70 research outputs found
Single agent subcutaneous blinatumomab for advanced acute lymphoblastic leukemia
Blinatumomab is a BiTE® (bispecific T-cell engager) molecule that redirects CD3+ T-cells to engage and lyse CD19+ target cells. Here we demonstrate that subcutaneous (SC) blinatumomab can provide high efficacy and greater convenience of administration. In the expansion phase of a multi-institutional phase 1b trial (ClinicalTrials.gov, NCT04521231), heavily pretreated adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) received SC blinatumomab at two doses: (1) 250 μg once daily (QD) for week 1 and 500 μg three times weekly (TIW) thereafter (250 μg/500 μg) or (2) 500 μg QD for week 1 and 1000 μg TIW thereafter (500 μg/1000 μg). The primary endpoint was complete remission/complete remission with partial hematologic recovery (CR/CRh) within two cycles. At the data cutoff of September 15, 2023, 29 patients were treated: 14 at the 250 μg/500 μg dose and 13 at 500 μg/1000 μg dose. Data from two ineligible patients were excluded. At the end of two cycles, 12 of 14 patients (85.7%) from the 250 μg/500 μg dose achieved CR/CRh of which nine patients (75.0%) were negative for measurable residual disease (MRD; <10−4 leukemic blasts). At the 500 μg/1000 μg dose, 12 of 13 patients (92.3%) achieved CR/CRh; all 12 patients (100.0%) were MRD-negative. No treatment-related grade 4 cytokine release syndrome (CRS) or neurologic events (NEs) were reported. SC injections were well tolerated and all treatment-related grade 3 CRS and NEs responded to standard-of-care management, interruption, or discontinuation. Treatment with SC blinatumomab resulted in high efficacy, with high MRD-negativity rates and acceptable safety profile in heavily pretreated adults with R/R B-ALL.</p
Single agent subcutaneous blinatumomab for advanced acute lymphoblastic leukemia
Blinatumomab is a BiTE® (bispecific T-cell engager) molecule that redirects CD3+ T-cells to engage and lyse CD19+ target cells. Here we demonstrate that subcutaneous (SC) blinatumomab can provide high efficacy and greater convenience of administration. In the expansion phase of a multi-institutional phase 1b trial (ClinicalTrials.gov, NCT04521231), heavily pretreated adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) received SC blinatumomab at two doses: (1) 250 μg once daily (QD) for week 1 and 500 μg three times weekly (TIW) thereafter (250 μg/500 μg) or (2) 500 μg QD for week 1 and 1000 μg TIW thereafter (500 μg/1000 μg). The primary endpoint was complete remission/complete remission with partial hematologic recovery (CR/CRh) within two cycles. At the data cutoff of September 15, 2023, 29 patients were treated: 14 at the 250 μg/500 μg dose and 13 at 500 μg/1000 μg dose. Data from two ineligible patients were excluded. At the end of two cycles, 12 of 14 patients (85.7%) from the 250 μg/500 μg dose achieved CR/CRh of which nine patients (75.0%) were negative for measurable residual disease (MRD; <10−4 leukemic blasts). At the 500 μg/1000 μg dose, 12 of 13 patients (92.3%) achieved CR/CRh; all 12 patients (100.0%) were MRD-negative. No treatment-related grade 4 cytokine release syndrome (CRS) or neurologic events (NEs) were reported. SC injections were well tolerated and all treatment-related grade 3 CRS and NEs responded to standard-of-care management, interruption, or discontinuation. Treatment with SC blinatumomab resulted in high efficacy, with high MRD-negativity rates and acceptable safety profile in heavily pretreated adults with R/R B-ALL.</p
Haploidentical vs. sibling, unrelated, or cord blood hematopoietic cell transplantation for acute lymphoblastic leukemia
The role of haploidentical hematopoietic cell transplantation (HCT) using posttransplant cyclophosphamide (PTCy) for acute lymphoblastic leukemia (ALL) is being defined. We performed a retrospective, multivariable analysis comparing outcomes of HCT approaches by donor for adults with ALL in remission. The primary objective was to compare overall survival (OS) among haploidentical HCTs using PTCy and HLA-matched sibling donor (MSD), 8/8 HLAmatched unrelated donor (MUD), 7 /8 HLA-MUD, or umbilical cord blood (UCB) HCT. Comparing haploidentical HCT to MSD HCT, we found that OS, leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and acute graft-versus-host disease (aGVHD) were not different but chronic GVHD (cGVHD) was higher in MSD HCT. Compared with MUD HCT, OS, LFS, and relapse were not different, but MUD HCT had increased NRM (hazard ratio [HR], 1.42; P = .02), grade 3 to 4 aGVHD (HR, 1.59; P = .005), and cGVHD. Compared with 7/8 UD HCT, LFS and relapse were not different, but 7/8 UD HCT had worse OS (HR, 1.38; P = .01) and increased NRM (HR, 2.13; P <_ .001), grade 3 to 4 aGVHD (HR, 1.86; P = .003), and cGVHD (HR, 1.72; P <_ .001). Compared with UCB HCT, late OS, late LFS, relapse, and cGVHD were not different but UCB HCT had worse early OS (<_18 months; HR, 1.93; P < .001), worse early LFS (HR, 1.40; P = .007) and increased incidences of NRM (HR, 2.08; P < .001) and grade 3 to 4 aGVHD (HR, 1.97; P < .001). Haploidentical HCT using PTCy showed no difference in survival but less GVHD compared with traditional MSD and MUD HCT and is the preferred alternative donor HCT option for adults with ALL in complete remission
Spontaneous Remission of an Untreated, MYC and BCL2 Coexpressing, High-Grade B-Cell Lymphoma: A Case Report and Literature Review
Non-Hodgkin lymphomas (NHL) are a heterogeneous group of hematologic malignancies typically treated with multiagent chemotherapy. Rarely, spontaneous remissions can be observed, particularly in more indolent subtypes. The prognosis of aggressive NHL can be predicted using clinical and histopathologic factors. In aggressive B-cell NHL, the importance of MYC and BCL2 proto-oncogene coexpression (as assessed by immunohistochemistry) and high-grade histologic features are particularly noteworthy. We report a unique case of spontaneous remission in a patient with an aggressive B-cell NHL which harbored high-risk histopathologic features, including MYC protein expression at 70–80%, BCL2 protein expression, and morphologic features suggestive of high-grade B-cell lymphoma, NOS (formerly B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma [BCLU]). After undergoing a biopsy to confirm this diagnosis, he opted to forego curative-intent chemotherapy. The single, yet relatively large area of involvement noted on 18F-fluorodeoxyglucose positron emission tomography-computed tomography steadily resolved on subsequent follow-up studies. He remained without evidence of recurrence one year later, having never received treatment. This case emphasizes the potential for spontaneous remission in NHL and demonstrates that this phenomenon can be observed despite contemporary high-risk histopathologic features
Reevaluating Patient Eligibility for Inotuzumab Ozogamicin Based on CD22 Expression: Is Dim Expression Sufficient?
Salvage options for patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL) include inotuzumab ozogamicin (InO), a recombinant, humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin. However, the benefit of InO in patients with dim CD22 expression remains unclear. We present a case of a patient with B-ALL who responded to InO despite only dim surface expression of CD22 by flow cytometry, achieving a survival benefit concordant with that reported in the literature and maintaining a good quality of life as a transfusion-independent outpatient. Our observation has broad relevance to clinicians who manage patients with B-ALL who are candidates for InO.Medicine, Faculty ofAlumniNon UBCReviewedFacult
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A Window Study of Ixazomib in Untreated B-NHL
Background: Window of opportunity studies are rarely conducted in lymphoma, but permit evaluation of novel therapies before resistance mechanisms emerge. Identification of a minimum acceptable response rate in the first-line setting may expedite drug development and is most attractive for testing relatively nontoxic, oral targeted agents that may offer substantial logistical and clinical benefits (1). Ixazomib, an orally bioavailable proteasome inhibitor, showed promising activity in a single small study that included relapsed/refractory indolent B-cell NHL (i-NHL) (2). We designed a frontline "window" study to assess the activity of ixazomib monotherapy in patients with i-NHL.
Methods: This single-arm, open-label investigator-initiated phase II trial (NCT 02339922) is being conducted at the University of Washington / Fred Hutch Cancer Research Center. Patients must have a diagnosis of i-NHL and a clinical indication for treatment per NCCN guidelines. Other criteria are ECOG ≤ 2, and no prior systemic anti-neoplastic treatment except in cases of mucosa-associated marginal zone lymphoma relapsed after or refractory to antibiotics.
Ixazomib is administered at 4 mg orally once a week on consecutive 28-day cycles until disease progression or unacceptable toxicity. The window period closes after 6 cycles, with four doses of weekly rituximab added during the 7th cycle to test the safety and efficacy of this combination.
The primary endpoint is investigator-assessed response rate performed every 2 cycles. An overall response rate of ≥ 19 of 36 is required to conclude promising efficacy. Secondary endpoints include duration of response, progression free survival, time to next treatment, and safety / tolerability. Correlative studies are being performed on tumor tissue samples collected pre-treatment and paired with biopsies obtained, as able, within 2 months after initiation of ixazomib and with clinically suspected disease progression to gain insight into potential molecular predictors of response. Correlates under investigation include gene expression profiling using the Nanostring platform and immunohistochemical evaluation of pathways associated with lymphoma proliferation and proteasome inhibition.
The study opened in May 2016 and as of June 2019, 32 patients were screened. Of 23 patients treated the median age is 64 (range 41 to 85) and 15 (65%) are male. Fifteen (65%) patients had follicular lymphoma, 4 (17%) mantle cell lymphoma, 3 (13%) marginal zone lymphoma, and 1 (4%) chronic lymphocytic leukemia. No unexpected toxicities have emerged to date. The study is supported by Takeda Oncology. Glimelius B, Lahn M. Window-of-opportunity trials to evaluate clinical activity of new molecular entities in oncology. Ann Oncol. 2011;22(8):1717-25.Assouline SE, Chang J, Cheson BD, Rifkin R, Hamburg S, Reyes R, et al. Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma. Blood Cancer J. 2014;4:e251.
Disclosures
Graf: BeiGene: Research Funding; AstraZeneca: Research Funding; TG Therapeutics: Research Funding. Lynch:Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Incyte Corporation: Research Funding; Juno Therapeutics: Research Funding; T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding; Takeda Pharmaceuticals: Research Funding. Ujjani:Gilead: Consultancy; Astrazeneca: Consultancy; Atara: Consultancy; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria; PCYC: Research Funding. Cowan:Abbvie: Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Cellectar: Consultancy; Juno: Research Funding; Janssen: Consultancy, Research Funding. Smith:Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Research Funding; Genentech: Research Funding; Ayala (spouse): Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Denovo Biopharma: Research Funding; Ignyta (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Incyte Corporation: Research Funding; Acerta Pharma BV: Research Funding; Bristol-Myers Squibb (spouse): Research Funding. Shadman:BeiGene: Research Funding; Sound Biologics: Consultancy; Celgene: Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutic: Research Funding; Sunesis: Research Funding; Astra Zeneca: Consultancy; Atara Biotherapeutics: Consultancy; Mustang Bio: Research Funding; ADC Therapeutics: Consultancy; Verastem: Consultancy; AbbVie: Consultancy, Research Funding; Acerta Pharma: Research Funding. Libby:Alnylam: Consultancy; Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy; Akcea: Consultancy. Cassaday:Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests. Fromm:Merck, Inc.: Research Funding. Gopal:Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy.
OffLabel Disclosure:
Ixazomib is not approved for use in indolent B-NHL
Time to Minimal Residual Disease (MRD) Negativity Is Independently Predictive of Outcome in Adults with Acute Lymphoblastic Leukemia (ALL) Receiving Hyper-CVAD
Phase I Study of a CD45-Targeted Antibody–Radionuclide Conjugate for High-Risk Lymphoma
Myeloablative I-131-Tositumomab with Escalating Doses of Fludarabine and Autologous Hematopoietic Transplantation for Adults Age ≥ 60 Years with B Cell Lymphoma
AbstractMyeloablative therapy and autologous stem cell transplantation (ASCT) are underutilized in older patients with B cell non-Hodgkin (B-NHL) lymphoma. We hypothesized that myeloablative doses of 131I-tositumomab could be augmented by concurrent fludarabine, based on preclinical data indicating synergy. Patients were ≥ 60 years of age and had high-risk, relapsed, or refractory B-NHL. Therapeutic infusions of 131I-tositumomab were derived from individualized organ-specific absorbed dose estimates delivering ≤ 27 Gy to critical organs. Fludarabine was initiated 72 hours later followed by ASCT to define the maximally tolerated dose. Thirty-six patients with a median age of 65 years (range, 60 to 76), 2 (range, 1 to 9) prior regimens, and 33% with chemoresistant disease were treated on this trial. Dose-limiting organs included lung (30), kidney (4), and liver (2) with a median administered 131I activity of 471 mCi (range, 260 to 1620). Fludarabine was safely escalated to 30 mg/m2 × 7 days. Engraftment was prompt, there were no early treatment-related deaths, and 2 patients had ≥ grade 4 nonhematologic toxicities. The estimated 3-year overall survival, progression-free survival, and nonrelapse mortality were 54%, 53%, and 7%, respectively (median follow up of 3.9 years). Fludarabine up to 210 mg/m2 can be safely delivered with myeloablative 131I-tositumomab and ASCT in older adults with B-NHL
Analysis of Pre-Transplant Therapy with Brentuximab Vedotin for Relapsed/Refractory Hodgkin Lymphoma on Outcomes of Reduced Intensity Conditioned Allogeneic Hematopoietic Cell Transplantation
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