), and PD 0.6% (1/158); 10.1% (16/158) of patients had missing data. Response rates were similar in non-fit (34.5% CR/CRi, 41.7% PR, 10.7% SD, and 1.2% PD) and fit (29.7% CR/CRi, 51.4% PR, 10.8% SD, and 0% PD) patients. In an intent-to-treat analysis including all missing (not taken or evaluable) MRD results, MRD negativity was 58.9% (93/158, including 56 missing) in blood and 27.8% (44/158, including 95 missing) in bone marrow. With a median observation time of 11.2 months, PFS data were immature and the median was not reached. Conclusions Treatment with G-B in previously-untreated CLL patients is generally well tolerated and the observed toxicities are manageable and not unexpected. G-B achieves a promising rate of CRs and a high rate of MRD-negative remissions, and may offer a new treatment option for fit and non-fit patients with CLL. Disclosures Stilgenbauer: Gilead: Honoraria, Research Funding. Off Label Use: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated, in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). This abstract reports on obinutuzumab alone or in combination with chemotherapy for previously untreated or relapsed/refractory CLL. Renner:Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Böttcher:Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Celgene: Research Funding; Beckton Dickinson: Honoraria. Tausch:Gilead: Other: Travel support. Moore:Roche: Employment. Tyson:Roche: Employment, Equity Ownership. Adamis:Roche: Employment. Leblonde:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Speakers Bureau. Bosch:Roche: Consultancy, Research Funding, Speakers Bureau. Foà:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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A Phase I Study of Romidepsin, Gemcitabine, Dexamethasone and Cisplatin Combination Therapy in the Treatment of Peripheral T-Cell and Diffuse Large B-Cell Lymphoma: Canadian Cancer Trials Group Study LY.15

Blood ◽

10.1182/blood.v128.22.4162.4162 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4162-4162 ◽

Cited By ~ 2

Author(s):

Tony Reiman ◽

Kerry J. Savage ◽

Michael Crump ◽

Matthew Cheung ◽

David A. MacDonald ◽

...

Keyword(s):

Febrile Neutropenia ◽

Phase I ◽

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Hematological Toxicity ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Large B Cell

Abstract Background: The outcome of peripheral T-cell lymphomas (PTCLs) remains poor and improved therapies are needed. Retrospective data suggest that integration of anthracyclines in the primary therapy may not impact outcome, providing the rationale to explore alternative regimens. Histone deacetylase inhibitors appear to have a class effect in PTCLs andromidepsin monotherapy demonstrates activity in a proportion of patients with relapsed/refractory PTCLs and can induce durable remissions. Gemcitabine is reported to be a highly active agent in PTCL, and the GDP (gemcitabine, dexamethasone, cisplatin) regimen has become a standard chemotherapy backbone for relapsed aggressive lymphomas (Crump, JCO 2014). We investigated the feasibility, safety and efficacy of GDP combined with romidepsin in a phase I dose escalation trial. Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) were also included. Methods: Patients with relapsed/refractory PTCL or DLBCL, PS 0-2, with measurable disease and who had received one or two prior lines of systemic therapy, were treated with standard doses of GDP (gemcitabine, 1000 mg/m2 d1, d8; dexamethasone, 40 mg po d1-4; cisplatin, 75 mg/m2 d1) every 21 days, plus escalating doses of romidepsin (6, 8, 10 and 12 mg/m2) on days 1 and 8 to a maximum of 6 cycles in a standard 3+3 design. After the first 4 patients were enrolled, based on the observed pattern of thrombocytopenia, the treatment schedule was modified so that gemcitabine and romidepsin were given on days 1 and 15 and cycles extended to every 28 days. Dose-limiting toxicities (DLTs) were assessed during the first 2 cycles and defined as requiring platelet transfusion for bleeding, grade 3 hematological toxicity lasting >10 days, grade 4 hematological toxicity lasting >7 days, febrile neutropenia, or grade 3-4 non-hematological toxicity attributable to romidepsin. Responses were as per Cheson, JCO 2007 excluding PET scans. Results: 20 eligible patients (PTCL n=10; DLBCL n=10) were enrolled between 10/2013 and 01/2016 and treated with GDP plus romidepsin. The main PTCL subtype was PTCL, not otherwise specified (50%). Median age was 65 years (24-74); 9 were female; ECOG performance status was 0 (n=2), 1 (n=13), or 2 (n=5). Number of prior therapies was 1 (n=17) or 2 (n=3). 17 (85%) patients received >90% of the planned dose each cycle. The median number of cycles was 2 (range, 1-6); one patient is still on therapy. The reasons for treatment discontinuation were lymphoma progression (n=10), toxicity (n=2), proceeding to autologous stem cell transplant (ASCT, n=3), intercurrent illness (n=1), or completion of 6 cycles (n=3). On the 21-day schedule at 6 mg/m2 romidepsin, there were 3 DLTs among four patients (2 with grade 3-4 thrombocytopenia, 1 venous thromboembolic event). On the 28-day schedule, there were no DLTs observed in the three patients treated at each of the 6, 8 or 10 mg/m2 dose levels. At 12 mg/m2 there were 4 observed grade 3 DLTs among six evaluable patients (hypotension, acute kidney injury, anorexia, thrombocytopenia >10 days). Notable toxicities during any cycle were: febrile neutropenia (n=2); grade 3-4 thrombocytopenia (n=9); grade 3-4 neutropenia (n=4); and grade 3-4 anemia (n=4); grade 2 atrial fibrillation (n=2); grade 2 QTc prolongation (n=1); grade 1 sinus tachycardia (n=1); grade 2-3 infections (n=16); grade 1-3 cutaneous toxicity (n=9); grade 1-3 thromboembolic events (n=2); TIA (n=2) or stroke (n=1). One patient died after cycle 1 due to sepsis. 7 other patients have died of progressive lymphoma. The overall response rate was 9/20 (45%), all were partial remissions (PR), 3 had stable disease (SD), 4 had progressive disease (PD), and 4 were not objectively evaluable. Of the responders, 5 had PTCL and 4 had DLBCL. Four patients went on to ASCT. With a median follow-up of 5.8 months, the median duration of response was 2.8 months and median PFS is 2.2 months. For all patients, the 1 year PFS was 6% and 1 year OS was 43% Discussion: Full doses of GDP can be combined with a recommended phase II romidepsin dose of 10 mg/m2 given on a day 1, 15 every 28 days schedule. Thrombocytopenia prohibits this combination on a 21-day schedule. Toxicity is otherwise acceptable and as expected. Further study at the recommended dose and schedule would be required to properly define the activity of this regimen in PTCLs and DLBCL. Disclosures Reiman: Celgene: Honoraria, Research Funding. Buckstein:Novartis: Honoraria; Celgene: Honoraria, Research Funding. Kuruvilla:Merck & Co., Inc.: Consultancy, Honoraria. Villa:Lundbeck: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria. Hay:Amgen: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Kite Pharmaceuticals: Research Funding.

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Long-Term Sustained Responses Following Ibrutinib Discontinuation after Frontline Therapy with Obinutuzumab Plus Ibrutinib in Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2020-143473 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 33-34

Author(s):

Paula A. Lengerke Diaz ◽

Michael Y. Choi ◽

Eider F. Moreno Cortes ◽

Jose V. Forero ◽

Juliana Velez-Lujan ◽

...

Keyword(s):

Bone Marrow ◽

Side Effects ◽

Chronic Lymphocytic Leukemia ◽

Disease Progression ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Combination Regimen ◽

Grade 3

Single oral targeted therapies have emerged as a standard of care in chronic lymphocytic leukemia (CLL). However, accessibility, side effects, and financial burden associated with long term administration limit their clinical use. Mainly, it is unclear in what clinical situation discontinuation of oral therapy can be recommended. The combination of type II anti-CD20 antibody obinutuzumab-Gazyva® with ibrutinib (GI) has shown a significant progression-free survival benefit in patients (pts) with CLL, including those with high-risk genomic aberrations. We conducted a phase 1b/2, single-arm, open-label trial to evaluate the safety and efficacy of GI as first-line treatment in 32 CLL pts. We report the outcome in pts that discontinued ibrutinib (either after 3 years of sustained complete response (CR) as stipulated in the clinical protocol, or due to other reasons). CLL pts enrolled in this protocol were ≥65 years old, or unfit/unwilling to receive chemotherapy. Pts received GI for six cycles, followed by daily single-agent ibrutinib. The protocol was designed to ensure that pts with a sustained CR after 36 months were allowed to discontinue ibrutinib. The median age was 66 years (IQR 59-73), and 6% of the evaluated pts had 17p deletion. All pts were able to complete the six planned cycles of obinutuzumab. The combination regimen was well-tolerated, and the most common adverse events (>5% CTCAE grade 3-4) were neutropenia, thrombocytopenia, and hyperglycemia. The rate and severity of infusion-related reactions (IRR) were much lower than expected (Grade≥ 3, 3%), and pts without IRR had lower serum levels of cytokines/chemokines CCL3 (P=0.0460), IFN-γ (P=0.0457), and TNF-α (P=0.0032) after infusion. The overall response rate was 100%, with nine pts (28%) achieving a CR, and four pts (12.5%) with undetectable minimal residual disease (uMRD) in the bone marrow, defined as <10-4 CLL cells on multicolor flow cytometry. At a median follow-up of 35.5 months (IQR 24.5-42.7) after starting treatment, 91% of the enrolled pts remain in remission with a 100% overall survival. Sixteen pts have completed a long-term follow-up of 36 months. Six pts showed CR, with three of them achieving uMRD in the bone marrow. Ten of these pts were in PR, and only one had disease progression and started treatment for symptomatic stage I disease with obinutuzumab plus venetoclax. In total, thirteen pts (41%) have stopped ibrutinib, with a median time on treatment prior to discontinuation of 35 months. Five (16%) of these pts had CRs and discontinued after 36 months. Eight additional pts (25%) had PRs and discontinued ibrutinib without being eligible: three pts discontinued prior to 36 months due to toxicities, and five pts discontinued after 36 months (3 due to side effects, and 2 due to financially driven decision). One patient eligible to discontinue ibrutinib, decided to remain on treatment despite sustained CR. After a median follow up time following ibrutinib discontinuation of 8 months (IQR 3.5-17), only two out of 13 pts have progressed (10 and 17 months after Ibrutinib discontinuation). None of the pts that stopped ibrutinib after achieving a CR have shown signs of disease progression. Of note, the pharmaceutical sponsor provided ibrutinib for the first 36 months, after which pts or their insurer became financially responsible. This particular scenario could bias the discontinuation pattern compared to a real world experience. It also provided us with a perspective about diverse factors affecting the treatment choices of pts. In summary, the obinutuzumab plus ibrutinib combination therapy was well-tolerated, with a much lower IRR rate. Efficacy compares favorably with historical controls with all pts responding to therapy, no deaths associated with treatment or disease progression, and a longer than expected time-to-progression after discontinuation of ibrutinib. The rate of ibrutinib discontinuation was higher than reported in the literature, most likely influenced by the protocol design and financial decisions driven by the switch from sponsor-provided ibrutinib to insurance or self-paid medication. Our observations regarding safety, efficacy and lack of disease progression after ibrutinib discontinuation are encouraging, and warrant confirmation in long-term prospective studies. Clinicaltrials.gov Identifier NCT02315768. Funding: Pharmacyclics LLC. Disclosures Choi: AbbVie: Consultancy, Speakers Bureau. Amaya-Chanaga:AbbVie: Ended employment in the past 24 months, Other: Research performed while employed as an investigator of this study at UCSD.. Kipps:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Castro:Kite Pharma: Research Funding; Pharmacyclics: Research Funding; Fate Therapeutics: Research Funding.

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Ibrutinib-Lenalidomide-Rituximab in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Final Results from the Nordic Lymphoma Group MCL6 (PHILEMON) Phase II Trial

Blood ◽

10.1182/blood-2020-133298 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-36

Author(s):

Mats Jerkeman ◽

Martin Hutchings ◽

Riikka Räty ◽

Karin Fahl Wader ◽

Anna Laurell ◽

...

Keyword(s):

Bone Marrow ◽

Mantle Cell Lymphoma ◽

Research Funding ◽

Tp53 Mutation ◽

Phase Ii Trial ◽

Cell Lymphoma ◽

Molecular Remission ◽

Mantle Cell ◽

Grade 3

Introduction: In spite of improvements in treatment of mantle cell lymphoma (MCL), this is still considered an incurable lymphoma entity, and the majority of patients eventually relapse. Ibrutinib is a very active agent in MCL, but in vitro has been shown to partially antagonize the activity of rituximab, by suppression of NK cell activity and subsequent ADCC. Lenalidomide, on the other hand, improves rituximab-induced ADCC. In this multi-centre open-label phase II trial, we evaluated safety and efficacy of this triplet combination in patients with relapsed or refractory MCL. Methods: Patients with MCL, relapsing after or refractory to at least one rituximab-containing chemotherapy regimen, WHO PS 0-3, and measurable disease were eligible. The primary endpoint was maximal overall response rate (ORR) measured with CT and PET/CT. Minimal residual disease (MRD) monitoring by PCR was performed during follow-up, according to EuroMRD criteria. Ion Torrent sequencing of the most frequently mutated genes in MCL was performed on frozen tumor cells from bone marrow at time of relapse. Health-related quality of life was assessed by the EORTC-QLQ C30 questionnaire before and during treatment. Treatment schedule: Induction phase: Up to twelve 28-day cycles with: Lenalidomide 15 mg p o daily, days 1-21, Ibrutinib 560 mg p o days 1-28, Rituximab 375 mg/m2 i v day 1 in cycle 1, then 1400 mg s c (or 375 mg/m2i v) days 8, 15 and 22 in cycle 1, then day 1 in cycles 3, 5, 7, 9 and 11. Maintenance phase: For patients in CR, PR or SD, not in need of other treatment, given until progression, cycle duration 56 days. Ibrutinib: 560 mg p o days 1-56, 2. Rituximab 1400 mg s c (or 375 mg/m2i v) day 1 of each cycle. Results: Accrual of 50 pts was completed in June 2016, at 10 centres in Sweden, Norway, Denmark and Finland. The median age was 69.5 years, with a median MIPI score of 6.2. Patients had received a median of two previous regimens, four had progressed after single agent ibrutinib, and three had received prior allo-SCT. A TP53 mutation was detected in 11 of 49 evaluable cases (22%), 8 cases were of blastoid/pleomorphic histology, and 22 of 40 evaluable cases had a Ki67 >30%. Treatment emergent-AEs of any grade in ≥20% of patients were rash (24%) and fatigue (20%). Five pts (10%) experienced rash grade 3, mainly during cycle 1. Hematological toxicity was generally of low grade, apart from grade 3-4 neutropenia in 5 patients. One patient died due to possible treatment-related toxicity (septic shock). In total, 27 patients achieved CR (54%) and 10 PR (20%). Among evaluable patients with a TP53 mutation, blastoid/pleomorphic histology or Ki67 >30%, the CR rates were 7/11 (64%), 15/8 (62%) and 11/22 (50%), respectively. After a median follow-up of 40 months, the median PFS is 18 months (95% CI 6.5-28), and median OS 47 months (95% CI 30-64). Patients with a detectable TP53 mutation at relapse (n=11) had a median PFS of 13 months (95% CI 4.2-21), whereas pts without a TP53 mutation had a median PFS of 34 months (95% CI 8.3-60). Of the 28 patients evaluable for MRD at 6 months, 15/27 (56%) patients achieved molecular remission in blood and 12/28 (43%) in bone marrow. After 12 months, MRD-negativity in BM was 68% (13/19). Out of 4 patients with TP53-mutated MCL, 2 were MRD-negative in BM after 12 months, as well as 2 out of 4 patients with blastoid/pleomorphic histology. By self-reported HRQOL, a lower level of emotional functioning (EF), as well as a higher level of pain (PA) at baseline, was associated with inferior PFS. In addition, low EF was associated with inferior OS. By a Cox regression multivariable analysis, including MIPI, TP53, histology, Ki67, EF and PA, only MIPI was prognostic for PFS or OS with this regimen. Conclusions: The combination of ibrutinib, lenalidomide and rituximab has been shown to be an active and well tolerated regimen in this cohort of high risk R/R MCL, associated with a high rate of molecular remission. The activity in TP53 mutated MCL is lower than in unmutated disease, but this regimen may still serve as an option for a bridge to an allogeneic transplantation or CAR-T therapy in this category of patients. Disclosures Jerkeman: Roche: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Gilead: Research Funding. Hutchings:Genmab: Honoraria; Genmab: Consultancy; Takeda: Consultancy; Roche: Research Funding; Celgene: Research Funding; Daiichi: Research Funding; Sankyo: Research Funding; Genmab: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Roche: Honoraria; Roche: Consultancy; Takeda: Honoraria.

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Recurrent bone marrow aplasia secondary to nilotinib in a patient with chronic myeloid leukemia: A case report

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155212438112 ◽

2012 ◽

Vol 18 (4) ◽

pp. 440-444 ◽

Cited By ~ 6

Author(s):

Prathima Prodduturi ◽

Anamarija M Perry ◽

Patricia Aoun ◽

Dennis D Weisenburger ◽

Mojtaba Akhtari

Keyword(s):

Bone Marrow ◽

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Bone Marrow Aplasia ◽

Line Therapy ◽

Grade 3

Nilotinib is a potent tyrosine kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL), which has been approved as front-line therapy for newly diagnosed chronic myeloid leukemia in chronic phase and as second-line therapy after imatinib failure in chronic or accelerated phase chronic myeloid leukemia. Tyrosine kinase inhibitors have been associated with myelosuppression and grade 3 or grade 4 cytopenias are not uncommon in chronic myeloid leukemia patients treated with these drugs. There are a few reports of imatinib-associated bone marrow aplasia, but to our knowledge only one reported case of bone marrow aplasia associated with nilotinib. Herein, we report a 49-year-old male patient with chronic phase chronic myeloid leukemia, who developed severe bone marrow aplasia due to nilotinib. Possible mechanisms for this significant adverse drug reaction are discussed along with a review of literature.

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Efficacy and Safety of Retreatment with Bortezomib in Patients with Multiple Myeloma: Interim Results From RETRIEVE, a Prospective International Phase 2 Study.

Blood ◽

10.1182/blood.v114.22.3866.3866 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3866-3866 ◽

Cited By ~ 2

Author(s):

Maria Teresa Petrucci ◽

Igor W. Blau ◽

Paolo Corradini ◽

Meletios A. Dimopoulos ◽

Johannes Drach ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Phase 2 ◽

Efficacy And Safety ◽

Advisory Committees ◽

Bortezomib Treatment ◽

Best Response ◽

Phase 2 Study ◽

Grade 3

Abstract Abstract 3866 Poster Board III-802 Bortezomib (Velcade®) retreatment has been shown to be active and well tolerated in patients with relapsed multiple myeloma (MM) in a number of retrospective studies and a small prospective phase 4 study (EVEREST). This large, prospective, international, multi-center, open-label phase 2 study was conducted to confirm the efficacy and safety of retreatment with bortezomib in MM patients who had previously responded (at least partial response [PR]) to bortezomib-based therapy as their most recent prior treatment. Patients had to have previously tolerated bortezomib 1.0 or 1.3 mg/m2 alone or in combination and have had a treatment-free interval (TFI; time from last dose of initial bortezomib treatment to first dose of bortezomib retreatment) of ≥6 months. Additional eligibility criteria included progressive disease or relapse from complete response (CR) by EBMT criteria, no MM therapy (except maintenance with dexamethasone, thalidomide, or interferon) since the last dose of initial bortezomib treatment, KPS ≥60, and adequate renal, hepatic, and hematologic function; patients with grade ≥2 peripheral neuropathy or neuropathic pain (as defined by NCI CTCAE v3.0) were excluded. Patients received bortezomib at the last tolerated dose (1.0 or 1.3 mg/m2) during initial treatment on days 1, 4, 8, and 11 for up to eight 21-day cycles, either alone or in combination with dexamethasone at the investigator's discretion. Response was assessed by EBMT criteria every 6 weeks during treatment and then every 2 months until disease progression. Adverse events (AEs) were graded according to NCI CTCAE v3.0. A total of 130 patients received at least 1 dose of bortezomib retreatment and were included in the safety population. Patients had a median age of 67 years, 57% were male, and 16% had KPS '70%. Median time from diagnosis of MM was 4.5 years (range 0–14 years); median number of prior therapies was 2; 15, 80, 23, and 12 patients had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib therapy). Best response by EBMT criteria to initial bortezomib treatment was CR in 26% and PR in 74% of patients; median time to progression and TFI after initial bortezomib treatment were 17.9 months and 14.3 months, respectively. Last tolerated dose of previous bortezomib therapy was 1.3 mg/m2 and 1.0 mg/m2 for 62% and 29% of patients, respectively; 9% received another dose. Patients received a median 7.0 (range 1–8) cycles of bortezomib retreatment (23% of patients completed all 8 cycles); 72% of patients received concomitant dexamethasone. A total of 126 patients were evaluable for response. In the 126 response-evaluable patients, the overall response rate (ORR; CR+PR) by best confirmed response (EBMT criteria) was 40%; in addition, 18% of patients achieved minimal response (MR), to give a CR+PR+MR rate of 58%. After a planned secondary efficacy analysis, the ORR (CR+PR) by single best response was 55% (75% ≥MR). Median time to best confirmed response (≥MR) was 2.9 months; time to first response was 1.5 months. Analysis of ORR by patient subgroups showed comparable results in patients who did versus did not receive concomitant dexamethasone (42% vs 32%), in those who received ≤1.0 mg/m2 vs 1.3 mg/m2 bortezomib (35% vs 41%), and in those aged ≤65 years vs >65 years (45% vs 36%). ORR was 67%, 39%, 33%, and 25% in patients who had received 1, 2, 3, and ≥4 prior lines of therapy (excluding initial bortezomib), respectively. Analysis of best confirmed responses according to response to initial bortezomib showed that 63% and 52% of patients who achieved a CR or PR, respectively, to initial bortezomib treatment responded to retreatment. Most (98%) patients experienced a treatment-emergent AE; 60% experienced a grade 3/4 AE, and 32% experienced a serious AE; there were 8 deaths, 2 of which (due to sepsis and stroke) were possibly treatment-related. The most common grade 3/4 AEs were thrombocytopenia (35%), neutropenia (7%), diarrhea (7%), and pneumonia (5%). AEs leading to dose reductions or discontinuations were reported for 22% and 12% of patients, respectively. The incidence of neuropathy was 39%, including 9% grade 3; 4% of patients discontinued treatment due to PN; 61% of neuropathy events resolved or improved within a median 1.3 months. These results confirm that bortezomib retreatment is a well-tolerated, feasible, and active therapeutic option for heavily pretreated MM patients without evidence of cumulative toxicity. Disclosures: Petrucci: Janssen-Cilag: Honoraria; Celgene: Honoraria. Dimopoulos:Ortho-Biotech: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Honoraria. Drach:Janssen-Cilag: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Honoraria. Blade:Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Johnson and Johnson: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Efficacy and Safety of Nilotinib in Elderly Patients with Imatinib-Resistant or -;Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP): A Sub-Analysis of the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Blood ◽

10.1182/blood.v114.22.3286.3286 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3286-3286 ◽

Cited By ~ 5

Author(s):

Philipp D. le Coutre ◽

Anna Turkina ◽

Dong-Wook Kim ◽

Bernadeta Ceglarek ◽

Giuliana Alimena ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Study Drug ◽

Cytogenetic Response ◽

Efficacy And Safety ◽

Advisory Committees ◽

Imatinib Resistant ◽

Grade 3

Abstract Abstract 3286 Poster Board III-1 Introduction: Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib in adult pts with imatinib-resistant or intolerant CML in a clinical practice setting outside of a registration program. It is the largest single source of efficacy and safety information of any available tyrosine kinase inhibitor (TKI) in CML, particularly among the elderly. Methods: The present is a sub-analysis of the ENACT study on the efficacy and safety of 400 mg twice daily nilotinib in elderly (aged =60 years) pts initiating treatment in CML-CP who were resistant and/or intolerant to imatinib. Results: Of the 1,422 CML-CP pts enrolled in the ENACT study between January 2006 and October 2008, 452 (32%) were elderly (=60 years) at study initiation and 165 (37%) of these pts were =70 years [10 (2%) were =80 years]. Countries that enrolled =20 elderly pts include France, Italy, USA, Germany, UK, Spain, Canada, and Brazil. At study initiation, elderly pts had longer median durations of CML (<60: 51.1 months; =60: 69.3; =70: 66.6) and higher proportions with CML duration >5 years (<60: 43%; =60: 56%; =70: 52%). Besides imatinib, prior CML treatments received by elderly pts included dasatinib (=60: 20%; =70: 19%), cytarabine (=60: 23%; =70: 19%), busulfan (=60: 10%; =70: 7%), and interferons (=60: 50%; =70: 42%). Elderly pts were previously treated with imatinib for longer median durations (<60: 27.4 months; =60: 32.7; =70: 29.9), with higher proportions treated for >5 years (<60: 12%; =60: 19%; =70: 18%). The proportion of imatinib-intolerant to resistant elderly pts was about 1:1, which was higher than the proportion among <60 pts at about 0.6:1, such that relatively few elderly pts had prior highest imatinib dose >800 mg (<60: 34%; =60: 26%; =70: 21%). While response rates to prior imatinib were similar, among pts who required therapy after failing imatinib, elderly pts had lower cytogenetic response rates (<60: 22%; =60: 17%; =70: 19%) to prior dasatinib. During ENACT, less than 50% of elderly pts experienced nilotinib dose interruptions (=60: 46%; =70: 41%) and reductions (=60: 7%; =70: 6%) lasting >5 days, which was consistent with the overall ENACT dataset. The median duration of dose interruptions and reductions was 15 (=70: also 15) and 41 (=70: 32) days, respectively. The main reason for dose interruptions and reductions was adverse events (AEs). The median duration of nilotinib exposure was 227 days (=70: 219) and the median dose intensity was 749 mg/day (=70: 775). Efficacy was similar among elderly pts, with 39% (=70: 35%) of pts achieving complete hematologic response (CHR), 41% (=70: 39%) achieving major cytogenetic response (MCyR) and 31% (=70: 33%) achieving complete cytogenetic response (CCyR). MCyR rate was also similar among elderly hematologic responders (=60: 64%; =70: 65%). Among elderly pts requiring nilotinib therapy after both imatinib and dasatinib, and therefore have more resistant CML, CHR rate was 39% (=70: 32%), MCyR rate was 28% (=70: 29%) and CCyR rate was 20% (=70: 16%). Safety was likewise similar among elderly pts, with grade 3/4 study drug-related AEs occurring in 56% of pts (=70: 53%). The most frequent of these AEs were thrombocytopenia (=60: 24%; =70: 21%) and neutropenia (=60: 14%; =70: 11%). The most common method of managing these AEs was brief dose interruptions and/or reductions [thrombocytopenia (=60:86/108 pts; =70: 30/35), neutropenia (=60: 42/62 pts; =70: 9/18)]. Among elderly pts with prior dasatinib, 53% (=70: 58%) experienced grade 3/4 study drug-related AEs, while 7 out of 8 pts with pleural effusion on dasatinib no longer had it on nilotinib. Conclusions: In ENACT, pts aged =60 years at study initiation appear to have longer durations of CML, be more heavily pre-treated and more intolerant to imatinib than the younger cohort. Nonetheless, nilotinib induced comparable clinical responses in CML-CP pts regardless of age. Importantly, the safety profile of nilotinib is maintained in elderly pts. Disclosures: le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Kim:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Ceglarek:Novartis Pharmaceuticals: Honoraria. Shen:Novartis Pharmaceuticals: Honoraria. Smith:Novartis Pharmaceuticals: Honoraria. Rizzieri:Novartis Pharma: Honoraria, Research Funding, Speakers Bureau. Szczudlo:Novartis: Employment. Berton:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Research Funding. Nicolini:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau.

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A Phase I Study of Escalated Dose Subcutaneous Alemtuzumab Given Weekly with Rituximab In Relapsed CLL/SLL.

Blood ◽

10.1182/blood.v116.21.1381.1381 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1381-1381

Author(s):

Jennifer R Brown ◽

Bradley Messmer ◽

Lillian Werner ◽

Evgeny Mikler ◽

David C. Fisher ◽

...

Keyword(s):

Bone Marrow ◽

Injection Site ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Study Entry ◽

Ct Scans ◽

Advisory Committees ◽

Grade 3 ◽

Study Therapy

Abstract Abstract 1381 Alemtuzumab is an anti-CD52 antibody originally approved for intravenous administration three times per week to CLL patients refractory to fludarabine and previously exposed to alkylators. Since that time subcutaneous administration three times per week has become widespread because of its reduced infusional toxicity and recently demonstrated equivalent efficacy. In this study we assessed the tolerability, efficacy and pharmacokinetics of administering alemtuzumab subcutaneously weekly at up to 90 mg per dose following an initial 3+3 dose escalation (see table); we further added weekly rituximab in hopes of enhancing activity in lymph nodes. Treatment was administered in up to two eight week blocks with response evaluation between; the second 8 week block continued the dose and schedule used in weeks 5–8. No more than 45 mg was given per subcutaneous injection site. 28 patients were enrolled on this study between 7/2006 and 1/2010. The median age was 62 (range 47–76), and 75% were male. The median time from diagnosis to starting study therapy was 94 mos (14-236 mos). A majority of patients (82%) had Rai stage 3–4 disease and the median number of prior therapies was 4 (1-11). 20/28 patients (71%) had high risk deletions of 17p or 11q. 13/16 (81%) had unmutated IGVH, and 14/19 (74%) were positive for ZAP70. Early study withdrawals occurred due to pre-existing and persistent thrombocytopenia requiring study therapy to be held (n=2), persistent fever attributed to alemtuzumab (n=1), PML in retrospect present prior to study entry (n=1), and a DLT (grade 3 rituximab reaction) which was observed on dose level 2 prior to dose escalation of alemtuzumab. Overall, therapy was well tolerated; injection site reactions were minimal, primarily grade 1 (n=11) with only two grade 2 events. Other toxicities were as expected with alemtuzumab in this patient population, including grade 3–4 neutropenia (54%), grade 3–4 thrombocytopenia (57%), and single cases each of grade 3 rash, AIHA, pulmonary embolism, MRSA bacteremia, diverticular abscess, pulmonary Cryptococcus, EBV lymphoma and metastatic colon cancer. The ORR by NCI-WG criteria at wk 8 was 61% (95% CI 42–76%), with CR rate 11% (95% CI 4–27%). Two of 14 patients who completed a second eight week cycle improved their response (one PR from SD, and one CR from PR). A planned endpoint of this study was to compare lymph node staging by CT to PE, and we found that using CT scans to evaluate nodal response at 8 weeks decreased the ORR rate to 14% (95% CI 6–31%), with no CRs. Bone marrow was completely cleared of disease by 8 weeks in 8 patients and by 16 weeks in an additional 4 patients. The median PFS for the entire population was 13 months with a median follow-up of 9 months in patients who have not progressed. 10 patients have died, 5 of disease, 3 of second malignancies, 1 of PML and 1 of SCT complications. The median OS from study entry is 47 months, with 10 patients having undergone subsequent SCT. Following initiation of therapy we observed a >1,700X decrease in the median CD19+5+ cell count in peripheral blood by the start of week 3. Similar rapid depletion of all T and NK cell subsets was also observed, with first signs of recovery at week 28, and more definite recovery at week 40. Preliminary pharmacokinetic data demonstrated lower maximum levels of rituximab (p=0.06) and alemtuzumab (p=0.05) in patients with >80% bone marrow replacement by CLL but not in those with bulky lymphadenopathy. A trend toward higher alemtuzumab levels was observed in those patients with complete bone marrow clearance (p=0.1) but not in those with objective response. In conclusion, we found that administration of alemtuzumab at 90 mg subcutaneously weekly in combination with rituximab was well-tolerated, convenient and resulted in sustained adequate blood levels of both drugs in most patients. Response rates were high although in this relapsed refractory CLL population, abdominal lymphadenopathy was common, resulting in a decreased response rate when CT scans were included in staging. PFS and OS were favorable for this novel combination regimen and many patients went on to SCT. Disclosures: Brown: Genzyme: Research Funding; Celgene: Consultancy, Research Funding; Calistoga: Consultancy; Genentech: Consultancy. Off Label Use: alternative schedule of alemtuzumab. Kipps:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding; Memgen: Research Funding; Igenica: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Research Funding; Abbott Laboratories: Research Funding.

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Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v116.21.3055.3055 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3055-3055

Author(s):

Donna E. Reece ◽

Esther Masih-Khan ◽

Arooj Khan ◽

Saima Dean ◽

Sharon Fung ◽

...

Keyword(s):

Multiple Myeloma ◽

Dose Level ◽

Research Funding ◽

Response Rate ◽

Objective Response ◽

Median Number ◽

Prior Therapy ◽

Best Response ◽

Level 3 ◽

Grade 3

Abstract Abstract 3055 Lenalidomide (Revlimid®) and dexamethasone is an effective regimen for relapsed/refractory (rel/ref) multiple myeloma (MM) patients (pts) with an overall response rate of 60% and median time to progression of 13.4 months (Dimopoulos ME, et al. Leukemia 2009; 23: 2147-52). We combined lenalidomide with the alkylating agent combination of cyclophosphamide and prednisone—an older regimen with minimal cumulative myelosuppression and good activity as second or third line therapy (Trieu Y, et al, Mayo Clin Proc 2005; 80: 1582). The CPR regimen consisted of cyclophosphamide (CY) on days 1, 8, and 15, lenalidomide on days 1–21 and prednisone 100 mg q 2 days in a 28-day cycle. ASA 81 mg/day was given as DVT prophylaxis. Three dose levels were evaluated using a 3 × 3 dose escalation design. Thirty-two pts were entered between 11/2007-06/2009; median age was 64 (42-80) yrs, 60% were male, and immunoglobulin isotype was IgG in 19 (62%), IgA in 8 (25%) and light chain in 4 (13%) pts. Median β2-microglobulin level was 257 (92-767) nm/L, albumin 39 (34-48) g/L, creatinine 83 (50-126) μmol/L, platelet count 355 (75-479) × 109/L and ANC 2.5 (1.1-6.1) × 109/L. The median number of prior regimens was 2 (1-5). Prior therapy included: ASCT (single in 91%; double in 19%), thalidomide (28%) and bortezomib (50%). FISH cytogenetics were available in 13 pts; 1 had del 13q but none had t(4;14) or del p53. Table 1 summarizes protocol treatment delivered. Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 12 (12–34+) 2 3 150 25 100 10 (9–23) 3 26 300 25 100 17 (5–28+) 1–3 (All) 32 150–300 15–25 100 19 (5–34+) Dose limiting toxicity was not observed during cycle 1 at any dose level. Grade 3–4 toxicities during the trial included: thrombocytopenia in 7 (22%) and neutropenia in 9 (29%), managed with dose reduction and/or growth factors; five episodes of febrile neutropenia occurred, all at dose level 3. In cohort 3, other grade 3–4 non-hematologic toxicities included 1 episode each of abdominal pain/bacteremia, hypokalemia, fatigue, sick sinus syndrome, cardiac amyloidosis, perforated diverticulum and 2 episodes of DVT. Two heavily pretreated pts developed 2° MDS, including 1 previously treated for lymphoma, 43 and 190 mos after the diagnosis of MM. The best response using modified EBMT criteria was documented at a median of 7 (1-26) cycles and included the following: dose level 1 (1 CR, 2 PR); dose level 2 (1 VGPR, 2 PR); dose level 3 (4 CR, 14 VGPR, 11 PR, 1 MR and 1 stable disease). At a median F/U of 16 (5-34) months, 13 pts remain on study and 18 have progressed at a median of 10 (2-23) mos; 1 was lost to F/U and 9 have died of progressive MM. The 1-year actuarial OS and PFS rates are 93% (95% CI 76–98%) and 78% (95% CI 60–89%), respectively. We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28 day cycle with an acceptable safety profile; 2) the objective response rate (CR + PR + MR) in all 32 pts to date is 94%; 3) the 1-year OS of 93% and PFS of 78% compare favorably with other 3-drug combinations in rel/ref MM pts; 4) further evaluation of this regimen in newly diagnosed pts would be of interest. Disclosures: Reece: Celgene: Honoraria, Research Funding. Off Label Use: Combination of lenalidomide and cyclophosphamide and prednisone in relapsed and refractory myeloma patients. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria.

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