A Meta-Analysis of Hypersensitivity to Pegylated Escherichia coli Asparaginase Used As First-Line Treatment in Contemporary Pediatric Acute Lymphoblastic Leukemia Protocols

Abstract PURPOSE Asparaginase is a key component of acute lymphoblastic leukemia (ALL) therapy. Hypersensitivity reactions challenge its use and occur frequently (30-75%) after native Escherichia. Coli (E.coli) asparaginase (Appel et al., 2008; Muller et al., 2001; Panosyan et al., 2004; Silverman et al., 2001). The international ALL Ponte di Legno Toxicity Work Group (PTWG) classifies hypersensitivity to asparaginase as (i) allergy in case of symptoms of allergy (always associated with undetectable asparaginase activity levels), (ii) allergic-like reactions in case of symptoms without inactivation, and (iii) silent inactivation (SI) with inactivation of asparaginase activity, but without hypersensitivity symptoms (Schmiegelow et al., 2016). Allergic-like reactions and SI can only be diagnosed with monitoring of asparaginase activity levels. A meta-analysis was performed based on data from the PTWG to estimate the incidence of hypersensitivity and risk factors for hypersensitivity to asparaginase in ALL protocols using pegylated E.coli asparaginase (PEGasparaginase) as first line of treatment. PATIENTS AND METHODS Questionnaires were sent to all members of the PTWG. Information on protocol level regarding PEGasparaginase dose, dosing regimen (e.g. dosing frequency, total number of doses, PEGasparaginase-free intervals(s)), administration route, total induction and post-induction hypersensitivity rates per protocol and per risk group and use of therapeutic drug monitoring (TDM). To facilitate comparison between protocols with and without TDM, we defined allergic reactions as the sum of allergies and allergic-like reactions. Silent inactivation was analyzed separately. RESULTS A total of 5880 patients with newly diagnosed ALL, aged 1 to 24 years old, were enrolled in seven different upfront ALL protocols using PEGasparaginase as first-line treatment. The overall incidence of allergic reactions along with 95% confidence interval (CI) were 9% [6%; 13%], 2% [1%; 3%] and 8% [5%; 11%] in the overall protocol, induction and post-induction, respectively (Figure 1). Severity of allergic reactions were described, according to the CTCAE version 3.0 or 4.03, per protocol. 47% of the reactions were classified as grade 3/4. Univariate meta-regression analysis showed a positive association between the incidence of allergic reactions and number of PEGasparaginase-free intervals (P=0.005). High risk group stratification (P<0.001), post-induction treatment phase (P<0.001) and start of PEGasparaginase treatment in post-induction (P=0.006) were also associated with a higher incidence of allergic reactions. Route of administration (IV (8.9%, range 8.6-10.5%) versus IM (6.5%, range 5.5-14.8%)) did not significantly influence risk of hypersensitivity. Number of doses, duration of first PEGasparaginase-free interval and dosage did not significantly influence risk of hypersensitivity. Multivariate meta-regression analysis showed a positive association between the incidence of allergic reactions and the number of PEGasparaginase-free intervals (P=0.006) and start of PEGasparaginase in the post-induction treatment phase (P=0.02). Two out of seven study groups reported an incidence of allergic reactions of 1.6-2.0%, which was 9-16% of all hypersensitivity. Three out of seven study groups reported an incidence of SI of 3.7-4.1%, which was 23-29% of all hypersensitivity reactions. All protocols prescribed a switch to Erwinia asparaginase in case of clinical hypersensitivity and/or SI. 308 out of 348 (89%) of the patients with hypersensitivity to PEGasparaginase received Erwinia asparaginase. 19 out of these 308 (6%) exposed patients had an allergic reaction to Erwinia asparaginase, of which 7 out of 19 (37%) were grade 3/4. CONCLUSION The incidence of allergic reactions is lower in protocols using PEGasparaginase as first-line treatment compared to that reported for native E.coli asparaginase or PEGasparaginase after native E.coli asparaginase. Post-induction phase, a higher number of PEGasparaginase-free intervals, and initiation of PEGasparaginase in post-induction phase are risk factors for allergic reactions. These results are important for planning of PEGasparaginase administrations in future frontline therapy. Figure 1 Figure 1. Disclosures Albertsen: Erytech: Honoraria, Speakers Bureau; Servier: Speakers Bureau; BKA: Other: Sponsor of the investigator-initiated trial NOR-GRASPALL2016.

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mFOLFOX-bevacizumab or XELOX-bevacizumab then bevacizumab (B) alone or with erlotinib (E) in first-line treatment of patients with metastatic colorectal cancer (mCRC): Interim safety analysis of DREAM study

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.4077 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 4077-4077

Author(s):

C. Tournigand ◽

B. Samson ◽

W. Scheithauer ◽

C. Louvet ◽

T. Andre ◽

...

Keyword(s):

Colorectal Cancer ◽

Safety Analysis ◽

Clinical Activity ◽

Induction Phase ◽

Line Treatment ◽

First Line ◽

Primary Tumors ◽

M Phase ◽

Synchronous Metastases ◽

First Line Treatment

4077 Background: Anti-VEGF or EGFR inhibitors demonstrated clinical activity in combination with chemotherapy (CT) in mCRC. The DREAM trial compares, after an induction CT of 6 cy of FOLFOX-B or XELOX-B, a maintenance with B ± E. We report here a pre-planned safety analysis of induction (I) and maintenance (M) phase for the first 200 patients. Methods: Patients (pts) with untreated mCRC were randomly assigned to 2 arms (I): mFOLFOX+B (n=100), or mXELOX+B (n=100). mFOLFOX-B: LV 400 mg/m2, Oxaliplatin (ox) 100 mg/m2, B 5 mg/kg d1, 5FU ci 2.4g/m2 46h, q2w, mXELOX-B: Ox 100 mg/m2 d1, capecitabine 2.5 g/m2 d1–7, B 5mg/kg, q2w. To date, 117 pts with a disease control after 6 cy have had a 2nd randomisation (M): B alone (7.5 mg/kg q3w, n=56) or B+E 150 mg/d (n=61) until PD. Results: Pts characteristics were: sex: 124M/76F, median age: 62.4 years (26–80), primary tumors: colon 152, rectum 53, synchronous metastases: 150 pts, > 1 metastase site: 115, PS 0/1: 134/66, Alk. Ph.>UNL: 87 pts, and LDH>UNL: 88pts. For I, 92 pts in mFOLFOX-B and 93 in XELOX-B were evaluable for toxicity (tox). Tox (%) for mFOLFOX-B/XELOX-B were: any toxicity grade (gr) 3 or 4: 21/30; neutropenia gr 3 6/1, gr 4 0/2; febrile neutropenia gr 3 1/1, gr 4 0/1; thrombopenia gr 3 0/1, gr 4 0/2; anemia gr 2 8/15, gr 3 2/1; nausea gr 2 17/15, gr 3 4/6; vomiting gr 2 10/12, gr 3 2/5; mucositis gr 2 6/6, gr 3 0/4; diarrhea gr 2 8/12, gr 3 5/20, gr 4 0/1; neuropathy gr 2 23/17 gr 3 3/1; HFS gr 2 0/7, gr 3 0/2; hypertension gr 2 2/3, gr 3 1/0; proteinuria gr 2 1/5; SAEs 14/25. For M, 56 pts in B and 61 pts in B+E were evaluable. Tox (% B/B+E) were: neutropenia gr 2 0/3; thrombopenia gr 2 2/0; nausea gr 2 2/2, gr 3 2/0; vomiting gr 3 2/0; mucositis gr 2 2/3; diarrhea gr 2 0/6, gr 3 2/6; skin tox gr 1 9/31, gr 2 0/38, gr 3 0/16, gr 4 0/2; proteinuria gr 2 5/5; hypertension gr 1 9/15, gr 2 3/8, gr 3 3/0. Conclusions: This interim safety analysis demonstrated that induction with mFOLFOX-B or XELOX-B as well as maintenance with B or B + E appears to be well-tolerated, without unexpected side effects. The DREAM study is ongoing, with a prolonged induction phase of 6 months (3 mo with ox then 3 mo with fluoropyrimidines-B) before randomisation for maintenance therapy. [Table: see text]

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Soluble CD87 (s-uPAR) predicts bevacizumab-based first line treatment of metastatic colorectal cancer (mCRC): Results from a prospective multi-center study.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.604 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 604-604 ◽

Cited By ~ 1

Author(s):

Matthias Unseld ◽

Gabriele Kornek ◽

Andreas Gleiss ◽

Svitlana Demyantes ◽

Jost Schwarzwald ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Predictive Marker ◽

Endothelial Cell Migration ◽

Migration And Invasion ◽

Induction Treatment ◽

Line Treatment ◽

First Line ◽

Urokinase Plasminogen Activator Receptor ◽

First Line Treatment

604 Background: Bevacizumab-combined chemotherapy is well established in the induction treatment of metastatic colorectal cancer (mCRC). Despite tremendous efforts, no valid predictive marker for anti-VEGF treatment has so far been defined. CD87, the urokinase plasminogen activator receptor (uPAR), is centrally regulating VEGF-induced angiogenesis via adapting endothelial cell migration and invasion (Unseld et al.; ThrombHaem,2015, Brunner et al.; Blood 2011, Prager et al; Blood 2009; Prager et al; Blood 2004). Preoperative plasma s-uPAR levels were shown to independently predicted survival of patients resectable colorectal cancer. This study aimed to identify any prognostic or predictive value of s-uPAR in front-line bevacizumab-treated mCRC patients. Methods: In this prospective multi-center trial (NCT02119026), patients were either treated with bevacizumab plus FOLFOX or bevacizumab plus FOLFIRI. Baseline s-uPAR levels were assessed in 80 patients (40 ea. group) using respective CE-certified electro-chemiluminescence immunoassay (ECLIA). Biomarkers were explored using Kaplan-Meier curves and were log transformed for survival analysis by Cox proportional hazards models. All P values reported are two-sided. Results: Data from eighty patients were available for analysis. Progression free survival (PFS) and overall survival (OS) were assessed. Data indicate significance for the angiogenic biomarker uPAR to determine prognostic (HR = 3.06, CI 1.45 - 6.53, p = 0.003) and predictive (HR = 3.41, CI 2.03 - 5.74, p < 0.001) value in the treatment of Bevacizumab. Conclusions: This is the first prospective analysis of baseline s-uPAR. High baseline-s-uPAR levels were an independent predictive marker for worse bevacizumab-based first-line treatment response.

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First-line treatment failure in childhood acute lymphoblastic leukemia

Medicine ◽

10.1097/md.0000000000019241 ◽

2020 ◽

Vol 99 (7) ◽

pp. e19241

Author(s):

Joanna Zawitkowska ◽

Monika Lejman ◽

Katarzyna Drabko ◽

Agnieszka Zaucha-Prażmo ◽

Marcin Płonowski ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Treatment Failure ◽

Lymphoblastic Leukemia ◽

Childhood Acute Lymphoblastic Leukemia ◽

Line Treatment ◽

First Line ◽

First Line Treatment

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Impact Of Rituximab Maintenance Schedule On Prognosis In First Line Treatment Of Follicular Lymphoma. Retrospective Analysis From Czech Lymphoma Group (CLG) Database

Blood ◽

10.1182/blood.v122.21.4387.4387 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4387-4387

Author(s):

Andrea Janikova ◽

Zbynek Bortlicek ◽

Vit Campr ◽

Leos Kren ◽

David Belada ◽

...

Keyword(s):

Overall Survival ◽

Follicular Lymphoma ◽

Retrospective Analysis ◽

Research Funding ◽

Statistical Significance ◽

Induction Treatment ◽

Line Treatment ◽

First Line ◽

Rituximab Maintenance ◽

First Line Treatment

Abstract Introduction Results of randomized studies showed benefit of maintenance therapy with monoclonal anti-CD20 antibody (rituximab) in terms of time to progression (PFS) and overall survival (OS) in follicular lymphoma (FL). General recommendation, based on large clinical trial, is to give 2 years of rituximab maintenance á 375mg/m2every 2 months (12 doses) in first line setting. On the other hand, there are various rituximab maintenance schedules; however, the clear comparison of clinical efficacy is missing. Our retrospective analysis compared two different schedule of rituximab maintenance in first-line treatment of FL used in university centers participating on CLG registry. Methods Data were recruited from 1702 FL patients registered in the prospectively maintained multicentric database (Czech Lymphoma Group; CLG). For the analysis, patients with stage II-IV of new diagnosed FL (grade 1-3a) responding (complete or partial remission) to 6-8 cycles first-line RCHOP (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone) followed with rituximab maintenance (RM) were included. Completed planned maintenance was inclusion criterion. Patients with previous watch and wait or additional first line therapy (radiotherapy, other chemotherapy, transplant therapy) were excluded. Results Totally, 168 evaluable FL patients with median age 57ys (range 28-82) including 70 (41.7%) men treated with RCHOP + RM were found in CLG database. 52/168 patients received totaly 8 doses of rituximab maintenance every 3 months for 2 years (RM8 arm), whereas 47/168 patients were treated with totaly 12 doses (RM12 arm) of rituximab maintenance every 2 months for 2 years. All patients in both subgroups completed planned RM therapy. There was no difference in distribution of age, gender, FLIPI, grade, B-symptoms, bone marrow involvement, performance status, LDH and beta2microglobuline level between both arms. Induction treatment in terms of administered cycles CHOP (6xCHOP in 41/52 and 35/45 pts., for RM8 and RM12 arm) and rituximab doses (8xR in 48/52 and 41/45 pts., for RM8 and RM12 arm) was similar between arms (ns). There were 4/52 (7.7%) and 5/47 (10.6%) relapses in subgroups RM8 and RM12, with no statistical significance. Median PFS was 3.8 (2.1-5.8) years vs. 3.9 (2.4-7.8) years in RM8 and RM12 arms (not significant), and median OS 3.91 (2.2-6.94) years vs. 3.1 (2.48-8.6) years also with no statistical significance. Conclusion Our results show, that rituximab maintenance given every 2 or every 3 months for two years in first line treatment brings similar benefit to the FL patients in terms of remission duration and overall survival. Despite the fact, that presented data are retrospective observation, this is the first report comparing two different rituximab maintenance regimens in FL. Further prospective study and longer follow up are needed to confirm our preliminary data. This work was supported by grant NT/12193-5 and MHCZ-DRO (FNBr 65269705) Disclosures: Mayer: Roche: Consultancy, Research Funding; Glaxo: Consultancy, Research Funding. Trneny:Roche: Honoraria, Research Funding.

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Rituximab-Lenalidomide (REVRI) in Relapse or Refractory Primary Central Nervous System (PCNSL) or Vitreo Retinal Lymphoma (PVRL): Results of a "Proof of Concept" Phase II Study of the French LOC Network

Blood ◽

10.1182/blood.v128.22.785.785 ◽

2016 ◽

Vol 128 (22) ◽

pp. 785-785 ◽

Cited By ~ 36

Author(s):

Herve Ghesquieres ◽

Caroline Houillier ◽

Olivier Chinot ◽

Sylvain Choquet ◽

Cecile Molucon-Chabrot ◽

...

Keyword(s):

Phase Ii ◽

Research Funding ◽

Phase Ii Study ◽

Primary Cns Lymphoma ◽

Maintenance Phase ◽

High Dose ◽

Induction Phase ◽

Line Treatment ◽

First Line ◽

First Line Treatment

Abstract Background Primary CNS lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL), predominantly of non-germinal center (non-GC) subtype. Despite improvement of therapeutic results since the introduction of high-dose methotrexate (MTX) in first-line treatment, improvements of therapeutic results are needed in PCNSL, both in first-line treatment and at relapse. The roles of consolidation and maintenance therapy need to be addressed as well. The association of Rituximab and Lenalidomide has shown activity in non-CNS non-GC DLBCL, but its activity in PCNSL was unknown. Methods In this prospective, multicenter open-label phase II study, we enrolled patients over 18 with a refractory or relapse PCNSL or primary vitreo-retinal lymphoma (PVRL) of DLBCL type. The treatment consisted in an induction phase with 8 cycles of 28 days with R2 (Rituximab 375/m2 IV D1; Lenalidomide 20 mg/D D1-D21 for the first cycle then 25 mg/D D1-D21 for the subsequent cycle in the absence of hematologic toxicity), followed, in responder patients by a maintenance phase with 12 cycles of 28 days with Lenalidomide alone (10 mg/D, D1-D21). Corticosteroids were allowed during the first induction cycle in case of a threatening or symptomatic edema. Deep vein thrombosis prophylaxis was mandatory. Patient who received a complete month of treatment were evaluable for response. The primary end-point was the objective response rate (ORR) at the end of the induction phase, according to the international primary CNS lymphoma collaborative group (IPCG) criteria. The analysis was based of a Fleming's two-step design (P0 = 10 %; P1= 30%). A pilot exploration of circulating NK and T cells before and after treatment and correlation with therapeutic response was conducted. This study is registered with ClinicalTrials.gov, number NCT01956695 Results Between September 17, 2013 and September 29, 2015, fifty patients (median age: 69, range 46-86) were recruited from 10 centers. All the patients had previously received high-dose (HD) MTX. Median number of previous lines of chemotherapy was 2 (range, 1-4). Nine patients had previous received an HD chemotherapy followed by hematopoetic stem cell rescue. Initial diagnoses were PCNSL (n = 42) and PVRL (n = 8). At time of inclusion in the study, diagnoses were PCNSL (n = 41) and PVRL or isolated intra-ocular (IO) relapse of PCNSL (n=9). Seven patients had concomitant involvement of the cerebrospinal fluid (CSF). Patients were included either for a relapse after last treatment (80 %; median time to relapse = 5.5 months), or for a refractory disease (20 %). Thirty-four patients received concomitant corticosteroids during the first month of treatment. Forty-five patients were evaluable for response after the first cycle of treatment. Median number of induction cycles was 7 (range, 1-8). Grade 3 or 4 adverse events were reported in 11 patients (infection: n = 10, cutaneous rash: n =1). A second cancer (melanoma) occurred in one patient. Two patients withdrew their consent. During the induction phase, best observed responses were CR (n = 16), PR (n = 11), stable disease (n = 5) and progressive disease (n = 11) for an ORR of 63% (27/43). . At the end of the induction phase, 43 patients were evaluable for the primary objective. ORR was 39 % (17/43) including 13 CR (30%). A response has been observed in patients included for a PCNSL (n = 13, 32%) and for an IO relapse or PVRL (n = 4, 44%). Seventeen patients started the maintenance phase. With a median follow-up of 9 months (range, 1.1-15.4), median overall and progression-free survivals of the whole population were 15.3 months (95 % CI, 9.6 - non reached) and 8.1 months (95 % CI, 4.2 - non reached) respectively. Median duration of response in the responder patients was 8.9 months (95 % CI, 7.6- non reached). The results of the maintenance phase are pending. Results will be further updated. Conclusion This phase II study demonstrates a significant activity of the rituximab-lenalidomide regimen in relapse or refractory PCNSL or PVRL. Updated results with a longer follow-up are awaited to better evaluate the PFS and the median duration of response. This regimen warrants to be added in the armamentarium drugs for PCNSL and further explored in combination with other chemotherapies in first-line treatment, as maintenance therapy, or as a chemo-free regimen for patients unfit for high-dose methotrexate. Funding: Celgne, Roche Figure. Figure. Disclosures Ghesquieres: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche France: Research Funding; Mundipharma: Consultancy. Choquet:Celgene: Consultancy; Janssen: Consultancy. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Soussain:Roche: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding.

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Imatinib Given Concurrently with Induction Chemotherapy Is Superior to Imatinib Subsequent to Induction and Consolidation in Newly Diagnosed Philadelphia-Positive Acute Lymphoblastic Leukemia (PH+ALL).

Blood ◽

10.1182/blood.v104.11.685.685 ◽

2004 ◽

Vol 104 (11) ◽

pp. 685-685 ◽

Cited By ~ 10

Author(s):

Oliver G. Ottmann ◽

Barbara Wassmann ◽

Heike Pfeifer ◽

Nicola Goekbuget ◽

Gesine Bug ◽

...

Keyword(s):

Hematologic Toxicity ◽

Induction Phase ◽

Line Treatment ◽

Rt Pcr ◽

First Line ◽

Imatinib Resistance ◽

Term Survival ◽

Log Reduction ◽

Grade Iii ◽

First Line Treatment

Abstract Background and study design: Despite intensive chemotherapy (ChThx), preferably followed by allogeneic SCT, the prognosis of adult patients with Ph+ALL is poor. Adding Imatinib to first-line treatment may improve efficacy and outcome and reduce the occurrence of Imatinib-resistance. However, it has not yet been established how Imatinib is best incorporated in front-line treatment of Ph+ALL. In a prospective, multicenter study of the GMALL, we compared the safety, anti-leukemic efficacy and MRD response of two strategies in which Imatinib was incorporated either intercurrently between (cohort 1) or simultaneously with (cohort 2) induction and consolidation cycles. Cohort 1 patients had to have a CR after induction therapy, with persistance of minimal residual disease (MRD) by RT-PCR; in contrast, patients in cohort 2 received Imatinib simultaneously with the 2nd phase of induction irrespective of remission status, with continuation of Imatinib for up to 8 weeks after the first consolidation cycle. Results: Cohort 1 encompasses 48 pts. (median age 47 y, range: 24–72), 46 of whom were in CR and 2 in PR upon starting Imatinib at 400 mg/d (n=36) or 600 mg (n=12). Imatinib was initiated 18 (5–52) days after completion of induction and given for a median of 28 (13–176) days. No patient relapsed during post-induction Imatinib, three pts. relapsed prior to SCT and one death occurred in CR after consolidation therapy due to septicaemia. Hematologic and non-hematologic toxicities were limited to WHO grades I/II. Cohort 2 encompasses 46 pts. (median age 39 y, range: 19–62) enrolled to date; 58% (19/33) had achieved a CR prior to initiation of Imatinib after induction phase I, a PR or non-response was documented in 18% and 24%, respectively. After completion of induction phase II concurrent with Imatinib, 96% (23/24 evaluable) had achieved a CR, one pt. (4%) failed and died. Comparison of median bcr/abl transcripts prior to and after induction II showed no significant decrease in cohort I (ChThx alone) in contrast to a 1.4 log reduction in cohort 2 (ChThx+Imatinib). Comparison of bcr/abl transcripts prior to consolidation I with pre-induction II levels showed a 3.9 log reduction in cohort 2 versus a 1.5 log reduction in cohort 1. Moreover, the frequency with which bcr/abl transcripts became undetectable by RT-PCR prior to consolidation I increased from 10% in cohort 1 to 50% in cohort 2. The duration of grade III/IV thrombocytopenia and neutropenia in cohort 2 was 12 (3–57) days and 16 (3–47) days, respectively, with cytopenias and/or infectious complications entailing Imatinib dose reductions in 40% and interruption of Imatinib in 77% of pts. The most frequent grade III/IV non-hematologic toxicity was hepatic (43% of evaluable pts.). There were no treatment related deaths. Summary: Imatinib given concurrently with and subsequent to induction and consolidation is highly effective first-line treatment for adult Ph+ALL, with a CR rate exceeding 90% and 50% MRD negativity. This strategy is more effective than alternating chemotherapy and Imatinib cycles, but is accompanied by substantial hematologic and non-hematologic toxicity. The overall impact on long-term survival in this very high risk group or patients remains to be determined, particularly in light of subsequent allogeneic SCT in a large proportion of patients.

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RAD (Lenalidomide, Adriamycin and Dexamethasone) Is a Novel and Very Effective Induction Regimen in Newly Diagnosed Multiple Myeloma Preceding a Risk-Adjusted Transplant Strategy,

Blood ◽

10.1182/blood.v118.21.3967.3967 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3967-3967

Author(s):

Stefan Knop ◽

Christian Langer ◽

Monika Engelhardt ◽

Lars O Muegge ◽

Christoph Röllig ◽

...

Keyword(s):

Multiple Myeloma ◽

Interim Analysis ◽

Research Funding ◽

Current Phase ◽

Induction Treatment ◽

High Dose ◽

Line Treatment ◽

Newly Diagnosed ◽

First Line ◽

First Line Treatment

Abstract Abstract 3967 Background Triple combinations utilizing dexamethasone, at least one of the “novel drugs” and either an alkylating agent or an anthracycline are currently considered standard induction regimens in newly diagnosed multiple myeloma (MM). In patients (pts) deemed medically fit, subsequent autologous (auto) stem cell transplantation (SCT) yet is a mainstay of care. Whether allogeneic (allo) SCT in first line treatment of MM further improves prognosis remains, however, a matter of debate. We have shown the RAD regimen to be highly effective and well tolerated in relapsed and refractory MM. Therefore, we decided to integrate this combination as a means of induction into the up-front management. Patients and methods The current phase-II trial (DSMM XII) was designed to include pts up to the age of 65 years with newly diagnosed, symptomatic MM. We chose four cycles of RAD induction (lenalidomide 25 mg/day d 1–21; infusional adriamycin 9 mg/m2 and day d1-4; dex 40 mg d1-4 and 17–20; pegfilgrastim 6 mg d 6) every 4 weeks followed by chemomobilization (cyclophosphamide, etoposide) of peripheral blood stem cells. Thromboprophylaxis by low molecular weight heparin is mandatory. All pts are scheduled to receive two transplants, the first of which being an auto SCT following standard high-dose melphalan (200 mg/m2). A subsequent allo SCT after preparation with treosulfan/fludarabin is scheduled for pts featuring at least one cytogenetic or serologic risk factor (RF). Those without any RF (“very favourable risk”) are to proceed to a second auto SCT. All patients will receive 12 months of lenalidomide maintenance. The primary end point of this trial is response to risk-adapted transplant as assessed after second SCT. This is the first planned efficacy interim analysis after 50 pts having terminated induction treatment. Results 148 pts with a median age of 55.5 (range, 30–66) years have been enrolled by 16 German centers between 9/2009 and 7/2011. In addition to the intended sample size, 2 pts had progressive disease for a total of 52 pts being evaluable for post-induction response according to the IMWG criteria. 32 pts (62%) had ISS stage II and III disease and all except three were evaluable for cytogenetic analysis based on fluorescence in situ hybridization (FISH). Incidences of chromosomal abnormalities were as follows: deletion of 13q, 31%; translocation (4;14), 15%; and deletion of 17p, 12%. Overall response rate was 79% including a 52% rate of at least very good partial response (VGPR). Seven pts (13%) achieved confirmed complete response (CR) and stringent CR. 18/52 pts (35%) experienced severe treatment-emergent adverse events (t-SAEs) with an incidence of hematologic events of 4%. Incidences of infections and venous thromboembolism were 8% and 6%, respectively. Conclusions Results from this interim analysis indicate RAD to be a very effective and well tolerated induction protocol in newly diagnosed MM. High-quality response (VGPR or better) to induction is known to be a major prognosticator for long-term prognosis in a given patient. Thus, combination of RAD with risk-adjusted SCT may contribute to enhanced disease control in a substantial proportion of pts. Disclosures: Knop: Celgene Germany GmbH: Consultancy. Off Label Use: Lenalidomide in combination with dexamethasone and adriamycine in first line treatment of multiple myeloma. Langer:Celgene Germany GmbH: Consultancy. Gramatzki:Novartis, Celgene: Consultancy, Research Funding. Einsele:Celgene Germany GmbH: Consultancy, Honoraria. Bargou:Celgene Germany GmbH: Consultancy, Honoraria, Research Funding.

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Pegaspargase Re-Challenge after Grade 2 Hypersensitivity Reaction in Childhood Acute Lymphoblastic Leukemia: Results from DFCI 16-001

Blood ◽

10.1182/blood-2020-138840 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 30-31

Author(s):

Lynda M. Vrooman ◽

Yael Flamand ◽

Victoria Koch ◽

Melissa A. Burns ◽

Sarah M. Cronholm ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Allergic Reaction ◽

Lymphoblastic Leukemia ◽

Advisory Board ◽

Challenge Dose ◽

Post Induction ◽

Asparaginase Activity ◽

Erwinia Asparaginase ◽

Grade 3 ◽

Experienced Grade

Introduction: Hypersensitivity reactions with asparaginase occur frequently in pediatric patients (pts) with acute lymphoblastic leukemia (ALL). The standard approach for pts with reaction to E.coli-derived asparaginase is to switch to Erwinia asparaginase, given concern that clinical reactions reflect presence of neutralizing antibodies; however, Erwinia requires more frequent dosing and is often unavailable. Therapeutic drug monitoring allows for discrimination between pts with pegaspargase hypersensitivity who have sub-therapeutic asparaginase activity and those still able to derive therapeutic benefit from pegaspargase. We prospectively piloted re-challenging pts with pegaspargase after initial Grade 2 hypersensitivity to this agent, with premedication at re-challenge and assessment of serum asparaginase activity (SAA). Methods: Pts aged 1 to < 22 years with newly diagnosed ALL were eligible for DFCI 16-001. Pts received 1 dose of intravenous pegaspargase during Induction, and every 2 weeks for 15 total doses in Post-Induction phases, without routine premedication. Pts were monitored during/after pegaspargase for allergy, with CTCAE version 4.0 event grading. Those with ≥Grade 3 allergy discontinued pegaspargase and were switched to Erwinia. Those with Grade 2 allergic reaction were eligible for pegaspargase re-challenge with pre-medication (acetaminophen, diphenhydramine, and hydrocortisone, or per institutional standard) and slower infusion rate. If < 50% of the intended dose had been administered when reaction occurred, re-challenge was within 1-7 days of initial reaction. If ≥ 50% of the intended dose had been given, re-challenge was at next planned pegaspargase dose. SAA was measured 1-hour, 7-days, and 14-days after the re-challenge infusion (if dose completed). If 1-hour or 7-day level ≥ 0.1 IU/mL, and 14-day level ≥ 0.025 IU/mL, SAA was considered adequate, and the pt continued to receive pegaspargase with premedication. Pts with an inadequate SAA level, or with new ≥ Grade 2 allergic reaction with the re-challenge dose were considered to have failed re-challenge and were changed to Erwinia (or enrolled on a clinical trial of recombinant crisantaspase, an alternative Erwinia preparation). Results: Between 3/2017- 7/2020, 317 eligible pts enrolled. Overall, 81 of 299 (27%) total evaluable pts experienced a first allergic reaction to pegaspargase, 68 pts with Grade 2 reaction, 13 with Grade ≥3. During Induction, 17 of 299 (6%) evaluable pts had allergic reaction to pegaspargase; all Grade 2. Of the 17 Grade 2 reactions, 13 pts (76%) underwent re-challenge in Induction, 9 (69%) re-challenges successful and 4 failed. Post-Induction, 64 of 241 evaluable pts (27%) had a first allergic reaction; 51 Grade 2 and 13 Grade ≥3. Thirty-six of 51 (71%) pts with Grade 2 allergy during Post-Induction underwent re-challenge, as did 1 additional pt with allergy during Induction who was re-challenged with first Post-Induction pegaspargase dose (per protocol guideline, due to receiving ≥50% of Induction dose). Among these re-challenges, 16 were successful, 21 failed. Overall, 25 of 50 (50%) pts who were re-challenged after Grade 2 reaction had a successful challenge and were able to continue pegaspargase. Among the 25 pts with failed re-challenge, 6 pts (24%) had inadequate SAA alone as cause of failure, 17 pts (68%) had an allergic reaction with the re-challenge dose, and 2 (8%) additional patients had both allergic reaction and documented inadequate SAA. Three pts who were successfully re-challenged had a subsequent allergic reaction to pegaspargase. Among the 22 pts who experienced another allergic reaction with pegaspargase (at re-challenge or subsequent dose), 19 pts (86%) experienced Grade 2, and 3 pts experienced Grade 3 reaction. Conclusion: Fifty percent of pts with a Grade 2 reaction to pegaspargase were able to tolerate and achieve adequate SAA when re-challenged with premedication. For those who did react with or after re-challenge, reactions were not more severe. The re-challenge approach limits premedication exposure only to a minority of pts with a history of prior reaction and substantially decreases the number of pts needing to switch to Erwinia asparaginase, which can be challenging to deliver due to administration schedule and drug shortage. Disclosures Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Silverman:Takeda: Other: advisory board; Servier: Other: advisory board; Syndax: Other: advisory board.

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First-line treatment of acute lymphoblastic leukemia with pegasparaginase

Biologics: Targets and Therapy ◽

10.2147/btt.s3295 ◽

2009 ◽

pp. 359 ◽

Cited By ~ 1

Author(s):

Andrea Pession

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Line Treatment ◽

First Line ◽

First Line Treatment

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Treatment of New Cases of Acute Promyelocytic Leukaemia by Arsenic Trioxide.

Blood ◽

10.1182/blood.v104.11.396.396 ◽

2004 ◽

Vol 104 (11) ◽

pp. 396-396 ◽

Cited By ~ 2

Author(s):

Ardeshir Ghavamzadeh ◽

Kamran Alimoghaddam ◽

Hamidolah Ghaffari ◽

Shahrano Rostami ◽

Yousef Mortazavi ◽

...

Keyword(s):

Complete Remission ◽

Arsenic Trioxide ◽

Induction Phase ◽

Line Treatment ◽

Rt Pcr ◽

First Line ◽

Common Cause ◽

One Year ◽

First Line Treatment

Abstract Purpose: Arsenic Trioxide approved for treatment of relapsed or refractory APL to ATRA. We studied the effects of Arsenic Trioxide as first line treatment of new cases of APL and their follow up. Material and methods: we studied 73 new cases of APL diagnosed by morphologic criteria and confirmed by cytogenetic, RT-PCR for PML/RARA and/or FISH and followed patients for MRD by sensitive nested RT-PCR. Our patients were 30 males and 43 females with median age 30+/− 12. Patients treated by infusion of 0.15mg/kg/d of Arsenic Trioxide to complete remission by morphologic criteria or till day +60. In patients who complete remission achieved, after 28 days rest, again we began Arsenic Trioxide 0.15mg/kg/d for 28 days as consolidation. Results: complete remission were achieved in 66 patients( 90.4%) and 7 early mortality. Median time to complete remission was 30+/−6.4 days. Most common cause of mortality was APL maturation syndrome ( 4 cases) Most common toxicities during induction phase were, APL maturation syndrome (10 cases), serositis(6 cases) and hepatotoxicity (19 cases). 63 cases(86.3%) are alive with a median follow up of 17+/−12.65 months. 14 relapses observed in our patients and complete remission achieved with re-treatment by Arsenic trioxide in 11 of them. Also we could control 3 fatal bleeding by infusion of activated factor 7(NovosevenÒ) which stopped hemorrhage . One year and two/three years survival of patients were 86% and 84%. Most common cause of death was APL maturation syndrome in 4 patients and relapse in 3 cases.Conclusion: Arsenic Trioxide is acceptable as first line treatment of APL and its result is comparable to ATRA with chemotherapy.

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