Subcutaneous Low Dose Alemtuzumab: Role As a Salvage Therapy in Immune -Mediated Marrow Failure Conditions

Abstract Aplastic anemia (AA), pure red cell aplasia (PRCA), pure white cell aplasia (PWCA), idiopathic neutropenia (IN) and T cell large granular lymphocytic leukemia (LGL) are bone marrow failure (BMF) conditions unified by immune-mediated pathogenesis leading to cytopenias. Intravenous alemtuzumab, a CD52 monoclonal antibody approved for the treatment of chronic lymphocytic leukemia (CLL) and used for relapsed AA, has a response rate in AA of 37-58%. However, dosing and route was likely based on those used in CLL regimens and resulted in significant immunosuppressive complications. Here we summarize our experience with sc alemtuzumab given at the maximum dose of total 100 mg as etiologic treatment (either salvage therapy or preferred therapy) to patients with various BMF. We investigated the therapies administered to patients seen at the Cleveland Clinic or at the University of Naples (NCT00895739) between years 2002-2015. Of 484 patients with BMF conditions (Cleveland: AA: 204, LGL: 174, PRCA: 56; Naples: AA: 24, LGL: 2, PRCA: 14), 65 patients with AA (N=22), PRCA (N=22), LGL (N=18) and 3 cases of IN/PWCA were treated sc alemtuzumab, given according 2 distinct schedules: i. initial dose of 3 mg sc followed by 10 mg once or twice weekly for at least 8 consecutive weeks; ii. 4-5 day dose escalation (3-10-30-30-30 mg) regimen. In both schedules, some patients received a much longer course with maintenance treatment or occasional boosts to prevent or treat relapse. Patients received bactrim and acyclovir prophylaxis, IVIG for hypoglobulinemia and underwent CMV monitoring. The median age of patients was 57.5 years (range: 31-84 years). Alemtuzumab was used as salvage therapy in Cleveland (except for 3 AA cases with contraindication to anti-thymocyte globulin or cyclosporine), whereas in Naples untreated patients were allowed per protocol. As a result, patients had a median of 2 lines of therapy (range: 0-6), had either untreated (35%), relapsed (22%) or refractory (43%) BMF condition. Among the 22 AA patients 12 were untreated, or had relapsed (N=4), or refractory disease (N=6), with concomitant PNH clone in 8/22 patients. LGL patients (N=18) treated with alemtuzumab were younger, had a median of 2 prior therapies, 50% were STAT3 mutants, with comparable degree of cytopenias but excess splenomegaly (60% vs. 38%, p=.012) at presentation, compared to the remainder LGL cohort. Amongst these patients, 18% had relapsed LGL while the rest had refractory disease. PRCA cases treated were either idiopathic (N=18, of whom 3 associated with thymoma) or LGL-associated (N=4); this group was very heterogeneous, including 9 untreated patients (in Naples) and a subgroup of heavily pretreated patients (5 with refractory disease) with a median of 5 prior therapies, with mean hemoglobin of 7.5 g/dL. Among the group of PWCA/IN, one case of PWCA was LGL-associated. The treatment was well tolerated in 92% of the patients, except in four patients who did not complete treatment course due to adverse events. The main adverse events include infectious complications with 7/65 developing CMV reactivation, 4/65 HSV reactivation, and more rarely other viral reactivation (VZV and HBV, 1/65 each). Two fatal infections were recorded: 1 fungemia (heavily pretreated with other therapies) and 1 JCV-related PML (in a patients also receiving chemotherapy for refractory thymoma). The overall response rate was 55%; by disease subtype 54% of AA, 44% of LGL, 59% of PRCA and all three cases of PWCA/IN responded. The median time to response in AA was 12 weeks (range: 6-24 weeks), and responses lasted a median of 6 months (range: 2-72 months). In AA, we observed responses in 72% of the cases treated with almetuzumab upfront and 45% of the relapsed/refractory disease. Similarly in PRCA cases, 77% of the alemtuzumab upfront and 46% of the relapsed/refractory disease responded. With a median follow up >4 years, no late treatment-related complication emerged; treatment failures were mostly due to relapses (sometimes refractory to further immunosuppressive treatment), with clonal evolution around 15% (mostly in non-responders). In summary, low-dose sc alemtuzumab is a reasonable alternative option for patients with BMF conditions, especially in relapsed/refractory cases; patients need to be monitored with a heightened vigilance for infectious complications, as well as for possible recurrence of their underlying disease. Disclosures Risitano: Alexion Pharmaceuticals: Other: lecture fees, Research Funding; Alnylam: Research Funding; Rapharma: Research Funding; Novartis: Research Funding.

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A Multicenter, Phase IV Observational Study Of Ofatumumab In Chronic Lymphocytic Leukemia (CLL): A European Research Initiative On CLL (ERIC) Study

Blood ◽

10.1182/blood.v122.21.1645.1645 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1645-1645 ◽

Cited By ~ 1

Author(s):

Carol Moreno ◽

Marco Montillo ◽

Panayiotidis Panayiotis ◽

Adrian Bloor ◽

Jehan Dupuis ◽

...

Keyword(s):

Clinical Trials ◽

Adverse Events ◽

Board Of Directors ◽

Safety Profile ◽

Research Funding ◽

Response Rate ◽

Lymphocytic Leukemia ◽

Hematologic Toxicity ◽

Phase Ii Trials ◽

Advisory Committees

Abstract Background Ofatumumab was given a conditional approval in the EU on April 2010 for the treatment of CLL refractory to fludarabine (F-ref) and alemtuzumab (A-ref), encouraging the retrieval of further data in patients treated in a “daily life” setting and to investigate treatment safety. Aims The main objective of this study was to obtain information on the safety profile of ofatumumab given outside clinical trials in patients with previously treated CLL. The secondary endpoints were efficacy, progression-free-survival (PFS), and overall survival (OS). Methods This was an observational, retrospective study. Patients were eligible regardless of prior treatments or disease status and provided they had not been included in ofatumumab clinical trials. Data on patients’ characteristics at diagnosis, prior treatment, adverse events response rate, PFS and OS were recorded. Results One-hundred and twenty patients were screened of which 103 from 25 centers in 10 European countries were eventually eligible for the study. There were 71 males; median age at initiation of ofatumumab was 64 years (range, 38-84); 66% patients were in advanced clinical stage (Rai III-IV/Binet C) and 33 patients presented bulky lymphadenopathy. Number of prior lines of therapy was 4 (range, 1-13). 94% had received prior F-based therapy, 54% received A-based therapy and 51% received both. Eighty-one percent had been previously exposed to rituximab-combination regimens. Fifty-four percent were F-ref, 70% A-ref and 41% were both F- and A-refractory. Cytogenetics within 3 months prior therapy was available in 52 patients of which 34 presented abnormalities (11 patients: 17p-; 9 patients: 11q-; 2 patients: 13q-; 1 patient: trisomy 12; 11 patients: two or more abnormalities including 17p- or 11q-). Forty-two of 50 patients showed unmutated IGHV genes. The median number of cycles of ofatumumab given was 9 (range, 0-16) and the median percentage of given/planned cycles was 83.3% (range, 0-133). In most patients the treatment dose and schedule were as follows: 300 mg 1st infusion followed by 2000 mg for subsequent infusions (8 weekly followed by 4 doses monthly). One hundred and sixty-one adverse events were reported in 68 patients, with 28 (17%) of them being considered as ofatumumab-related. Infusion related-reactions occurred in 19 (28%) patients (III-IV: 6%). Neutropenia was reported in 26% (III-IV: 19%), thrombocytopenia in 15% (III-IV: 12%) and anemia in 15% (III-IV: 7%). The non-hematological adverse events, included infection 44% (III-IV: 36%), fatigue 10% (III-IV: 4%), fever 10% (III-IV: 6%), rash 10% (III-IV: 3%), cough 7% (III-IV: 1%), diarrhea 6% (grade III-IV: 0%) and nausea 1% (III-IV: 0%). Hematologic toxicity correlated with the number of prior lines of therapy. Autoimmune hemolytic anemia and Richter syndrome were reported in one patient each. Two heavily pre-treated patients (5 and 6 prior lines of therapy, respectively) developed progressive multifocal leukoencephalopathy. The overall response rate (ORR) was 23% and the median PFS and OS were 5 and 12 months, respectively. The main causes of death were disease progression (61%) and infection (28%). Conclusions The safety profile of ofatumumab given outside clinical trials to patients with poor-prognosis and heavily pre-treated CLL was consistent with that observed in clinical trials. Although not unexpectedly the ORR was lower in this study, PFS and OS were in line with those reported in phase II trials. Disclosures: Montillo: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Bloor:GSK: Consultancy, Honoraria, Paid speaker Other. Schuh:GSK: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria. Geisler:Roche: Consultancy; GSK: Consultancy. Hillmen:GlaxoSmithKline: Honoraria, Research Funding. Stilgenbauer:GSK: Honoraria, support Other. Smolej:GSK: Consultancy, Honoraria, travel grants Other. Jaeger:GSK: Honoraria, Research Funding. Leblond:Roche : Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Kimby:Roche: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria, Research Funding; Emergent BioSolutions: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy, Honoraria, Research Funding; Jansen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding.

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An Effective and Tolerable Chemoimmunotherapy Regimen For Relapsed/Refractory and Very-High Risk Chronic Lymphocytic Leukemia Combining Alemtuzumab With Pentostatin and Low Dose Rituximab

Blood ◽

10.1182/blood.v122.21.1641.1641 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1641-1641

Author(s):

Clive S. Zent ◽

Betsy R LaPlant ◽

Wenting Wu ◽

Timothy G. Call ◽

Deborah Bowen ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Adverse Events ◽

Phase Ii ◽

Research Funding ◽

Low Dose ◽

Lymphocytic Leukemia ◽

Bulky Disease ◽

Purine Analogue ◽

Very High

Abstract Patients with very-high risk (purine analogue refractory and TP53 defective) CLL have limited treatment options. In these patients alemtuzumab can be effective against CLL cells in the circulation and bone marrow, and in combination therapy with fludarabine can be active in patients with bulky disease, but these regimens have a high risk of serious infections. Addition of rituximab to alemtuzumab can also improve efficacy but has limited activity against bulky disease. We conducted a phase II clinical trial to determine the efficacy and toxicity of therapy with pentostatin, alemtuzumab, and low dose higher frequency rituximab (PAR) in patients with relapsed/refractory or progressive CLL with 17p13 deletion. The rituximab schedule was designed to decrease the loss of CD20 expression by circulating CLL cells. Methods This two-stage phase II trial study (NCT00669318) conducted at the Mayo Clinic Rochester and University of Iowa with IRB approval had an accrual goal of 38 evaluable patients. Eligibility required a diagnosis of progressive CLL by standard criteria and either previous treatment for CLL (<4 purine analogue regimens) or 17p13 deletion (17p13-). Exclusion criteria were organ failure, poor performance status (ECOG >3), infection with HIV, hepatitis B, hepatitis C, active autoimmune cytopenia, or alemtuzumab therapy within the past 2 months. Rituximab 20 mg/m2 IV M-W-F started on day 1, alemtuzumab started on day 3 with an escalation of 3-10-30 mg/d SQ and then 30 mg M-W-F from day 8, and pentostatin 2 mg/m2 IV every 2 weeks started on day 8. Peg-G-CSF or GM-CSF was used after each dose of pentostatin and patients received Pneumocystis and Varicella prophylaxis. CMV PCR assays were done weekly during treatment and viremia was treated with either valganciclovir or ganciclovir. Cycle 1 was 5 weeks and subsequent cycles were 4 weeks. At the end of cycle 2 patients with a clinical CR had a CT scan and a bone marrow study with immunohistochemical (IHC) staining for residual CLL cells, and therapy was stopped if there was no radiological or IHC evidence of residual CLL (stringent CR). Patients with residual disease received a 3rd cycle of therapy. Results Forty-one patients were enrolled (July 2008 - February 2013) and all 39 who started therapy were evaluable for response: Median age 61 years (range 47-78), 30 (77%) males, 36 (92%) relapsed/refractory CLL (median prior regimens = 2, range 1-10), 3 (8%) previously untreated, 23 (59%) advanced stage (Rai III-IV), 16 (41%) intermediate stage (Rai I-II). Prognostic factors: FISH (hierarchical classification) 15 (38%) 17p13-, 6 (15%) 11q22-, 5 (13%) 12+, 3 (8%) no defects, 8 (21%) 13q14-, and 2 (5%) other abnormalities, IGHV analysis (n=38) 27 (71%) unmutated (<2%), ZAP-70 (n=37) 28 (76%) positive (>20%). Thirty (77%) patients completed planned therapy (28 had 3 cycles, 2 had 2 cycles with stringent CR). Nine patients received one (n=4) or two (n=5) cycles of therapy because of disease progression or complications. Grade 3-4 hematological adverse events (n=37) at least possibly related to treatment included neutropenia (n=22), thrombocytopenia (n=11), anemia (n=2) and hemolysis (n=2). Non-hematological adverse events (n=17) included infections/neutropenic fever (n=8), fatigue (n=3), and hemorrhage (n=2). CMV reactivation was detected and treated in 14 patients (grade 1-2). No patients died during treatment or from treatment related complications. The overall response rate was 56% (95% CI 40-72) with 4 (10%) CR, 7 (18%) CRi, 11 (28%) PR, 7 (18%) SD, and 10 (26%) PD. Four patients (3 CR and 1 CRi) had IHC negative bone marrow studies. Thirteen (33%) patients have died due to progressive CLL (n = 11), sepsis (n=1), and pneumonia (n=1). Median follow up for surviving patients is 23 months (range 3-55). Seven (18%) patients proceeding to RIC allogeneic transplant were censored for time to next treatment. Twenty-one (54%) patients required therapy for progressive CLL and 7 (18%) have required no further therapy. Median progression free survival was 7 months (95% CI: 5-16), time to next treatment 9 months (95% CI: 6-27) and median overall survival has not been reached. Discussion PAR was effective and tolerable therapy for high-risk CLL. This study suggests that alemtuzumab can be used safely in combination with a purine analogue in a short-duration regimen. Disclosures: Zent: Genentech : Research Funding; Genzyme: Research Funding; Biothera: Research Funding; GlaxSmithKline: Research Funding; Novartis: Research Funding. Off Label Use: Pentostatin therapy for CLL, use of lower doses of rituximab.

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The dual PI3Kδ/CK1ε inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells

Blood Advances ◽

10.1182/bloodadvances.2020001800 ◽

2020 ◽

Vol 4 (13) ◽

pp. 3072-3084 ◽

Cited By ~ 2

Author(s):

Kamira Maharaj ◽

John J. Powers ◽

Alex Achille ◽

Melanie Mediavilla-Varela ◽

Wael Gamal ◽

...

Keyword(s):

Clinical Trials ◽

T Cells ◽

Adverse Events ◽

Safety Profile ◽

Lymphocytic Leukemia ◽

Casein Kinase 1 ◽

Pi3k Inhibitors ◽

Treg Number ◽

Immune Mediated ◽

And Function

Abstract The in-clinic phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib (CAL-101) and duvelisib (IPI-145) have demonstrated high rates of response and progression-free survival in clinical trials of B-cell malignancies, such as chronic lymphocytic leukemia (CLL). However, a high incidence of adverse events has led to frequent discontinuations, limiting the clinical development of these inhibitors. By contrast, the dual PI3Kδ/casein kinase-1-ε (CK1ε) inhibitor umbralisib (TGR-1202) also shows high rates of response in clinical trials but has an improved safety profile with fewer severe adverse events. Toxicities typical of this class of PI3K inhibitors are largely thought to be immune mediated, but they are poorly characterized. Here, we report the effects of idelalisib, duvelisib, and umbralisib on regulatory T cells (Tregs) on normal human T cells, T cells from CLL patients, and T cells in an Eμ-TCL1 adoptive transfer mouse CLL model. Ex vivo studies revealed differential effects of these PI3K inhibitors; only umbralisib treatment sustained normal and CLL-associated FoxP3+ human Tregs. Further, although all 3 inhibitors exhibit antitumor efficacy in the Eμ-TCL1 CLL model, idelalisib- or duvelisib-treated mice displayed increased immune-mediated toxicities, impaired function, and reduced numbers of Tregs, whereas Treg number and function were preserved in umbralisib-treated CLL-bearing mice. Finally, our studies demonstrate that inhibition of CK1ε can improve CLL Treg number and function. Interestingly, CK1ε inhibition mitigated impairment of CLL Tregs by PI3K inhibitors in combination treatment. These results suggest that the improved safety profile of umbralisib is due to its role as a dual PI3Kδ/CK1ε inhibitor that preserves Treg number and function.

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Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia

Blood ◽

10.1182/blood.2019002118 ◽

2019 ◽

Vol 134 (21) ◽

pp. 1811-1820 ◽

Cited By ~ 16

Author(s):

Matthew Lunning ◽

Julie Vose ◽

Loretta Nastoupil ◽

Nathan Fowler ◽

Jan A. Burger ◽

...

Keyword(s):

B Cell ◽

Response Rate ◽

Complete Response Rate ◽

Complete Response ◽

Lymphocytic Leukemia ◽

Hepatic Toxicity ◽

B Cell Malignancies ◽

Non Hodgkin Lymphoma ◽

Immune Mediated ◽

Key Points

Key Points U2 exhibited low rates of immune-mediated toxicities associated with other PI3K-δ, including diarrhea, colitis, pneumonia, and hepatic toxicity. This combination had promising preliminary activity across a broad range of B-cell malignancies, including a 17% complete response rate.

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Activity Of Single Agent Temsirolimus and Associated Impact On Bone Marrow Vascularization and T-Cell Composition In Patients With Myelodysplastic Syndromes – Result Of The Prospective Temds Trial Of The German MDS-SG

Blood ◽

10.1182/blood.v122.21.2808.2808 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2808-2808

Author(s):

Martin Wermke ◽

Claudia Schuster ◽

Claudia Schönefeldt ◽

Christiane Jakob ◽

Malte von Bonin ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

Adverse Events ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Single Agent ◽

Infectious Complications ◽

T Cell Subsets ◽

Concentration Data ◽

Cell Composition

Abstract Introduction Enhanced progenitor proliferation, bone marrow (BM) hypervascularization and disturbed immune regulation contribute to the pathogenesis of myelodysplastic syndromes (MDS). Inhibition of mammalian-target of rapamycin (mTor) by temsirolimus (TEM) might be a promising strategy to target these disease-specific cellular alterations. We report on the effects of single agent TEM on the clinical course as well as on immune composition and BM vascularization of MDS patients treated within the prospective, multicenter “TEMDS”-trial (NCT01111448). Patients, Materials and Methods Twenty patients being either IPSS low/int-1 MDS (n = 9) or IPSS int-2/high after azacitidine failure were treated with TEM at a dose of 25 mg/week in the absence of toxicity or disease progression. BM was reevaluated after 4 months of treatment with the option of TEM continuation for a maximum of 12 months in responding patients. Translational research within this study included flowcytometry-based measurement of changes in T-cell composition as well as determination of cytokine levels and BM-vascularization prior to and after TEM. Results Of 20 patients treated, 15 discontinued TEM treatment prematurely due to intolerable side effects (n = 11), infectious complications (n = 3), or progression to AML (n = 1). Fatigue, stomatitis and profound leukopenia were the most frequent adverse events. A total of 13 severe adverse events were encountered in 10 patients and 1 patient died of infectious complications during TEM treatment. Of the 5 patients who were treated for at least 4 months and underwent regular BM reevaluation, none showed signs of response according to IWG criteria. TEM treatment resulted in a remarkable, although non-significant, decrease in total number of lymphocytes in the pB (pre: 74.6%, post: 48.4%, p = 0,083) and BM (pre: 23.5% post: 20.1%, p = 0.123). Within the T-helper cell compartment a trend towards an increase in regulatory T-cell (Treg) frequency was observed (pB: pre: 6.0 %, post: 6.4 %, p = 0.083). Moreover, the balance between naive (CD45RA+/CD45RO-) and activated/memory (CD45RA-/CD45RO+) Treg shifted significantly in favor of the latter (p = 0.004). Plasma analysis in BM and pB revealed, that these changes were obviously not mediated by alterations in TGFβ plasma levels. In a total of 12 assessable patients, a significant (p = 0.006) decrease of BM vascularization was observed after treatment with TEM for a median of 5 weeks (Fig. 1). There were, however, no changes in the medullary or peripheral blood VEGF concentration (data not shown). Conclusions Selective inhibition of the mTOR signaling cascade in MDS patients results in specific alterations of the composition of T-cell subsets as well as BM vascularization. Given the absence of any hematological response we suggest that these drug-induced modifications cannot alter the natural course of the disease. Disclosures: Wermke: Pfizer: Research Funding. Off Label Use: Temsirolimus is licensend for the treatment of MCL and RCC but not MDS. Platzbecker:Pfizer: Research Funding.

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Phase 1b Study Of Otlertuzumab (TRU-016), An Anti-CD37 ADAPTIR™ Protein, In Combination With Rituximab In Patients With Previously Untreated Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v122.21.4165.4165 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4165-4165

Author(s):

Kami Maddocks ◽

John M. Pagel ◽

Susan O'Brien ◽

John C. Byrd ◽

Scott Stromatt ◽

...

Keyword(s):

Bone Marrow ◽

Adverse Events ◽

Inflammatory Response ◽

Research Funding ◽

Response Rate ◽

Systemic Inflammatory Response ◽

Hematologic Toxicity ◽

Color Flow ◽

Wide Range ◽

Phase 1B

Abstract Background CD37 is a tetraspanin protein expressed on the surface of normal and transformed B-cells across a wide range of maturational stages and demonstrates death signaling via SHP1. Otlertuzumab is a CD37-specific therapeutic protein built on the ADAPTIR™(modular protein technology) platform that has shown significantly greater direct killing of CLL cells than rituximab and higher levels of Fc-mediated cellular cytotoxicity of CLL cells than either alemtuzumab or rituximab in pre-clinical models. This phase 1b trial was conducted to evaluate the safety and efficacy of otlertuzumab in combination with rituximab in patients with previously untreated CLL. Methods Patients with untreated CLL that required treatment, had adequate organ function, ECOG ≤2, and absolute neutrophil count ≥800/μL were eligible. Patients were ineligible for chemotherapy as first-line therapy due to patient age, comorbidity, or patient refusal of chemotherapy Patients received otlertuzumab (20 mg/kg) weekly by IV infusion for two 28-day cycles then once a month for 4 months. Rituximab (375 mg/m2 the first dose then 500 mg/m2) was administered after otlertuzumab by IV infusion on the same schedule. Safety was evaluated using CTCAE and IWCLL 2008 Grading scale for Hematologic Toxicity in CLL Studies. Response was determined using the 1996 NCI and the 2008 IWCLL Criteria. Results 24 patients have been treated. Patient characteristics and adverse events are shown in the table. The majority of the patients have not completed 6 cycles of therapy. The preliminary response by investigator assessment using NCI criteria at the last assessment is an ORR 88% (21/24); 2 patients have had PD. Six patients have had CT scans and bone marrow assessments 3 months after their last dose of study drug; by IWCLL criteria 1 has a CR, 4 have a PR and 1 has SD. The patient with a CR was MRD negative by five color flow cytometry of bone marrow aspirate. One patient discontinued therapy for a systemic inflammatory response. Severe (Grade 3 or 4) neutropenia was reported in 13% of patients; the incidence of severe infections was low (8%). Serious adverse events were reported for 4 patients: pneumonia, systemic inflammatory response, and deep vein thrombosis in 1 patient; and lymph node pain, worsening sinusitis, and fever in 1 patient each. Conclusions The preliminary response rate with otlertuzumab in combination with rituximab is promising. Follow-up is ongoing and the IWCLL response rate will be presented. Disclosures: O'Brien: Emergent Product Development: Research Funding. Stromatt:Emergent Biosolutions: Employment. Awan:Lymphoma Research Foundation - Research Funding: Research Funding, Speakers Bureau; Spectrum Pharmaceuticals, Inc. - Speakers bureau: Research Funding, Speakers Bureau.

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Chemoimmunotherapy With Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Versus Bendamustine and Rituximab (BR) In Previously Untreated and Physically Fit Patients (pts) With Advanced Chronic Lymphocytic Leukemia (CLL): Results Of a Planned Interim Analysis Of The CLL10 Trial, An International, Randomized Study Of The German CLL Study Group (GCLLSG)

Blood ◽

10.1182/blood.v122.21.526.526 ◽

2013 ◽

Vol 122 (21) ◽

pp. 526-526 ◽

Cited By ~ 30

Author(s):

Barbara Eichhorst ◽

Anna-Maria Fink ◽

Raymonde Busch ◽

Elisabeth Lange ◽

Hubert Köppler ◽

...

Keyword(s):

Adverse Events ◽

Interim Analysis ◽

Research Funding ◽

Response Rate ◽

Phase Iii ◽

Severe Neutropenia ◽

Line Treatment ◽

First Line ◽

Free Survival ◽

First Line Treatment

Abstract Introduction FCR is the current standard first line treatment regimen in advanced CLL (Hallek et al., Lancet, 2010), but is associated with significant side effects. The GCCLSG initiated an international phase III study in order to test the non-inferiority regarding efficacy and potentially better tolerability of BR compared to FCR in first-line therapy of physically fit pts without del(17p). Methods and Patients 688 CLL pts from 158 sites in five countries (Germany, Austria, Switzerland, Denmark and Czech Republic) were screened centrally for immunophenotype, genomic aberrations by FISH, IGHV sequenzing, comorbidity burden and renal function. 564 CLL pts with CIRS score ≤ 6, creatinine clearance > 70 ml/min and without del(17p) were enrolled between October 2008 and June 2011. Pts were randomly assigned to receive 6 courses of either FCR (N= 284; F 25mg/m2 i.v. d1–3, C 250 mg/m2 i.v. d1–3, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent courses; q 28 days) or BR (N=280; B 90mg/m2 i.v. d1+2, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent courses; q 28 days). The intent-to-treat population consisted of 561 pts, because three patients were excluded due to deferred treatment (1 pt decision, 1 treatment before randomization, 1 misdiagnosis). 22 % were Binet A, 38 % Binet B and 40 % Binet C. The median age was 62 years (yrs) (range 33 to 82), median CIRS score 2 (range 0-6). There were significantly more pts with unmutated IGVH in the BR arm (68%) in comparison to the FCR arm (55%; p=0.003). All other characteristics including median age were well balanced. A mean number of 5.27 courses was given in the FCR arm versus 5.41 courses in the BR arm (p=0.022). 70.6% (FCR) and 80.3% (BR) of pts received 6 courses (p=0.008). Dose was reduced by more than 10% in 27.3% (FCR) and 31.6% (BR) of all courses given (p = 0.012). Results The median observation time was 27.9 months (mo) in all pts alive. While response evaluation was missing in 14 pts, 547 pts (274 FCR; BR 273) were evaluable for response and all 561 pts (282 FCR; 279 BR) for progression-free survival (PFS), event-free survival (EFS) and OS. The overall response rate was identical in both arms with 97.8% (p=1.0). The complete response rate (CRR) (confirmed by central immunhistology) with FCR was 47.4% as compared to 38.1% with BR (p=0.031). MRD data were available at interim analysis from 192 pts (99 FCR; 93 BR) of the first 300pts. 71.7% of pts in the FCR and 66.7% in the BR arms achieved MRD-levels below 10-4 in peripheral blood at final staging (p=0.448). The complete MRD data set will be available by November. PFS was 85.0% at 2 yrs in the FCR arm and 78.2% in the BR arm (p=0.041). EFS was 82.6% at 2 yrs in the FCR arm and 75.7% in the BR arm (p=0.037).There was no difference in OS rate for the FCR vs BR arm (94.2% vs 95.8% at 2 years p=0.593). Hazard Ratio for PFS, EFS and OS was 1.385, 1.375 and 0.842 respectively. PFS was assessed in pts < 65 yrs and ≥ 65 yrs. While there was a significant difference in pts < 65 yrs between both treatment arm (median PFS for BR 36.5 mo vs not reached for FCR; p=0.016), the difference disappeared in elderly pts (not reached vs. 45.6 mo; p=0.757). A multivariate analysis including treatment arm, Binet stage, age, sex, comorbidity, serum TK, serum beta2-microglobulin (Beta2M), del(11q) and IGHV status identified treatment arm, Beta2M, del(11q) and IGHV as independent prognostic factors for PFS and EFS. FCR treated pts had significantly more frequent severe, CTC grade 3 to 5, adverse events during the whole observation period (90.8% vs 78.5%; p<0.001). Especially severe hematotoxicity was more frequent in the FCR arm (90.0% vs 66.9%, p<0.001). The higher rate of severe neutropenia (81.7% vs 56.8%, p<0.001) resulted in a significantly higher rate of severe infections (39.0% vs 25.4%, p=0.001) in the FCR arm, especially in the elderly (FCR: 47.4% vs BR: 26.5%; p=0.002). Treatment related mortality occurred in 3.9% (n=11) in the FCR and 2.1% (n=6) in the BR arm. Conclusion The results of this planned interim analysis show that FCR seems more efficient than BR in the first-line treatment of fit CLL pts with regard to higher CRR, as well as longer PFS and EFS. These advantages might be balanced by a higher rate of severe adverse events, in particular neutropenia and infections, associated with FCR. In light of these results, no firm recommendation of one regimen over the other can be given at the present time regarding the first-line use in CLL pts with good physical fitness. Disclosures: Eichhorst: Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding. Gregor:Roche: Consultancy, Honoraria, Travel Support Other; Mundipharma: Travel Support, Travel Support Other. Plesner:Mundipharma: Research Funding. Trneny:Roche: Honoraria, Research Funding. Fischer:Roche: Travel grants Other; Mundipharma: Travel grants, Travel grants Other. Kneba:Roche: Consultancy, Research Funding. Wendtner:Roche: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding. Kreuzer:Roche: Honoraria; Mundipharma: Honoraria. Stilgenbauer:Roche: Consultancy, Research Funding, Travel grants Other; Mundipharma: Consultancy, Research Funding. Böttcher:Roche: Honoraria, Research Funding. Hallek:Janssen: Research Funding; Gilead: Research Funding; Roche: Research Funding.

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Ibrutinib In Combination With Rituximab (iR) Is Well Tolerated and Induces a High Rate Of Durable Remissions In Patients With High-Risk Chronic Lymphocytic Leukemia (CLL): New, Updated Results Of a Phase II Trial In 40 Patients

Blood ◽

10.1182/blood.v122.21.675.675 ◽

2013 ◽

Vol 122 (21) ◽

pp. 675-675 ◽

Cited By ~ 21

Author(s):

Jan A. Burger ◽

Michael J. Keating ◽

William G. Wierda ◽

Julia Hoellenriegel ◽

Ghayathri Jeyakumar ◽

...

Keyword(s):

High Risk ◽

Subdural Hematoma ◽

Research Funding ◽

Tp53 Mutation ◽

Single Agent ◽

Infectious Complications ◽

Lymphocytic Leukemia ◽

High Rate ◽

Grade 3

Abstract The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is a promising new targeted therapy for patients with mature B cell malignancies, especially CLL and mantle cell lymphoma (MCL). Single agent ibrutinib induces an overall response rate (ORR) of 71% in relapsed CLL, based on the Phase 1/2 experience. To accelerate and improve responses to ibrutinib in high-risk CLL, ibrutinib was combined with rituximab; we update this Phase 2 single-center clinical trial with a median follow-up of 14 months. Methods Patients were treated with ibrutinib 420 mg PO daily continuously throughout the study Rituximab (375 mg/m2) was administered weekly for the first four weeks (cycle 1), then monthly until cycle 6.at which point patients continued on ibrutinib monotherapy. Study inclusion required high-risk disease (del17p or TP53 mutation [treated or untreated]), PFS < 36 months after frontline chemo-immunotherapy, or relapsed CLL with del11q. Results Characteristics of the 40 patients enrolled included median age of 65 (range 35–82) with a median of 2 prior therapies. There were14 female and 26 male patients. 20 patients had del17p or TP53 mutation (4 without prior therapy), and 13 patients had del11q. 32 patients had unmutated IGHV, only one patient mutated IGHV, the remaining patients had inconclusive IGHV results. The median β2 microglobulin was 4.2 mg/L (2.2 – 12.3), At a median follow up of 14 months, 32 of 40 patients continue on therapy (16 out of 20 with del17p or TP53 mutation) without disease progression. 39 patients were evaluable for response assessment per 2008 IWCLL guidelines; 34 (87%) achieved partial remission (PR), and three (8%) complete remission (CR), accounting for an ORR of 95%. One CR was negative for MRD by flow cytometry, The ORR in the 20 patients with del17p or TP53 mutation was 90% (16 PR, 2 CR). Among the 8 patients that came off study, 3 patient died from unrelated infectious complications (2 cases of sepsis, 1 case of pneumonia), and 1 died from unrelated respiratory and cardiovascular failure. Two patients came off study because of possibly ibrutinib-related toxicity (one subdural hematoma, one grade 3 mucositis), one patient had progressive disease, and one proceeded to stem cell transplantation. Treatment generally was well tolerated, with infectious complications (6 cases of pneumonia and 3 cases of upper respiratory infections) being the most common complication. There were two Grade 3, possibly related AEs: mucositis (n=1), and peripheral neuropathy (n=1). Milder toxicities included Grade 1-2 bruising (n=7), Grade 1 subdural hematoma (n=1), fatigue (n=2), bone pain, myalgias, and arthralgia (n=5), or diarrhea (n=1). Questionnaires revealed significantly improved overall health and quality of life (QOL) after 6 months, based on the EORTC-QOL-v.3 questionnaire, which coincided with a significant weight gain at 3 and 6 months. Conclusion Ibrutinib in combination with rituximab is a safe, well tolerated regimen for high-risk CLL patients, which induces high rates of durable responses. Responses were associated with significant improvements in QOL. Compared to ibrutinib monotherapy, the redistribution lymphocytosis resolves more rapidly and completely (see Figure), and consequently the ORR is higher. Whether the addition of rituximab to ibrutinib therapy translates into longer progression-free and overall survival will be addressed in an upcoming larger, randomized trial of ibrutinib versus iR in relapsed/refractory CLL. Disclosures: Burger: Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Ibrutinib (PCI-32765) for treatment of high-risk CLL patients. O'Brien:Pharmacyclics: Research Funding.

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Toxicity Is Not Associated with Age or Comorbidity Score in a Randomised Study of Oral Fludarabine and Cyclophosphamide and IV Rituximab (FCR) As First-Line Therapy of Fit, Elderly Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v124.21.4695.4695 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4695-4695 ◽

Cited By ~ 2

Author(s):

Stephen P. Mulligan ◽

Devinder Gill ◽

Paul Turner ◽

William E. P. Renwick ◽

Maya Latimer ◽

...

Keyword(s):

Febrile Neutropenia ◽

Adverse Events ◽

Research Funding ◽

Rating Scale ◽

Lymphocytic Leukemia ◽

Early Stopping ◽

First Line ◽

Significant Difference ◽

Skin Allergy ◽

Grade 3

Abstract BACKGROUND Fludarabine (F), cyclophosphamide (C) and rituximab (R) gave superior progression free (PFS) and overall survival (OS) versus (vs) FC in the CLL8 Study. The median age in CLL8 was 61 years compared to 72 years for CLL overall. There has been considerable debate regarding the tolerability and toxicity of FCR based therapy in older patients (pts) and those with comorbidities. METHODS Previously untreated fit pts with progressive CLL aged ≥65 were randomised to one of 3 therapy arms: (i) FR5: F 24mg/m2 po D1-5 + R iv D1 (375mg/m2 cycle 1, 500mg/m2 cycles 2-6), (ii) FCR3: F 24mg/m2 po and C 150mg/m2 po D1-3 + R iv D1 or (iii) FCR5: F 24mg/m2 po+ C 150mg/m2 po D1-5 + R iv D1 all at 4 weekly intervals for an intended 6 cycles. Cycles could be delayed up to 2 weeks for grade 3+ toxicity, and if unresolved by 2 weeks, pts were taken off study. Fitness was assessed using the Cumulative Illness Rating Scale (CIRS) score with eligibility restricted to CIRS ≤6. RESULTS Recruitment of 120 pts was completed in July 2012. 117 fulfilled eligibility and 1 had no treatment or follow-up reducing the cohort to 116. Median age was 71 (range 65-82) years (yrs) with 78 males (67%) and 39 females (33%). Patient registration by age was 65-69 yrs – 44, 70-74 yrs – 44, 75-79 yrs – 20 and 80-84 yrs – 8 pts, and by CIRS score was 0-2 – 61, 3-4 – 38, 5-6 – 17 pts. Toxicity data by age and CIRS score are shown in tables 1 and 2 respectively. All 6 protocol cycles were completed in 69% but less on FCR5 44% vs FR5 89% and FCR3 76% (p<0.001). Selected toxicity and early stopping rates in table 3. Overall response and toxicity are presented separately. Table 1:Grade 3+ Adverse Events by AgeAgeTotal65-6970-7475-7980-84(n=116)(N=44)(N=44)(N=20)(N=8)Hematological28 (64%)29 (66%)10 (50%)3 (38%)70 (60%)Neutropenia24 (55%)21 (48%)10 (50%)3 (38%)58 (50%)Thrombocytopenia9 (20%)9 (20%)1 (5%)0 (0%)19 (16%)Anaemia7 (16%)6 (14%)2 (10%)0 (0%)15 (13%)Haemolytic Anaemia1 (2%)2 (5%)1 (5%)1 (12%)5 (4%)Febrile Neutropenia / Infection9 (20%)5 (11%)8 (40%)2 (25%)24 (21%)Skin/Allergy/Fatigue/hypersensitivity3 (7%)2 (5%)4 (20%)2 (25%)11 (9%)Other (Card / resp / neuro / metabolic)13 (30%)10 (23%)3 (15%)1 (12%)27 (23%)At least 1 grade 3+ AE37 (84%)34 (77%)13 (65%)6 (75%)90 (78%) There was no statistically significant difference by age (p=0.429). Table 2:Grade 3+ Adverse Events by CIRS scoreCIRS scoreTotal0-23-45-6(n=116)(N=61)(N=38)(N=17)Hematological38 (62%)21 (55%)11 (65%)70 (60%)Neutropenia31 (51%)16 (42%)11 (65%)58 (50%)Thrombocytopenia11 (18%)6 (16%)2 (12%)19 (16%)Anaemia7 (11%)5 (13%)3 (18%)15 (13%)Haemolytic Anaemia1 (2%)4 (11%)0 (0%)5 (4%)Febrile Neutropenia / Infection11 (18%)9 (24%)4 (24%)24 (21%)Skin/Allergy/Fatigue/hypersensitivity6 (10%)4 (11%)1 (6%)11 (9%)Other (Card / resp / neuro / metabolic)12 (20%)9 (24%)6 (35%)27 (23%)At least 1 grade 3+ AE78 (79%)27 (71%)15 (88%)90 (78%) There was no statistically significant difference by CIRS score (p=0.355). Table 3:Abbreviated Grade 3+ Adverse Events by Treatment ArmTreatment armTotal (n=116)FR5 (N=37)FCR3 (N=41)FCR5 (N=38)Hematological15 (41% )26 (63% )29 (76% )70 (60%)At least 1 grade 3+ AE21 (57%)34 (83%)35 (92%)90 (78%)Early cessation due to toxicity2 (5.6%)1 (2.4%)13 (34%)16 (14%) Early cessation due to toxicity was significantly more common with FCR5 (p<0.001). However, of the 13 patients on FCR5 arm that stopped early due to toxicity, there was no difference by age or CIRS score: by age, 5 were 65-69 yrs, 3 were 70-74 yrs, 4 were 75-79 yrs and 1 was 80-84 yrs and by CIRS score, 3 were 0-2, 6 were 3-4 and 4 were 5-6. CONCLUSIONS Final analysis in this randomised dose de-escalation study shows oral FCR therapy is generally safe and well tolerated in CLL pts aged ≥65 years requiring first-line treatment, when early stopping is utilised if prolonged toxicity occurs. Early cessation due to toxicity was more common with full dose FCR5, but not associated with age or CIRS score within this arm. Overall in this relatively fit elderly CLL cohort, neither age nor CIRS score were associated with toxicity, or early cessation of therapy due to toxicity. The results highlight the difficulty of predicting toxicity based on age and comorbidity in elderly CLL pts. Disclosures Mulligan: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Aventis: Research Funding; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria. Gill:Roche: Research Funding; Sanofi Aventis: Research Funding. Turner:Roche: Research Funding; Sanofi Aventis: Research Funding. Renwick:Roche: Research Funding; Sanofi: Research Funding. Latimer:Roche: Research Funding; Sanofi: Research Funding. Mackinlay:Roche: Research Funding; Sanofi: Research Funding. Berkahn:Roche: Research Funding; Sanofi: Research Funding. Simpson:Roche: Research Funding; Sanofi: Research Funding. Forsyth:Roche: Research Funding; Sanofi: Research Funding. Harrup:Roche: Research Funding; Sanofi: Research Funding. Kuss:Roche: Research Funding; Sanofi: Research Funding.

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Outcomes of Patients with Chronic Lymphocytic Leukemia (CLL) after Idelalisib Therapy Discontinuation

Blood ◽

10.1182/blood.v126.23.4155.4155 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4155-4155 ◽

Cited By ~ 7

Author(s):

Jacqueline C. Barrientos ◽

Manmeen Kaur ◽

Alexis Mark ◽

Jaewon Chung ◽

Nancy Driscoll ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Salvage Therapy ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Therapy Discontinuation ◽

Progression Of Disease ◽

Grade 3 ◽

Extension Trial ◽

Parent Trial

Abstract Objective Idelalisib is a first-in-class oral PI3Kd inhibitor approved for use in combination with rituximab in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL). We describe the characteristics, causes of discontinuation, and outcomes in patients who discontinued treatment after idelalisib therapy. Methods 38 R/R CLL patients participated in 5 idelalisib combination trials at the North Shore-LIJ Cancer Institute and were included in this analysis. The patients were enrolled from 2011 until 2014, and data were locked in March 1st, 2015. Patients were evaluated for time to therapy discontinuation and reasons for discontinuation. The majority of the patients had been heavily pretreated and 39% of the patients had a high risk prognostic marker including deletion of 11q or 17p. 21 R/R CLL patients participated in the Phase Ib trial of idelalisib in combination with several agents including Rituximab (R), Bendamustine (B) ± R, Fludarabine, Chlorambucil ± R, and Ofatumumab. The trial was designed for 48 weeks and patients were allowed to continue on an extension trial with idelalisib if still deriving benefit. Patients on the parent trial were on therapy a median of 335 days. 42% (11/21) continued in the extension trial at the end of the parent trial. Causes of discontinuation from initial 48-week trial included: grade 4 transaminitis (1) on day 64 with failed rechallenge at lower doses; Richter's transformation (1) on day 161; grade 3/4 diarrhea/colitis (4) on days 52, 231, 255, and 365; refractory/progressive CLL (2) on days 8 and 170; aplastic anemia (1) on day 172; and septic shock in a patient with uncontrolled autoimmune hemolytic anemia (1) on day 271. Of the patients on the extension trial, the median time on drug was 412 days with 27% (3/11) discontinuing due to grade 3/4 diarrhea/colitis; 36% (4/11) due to progression, 9% (1/11) due to pneumonia and subsequent progression 2 months later. Of the 3 patients that remain on study, their median time on therapy is 1072 days without evidence of toxicities. Of the 17 patients that participated in placebo-controlled phase III studies, 11 participated in R +/- idelalisib (study 116) and 6 on BR+/-idelalisib (study 115). Study 116 was unblinded during the trial: 35% (4/11) received idelalisib + R upfront. Of these, only 2 patients (50%) were able to continue on extension study as the other 2 patients developed pneumonitis and were taken off study early. One patient is continues on study at day 1011 whereas the second patient developed progressive multifocal leukoencephalopathy on day 714 and died days after being taken off drug. 86% (6/7) of the remaining patients initially randomized to placebo crossed over to idelalisib at the time of confirmed progression. Of these, 14% (1/6) developed both colitis and later pneumonitis, 14% (1/6) withdrew consent, and 14% (1/6) had progression of disease. For blinded study 115 (BR+/-idelalisib), 6 patients participated: 33% (2/6) developed grade 3/4 diarrhea/colitis, 16% (1/6) developed pneumonitis, and 16% (1/6) has progressed. In our experience, none of the patients with severe diarrhea/colitis were able to maintain lower doses for a prolonged period of time without recurrent colitis or the development of pneumonitis. Since the start of these trials, 31% (12/38) of the patients have died: the overall survival after discontinuation for these patients varies widely from 0 to 303 days with a median overall survival of 64 days after discontinuation. Most patients with relapsed/refractory CLL who discontinued idelalisib early were difficult to treat and had poor outcomes. Over the course of the trials, the Bruton's tyrosine kinase inhibitor ibrutinib was approved and used as salvage therapy in 10 patients with confirmed progression; except for 1 patient, all patients successfully achieved a prolonged response with ibrutinib suggesting salvage therapy with a targeted agent may be a reasonable therapeutic approach for patients after idelalisib failure. Interestingly, the rate of Richter's transformation was extremely rare in this study (2%). Conclusions This single-institution experience with idelalisib identifies baseline factors associated with therapy discontinuation, mainly grade 3/4 diarrhea/colitis and progression of disease as a reason for discontinuation from therapy. Our data suggest the use of ibrutinib may be a reasonable choice in patients after idelalisib failure. Disclosures Barrientos: ASH-AMFDP: Research Funding; Gilead: Research Funding; NIH/NCATS: Research Funding. Off Label Use: idelalisib is approved in combination with rituximab only. I will discuss our experience of idelalisib in combination with other agents.

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