scholarly journals Midostaurin in Combination with Intensive Induction and As Single Agent Maintenance Therapy after Consolidation Therapy with Allogeneic Hematopoietic Stem Cell Transplantation or High-Dose Cytarabine (NCT01477606)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 322-322 ◽  
Author(s):  
Richard Schlenk ◽  
Konstanze Döhner ◽  
Helmut Salih ◽  
Andrea Kündgen ◽  
Walter Fiedler ◽  
...  
Keyword(s):  
Stem Cell ◽  
Maintenance Therapy ◽  
Induction Therapy ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
High Dose ◽  
Consolidation Therapy ◽  
Hematopoietic Stem ◽  
High Dose Cytarabine ◽  
Induction Cycle

Abstract Background: Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in roughly 25% of younger adult patients (pts) with acute myeloid leukemia (AML), implicating FLT3 as a potential target for kinase inhibitor therapy. The multi-targeted kinase inhibitor midostaurin shows potent activity against FLT3 as a single agent but also in combination with intensive chemotherapy. Aims: To evaluate the feasibility and efficacy of midostaurin in combination with intensive induction therapy and as single agent maintenance therapy after allogeneic hematopoietic stem cell transplantation (alloHSCT) or high-dose cytarabine (HIDAC). Methods: The study includes adult pts (age 18-70 years (yrs)) with newly diagnosed FLT3-ITD positive AML enrolled in the ongoing single-arm phase-II AMLSG 16-10 trial (NCT: NCT01477606). Pts with acute promyelocytic leukemia are not eligible. The presence of FLT3-ITD is analyzed within our diagnostic study AMLSG-BiO (NCT01252485) by Genescan-based fragment-length analysis (allelic ratio >0.05 required to be FLT3-ITD positive). Induction therapy consists of daunorubicin (60 mg/m², d1-3) and cytarabine (200 mg/m², continuously, d1-7); midostaurin 50 mg bid is applied from day 8 onwards until 48h before start of the next treatment cycle. A second cycle is optional. For consolidation therapy, pts proceed to alloHSCT as first priority; if alloHSCT is not feasible, pts receive three cycles of age-adapted HIDAC in combination with midostaurin from day 6 onwards. In all pts maintenance therapy for one year is intended. This report focuses on the first cohort of the study (n=149) recruited between June 2012 and April 2014 prior to the amendment increasing the sample size; the amendment to the study is active since October 2014. Results: At study entry patient characteristics were median age 54 years (range, 20-70, 34% ≥ 60 yrs); median white cell count (WBC) 48.4G/l (range 1.1-178G/l); karyotype, n=103 normal, n=3 t(6;9), n=2 t(9;11), n=20 intermediate-2 and n=7 high-risk according to ELN recommendations, n=14 missing; mutated NPM1 n=92 (62%). Data on response to first induction therapy were available in 147 pts; complete remission (CR) 58.5%, partial remission (PR) 20.4%, refractory disease (RD) 15% and death 6.1%. A second induction cycle was given in 34 pts. Overall response after induction therapy was CR 75% and death 7.5%. Adverse events 3°/4° reported during the first induction cycle were most frequently gastrointestinal (n=34) and infections (n=81). During induction therapy midostaurin was interrupted, dose-reduced or stopped in 55% of the pts. Overall 94 pts received an alloHSCT, 85 in first CR (n=65 age<60 yrs, n=20 age ≥60 yrs) and 9 pts after salvage outside the protocol or after relapse (n=70 from a matched unrelated and n=24 from a matched related donor). In pts receiving an alloHSCT within the protocol in median 2 chemotherapy cycles were applied before transplant (range 1-4) and the cumulative incidence of relapse and death at 12 months were 9.2% (SE 3.3%) and 19.5% (SE 4.8%). Maintenance therapy was started in 52 pts, 40 pts after alloHSCT and 12 pts after HIDAC. Only 4 adverse events 3°/4° were attributed to midostaurin. First analyses revealed a low cumulative incidence of relapse irrespective of the FLT3-ITD mutant to wildtype ratio (<0.5 versus ≥0.5) in patients proceeding to alloHSCT with 12% and 5% as well as for those after HIDAC consolidation with 28% and 29%, respectively. Conclusions: The addition of midostaurin to intensive induction therapy and as maintenance after alloHSCT or HIDAC is feasible and compared to historical data may be most effective in those patients with a high FLT3-ITD mutant to wildtype ratio. Disclosures Schlenk: Novartis: Honoraria, Research Funding. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Götze:Celgene Corp.: Honoraria; Novartis: Honoraria.

INNV-28. POTENTIAL EFFECTIVE CONSOLIDATION THERAPY WITH SINGLE AGENT IBRUTINIB FOR A CASE WITH PRIMARY CNS LYMPHOMA AFTER INITIAL HD-MTX AND RITUXIMAB INDUCTION THERAPY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi111-vi111
Author(s):  
Steven Du ◽  
Uvin Ko ◽  
Daniela Bota ◽  
Xiao-Tang Kong
Keyword(s):  
Induction Therapy ◽  
Kinase Inhibitor ◽  
Brain Mri ◽  
Single Agent ◽  
Primary Cns Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
Consolidation Therapy ◽  
Left Lateral Ventricle

Abstract INTRODUCTION Primary CNS Lymphoma (PCNSL) is a rare and aggressive cancer that originates from lymphocytes and develops in the central nervous system. Standard induction therapy involves high-dose methotrexate (HD-MTX)-based chemotherapy, which achieves complete or partial response in most PCNSL patients. However, there is no standard consolidation therapy. We report one case in which ibrutinib, a Bruton’s tyrosine kinase inhibitor, replaced low-dose WBRT as consolidation therapy after induction by HD-MTX and rituximab. Ibrutinib treatment yielded good tolerance and further resolution of small residue lymphoma. CASE REPORT The patient is a 77-year-old female who presented with slurred speech, right-sided weakness, and difficulty word-finding in early 2020. Brain MRI found multifocal lesions, and biopsy of the largest lesion near the left lateral ventricle revealed diffuse large B cell lymphoma. The patient began HD-MTX at 6 g/m2 for the first cycle of induction therapy. She continued HD-MTX every two weeks, but dosage was reduced every cycle due to worsening renal function. Ultimately, MTX was discontinued after 6 cycles. Brain MRI showed significant response after HD-MTX except for small residue lymphoma at the biopsy area. 2nd line regimen rituximab and temozolomide was given to complete induction. Brain MRI was stable, but the small enhancing residue lymphoma at left peri-ventricle area was persistent after the induction therapy (uCR). Ibrutinib as consolidation therapy began after discussion with the patient. The patient tolerated 560 mg ibrutinib for 6 cycles initially, then switched to a reduced dose of 420 mg for cycles 7 and 8 due to neutropenia. Brain MRIs have been stable with resolution of the small lymphoma residue after 6 cycles of ibrutinib. The patient continues ibrutinib for the goal of one year of consolidation therapy. DISCUSSION Our case highlights the potential of single-agent ibrutinib as consolidation therapy for PCNSL after HD-MTX and rituximab/temzolomide induction therapy.

scholarly journals Varying intensity of postremission therapy in acute myeloid leukemia

Blood ◽  
1992 ◽  
Vol 79 (8) ◽  
pp. 1924-1930 ◽  
Author(s):  
PA Cassileth ◽  
E Lynch ◽  
JD Hines ◽  
MM Oken ◽  
JJ Mazza ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mortality Rate ◽  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Allogeneic Bone ◽  
Consolidation Therapy ◽  
High Dose Cytarabine ◽  
Postremission Therapy ◽  
Acute Myeloid

The Eastern Cooperative Oncology Group (ECOG) conducted a randomized trial in patients less than or equal to 65 years old (median, 44 years) to determine whether increasing the intensity of postremission therapy in acute myeloid leukemia (AML) would improve the outcome. After uniform induction therapy, patients in complete remission (CR) who were less than 41 years old and who had a histocompatible sibling underwent allogeneic bone marrow transplantation (alloBMT) (54 patients). The remainder of patients in CR were randomized to receive either 2 years of continuous outpatient maintenance therapy with cytarabine and 6- thioguanine (83 patients) or a single course of inpatient consolidation therapy consisting of 6 days of high-dose cytarabine plus 3 days of amsacrine (87 patients). The median duration of follow-up is now 4 years, and patients are included in the analyses of outcome regardless of whether they relapsed before starting the intended treatment. Four- year event-free survival (EFS) was 27% +/- 10% for consolidation therapy versus 16% +/- 8% for maintenance therapy (P = .068) and 28% +/- 11% versus 15% +/- 9% (P = .047) in patients less than 60 years old. The outcome for patients receiving alloBMT was compared with the subset of patients less than 41 years old who received consolidation therapy (N = 29) or maintenance therapy (N = 21). Four-year EFS was 42% +/- 13% for alloBMT, 30% +/- 17% for consolidation therapy, and 14% +/- 15% for maintenance therapy. AlloBMT had a significantly better EFS (P = .013) than maintenance therapy, but was not different from consolidation therapy. In patients less than 41 years old, 4-year survival after alloBMT (42% +/- 14%) did not differ from consolidation therapy (43% +/- 18%), but both were significantly better than maintenance therapy (19% +/- 17%), P = .047 and .043, respectively. The mortality rate for maintenance therapy was 0%, consolidation therapy, 21%; and alloBMT, 36%. Consolidation therapy caused an especially high mortality rate in the patients greater than or equal to 60 years old (8 of 14 or 57%). The toxicity of combined high-dose cytarabine and amsacrine is unacceptable, especially in older patients, and alternative approaches to consolidation therapy such as high-dose cytarabine alone need to be tested. In AML, a single course of consolidation therapy or alloBMT after initial CR produces better results than lengthy maintenance therapy. Although EFS and survival of alloBMT and consolidation therapy do not differ significantly, a larger number of patients need to be studied before concluding that they are equivalent.

A Multicenter Phase II Trial of Etoposide, Methylprednisolone, High-Dose Cytarabine, and Oxaliplatin (ESHAOx) for Patients with Refractory/Relapsed Aggressive Non-Hodgkin’s Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3446-3446
Author(s):  
Sun Jin Sym ◽  
Hye Jin Kang ◽  
Seung-Hyun Nam ◽  
Hoyoung Kim ◽  
Seok Jin Kim ◽  
...  
Keyword(s):  
Hodgkin’S Lymphoma ◽  
Single Agent ◽  
Hodgkin's Lymphoma ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Salvage Regimen ◽  
Hematopoietic Stem ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
High Dose Cytarabine

Abstract Etoposide (E), methylprednisolone (S), high-dose cytarabine (HA), and cisplatin (P) (ESHAP) combination is commonly used salvage regimen for non-Hodgkin’s lymphoma (NHL). Oxaliplatin (Ox), a new platinum derivative, showed substantially different cytotoxic activity and adverse effects from both cisplatin and carboplatin. In addition, single-agent oxaliplatin was reportedly active in patients with NHL. We conducted to investigate the efficacy and toxicity of ESHAOx combination, substituting oxaliplatin for cisplatin in ESHAP combination, for relapsed/refractory aggressive NHL patients. Main eligibility criteria included aggressive NHL and failure to achieve a complete remission or recurrent disease after previous chemotherapy. ESHAOx consisted of E, 40 mg/m2 on days 1 to 4; S, 500 mg on days 1 to 5; HA, 2 g/m2 on day 5; and Ox, 130 mg/m2 on day 1, every 3 weeks. Eligible patients were scheduled to receive a maximum of 6 cycles, and high dose chemotherapy and hematopoietic stem cell rescue allowed. Responses were evaluated every 3 cycles. All patients gave written informed consent before study entry. Between May 2006 and January 2007, 27 patients were enrolled. Nineteen (70%) patients with relapsed, 8 patients with refractory, and 10 (37%) patients with IPI 3–5 were included in this study. A total of 102 cycles were administered for a median number of 4 (range 1–6 cycles) per patient. There were 8 (30%) complete responses and 9 (33%) partial responses, producing an overall response rate of 63% (95% CI, 45–81%). Most common grade 3/4 toxicity of the courses was myelosuppression with including neutropenia (55%) and thrombocytopenia (33%). Non-hematologic toxicity was very favorable. No significant renal and neurotoxicity was demonstrated. There was one treatment-related death due to neutropenic sepsis. The results of ESHAOx combination showed highly antitumor activity and favorable toxicity profile, suggesting it can be used as salvage regimen for relapsed/refractory aggressive NHL patients.

Gemtuzumab Ozogamicin-Based Salvage, Followed by Allogeneic Hematopoietic Stem Cell Transplantation, Is Highly Effective in Young Patients with Core Binding Factor (CBF) Acute Myeloid Leukemia (AML) in First Relapse

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2603-2603 ◽  
Author(s):  
Marie-Anne Hospital ◽  
Christian Recher ◽  
Xavier Thomas ◽  
Emmanuelle Tavernier ◽  
Bruno Lioure ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Complete Remission ◽  
Gemtuzumab Ozogamicin ◽  
High Dose ◽  
Intensive Chemotherapy ◽  
Hematopoietic Stem ◽  
High Dose Cytarabine ◽  
First Relapse

Abstract Abstract 2603 Purpose Although CBF-AML (i.e. with t(8;21) or inv(16)/t(16;16)) represents a favorable cytogenetic AML subgroup (Döhner, Blood 2010), 35–45% of these patients still relapse after standard intensive chemotherapy. The immunoconjugate gemtuzumab ozogamicin (GO) was shown to be effective in patients with relapsed AML in non randomized studies and has been recently demonstrated in a Phase 3 trial as associated with a significant benefit in younger adults with CBF-AML (Burnett, JCO 2011). In this study, we thus investigated the impact of GO-based salvage at first relapse in this specific subgroup of patients with CBF-AML. Patients and Methods We retrospectively analysed the medical records of 84 patients aged 60 years or less with CBF-AML in first relapse after intensive chemotherapy and treated in 18 French centers. None of these patients received allogeneic (alloSCT) or autologous (autoSCT) hematopoietic stem cell transplantation in first complete remission (CR). As salvage, 27 patients received GO, combined with high-dose cytarabine in most of them; 21 patients received high-dose cytarabine and anthracycline without GO; 36 patients received conventional chemotherapy based on standard-dose cytarabine and anthracycline. Post-remission therapy was alloSCT in 49 patients, autoSCT in 17 patients, and chemotherapy alone in 11 patients. Results Among 84 patients with a median age of 39 years [16–58], 36 patients had t(8;21) AML and 48 patients had inv(16)/t(16;16) AML. Median CR1 duration was 12.9 months [2.6–55.3]. Second complete remission (CR2) rate was 92% (77/84), and early death rate was 1% (1/84). The median follow up was 4.0 years. The 5-year overall survival (5y-OS) and relapse-free survival (5y-RFS) was 52% [39–64%] and 48% [36–60%] respectively. Patients receiving alloSCT in CR2 had a better outcome (5y-OS, 56% versus 43%; p=0.05). In patients not allografted in CR2, RFS was similar after autoSCT and chemotherapy alone (5y-RFS, 44% versus 47%, respectively). Patients treated with GO had similar CR rate but a lower risk of second relapse and a better survival than other patients (5y-RFS, 89% versus 55%; p=0.05 and 5y-OS, 90% versus 45%; p=0.03). In univariate analysis, other factors associated with a better OS were younger age, longer CR1 duration, but not CBF subtype (p=0.03, 0.01, and 0.20, respectively). In multivariate analysis adjusted on age, CR1 duration, and CBF subtype, GO salvage was still associated with a significant benefit in OS (HR=0.16 [0.04–0.69], p=0.01) and RFS (HR=0.19 [0.04–0.80], p=0.02). With a median post-relapse follow-up of 2.2 years, no relapse nor death were observed in the 19 patients who received GO salvage followed by alloSCT in CR2 (p=0.007 for RFS; p=0.008 for OS). Moreover, in patients who received alloSCT, previous GO therapy significantly improved post-transplantation outcome. Conclusion Younger patients with CBF-AML in first relapse had a high second complete remission rate regardless the intensive chemotherapy salvage. More interestingly, the outcome of these patients was significantly improved by the addition of GO-based salvage, especially when followed by alloSCT. Disclosures: Off Label Use: GO is available in Europe as a compassionate treatment for relapsed AML.

Dose Dense, High Intensity Induction Therapy Followed by Early High Dose Chemotherapy (HDT) and Autologous Hematopoietic Stem Cell Transplantation(AHSCT) for Mantle Cell Lymphoma (MCL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 913-913
Author(s):  
Liang-Piu Koh ◽  
Jon P. Gockerman ◽  
Joseph O. Moore ◽  
Carlos DeCastro ◽  
Gwynn D. Long ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Stem Cell ◽  
Induction Therapy ◽  
High Intensity ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Dose Dense ◽  
The Impact ◽  
Disease Free

Abstract Introduction: Though response may occur with standard therapy, early relapse is common with advanced stage MCL, suggesting the importance of drug resistance in this disease process.It appears that repeated cycles of aggressive chemotherapy to a point of maximum response, followed by HDT and AHSCT, provides improved disease free intervals, though the impact on overall survival (OS) remains uncertain. A concern with this approach is that the eventual high relapse rate seen in most trials may be due to the emergence of drug resistance prior to HDT. In an attempt to circumvent the problem of drug resistance due to multiple cycles of chemotherapy, we designed a dose dense approach using only one cycle of an aggressive induction regimen. Patients demonstrating at least PR and a BM uninvolved by morphology and flow cytometry studies proceeded with chemotherapy-primed PBPC collection, before receiving HDT and AHSCT. Patients and Methods: HIDAC 3 gm/m2 over 1 hour q12 hours for 12 doses in combination with mitoxantrone 12mg/m2 daily for 3 days were given as induction therapy. Responders were mobilised with either VP-16 2 gm/m2 or cyclophosphamide 4 gm/m2 followed by G-CSF 10 mcg/kg daily until stem cell collection. The preparative regimen consisted of BCNU 15mg/kg over 2 hours D-6, VP-16 60mg/kg over 4 hours D-4 and cyclophosphasmide 100mg/kg over 2 hours D-2. Results: Twenty one stage IV patients and 2 stage III patients were enrolled, including 7 with relapsed/refratory disease. Median age was 56 yo(40–74). Nine (39%) patients achieved CR and 11 (48%) patients achieved PR with all showing >80% reduction in tumor size. Three patients died after induction: 1 from sepsis; 2 from disease progression. Seventeen (74%) of the 20 patients with CR or > 50% PR proceeded to PBPC mobilisation whereas 3 were deemed too ill to undergo HDT (2 of these were in CR from induction). A total of 14 (10 previously untreated and 4 had failed prior therapy) eventually had adequate stem cell collected and underwent planned HDT and were fully evaluable for outcome. There was no TRM to HDT and while only 6 patients entered HDT in CR, all 14 patients attained a CR at recovery from transplant. With a median follow-up from study entry for these 14 autotransplant patients of 36 months (17–68), 8 patients are still alive and in CR. The estimated 4 year OS and event free survival (EFS) for these 14 patients were both 64% and the median survival was 57 months.(see figure) Conclusions: The study shows that a dose dense, high intensity approach for advanced MCL provides a very high CR and PR rate. Those who were able to complete this protocol have a high chance of achieving favorable disease free survival. Figure. Figure.

Autologous Stem Cell Collection In Lymphoma and Myeloma Patients: Single Center Analysis With Intention To Successful Mobilization and Collection Under Restricted Permission For Use Of Plerixafor

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5443-5443
Author(s):  
Baris Hasbal ◽  
Hulya Bilgen ◽  
Tulay Ozcelik ◽  
Fehmi Hindilerden ◽  
Serkan Guvenc ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Conflicts Of Interest ◽  
Single Agent ◽  
Previous Treatment ◽  
Autologous Bone Marrow ◽  
Close Correlation ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Cd34 Cells

Abstract High dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation (HSCT) rescue is a potentially curative&consolidative therapy for advanced hematological malignancies, and it also permits the administration of higher doses of chemotherapy to overcome tumor cell resistance. In this study, our aim is to evaluate 167 consecutive myeloma (MM) and lymphoma (ML) patients referred to our center between August 2010 and May 2013. Patients data are analyzed in intent to successful hematopoietic stem cell (HSC) mobilization and collection. In our country we have limited access to plerixafor, as salvage HSC mobilizing agent, permitted only after a failed mobilization&collection trial of chemotherapy and G-CSF. Our center's policy is to collect HSC with G-CSF in all MM (exception of prolonged revlimide use and prior autologous HSCT), and non-heavily pretreated ML patients. Candidates for poor mobilization underwent first CT and G-CSF, and second line receive plerixafor. Under these circumstances 86 lymphoma patients (31 Hodgkin and 55 NHL) and 81 MM patients (F/M: 57/110, med. age 52, range 18-72) were included in this study. Nearly >15% of the patients received more than 2 cycles of chemotherapy before HSC collection. Mobilization with G-CSF as a single agent resulted in optimal CD34+ cell yield for 121 (72%) patients. In myeloma G-CSF as first line resulted with 92.7% successful HSC mobilization and collection. Overall 17 patients received plerixafor as 2nd or 3rd line, and resulted with sufficient HSC collection in 57.3%. In three cases (MM:1, ML:2) additional support with autologous bone marrow collection necessary. Only in 9 (5.3%) patients all attempts for mobilization failed including plerixafor. After any type of mobilization regimen median count for pCD34+ cells obtained was 18/mcl. Median yield of 3.3 x 106/kg CD34+ cells/kg was collected with range of 0.2-33.9x106/kg in total apheresis sessions. MM patients have significant high levels of preapheresis circulating CD34+ count in comparison to ML patients (29 vs 15, p=0.001). pCD34+ cell did not correlate with body mass index, age, underlying disease and previous treatment cycles. There is a close correlation between pCD34+ cell count and collected CD34+ cells in all types of mobilization regimens as G-CSF, chemotherapy and plerixafor (relatively; p<0.001, p=0.002 and p=0.001). Successful ASCT is achieved in 144 patients transplanted so far. Mobilization is achieved in almost all multiple myeloma patients and most of lymphoma patients with only G-CSF based regimen in our cohort. Half of patients not mobilized with G-CSF were successfully mobilized with chemotherapy and plerixafor as second or third line regimen. The restricted use of plerixafor resulted in time and expense for additional chemotherapy and collection attempt, whereas this inconvenience did not impact the success of stem mobilization and collection in our current policy within 3 years. Disclosures: No relevant conflicts of interest to declare.

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