Anti-CD19 BiTE Blinatumomab Induces High Complete Remission Rate In Adult Patients with Relapsed B-Precursor ALL: Updated Results of An Ongoing Phase II Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 252-252 ◽  
Author(s):  
Max S. Topp ◽  
Nicola Goekbuget ◽  
Gerhard Zugmaier ◽  
Andreas Viardot ◽  
Matthias Stelljes ◽  
...  
Keyword(s):  
Complete Remission ◽  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Adult Patients ◽  
Quantitative Detection ◽  
Hematopoietic Stem ◽  
Dismal Prognosis

Abstract Abstract 252 Adult patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL) have a dismal prognosis with low complete remission (CR) rates with intensive salvage chemotherapy which are not durable. Blinatumomab is a bispecific T-cell engaging (BiTE®) antibody construct that directs cytotoxic T-cells to CD19 expressing B-cells. In collaboration with the German Multicenter Study Group for Adult Lymphoblastic Leukemia (GMALL), an open-label, multicenter, single-arm, exploratory phase II trial is being conducted to evaluate efficacy and safety of blinatumomab in adult patients with relapsed/refractory B-precursor ALL. The primary endpoint for this trial is the rate of patients who reach CR or CR with partial hematological recovery (CRh*) within 2 cycles of blinatumomab treatment. Secondary endpoints are the rate of minimal residual disease (MRD) response (defined by an MRD level below the quantitative detection limit of 10−4), time to hematological relapse and overall survival. Blinatumomab is administered by continuous intravenous infusion for 28-days followed by a 14-day treatment-free interval. Responding patients could proceed to allogeneic hematopoietic stem cell transplantation (HSCT) or receive a total of up to 5 cycles of blinatumomab treatment. Three dose levels have been explored as shown in Table 1.Table 1.Summary of Dose Cohorts and OutcomesCohortPatients TreatedInitial Dose Week 1, Cycle 1 μg/m2/dayDose Week 2, Cycle 1 μg/m2/dayDose Weeks 3–4, Cycle 1 μg/m2/dayMaintenance Dose, Subsequent Cycles μg/m2/dayCR or CRh*Serious Adverse EventsnPts171515151551562a551515154222b65153030354310 planned5151515n.a.n.a.n.a. As of June 30, 2011, 43 cycles have been administered to a total of 18 patients (range 1–5; median 2). Twelve out of 18 patients have reached a complete remission within the first 2 cycles of single agent blinatumomab corresponding to a response rate of 67%. Of these 12 responding patients, 75% had complete hematologic recovery of peripheral blood counts. All 12 responders reached MRD negativity within the first 2 cycles and included 3 patients with t(4;11) and 1 patient with Ph-positive B-precursor ALL. Four responders proceeded to allogeneic HSCT; one experienced a CD19-negative hematological relapse after HSCT. Two responders relapsed during treatment; one had a CD19-positive extramedullary, and one a CD19-negative bone marrow relapse. The remaining 6 non-transplanted responders are still in hematological complete remission. The most common adverse events were pyrexia and chills. In cohort 1, one patient with a high tumor burden developed disseminated intravascular coagulation (DIC)/cytokine release syndrome (CRS) leading to treatment discontinuation. The implementation of a cytoreductive pre-phase and a lower initial dosing at 5μg/m2/day during the first week prevented further treatment discontinuations in such patients. Four patients had fully reversible CNS serious adverse events that led in 1 patient to discontinuation of treatment, and in 3 patients to temporary interruption of treatment. These 3 patients resumed treatment at a lower dose without further interruptions during the following cycles. There were no deaths related to blinatumomab. Blinatumomab as single agent induced an unprecedented high rate of complete hematological and MRD responses in adult patients with relapsed/refractory B-precursor ALL. A lower dose of 5μg/m2/day for the initial week of treatment, as tested in cohort 2a, demonstrated a favorable safety profile while maintaining efficacy. A maintenance dose of 30μg/m2/day, as tested in cohort 2b, did not further improve the already high efficacy but increased the number of adverse events. Therefore, the dosing of cohort 2a was selected as the basis for cohort 3 and will be applied to further clinical development in this patient population. Updated results of the study will be presented. Disclosures: Topp: Micromet: Consultancy, Honoraria. Goekbuget:Micromet: Consultancy. Zugmaier:Micromet: Employment. Klappers:Micromet AG: Employment. Mergen:Micromet Inc: Employment. Bargou:Micromet: Consultancy, Honoraria.

Phase II Trial of the Anti-CD19 Bispecific T Cell–Engager Blinatumomab Shows Hematologic and Molecular Remissions in Patients With Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia

2014 ◽  
Vol 32 (36) ◽  
pp. 4134-4140 ◽  
Author(s):  
Max S. Topp ◽  
Nicola Gökbuget ◽  
Gerhard Zugmaier ◽  
Petra Klappers ◽  
Matthias Stelljes ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Clinical Activity ◽  
Hematopoietic Stem ◽  
Dismal Prognosis ◽  
Bispecific T Cell Engager

Purpose Patients with relapsed or refractory acute lymphoblastic leukemia (ALL) have a dismal prognosis. CD19 is homogenously expressed in B-precursor ALL and can be targeted by the investigational bispecific T cell–engager antibody blinatumomab. A phase II trial was performed to determine clinical activity in this patient cohort. Patients and Methods Thirty-six patients with relapsed or refractory B-precursor ALL were treated with blinatumomab in cycles of 4-week continuous infusion followed by a 2-week treatment-free interval in a single-arm study with a dose-finding stage and an extension stage. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh). Major secondary end points included minimal residual disease (MRD) response, rate of allogeneic hematopoietic stem-cell transplantation (HSCT) realization, relapse-free survival (RFS), overall survival (OS), and incidence of adverse events (AEs). Results Median age was 32 years (range, 18 to 77 years). Twenty-five patients (69%) achieved a CR or CRh, with 88% of the responders achieving an MRD response. Median OS was 9.8 months (95% CI, 8.5 to 14.9), and median RFS was 7.6 months (95% CI, 4.5 to 9.5). Thirteen responders (52%) underwent HSCT after achieving a CR or CRh. The most frequent AE during treatment was pyrexia (grade 1 or 2, 75%; grade 3, 6%). In six patients with nervous system or psychiatric disorder AEs and in two patients with cytokine release syndrome, treatment had to be interrupted or discontinued. These medical events were resolved clinically. Conclusion The data support further investigation of blinatumomab for the treatment of adult patients with relapsed or refractory ALL in a larger confirmatory study.

Phase II trial of single-agent sorafenib in patients with advanced non-small cell lung carcinoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7002-7002 ◽  
Author(s):  
U. Gatzemeier ◽  
G. Blumenschein ◽  
F. Fosella ◽  
R. Simantov ◽  
J. Elting ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Small Cell ◽  
Tumor Shrinkage ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Biomarker Analysis

7002 Background: Sorafenib, an oral multi-kinase inhibitor, targets the Raf/MEK/ERK pathway at the level of Raf kinase and receptor tyrosine kinases, and has shown efficacy against several tumor types in phase I/II trials. Non-small-cell lung cancer (NSCLC) is associated with mutations in k-ras, upstream of Raf/MEK/ERK. Methods: This multi-center, uncontrolled, phase II trial evaluated efficacy (every 8 weeks using RECIST) and safety of sorafenib (400 mg bid, continuous) in patients with relapsed or refractory advanced NSCLC. Plasma for proteomic biomarker analysis (ELISA [n=44]; mass-spectrometry [n=43]) was taken at screening, Day 21 of Cycle 1, and Day 1 of Cycle 3. Results: Fifty-two of 54 patients enrolled received sorafenib. Most (49/52) patients who received sorafenib had stage IV NSCLC. Thirty patients (59%) out of 51 evaluable for efficacy had SD. Although there were no confirmed PRs, tumor shrinkage was observed in 15 (29%) patients (four had ≥30% shrinkage). Patients with SD had a median progression-free survival (PFS) of 23.7 weeks, while all evaluable patients (n=51) had a median PFS of 11.9 weeks and median overall survival of 29.3 weeks. The most frequent drug-related adverse events observed in 52 patients were diarrhea (21 [40%] patients), hand-foot skin reaction (HFS; 19 [37%]), fatigue (14 [27%]), and nausea (13 [25%]). Frequent drug-related adverse events ≥ grade 3 included HFS (n=5 [10%]) and hypertension (n=2 [4%]). Three patients discontinued due to adverse events (HFS, elevated lipase, and myocardial infarction). There were nine deaths within 30 days of discontinuation of sorafenib (n=5 PD; n=2 cardiopulmonary arrest; n=1 hemoptysis; and n=1 unknown cause). The levels of five proteins measured by ELISA, either at screening or change over treatment duration, correlated significantly with time to progression (TTP) or maximum tumor shrinkage. Levels of five additional proteins, identified by mass-spectrometry, also correlated with TTP. Conclusions: Identified biomarkers may help assess efficacy of sorafenib in NSCLC patients. Sorafenib 400 mg bid is generally well tolerated and shows promising efficacy in patients with advanced, progressive NSCLC, with approximately 60% of pts achieving disease stabilization. [Table: see text]

Phase II Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Lymphoblastic Leukemia

2006 ◽  
Vol 24 (12) ◽  
pp. 1917-1923 ◽  
Author(s):  
Sima Jeha ◽  
Paul S. Gaynon ◽  
Bassem I. Razzouk ◽  
Janet Franklin ◽  
Richard Kadota ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Phase Ii ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Median Number ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Heavily Pretreated

Purpose To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in pediatric patients with refractory or relapsed acute lymphoblastic leukemia (ALL). Patients and Methods In a phase II, open-label, multicenter study, 61 pediatric patients with refractory or relapsed ALL received clofarabine 52 mg/m2 intravenously over 2 hours daily for 5 days, every 2 to 6 weeks. The median age was 12 years (range, 1 to 20 years), and the median number of prior regimens was three (range, two to six regimens). Results The response rate was 30%, consisting of seven complete remissions (CR), five CRs without platelet recovery (CRp), and six partial remissions. Remissions were durable enough to allow patients to proceed to hematopoietic stem-cell transplantation (HSCT) after clofarabine. Median CR duration in patients who did not receive HSCT was 6 weeks, with four patients maintaining CR or CRp for 8 weeks or more (8+, 12, 37+, and 48 weeks) on clofarabine therapy alone. The most common adverse events of grade ≥ 3 were febrile neutropenia, anorexia, hypotension, and nausea. Conclusion Clofarabine is active as a single agent in pediatric patients with multiple relapsed or refractory ALL. The toxicity profile is as expected in this heavily pretreated patient population. Studies exploring rational combinations of clofarabine with other agents are ongoing in an effort to maximize clinical benefit.

scholarly journals Chemotherapy with the Use of TKIs Based on MRD Has the Potential to Avoid Hematopoietic Stem Cell Transplantation in Treatment for Children with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL). Results of the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Study ALL-Ph13

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3394-3394
Author(s):  
Atsushi Sato ◽  
Hirohide Kawasaki ◽  
Takao Deguchi ◽  
Yoshiko Hashii ◽  
Yuka Iijima-Yamashita ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Hematopoietic Stem Cell Transplantation ◽  
Complete Remission ◽  
Adverse Events ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Hematopoietic Stem ◽  
Fatal Adverse Events ◽  
First Complete Remission

Abstract Aims: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) patients generally have a poor prognosis when treated with chemotherapy alone. In adults, allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission is still the standard strategy for Ph+ALL. However, in children, HSCT should be avoided as much as possible to eliminate late complications. There are some reports showing that the combination of tyrosine kinase inhibitors (TKIs) with chemotherapy may avoid HSCT in childhood Ph+ALL. Thus, we planned this clinical trial (JPLSG ALL-Ph13) with the aim of improving outcomes with as few HSCT by chemotherapy with TKIs based on Ig/TCR minimal residual disease (MRD). Methods: Patients aged 1 to 19 with Ph+ALL were enrolled in JPLSG ALL-Ph13 Study. The diagnosis of Ph+ALL was performed using reverse-transcription PCR for BCR-ABL1. Chemotherapy follows the BFM ALL high-risk regimen (IA, IB, HR3, HR2, HR1, III, IM, III, IM, III, and maintenance). Imatinib was started on day 15 of induction therapy and continued until the final day of maintenance therapy (Ima group). If Ig/TCR MRD was positive (≥10 -4) at the end of IB, imatinib was changed to dasatinib and chemotherapy was continued (Dasa group). If MRD was positive at the end of the HR blocks, HSCT was performed (HSCT group). Results: During the period 2013-17, 43 patients were registered in this study, and 2 patients were excluded by not meeting inclusion criteria. Thirty-three, 7, and 1 patient were stratified into Ima, Dasa, and HSCT groups, respectively. Induction rate was 52.6% at the end of IA and 89.2% at the end of IB. MRD-negative rate was 61.3% at the end of IB and 87% at the end of HR. Although 51.2% of patients eventually received HSCT, only 13.9% received HSCT at the first complete remission. In all patients, the 3-year event-free survival (EFS) rate was 65.1%, and the 3-year overall survival (OS) rate was 85.1%. Four patients died of serious infections during treatment (2 in IA, 2 in 1st III). Interpretation: In our previous study for children with Ph+ALL (the JPLSG Ph+ALL04 study), all patients underwent HSCT, with the 3-year EFS rate of 57% and the OS rate of 80%. In this ALL-Ph13 study, the EFS and OS are almost the same as those in the Ph+ALL04. These are also almost the same as those in the EsPhALL2010 study, which aimed at avoiding HSCT. However, as in the EsPhALL2010 study, the comparatively high incidence of fatal adverse events was a problem with this study. Conclusion: Chemotherapy with the use of TKIs based on MRD has the potential to avoid HSCT in treatment for children with Ph+ALL. Reducing the occurrence of fatal adverse events is a future challenge to overcome. Disclosures No relevant conflicts of interest to declare.

High Complete Remission Rate and Promising Outcome by Combination of Imatinib and Chemotherapy for Newly Diagnosed BCR-ABL–Positive Acute Lymphoblastic Leukemia: A Phase II Study by the Japan Adult Leukemia Study Group

2006 ◽  
Vol 24 (3) ◽  
pp. 460-466 ◽  
Author(s):  
Masamitsu Yanada ◽  
Jin Takeuchi ◽  
Isamu Sugiura ◽  
Hideki Akiyama ◽  
Noriko Usui ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Severe Toxicity ◽  
Newly Diagnosed ◽  
Hematopoietic Stem ◽  
Short Period

Purpose A novel therapeutic approach is urgently needed for BCR-ABL–positive acute lymphoblastic leukemia (ALL). In this study, we assessed the efficacy and feasibility of chemotherapy combined with imatinib. Patients and Methods A phase II study of imatinib-combined chemotherapy was conducted for newly diagnosed BCR-ABL–positive ALL in adults. Eighty patients were entered into the trial between September 2002 and January 2005. Results Remission induction therapy resulted in complete remission (CR) in 77 patients (96.2%), resistant disease in one patient, and early death in two patients, as well as polymerase chain reaction negativity of bone marrow in 71.3%. The profile and incidence of severe toxicity were not different from those associated with our historic chemotherapy-alone regimen. Relapse occurred in 20 patients after median CR duration of 5.2 months. Allogeneic hematopoietic stem-cell transplantation (HSCT) was performed for 49 patients, 39 of whom underwent transplantation during their first CR. The 1-year event-free and overall survival (OS) rates were estimated to be 60.0%, and 76.1%, respectively, which were significantly better than those for our historic controls treated with chemotherapy alone (P < .0001 for both). Among the current trial patients, the probability for OS at 1 year was 73.3% for those who underwent allogeneic HSCT, and 84.8% for those who did not. Conclusion Our results demonstrated that imatinib-combined regimen is effective and feasible for newly diagnosed BCR-ABL–positive ALL. Despite a relatively short period of observation, a major potential of this treatment is recognized. Longer follow-up is required to determine its overall effect on survival.

Marqibo® (vincristine sulfate liposomes injection; VSLI) In the Treatment of Adult Patients with Advanced, Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL): A Combined Analysis of the VSLI-06 and RALLY Studies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2143-2143
Author(s):  
Susan O'Brien ◽  
Deborah A Thomas ◽  
Leonard T Heffner ◽  
Wendy Stock ◽  
Gerald L. Messerschmidt ◽  
...  
Keyword(s):  
Salvage Therapy ◽  
Response Rate ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Complete Response ◽  
Adult Patients ◽  
Cell Transplant ◽  
Vincristine Sulfate ◽  
Hematopoietic Stem ◽  
To Receive

Abstract Abstract 2143 Background: The outcome of adults with relapsed/refractory ALL, and of those whose disease recurs after first salvage, in particular, is extremely poor. Second salvage therapy with single agents has historically produced a complete response (CR) in only 4% of patients. (O'Brien, S, et al. Cancer 2008; 113:3186-3191). Third salvage therapy has not been studied but would be expected to be even less effective. Conventional vincristine sulfate (VCR) is an effective anti-leukemia agent, widely used in the treatment of ALL as part of several intensive regimens. VCR is dosed at 1.4 mg/m2 with a 2 mg cap due to early onset of peripheral neuropathy. VSLI (Marqibo) is a nano-particle encapsulated formulation of VCR designed to facilitate dose intensification, improve duration of drug exposure, and enhance cancer and bone marrow drug delivery. Methods: Two distinct studies investigated VSLI in adult patients with advanced, relapsed/refractory ALL. Study VSLI-06 was a Phase 1/2, multi-center, 36 patient, dose-escalation study to determine safety, maximum tolerated dose, and anti-leukemia activity. Patients received VSLI intravenously (IV) weekly at doses of 1.5, 1.825, 2.0, 2.25 or 2.4 mg/m2 with no dose cap plus dexamethasone 40 mg on days 1–4 and 11–14 of each 4 week cycle. The RALLY Study was a Phase 2, multi-national, 65 patient study of single-agent VSLI (2.25 mg/m2 IV weekly without dose cap) in adults with ALL in second relapse or who had progressed following at least two prior lines of anti-leukemia therapy. All subjects had been previously treated with VCR, and all received at least one dose of VSLI. The median age in both studies was 32 years with a combined range of 19 to 83 years. Other than one subject in VSLI-06, all subjects were Philadelphia chromosome negative. Results: The combined overall response rate was 31% (31 of 101). The combined complete response (CR) rate including CR with incomplete platelet (CRp) or hematologic (CRi) recovery was 20% (20/101). This response rate was consistent across the studies (19.4% and 20%, respectively). Hematologic improvement (HI) was achieved in 4 patients (11%) in VSLI-06 and 9 (14%) in RALLY, thus reducing transfusions and hospital visits. Five patients were able to receive a post-VSLI hematopoietic stem cell transplant (HSCT) in VSLI-06, and 10 patients were able to receive a post-VSLI HSCT in RALLY. The table below summarizes key study characteristics. The most commonly reported safety events in the studies were similar and included constipation, neuropathy, fatigue, nausea, pyrexia, febrile neutropenia, and anemia. Conclusion: These two studies totaling 101 patients with similar populations of advanced relapsed/refractory ALL showed a combined 20% CR/CRp/CRi rate, dwarfing the rate in historical studies. This is particularly encouraging, given that 100% of subjects had received prior VCR and that historical control data were largely in a less heavily pre-treated population. Both VSLI alone and combined with pulse dexamethasone appear to be highly active. In total, 15% of combined study patients were able to “bridge” to HSCT. Use of VSLI in the frontline setting and in combination regimens should further improve ALL patient outcomes. Disclosures: Messerschmidt: Hana Biosciences, Inc.: Employment. Hagey: Hana Biosciences, Inc.: Employment. Deitcher: Hana Biosciences: Employment. Kantarjian: Hana Biosciences, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees.

L-Asparaginase Monotherapy in Patients with Relapsed or Refractory Extranodal NK/T-Cell Lymphoma, Nasal Type: Results of A Phase II Study.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2730-2730
Author(s):  
Ye Guo ◽  
Xuejun Ma ◽  
Zuguang Xia ◽  
Kai Xue ◽  
Qunling Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Single Agent ◽  
T Cell Lymphoma ◽  
Hematopoietic Stem ◽  
Nasal Type ◽  
Nk T Cell

Abstract Abstract 2730 Introduction: Recently, L-asparaginase-based combination chemotherapy was found to be effective in salvage treatment in patients with relapsed or refractory extranodal NK/T-cell lymphoma, nasal type. To explore the single-agent activity of L-asparaginase, we conducted a single-institute, prospective phase II study. Methods: Patients with relapsed or refractory extranodal NK/T-cell lymphoma, nasal type were eligible for enrollment regardless of prior treatment. L-asparaginase monotherapy (6000 U/m2 on days 1 to 7) was administered as the protocol treatment and repeated every 3 weeks for at most 8 cycles. For responding patients, the decision to proceed with hematopoietic stem-cell transplantation was made at the discretion of treating physicians. The primary endpoint was the best objective response after L-asparaginase. Results: A total of 40 patients were enrolled and treated with L-asparaginase for a median of 5 cycles (range, 1 – 8). The patient characteristics were shown in Table 1. Half of the patients had stage IV disease at enrollment and the vast majority (18 patients) presented with disseminated cutaneous and soft-tissue involvement. Thirty-seven patients (92.5%) had prior exposure to systemic chemotherapy and 14 of them (37.8%) received more than 1 line. The overall response rate was 82.5%. The complete response (CR) and partial response (PR) rates were 40% and 42.5%, respectively. The incidence of adverse events was shown in Table 2. In short, anemia, neutropenia, hypoalbuminemia, nausea and liver-related disorders were common toxicities, which were usually mild and manageable. No grade 4 adverse events and treatment-related mortality were observed. Five patients (12.5%) developed allergic reaction to L-asparaginase and 3 of them had to withdraw from the study since L-asparaginase re-challenge with prophylactic antiallergic agents was unsuccessful. After a median follow-up time of 31.6 months (range, 21.9 – 41.3), the median progression-free survival (PFS) was 12.8 months and median overall survival (OS) was not reached. Response status (CR, PR or no response) after L-asparaginase had a significant impact on either PFS (Figure 1) or OS (Figure 2). Moreover, its prognostic value was confirmed in the multivariate analysis. Conclusions: L-asparaginase demonstrated a high single-agent activity in salvage setting for patients with extranodal NK/T-cell lymphoma, nasal type. The first-line L-asparaginase-containing chemotherapy regimen warrants urgent investigation. Disclosures: Off Label Use: L-asparaginase, which was used in our study for NK/T-cell lymphoma, is approved to treat acute lymphocytic leukemia by US and Chinese FDA.

scholarly journals Molecular remission after combination therapy with blinatumomab and ponatinib with relapsed/refractory Philadelphia chromosome-positive acute lymphocytic leukemia: two case reports

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Junichiro Yuda ◽  
Nobuhiko Yamauchi ◽  
Ayumi Kuzume ◽  
Yong-Mei Guo ◽  
Nobue Sato ◽  
...  
Keyword(s):  
Complete Remission ◽  
Combination Therapy ◽  
Adverse Events ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Hematopoietic Stem ◽  
Safety And Efficacy ◽  
Old Japanese ◽  
Philadelphia Chromosome Positive

Abstract Background The outcomes of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) can improve with allogeneic hematopoietic stem cell transplantation (HSCT) during the first complete remission after treatment with a tyrosine kinase inhibitor (TKI) combined with chemotherapy. However, frail patients who are not eligible for allogeneic HSCT or those with TKI-resistant mutations within the BCR–ABL kinase domain have a poor clinical course. Blinatumomab (BLIN) is a bispecific T-cell engager antibody construct that directs cytotoxic T cells to CD19-expressing B-ALL cells. To date, only a few studies have shown the safety and efficacy of Blinatumomab (BLIN) + TKI combination therapy for relapsed/refractory (R/R) Ph+ ALL. Here we report the case of two patients with R/R Ph+ ALL who were treated with BLIN + TKI with durable molecular response. Case presentation Patient 1: A 69-year-old Japanese male with R/R Ph+ ALL was treated with conventional chemotherapy and dasatinib in April 2016. In May 2018, he developed molecular relapse due to the acquisition of T315I during dasatinib maintenance therapy. Thereafter, he achieved molecular complete remission (mCR) after switching from dasatinib to ponatinib. However, he developed a second relapse after the emergence of triple compound mutations (G250E/D276G/T315I) in November 2018. He subsequently received a total of nine cycles of BLIN and ponatinib combination therapy, which resulted in sustained mCR without any adverse events. Patient 2: A 69-year-old Japanese female with R/R Ph+ ALL was treated with chemotherapy and imatinib in April 2008. She developed molecular relapse due to the emergence of the T315I mutation in October 2017. She achieved mCR after switching from imatinib to ponatinib. However, she developed a second relapse after acquiring ABL exon4 skipping in addition to T315I. She subsequently received a total of seven cycles of BLIN and ponatinib combination therapy, which resulted in sustained mCR. Conclusion In our two cases, BLIN + ponatinib combination therapy was highly effective for R/R Ph+ ALL without any incidence of severe adverse events. Further studies with larger cohorts are warranted to validate the safety and efficacy of this potent combination therapy.

scholarly journals Interim Results of a Phase II Study of Dasatinib and Prednisone As an Oral, Chemo-Free Induction and Consolidation Regimen for Adults with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4402-4402
Author(s):  
Mixue Xie ◽  
Ying Lu ◽  
Guifang Ouyang ◽  
Liming Zhang ◽  
Huixian Hu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Phase Ii ◽  
Conflicts Of Interest ◽  
Remission Rate ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Hematopoietic Stem

Abstract Background Tyrosine kinase inhibitors (TKIs) combined with intensive chemotherapy as a first-line treatment regimen significantly improved the prognosis of Philadelphia (Ph) chromosomal positive acute lymphoblastic leukemia (Ph+ALL). However, it has been reported that 74% of patients fail to complete 8 cycles of chemotherapy, and the early mortality rate during induction was as high as 13%. Our previous retrospective study determined an oral, chemo-free regimen (dasatinib plus prednisone) as induction and consolidation yields 100% of complete remission (CR) rates in Ph+ ALL with minimal induction death (Li XY, et al. Br J Haematol. 2020;189:e231-e234). To further verify the effectiveness of this completely oral and chemo-free regimen, we conducted a phase II, one-arm and multicenter trial (ChiCTR200038053). Methods Adults ≥16 years of age with new diagnosed Ph+ALL were eligible. Induction (Course I) used dasatinib 100 mg daily on days 1-28 and prednisone 1mg/kg/daily on days 1-21, 0.5 mg/kg/daily on days 22-28. Patients not in CR/CRi received Course I as second induction again. Two courses of consolidation (Course II and III) used dasatinib 100 mg daily on days 1-28 and prednisone 1mg/kg/daily on days 1-7. CNS prophylaxis used intrathecal cytarabine and dexamethasone. Patients 16-65 years old underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) if they had a HLA-matched donor; otherwise they received 6 cycles of hyper-CVAD chemotherapy alternating regimen-B (methotrexate, cytarabine) and regimen-A (cyclophosphamide, doxorubicin, vincristine, dexamethasone). The dose of chemotherapy was reduced by a third in patients 60-70 years old and by half in patients over 70 years. The primary objectives were to determine induced complete remission rate and major molecular response of the dasatinib/prednisone oral, chemo-free regimen. Results To date, 32 patients from 10 centers enrolled. Median age was 54 years (range: 15-84). The dominant BCR-ABL1 isoform was p190 in 72%, p210 in 18%, rare types in 6.3% and not reported in 3.1%. Patients received an average of 2.5 courses of dasatinib/prednisone regimen (Course I-III). Most patients were tolerable the dose of dasatinib, and two patients were reduced to 50mg daily due to severe pleural effusion. Allo-HSCT was performed in 10 patients, 50% after remission and 50% after marrow relapse. As shown in Figure 1, the CR rate was 97% with one induction death due to sepsis. The major molecular response (MMR was defined as: 3-log reduction in BCR-ABL1 transcript) was 50% and the complete molecular response (CMR was defined as: the absence of a detectable BCR-ABL1 transcript with 0.01% sensitivity/4.5-log) was 40% either at 3 months after starting induction or before HSCT, respectively. From Course I to Course II, the CMR increased from 18.5% to 48%, but accompanied by an increase in marrow relapse rates, which were 16% and 18.75% at course II and course III, respectively. Marrow relapse occurred in 9 patients, all occurred within 6 months after starting induction. T315I mutation in ABL1 KD was detected in 5 of 7 marrow relapses (72%). With a median follow up of 232 days (range: 77-392 days), 1-year OS and 1-year event-free survival (events were defined as marrow relapse and death) was 97% and 54%, respectively (Figure 2). The cumulative molecular relapse rate (defined as BCR-ABL1:ABL1 ratio rises after reaching the CMR level) was 35% at 3 months, 48% at 6 months, and 54% at 1 year (Figure 2). Conclusions The chemotherapy-free, oral combination of dasatinib and prednisone appears promising induction efficacy in de novo Ph+ ALL; the high CR rates and acceptable molecular response rates were similar to results reported by GIMEMA LAL2116 study (Foà R, et al. N Engl J Med. 2020;383:1613-1623). However, two subsequent consolidation courses of the chemo-free regimen led to early molecular relapse with T315I mutations, which urged us to modify the study protocol such as strengthening consolidation therapy or incorporating promising drug blinatumomab. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals The use of methotrexate, vincristine, L-asparaginase and dexamethasone for salvaging adult acute lymphoblastic leukemia and lymphoma: a real-life experience

2019 ◽  
Vol 6 (10) ◽  
pp. 263-267
Author(s):  
Funda Pepedil Tanrikulu ◽  
Nurhilal Buyukkurt ◽  
Mahmut Yeral ◽  
Pelin Aytan ◽  
Soner Solmaz ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adverse Events ◽  
Life Experience ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Real Life ◽  
Lymphoblastic Lymphoma ◽  
Adult Patients ◽  
Hematopoietic Stem ◽  
Successful Transplantation

Despite recent improvements in the treatment options, adult relapsed/refractory Acute Lymphoblastic Leukaemia (ALL) and lymphoblastic lymphoma (LBL) exhibit poorer cure rates than in childhood. Since, the mainstay difference of childhood multidrug regimens is L-Asparaginase, we sought to salvage adult patients with a protocol containing methotrexate, vincristine, conventional L-asparaginase, and dexamethasone (MOAD). In this study, we aimed to summarize our experience. Methods: Adult patients with relapsed/refractory ALL and LBL followed-up in our institution between 2017 and 2018 were reviewed and those treated with MOAD protocol were retrospectively included in the study. Clinical data, treatment responses, and adverse events were summarised. The protocol featured 28-day cycles of methotrexate 200 mg/m2 intravenously (IV) on days 1 and 15; vincristine 1.4 mg/m2 IV on days 1, 8, and 15; L-asparaginase 10,000 IU/m2 IV twice weekly; and dexamethasone 40 mg IV or orally on days 1–4 and 15–18. Results: A total of eight patients were enrolled, of median age 37 years (range: 21–58 years). Four patients were recovered after transplantation. Complete remission was evident in 38%. Two such patients underwent allogeneic hematopoietic stem cell transplantation after the protocol. Another patient with lymphomatous disease achieved partial remission and underwent successful transplantation. L-asparaginase did not trigger any clinically evident hypersensitivity reaction; the most common adverse events associated with the protocol were hypofibrinogenemia, anemia, and febrile neutropenia. Conclusions: The MOAD protocol was effective and tolerable, enabling to salvage before and after transplantation, particularly in patients with relapsed/refractory T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma.

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