Cytological and molecular remissions with blinatumomab treatment in second or later bone marrow relapse in pediatric acute lymphoblastic leukemia (ALL).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10007-10007 ◽  
Author(s):  
Lia Gore ◽  
Gerhard Zugmaier ◽  
Rupert Handgretinger ◽  
Franco Locatelli ◽  
Tanya M. Trippett ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Phase I ◽  
Dose Level ◽  
Remission Rate ◽  
Lymphoblastic Leukemia ◽  
Recommended Dose ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Dose Levels

10007 Background: Pediatric B-precursor acute lymphoblastic leukemia (ALL) in second or later relapse is an aggressive malignancy that needs therapeutic approaches with new mechanisms of action. Blinatumomab, a bispecific T-cell engaging (BiTE) antibody, has shown a hematological remission rate of 69% in adult patients with relapsed/refractory ALL. In order to establish a recommended dose in pediatric patients, a phase I multicenter trial was initiated. Methods: The primary endpoint is to determine the maximum tolerable dose defined by ≤1 of 6 patients experiencing dose limiting toxicity (DLT) within the 1st course of treatment. Up to 6 different dose levels of blinatumomab are being evaluated. Eligible patients must be <18 years old and have B-precursor ALL that is refractory or in second or later bone marrow relapse, or in any marrow relapse after allogeneic hematopoetic stem cell transplantation (HSCT). Blinatumomab is administered by continuous IV infusion over 28 days followed by a 14-day treatment-free interval (up to 5 cycles). To date, 3 dose levels have been explored (Table). Results: Seventeen patients have been treated thus far with a total of 32 cycles. One DLT (gastrointestinal hemorrhage) at dose level 2 (15 µg/m²/d) and two DLTs at dose level 3 (30 µg/m²/d; both cytokine release syndrome) with 1 death have been observed. One patient had generalized seizures on the 3rd day of the 2nd treatment cycle at the first dose level of 5 µg/m2/d, which was completely reversible. The patient successfully underwent an allogeneic HSCT after blinatumomab. Eight (47%) of the 17 patients reached a cytological complete remission in bone marrow and a molecular remission defined as MRD by PCR <10-4. Conclusions: A phase I trial of blinatumomab in patients with relapsed/refractory pediatric ALL has shown hematological and molecular remissions. Dose-limiting cytokine release syndrome has been noted. Alternative dosing regimens are being explored in current cohorts to refine the recommended dose of blinatumomab in this patient population. Clinical trial information: NCT01471782. [Table: see text]

Risk-Adapted Preemptive Tocilizumab to Prevent Severe Cytokine Release Syndrome After CTL019 for Pediatric B-Cell Acute Lymphoblastic Leukemia: A Prospective Clinical Trial

2021 ◽  
pp. JCO.20.02477
Author(s):  
Stephan Kadauke ◽  
Regina M. Myers ◽  
Yimei Li ◽  
Richard Aplenc ◽  
Diane Baniewicz ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Phase I ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Tumor Burden ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
End Point ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Post Hoc

PURPOSE To prospectively evaluate the effectiveness of risk-adapted preemptive tocilizumab (PT) administration in preventing severe cytokine release syndrome (CRS) after CTL019, a CD19 chimeric antigen receptor T-cell therapy. METHODS Children and young adults with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia were assigned to high- (≥ 40%) or low- (< 40%) tumor burden cohorts (HTBC or LTBC) based on a bone marrow aspirate or biopsy before infusion. HTBC patients received a single dose of tocilizumab (8-12 mg/kg) after development of high, persistent fevers. LTBC patients received standard CRS management. The primary end point was the frequency of grade 4 CRS (Penn scale), with an observed rate of ≤ 5 of 15 patients in the HTBC pre-defined as clinically meaningful. In post hoc analyses, the HTBC was compared with a historical cohort of high-tumor burden patients from the initial phase I CTL019 trial. RESULTS The primary end point was met. Seventy patients were infused with CTL019, 15 in the HTBC and 55 in the LTBC. All HTBC patients received the PT intervention. The incidence of grade 4 CRS was 27% (95% CI, 8 to 55) in the HTBC and 3.6% (95% CI, 0.4 to 13) in the LTBC. The best overall response rate was 87% in the HTBC and 100% in the LTBC. Initial CTL019 expansion was greater in the HTBC than the LTBC ( P < .001), but persistence was not different ( P = .73). Event-free and overall survival were worse in the HTBC ( P = .004, P < .001, respectively). In the post hoc analysis, grade 4 CRS was observed in 27% versus 50% of patients in the PT and prior phase I cohorts, respectively ( P = .18). CONCLUSION Risk-adapted PT administration resulted in a decrease in the expected incidence of grade 4 CRS, meeting the study end point, without adversely impacting the antitumor efficacy or safety of CTL019.

scholarly journals Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

2016 ◽  
Vol 34 (36) ◽  
pp. 4381-4389 ◽  
Author(s):  
Arend von Stackelberg ◽  
Franco Locatelli ◽  
Gerhard Zugmaier ◽  
Rupert Handgretinger ◽  
Tanya M. Trippett ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Recommended Dosage ◽  
Disease Response ◽  
Grade 3 ◽  
Minimal Residual

Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children < 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 µg/m2/d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 µg/m2/d for the first 7 days, followed by 15 µg/m2/d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade ≥ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications.

scholarly journals Cytokine Release Syndrome Is an Independent Risk Factor Associated With Platelet Transfusion Refractoriness After CAR-T Therapy for Relapsed/Refractory Acute Lymphoblastic Leukemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Yadan Liu ◽  
Bin Liang ◽  
Yan Liu ◽  
Guoqing Wei ◽  
Wenjun Wu ◽  
...  
Keyword(s):  
Risk Factor ◽  
Acute Lymphoblastic Leukemia ◽  
Platelet Transfusion ◽  
Independent Risk Factor ◽  
Lymphoblastic Leukemia ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T ◽  
Grade 3 ◽  
Platelet Transfusions

Background: Chimeric antigen receptor T cell (CAR-T) therapy is successful in improving treatment outcomes for relapsed/refractory acute lymphoblastic leukemia (R/R ALL). However, toxicities associated with CAR-T therapy are being increasingly identified. Pancytopenia is one of the most common complications after CAR-T therapy, and platelet transfusions are an essential part of its supportive care.Study Design and Methods: This study aimed to assess the effectiveness of platelet transfusions for R/R ALL patients at our single center and identify associated risk factors. Overall, 44 R/R ALL patients were enrolled in this study, of whom 26 received CAR-T therapy and 18 received salvage chemotherapy.Result: Patients in the CAR-T group had a higher incidence of platelet transfusion refractoriness (PTR) (15/26, 57.7%) than those in the chemotherapy group (3/18, 16.7%) (p = 0.007). For patients receiving CAR-T therapy, multivariate analysis showed that the grade of cytokine release syndrome (CRS) was the only independent risk factor associated with PTR (p = 0.007). Moreover, higher peak serum IL-6 and IFN-γ levels suggested a higher risk of PTR (p = 0.024 and 0.009, respectively). Patients with PTR received more platelet infusion doses than those without PTR (p = 0.0426). Patients with PTR had more grade 3–4 bleeding events than those without PTR (21.4 vs. 0%, p = 0.230), and the cumulative incidence of grade 3–4 bleeding event was different (p = 0.023).Conclusion: We found for the first time that PTR is associated with the CRS grade. Improved knowledge on the mechanisms of PTR after CAR-T therapy is needed to design a rational therapeutic strategy that aims to improve the efficiency of transfusions.

Bortezomib Combined with VXLD Chemotherapy Is Highly Effective In Advanced B-Lineage Acute Lymphoblastic Leukemia Allowing Early Study Termination Due to Efficacy. A Therapeutic Advances in Childhood Leukemia (TACL) Consortium Phase II Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 251-251
Author(s):  
Yoav H Messinger ◽  
Paul Gaynon ◽  
Richard Sposto ◽  
Jeannette van der Giessen ◽  
Elena Eckroth ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Phase Ii ◽  
Response Rate ◽  
Remission Rate ◽  
Lymphoblastic Leukemia ◽  
Platelet Recovery ◽  
Off Label ◽  
B Lineage

Abstract Abstract 251 Literature review and TACL experience support an expected less than 40% complete remission rate with variety of regimens in patients with ALL in second and subsequent relapse (Ko, J Clin Oncol 2010; 28: 648–654). We had shown that bortezomib might be safely combined with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin (VXLD) in the phase I portion of our study (Messinger, Pediatr Blood Cancer 2010;55:254–9). We now report the phase II expansion of that study. ALL patients who relapsed or were refractory after 2 or 3 regimens were treated with bortezomib 1.3 mg/m2/dose on days 1, 4, 8 and 11, combined with VXLD. Patients between ages 1 to 21 years old, with more than 25% bone marrow blasts, were eligible. One patient from the phase I cohort with these criteria was included in the phase II extension. In the phase II extension 22 patients were treated with this combination and all are included in analyses. All patients had relapsed or failed at least 2 prior regimens. Overall 14 achieved complete remission (CR; M1 marrow with ANC and platelet recovery and no extramedullary disease or circulating blasts) and 2 achieved CRp (CR with no platelet recovery) for total 73% remission rate (Table). This level of response exceeded the predefined criteria, allowing for early termination of the study. Three patients (14%) died from bacterial infections and two patients (9%) had no response (Table). One patient (4.5%) was not evaluable for response due to protocol violation, when additional therapy was administered before CR was confirmed with peripheral blood count recovery. B-Lineage ALL patients fared best, with 16/20 achieving CR + CRp (overall response rate 80%), whereas the two patients with T-cell ALL did not respond. Similarly, B-Lineage ALL had superior bone marrow response (M1 marrow): B-Lineage = 17/20 (85%) vs. T-cell = 0/2 (0%). Severe grade 3 or more peripheral neuropathy (PN) was seen in 2 (9%) patients, (one had prior vincristine PN). One patient has developed mucor invasive sinus and orbital infection, requiring halting therapy after day 14 but achieved CRp. After the 3 (14%) septic deaths, the use of vancomycin, levofloxacin and voriconazole or posaconazole prophylaxis in the last 6 patients has prevented further infectious mortality.ResponseAllBTn22202CR14 (64%)14 (70%)0CRp2 (9%)2 (10%)0Total Response16 (73%)16 (80%)0Deaths3 (14%)3 (15%)0SD/PD2 (9%)02 (100%)N/E1 (4.5%)1 (5%)0 In conclusion, the regimen of bortezomib + VXLD is exceptionally effective in multiple relapsed B-Lineage ALL with the highest response rate for any multiply relapsed ALL trial reported thus far. The use of prophylactic antibiotics may be effective in reducing mortality. Bortezomib with VXLD should be further evaluated in randomized fashion on frontline relapse and high-risk pediatric B-Lineage ALL clinical studies. Disclosures: Messinger: Genzyme: Consultancy. Off Label Use: Bortezomib (Velcade®) is approved for multiple myeloma and mantle cell lymphoma both B cell malignancies. We are describing use in relapsed B cell Acute Lymphoblastic Leukemia which is off label.”

scholarly journals Case Report: Local Cytokine Release Syndrome in an Acute Lymphoblastic Leukemia Patient After Treatment With Chimeric Antigen Receptor T-Cell Therapy: A Possible Model, Literature Review and Perspective

2021 ◽  
Vol 12 ◽  
Author(s):  
Chengxin Luan ◽  
Junjie Zhou ◽  
Haixia Wang ◽  
Xiaoyu Ma ◽  
Zhangbiao Long ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cell Therapy ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Lymphoblastic Leukemia ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
T Cell Therapy ◽  
Car T ◽  
Local Cytokine

Chimeric antigen receptor T (CAR-T) cell therapy has achieved remarkable clinical efficacy in treatment of many malignancies especially for B-cell hematologic malignancies. However, the application of CAR-T cells is hampered by potentially adverse events, of which cytokine release syndrome (CRS) is one of the severest and the most studied. Local cytokine-release syndrome (L-CRS) at particular parts of the body has been reported once in a while in B-cell lymphoma or other compartmental tumors. The underlying mechanism of L-CRS is not well understood and the existing reports attempting to illustrate it only involve compartmental tumors, some of which even indicated L-CRS only happens in compartmental tumors. Acute lymphoblastic leukemia (ALL) is systemic and our center treated a B-cell ALL patient who exhibited life threatening dyspnea, L-CRS was under suspicion and the patient was successfully rescued with treatment algorithm of CRS. The case is the firstly reported L-CRS related to systemic malignancies and we tentatively propose a model to illustrate the occurrence and development of L-CRS of systemic malignancies inspired by the case and literature, with emphasis on the new recognition of L-CRS.

A Phase I Dose Escalation Study of the mTOR Inhibitor Sirolimus and MEC Chemotherapy Targeting Signal Transduction in Leukemic Stem Cells for Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 161-161 ◽  
Author(s):  
Selina Luger ◽  
Alexander Perl ◽  
Allison Kemner ◽  
Edward A. Stadtmauer ◽  
David Porter ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Stem Cells ◽  
Bone Marrow ◽  
Phase I ◽  
Dose Level ◽  
Mtor Inhibitor ◽  
Loading Dose ◽  
Dose Escalation Study ◽  
Mtor Inhibition ◽  
Dose Levels

Abstract In vitro studies have suggested that AML cells are sensitive to treatment with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin. In particular, mTOR inhibition is known to enhance the sensitivity of primary AML cells and AML stem cells to etoposide based chemotherapy leading to inhibition of leukemic SRC activity in NOD/SCID mice. To determine the feasibility of applying this approach in vivo, we performed a Phase I dose escalation study of the mTOR inhibitor sirolimus (rapamycin) with a combination chemotherapy induction regimen in adults with relapsed or refractory non-M3 AML. The purpose of this trial was to determine the safety and dose limiting toxicities of sirolimus and chemotherapy in this patient population. Patients received a loading dose of oral sirolimus on day 1 followed 24 hours later by daily doses of oral sirolimus on days 2–7 plus MEC (mitoxantrone 8 mg/m2/day IV, etoposide 100 mg/m2/day IV, and cytarabine 1000 mg/m2/day IV) on days 1–5. Five sirolimus dose levels were explored by a standard 3+3 design. Sirolimus was studied at loading doses from 3–15 mg and daily doses from 1–5 mg/d. Clinical response was assessed by bone marrow biopsy upon hematologic recovery or day 42, whichever occurred first. 23 adults (14 women, 9 men) of median age 58 (range 22 to 65) with relapsed, refractory, or secondary AML were treated with sirolimus and MEC. Five subjects had antecedent hematologic disorders or prior leukemogenic chemotherapy, 18 had relapsed or refractory disease. Sirolimus was well tolerated and did not increase non-hematologic toxicity of MEC chemotherapy. Asymptomatic, reversible liver transaminase or bilirubin elevations occurred in 4 patients, two of which were > grade 2. One patient with a history of prior cytarabine cerebellar toxicity (unknown at the time of study entry) developed reversible cerebellar ataxia. Three patients died of complications related to bacterial infections during chemotherapy-induced aplasia. Dose limiting toxicity was prolonged myelosuppression at the highest planned dose level and was responsible for one treatment-related death due to infectious complications from unresolved aplasia on study day 119. For the first four dose levels the median time to ANC recovery >500/uL among evaluable patients was 27 days (range16–38). Pharmacokinetic data showed that doses of 3 mg and higher consistently achieved rapamycin levels considered therapeutic in solid organ transplantation (4–9.2 ug/L). Bone marrow studies in 2/2 evaluable patients on dose level 4 (12 mg loading dose and 4 mg per day sirolimus) showed inhibition of p70S6 kinase phosphorylation consistent with effective inhibition of mTOR at this dose level. Complete remissions occurred in four patients, all treated for first relapse. Two patients subsequently proceeded to allogeneic transplantation. These results indicate that the combination of mTOR inhibition and chemotherapy is feasible in human AML and establish an appropriate dose for phase II studies to be 12mg loading dose followed by 4 mg daily. Patient recruitment at this dose is ongoing. Confirmation of the efficacy of this regimen, which targets signal transduction in leukemic < stem cells, is planned in a randomized phase II trial at the cooperative group level.

A Phase 1/2 Study Of Blinatumomab In Pediatric Patients With Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 70-70 ◽  
Author(s):  
Arend von Stackelberg ◽  
Gerhard Zugmaier ◽  
Rupert Handgretinger ◽  
Franco Locatelli ◽  
Carmelo Rizzari ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dose Level ◽  
Pediatric Patients ◽  
Treatment Cycle ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Cell Precursor ◽  
Equity Ownership ◽  
Grade 3 ◽  
Dose Levels

Abstract Introduction Novel approaches are needed to treat pediatric relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blinatumomab is a bispecific T-cell engager (BiTE®) antibody that has shown remission in an exploratory study of 36 adult patients with relapsed/refractory ALL. Primary toxicities in adults have been cytokine release syndrome (CRS) and central nervous system (CNS) related toxicity. We initiated a phase 1/2 multicenter study to identify, in the phase 1 part, the optimal dose of blinatumomab in pediatric patients with relapsed/refractory BCP-ALL. Methods In this ongoing study, eligible patients are <18 years old and must have BCP-ALL that is refractory, in second or later bone marrow relapse, or in any marrow relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Blinatumomab is administered by continuous intravenous infusion over 28 days, followed by a 14-day treatment-free interval (up to five cycles). Data from the five doses that have been explored to date are presented. Maximum tolerated dose (MTD), defined as the highest dose level with less than two of six patients experiencing dose-limiting toxicity (DLT) within the first treatment cycle, is the primary endpoint in the phase 1 part of the study (rolling 6 design). Serum samples were collected for pharmacokinetics evaluation and cytokine measurement. Results In the phase 1 part of the study, 34 patients received a total of 56 cycles. Six (18%) patients had refractory disease and 6 (18%) had experienced at least two bone marrow relapses. Twenty-two (65%) patients had relapsed following HSCT. DLTs for dose levels 1 through 4 are summarized in the Table. The MTD for this patient population was established at 15 µg/m²/day. In order to reduce the risk of CRS, a dose of 5 µg/m²/day for 7 days escalating to 15 µg/m²/day for the remainder of the first cycle and all following cycles (5→15 µg/m²/day; dose level 5) was evaluated as recommended dose. None of the 11 patients treated at this dose level developed CRS and no grade 3 CNS-related adverse events (AEs) occurred. Across dose levels, the most common AEs regardless of causality were pyrexia (62% of patients), headache (35%), anemia (29%), and hypertension (29%). One patient treated at 5 µg/m²/day had a grade 3 seizure at the beginning of the second treatment cycle, which resolved clinically and showed no changes on MRI. Across all dose levels, 11 (32%) patients had complete remission (CR), one (3%) had hypocellular blast-free bone marrow, and two (6%) had partial remission within the first two treatment cycles, for an overall response rate of 41%. Some efficacy assessments are still ongoing, and full response data for the phase 1 part of the study will be available at the time of presentation. Two patients experienced hematologic relapse (one each at dose levels 2 and 3, during the fifth and third cycles, respectively). Pharmacokinetic parameters, such as steady-state concentration (Css) and clearance, appeared to be similar to those from adult patients with relapsed/refractory BCP-ALL who received body surface area-based blinatumomab dosing. Transient elevations of serum cytokines were observed mainly in the first two days after infusion start, in particular IL-6, IFN-gamma, IL-10, and, to a lesser extent, IL-2 and TNF-α. Conclusions In the ongoing phase 1 part of this study in pediatric patients with relapsed/refractory BCP-ALL, a dose of 15 µg/m²/day was established as MTD. Cytokine-release syndrome has been dose-limiting. Pharmacokinetic analysis at the recommended dose of 5→15 µg/m²/day is ongoing. This dose de-escalation strategy has been successful in ameliorating severe CRS to date. Blinatumomab treatment has shown promising antitumor activity in this relapsed/refractory patient population. Disclosures: von Stackelberg: Amgen Inc.: Honoraria. Zugmaier:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Rheingold:Novartis: Research Funding. Holland:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Mergen:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Fischer:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Zhu:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Hijazi:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Gore:Amgen Inc.: Travel expenses paid for DSMC meeting (Feb 2013) Other.

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