Faculty Bibliography

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.

Relapsed/refractory (r/r) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) outcomes remain poor. A targeted cluster of differentiation (CD)33 × CD3 bispecific antibody, JNJ-67571244, was assessed to identify the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety and tolerability, and preliminary clinical activity in patients with r/rAML or r/rMDS. This first-in-human, open-label, phase I, dose-escalation/dose-expansion study included patients with r/rAML or r/rMDS who were ineligible for or had exhausted standard therapeutic options. JNJ-67571244 was administered intravenously or subcutaneously using step-up dosing until ≥1 discontinuation condition was met. Outcomes included safety/tolerability, preliminary clinical activity, and systemic pharmacokinetics and pharmacodynamics. The study was terminated after evaluating 10 dose-escalation cohorts (n = 68) and before starting dose-expansion. Overall, 11 (16.2%) patients experienced ≥1 dose-limiting toxicity; all experienced ≥1 treatment-emergent adverse event (TEAE; treatment related: 60 [88.2%]); and 64 (94.1%) experienced ≥1 TEAE of Grade ≥3 toxicity (treatment related: 28 [41.2%]). Although some patients had temporary disease burden reductions, no responses were seen. JNJ-67571244 administration increased multiple cytokines, which coincided with incidence of cytokine release syndrome, infusion-related reactions, and elevated liver function tests. A prolonged step-up strategy was tested to improve tolerability, though this approach did not prevent hepatotoxicity. T-cell activation following treatment suggested target engagement but did not correlate with clinical activity. Safely reaching the projected exposure level for JNJ-67571244 efficacy was not achieved, thus MTD and RP2D were not determined.

Reducing the incidence of graft-versus host disease (GvHD) following haploidentical hematopoietic stem cell transplantation (HSCT) is warranted. Post-transplant cyclophosphamide (PTCy) is the main agent used for GvHD prevention in this setting. It remains unknown if costimulation blockade can be safely combined with PTCy and enhance its efficacy. We performed a phase Ib-II clinical trial to examine the combination of PTCy, abatacept and a short course of tacrolimus (CAST) following peripheral blood haploidentical HSCT. The primary end-point was the incidence of acute GvHD grades II-IV at day +120. The study enrolled 46 patients with a median age of 60 years (range: 18 to 74). The cumulative incidence of acute GvHD grades II-IV and III-IV was 17.4% (95% CI, 9.2% to 32.9%) and 4.4% (95% CI, 1.1% to 17.1%). With a median follow-up of 15.3 months, the cumulative incidence of one-year treatment-related mortality is 4.4% (95% CI, 1.1% to 17.1%). The estimated one-year chronic GvHD moderate to severe rate, relapse rate, progression-free survival, overall survival, and GvHD- and relapse-free survival were 15.9% (95% CI, 8% to 31.7%), 11.7% (95% CI, 5% to 27.2%), 84.1% (95% CI, 73.8% to 95.7%), 85.9% (95% CI, 75.9% to 97.2%) and 66.1% (95% CI, 53.4% to 81.8%), respectively. Toxicities were similar to those expected in patients receiving haploidentical HSCT. This clinical trial showed that CAST regimen is safe and effective in reducing the rate of grades II-IV acute GvHD following haploidentical peripheral blood HSCT (NCT04503616 at https://clinicaltrials.gov/ct2/show/NCT04503616).

BACKGROUND:Acute myeloid leukemia (AML) is a disease of the hematopoietic system that remains a therapeutic challenge despite advances in our understanding of the underlying cancer biology in the past decade. It is also an affliction of the elderly that predominantly affects patients above 60 years of age. Standard therapy involves intensive chemotherapy that is often difficult to tolerate in older populations. Fortunately, recent developments in molecular targeting have shown promising results in treating leukemia, paving the way for novel treatment strategies that are easier to tolerate. SUMMARY/CONCLUSIONS:Venetoclax, a BCL-2 inhibitor, when combined with a hypomethylating agent, has proven to be a highly effective and well-tolerated drug, and established itself as a new standard for treating AML in patients who are unfit for standard intensive therapy. Other targeted therapies include clinically proven and FDA approved agents, such as IDH1/2 inhibitors, FLT3 inhibitors, and Gemtuzumab, as well as newer and more experimental drugs such as magrolimab, PI-kinase inhibitors, and T-cell engaging therapy. Some of the novel agents such as magrolimab and menin inhibitors are particularly promising, providing therapeutic options to a wider population of patients than ever before. Determining who will benefit from intense or novel low intense therapy remains a challenge and it requires careful assessment of individual patient's fitness and disease characteristics. KEY MESSAGES/CONCLUSIONS:This article reviews past and current treatment strategies that harness various mechanisms of leukemia-targeting agents and introduces novel therapies on the horizon aimed at exploring therapeutic options for elderly and unfit patient population. It also provides a strategy to select the best available therapy for elderly patients with both newly diagnosed and relapsed/refractory AML.

We present the case of a 56-year-old female with a diagnosis of acute T-cell lymphoblastic leukemia who received myeloablative conditioning for bone marrow transplant with total body irradiation (TBI) using volumetric modulated arc therapy (VMAT) to the upper body and anterior-posterior/posterior-anterior (AP/PA) open fields to the lower body followed by hematopoietic stem cell transplant. Her clinical course was complicated by high-grade pulmonary toxic effects 55 days after treatment that resulted in death. We discuss the case, planning considerations by radiation oncologists and radiation physicists, and the multidisciplinary medical management of this patient.

CONTEXT/BACKGROUND:Asparaginase remains an important component in many adult regimens for acute lymphoblastic leukemia (ALL). In pediatric patients (<21 years), calaspargase pegol (Cal-PEG) provides sustained asparagine depletion as compared to pegaspargase, with similar rates of complete remission (CR), minimal residual disease (MRD), event-free survival (EFS), and overall survival (OS), with a similar safety profile. OBJECTIVE:To confirm the recommended dose of Cal-PEG in adults (age ≥22 years) and to establish safety and PK/PD analysis. DESIGN/METHODS:. A minimum of 4 (initial cohort) and ~8 patients will be enrolled per group. The study will be conducted in ≤25 investigational centers in the US. Part 2 will comprise expansion cohorts after verifying safety and PK/PD analysis. PATIENTS/METHODS:Newly diagnosed patients with Philadelphia-negative B- or T-cell ALL ≥22 years with ECOG performance status 0-2, no known history of pancreatitis, coagulopathy, CNS thrombosis, or severe hepatic impairment. Approximately 114-122 patients are expected to be enrolled in the study, including 16-32 patients in Part 1. INTERVENTIONS/METHODS:. A total of 6 Cal-PEG doses will be administered during the treatment period as part of a multiagent chemotherapy regimen based on CALGB 10403, with an end-of-treatment visit 1 year after the induction dose, and an additional 2 years of survival follow-up. MAIN OUTCOME MEASURES/METHODS:The primary endpoints in part 1 are the safety of Cal-PEG, the incidence of pre-defined unacceptable toxicities within 30 days after the induction dose and achieving plasma asparaginase activity ≥0.1 U/mL 21 days after the consolidation day 43 dose. Secondary endpoints include immunogenicity, CR, end-of-induction and consolidation MRD, 1-, 2- and 3-year EFS, disease-free survival, and OS.

BACKGROUND:Large granular lymphocytic leukemia is a rare lymphocytic neoplasm that can pose a treatment challenge in patients with severe neutropenia in whom conventional therapies fail. We report one of the first cases in which allogeneic stem cell therapy was used as treatment for large granular lymphocytic leukemia. We report and discuss the case of a 42-year-old white Caucasian female who, despite multiple therapies including methotrexate, cyclophosphamide, prednisone, cyclosporine, and pentostatin, continued to show severe neutropenia and recurrent infections. The patient was treated successfully and cured by allogeneic stem cell transplant without any major complications. CONCLUSIONS:The significant importance of this case report is the introduction of a new treatment algorithm for challenging cases of T-cell large granular lymphocytic leukemia in which standard care fails. We hope that this case report will raise awareness of the potential benefits of allogeneic stem cell transplant in the treatment of aggressive forms of T-cell large granular lymphocytic leukemia.

Introduction. Prevention of graft-versus-host disease (GvHD) following allogeneic hematopoietic cell transplantation (AHCT) remains a major challenge. The combination of methotrexate (MTX) and a calcineurin inhibitor has been the standard regimen for prophylaxis in patients receiving matched sibling donor (MSD) or matched unrelated donor (MUD) transplants for the past few decades. However, over 50% of patients undergoing AHCT still develop acute or chronic GvHD or even both, causing high rates of morbidity and mortality. Moreover, calcineurin inhibitors also have untoward toxic side effects. High dose post-transplant cyclophosphamide (PTCy), initially introduced for GvHD prevention in the setting of haploidentical transplantation, has now been studied in MSD and MUD transplants. We adopted a novel approach to prevent GvHD using a short course of PTCy and bortezomib. We hypothesized that such combination is safe and effective and omits the need for calcineurin or m-TOR inhibitors. Study Design. We report the outcomes of a prospective cohort of patients who received PTCy and bortezomib for GvHD prevention following MSD or MUD transplants. Twenty-eight patients were treated in a phase I-II trial and their clinical outcomes were previously reported (al-Homsi AS et al, BBMT 2019). Most of the remaining patients were treated on an extension trial. GvHD prevention consisted of PTCy 50 mg/kg IV on day +3 and +4, and bortezomib 1.3mg/m ² IV 6 hours after transplant and again 72 hours after. Patients receiving MUD transplants also received rabbit ATG (thymoglobulin) 5mg/kg total IV fractionated on day -4 to -2. All patients received peripheral blood grafts and standard supportive care as per Institutional policy. G-CSF was administered routinely until neutrophil engraftment. Results. Fifty-eight patients are included in this analysis. Median age was 60 (range 22-78) years. Fifty-three percent of patients were male. Underlying malignancies consisted of myeloid and lymphoid malignancies in 79.3% and 20.6%, respectively. Acute myeloid leukemia (50%) and myelodysplastic syndromes (24.1%) were the most common diseases. At transplant, disease risk index was low, intermediate, high and very high in 19.0%, 48.3%, 31.0% and 1.7% of patients, respectively. Median Pretransplant Assessment of Mortality Score (PAM) was 16.7 (5.4-29.4). Grafts were from MSD in 24.1% or MUD in 75.9% of patients. Recipient (R)/Donor (D) CMV status at transplant was as follows: R+/D+: 43%; R+/D-: 21%; R-/D+: 14% and R-/D-: 22%. Conditioning regimens consisted of reduced intensity fludarabine and busulfan in all but 2 patients who were conditioned with myeloablative fludarabine and busulfan. Overall, the regimen was remarkably well tolerated. Median times to neutrophil and platelet engraftment were 16 (13-28) and 26 (15-57) days respectively. No patient experienced primary graft failure. CMV and EBV reactivation rates were 46.6% and 24%. Cumulative incidences of grade II-IV and grade III-IV acute GVHD were 35% (95% CI: 22%-47%) and 15% (95% CI: 7%-25%) at day +120, respectively. Cumulative incidence of chronic GvHD was 14% at 1 year. Overall, 34% of patients required immunosuppression with systemic steroids after day +4 either for grade III-IV acute or chronic GvHD. Disease relapse rate was 26%. One-year cumulative incidence of transplant-related mortality was 14% (95% CI: 6%-25%). Median overall survival was 30.7 (95% CI: 15.7-not yet reached) months. One-year overall survival was 72% (95% CI: 57%-82%). One-year composite GvHD (acute and chronic) free and relapse free survival (GRFS) was 41.6% (95% CI: 28.9%-54%). Conclusion. PTCy and bortezomib combination for GvHD prophylaxis following MSD and MUD transplants is well tolerated and effective. It offers an alternative regimen to calcineurin and m-TOR inhibitor-containing regimens and may be preferred in certain settings including patients with limited resources, poor medication compliance, and with impaired renal function. A comparison of this cohort to a matched control group of patients receiving methotrexate and cyclosporine for GvHD prevention is ongoing. Disclosures: Abdul-Hay: Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Other: Advisory Board, Speakers Bureau; Jazz: Other: Advisory Board, Speakers Bureau; Abbvie: Consultancy; Takeda: Speakers Bureau. Al-Homsi: Celyad: Other: Advisory Board; Daichii Sanyko: Consultancy. OffLabel Disclosure: Cyclophosphamide and Bortezomib are used for GvHD prevention
Copyright