Evaluation of the Regimen Brentuximab Vedotin Plus ESHAP (BRESHAP) in Refractory or Relapsed Hodgkin Lymphoma Patients: Preliminary Results of a Phase I-II Trial from the Spanish Group of Lymphoma and Bone Marrow Transplantation (GELTAMO)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 582-582 ◽  
Author(s):  
Ramon Garcia-Sanz ◽  
Anna Sureda ◽  
Sara Alonso-Alvarez ◽  
Ana Pilar Gonzalez ◽  
Antonia Rodriguez ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase I ◽  
Hodgkin Lymphoma ◽  
Complete Response ◽  
Brentuximab Vedotin ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Pet Ct ◽  
Grade 3 ◽  
Dose Limiting Toxicity

Abstract Introduction: Around 30% of Hodgkin Lymphoma (HL) patients are refractory or relapse (RR) after first line therapy. Salvage chemotherapy followed by high-dose chemotherapy and with Autologous Peripheral Blood Stem Cell Transplantation (APBSCT) can cure many patients, but those who are transplanted with active disease detectable by PET-CT have a very poor prognosis. Therefore, the current challenge in HL is to improve the results of the pre-transplant chemotherapy. Phase 2 single agent trials with Brentuximab Vedotin (BV) in highly RRHL patients have demonstrated overall and complete response rates of 75% and 34%, respectively (Younes, JCO 2012; 30:2183); as 2nd line, BV has provided very promising results in combination with chemotherapy (LaCasce, Blood 2014; 124(21):3099) Objectives: We conducted a phase I/II trial to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and response rate with combined Brentuximab vedotin with ESHAP chemotherapy [BRESHAP] as 2nd line therapy for RRHL prior to APBSCT (ClinicalTrials.gov #NCT02243436). Methods: The primary efficacy endpoint was the proportion of complete responses (CR) pre-APBSCT. It is a phase I-II trial with dose escalation followed by expansion. Treatment consisted of Etoposide (40 mg/m2/day IV, D1-4), Solumedrol (250 mg/day IV, D1-4), High dose AraC (2 g/m2 IV, D5) and cisPlatin (25 mg/m2/day IV, D1-4). BV was administered at three dose levels: 0.9, 1.2 or 1.8 mg/kg IV on day 1 to each cohort of patients, following the scheme of cohorts of 3 patients each, to assess the maximum tolerable dose (MTD). The dose limiting toxicity (DLT) was defined as Grade 4 hematologic toxicity extended over 3 weeks or non-hematologic toxicity grade ≥3 during the first treatment cycle. Patients were evaluated weekly. Results: Patients with relapsed or refractory classical HL (cHL) after one prior line of therapy were eligible. To date, 27 patients have been included in the trial. The first 9 have completed the three courses as scheduled, without TLD doses. Fifteen patients have received the first full cycle, presenting 4 episodes of severe adverse reactions: non-neutropenic fever due to IV AraC and to complicated catheter insertion; one pneumothorax after catheter insertion; and one febrile neutropenia recovered with antibiotic treatment. Grade 4 hematologic toxicity presented in three of these nine patients: 2 neutropenia and thrombocytopenia 1. All nine patients underwent stem cell mobilization after the 1st or the 2nd treatment cycle with subcutaneous G-CSF 5 mcg/Kg days +7 to +14, collecting >2·10e6/Kg peripheral blood CD34+ cells in all cases, with no grade 3-4 toxicity. The number of harvesting procedures was one & two in seven & two patients, respectively. The transplant has been done in 6 patients, with a median of 9 days and 10 days for neutrophil and platelet recovery, respectively. All nine patients had no evidence of disease before the transplant by PET-CT, although one patient had residual FGD uptaking areas without underlying anatomical lesions on CT (metabolic complete response: 89%). Six patients have been evaluated after the APBSCT and they are all in metabolic CR. The phase II of the trial was open on April the 12th 2015, with BV at the recommended dose of 1.8 mg/kg per course. At the submission of this report, there were 28 patients recruited, and 17 evaluated pre-transplant, achieving 16 CR. The complete results will be presented during the meeting; the projected recruitment by the meeting is 45 (65% of the total planned recruitment). Conclusions: BRESHAP is a tolerable treatment scheme as remission induction prior to transplant in patients with refractory or relapsed Hodgkin lymphoma, and it offers very promising results. Disclosures Off Label Use: Brentuximab Vedotin in Resistant or Relapsed Hodgkin Lymphoma patients who are candidates to Autologous Stem Cell Transplant. Sureda:Seattle Genetics Inc.: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau. Caballero:Takeda: Honoraria, Research Funding.

Phase I study of temozolomide in children and adolescents with recurrent solid tumors: a report from the Children's Cancer Group.

1998 ◽  
Vol 16 (9) ◽  
pp. 3037-3043 ◽  
Author(s):  
H S Nicholson ◽  
M Krailo ◽  
M M Ames ◽  
N L Seibel ◽  
J M Reid ◽  
...  
Keyword(s):  
Phase I ◽  
Children And Adolescents ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Cancer Group ◽  
Grade 3 ◽  
Dose Levels ◽  
Dose Limiting Toxicity

PURPOSE The Children's Cancer Group conducted a phase I trial of temozolomide stratified by prior craniospinal irradiation (CSI). PATIENTS AND METHODS Children and adolescents with recurrent or progressive cancer were enrolled. Temozolomide was administered orally daily for 5 days, with subsequent courses administered every 21 to 28 days after full hematologic recovery. Dose levels tested included 100, 150, 180, 215, 245, and 260 mg/m2 daily. RESULTS Twenty-seven patients on the non-CSI stratum were assessable for hematologic toxicity. During the first three dose levels (100, 150, and 180 mg/m2 daily), only grades 1 and 2 hematologic toxicity occurred. One patient at 215 mg/m2 daily had grade 3 hematologic toxicity. Three of eight patients (38%) treated at 245 to 260 mg/m2 daily had dose-limiting toxicity (DLT), which included both neutropenia and thrombocytopenia. Twenty-two patients on the CSI stratum were assessable for hematologic toxicity. Hematologic DLT occurred in one of six patients (17%) at 100 mg/m2 daily and in two of four patients (50%) at 215 mg/m2 daily. No nonhematologic DLT occurred; nausea and vomiting occurred in more than half of the patients. After two courses of temozolomide, 10 patients had stable disease (SD), and three patients had a partial response (PR), one of whom subsequently had a complete response (CR) that persists through 24 months of follow-up. CONCLUSION The maximum-tolerated dose (MTD) of temozolomide for children and adolescents without prior CSI is 215 mg/m2 daily and for those with prior CSI is 180 mg/m2 daily for 5 days, with subsequent courses that begin on day 28. Temozolomide is well tolerated and should undergo phase II testing in children and adolescents.

AMC-085: A Pilot Trial of AVD and Brentuximab Vedotin in the Upfront Treatment of Stage II-IV HIV-Associated Hodgkin Lymphoma. A Trial of the AIDS Malignancy Consortium

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1526-1526 ◽  
Author(s):  
Paul G. Rubinstein ◽  
Page Moore ◽  
David H. Henry ◽  
Lee Ratner ◽  
Elad Sharon ◽  
...  
Keyword(s):  
Phase I ◽  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
The United States ◽  
Brentuximab Vedotin ◽  
Stage Ii ◽  
Mixed Cellularity ◽  
Pet Ct ◽  
Grade 3 ◽  
Post Therapy

Abstract Introduction: Patients (pts) infected with HIV have a 6-8 fold increased risk of classic Hodgkin lymphoma (cHL). Incidence may have increased with the implementation of combined anti-retroviral therapy (cART) in the mid 1990s. Frontline therapy for HIV-associated cHL (HIV-cHL) using, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in the pre-cART era showed a 2 year overall survival (OS) of 48%, but outcomes are currently similar to the non-HIV population. Pts with advanced disease have a 30% chance of relapse with ABVD. Brentuximab vedotin (BV), an anti-CD30 an antibody drug conjugate that selectively induces apoptosis of CD30+ cells with a complete response of 34% in patients with relapsed/refractory cHL. An international trial of BV with doxorubicin, vinblastine, and dacarbazine (AVD) vs. ABVD is ongoing. Here we present the phase I portion of the first trial using BV with AVD in the upfront treatment of HIV-cHL. The Phase II portion is actively accruing in both the United States and France as part of an AIDS Malignancy Consortium (AMC)/Lymphoma Study Association (LYSA) collaboration. Methods: The Phase I was a 3+3 dose de-escalation design evaluating 3 dose levels of BV (1.2 mg/kg, 0.9 mg/kg, and 0.6 mg/kg) every 2 weeks combined with standard, fixed doses of doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2 (AVD) in a 28 day cycle. Eligibility: HIV+ pts diagnosed with untreated cHL stage II-IV with CD4 counts ≥50 cells/mm3 were required to take cART regimens for at least 1 week before treatment. Ritonavir, zidovidine, and cobisistat were excluded. Baseline, cycle 2, and post treatment PET/CT scans were required. Dose limiting toxicities (DLTs) were defined during cycle 1. Results: Sixpts (5 men and 1 woman) were treated in the phase I portion from 3/2013-5/2015. Staging: II (n=1), III (n=1) IV (n=4). Pathology: mixed cellularity (n=2), nodular sclerosis (n=3), and lymphocyte depleted/mixed cellularity (n=1) HIV-cHL. The median CD4 T cell count at lymphoma diagnosis was 499 cells/mm3 (range 86-784) and the median viral load was 44 copies/ml (range 20-77). No cycle 1 DLTs were identified in the first 6 eligible patients and only 3 grade 3 adverse events in later cycles were noted, pneumonia, n=1, and neuropathy n=2, and neutropenia, n=1. In 2 pts, toxicity required delays in therapy of over 3 weeks (after c5d1 and after c6d1) resulting in subject removal from further protocol therapy. One pt had a decrease in the diffusion lung capacity for carbon monoxide (DLCO) to 65% after cycle 2, and BV was withheld while AVD continued as per protocol. Two pts were later deemed ineligible, and excluded from any analysis, due to the concomitant use of ritonavir-based cART at enrollment. Both developed febrile neutropenia and one developed a grade 3 pancreatitis during cycle 1, emphasizing the importance of not treating patients with BV + AVD with concurrent CYP3A4 inhibitors. Five of the 6 pts achieved cycle 2 PET/CT negativity as defined by a Deauville score 1-3. The PET/CT positive patient ultimately had a negative post-therapy scan. The 5 pts who completed therapy achieved CR post-therapy, and one patient has yet to complete treatment. Phase II is enrolling at BV 1.2 mg/kg in combination with AVD. Conclusions: AVD-BV in stage II-IV HIV-cHL was well-tolerated therapy as no DLT were identified. Five of the 6 patients achieved a negative C2 PET/CT and 5/5 of the patients who completed therapy thus far achieved a CR. The recommended Phase II dose is 1.2 mg/kg +AVD every other week. The phase II portion (51 subjects) is actively accruing in both the USA and France, in an AMC/LYSA collaboration, clinicaltrials.gov NCT01771107. Disclosures No relevant conflicts of interest to declare.

A Phase I Study Of Panobinostat In Combination With ICE (Ifosfamide, Carboplatin and Etoposide) In Patients With Relapsed Or Refractory Classical Hodgkin Lymphoma (cHL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 252-252 ◽  
Author(s):  
Yasuhiro Oki ◽  
Michelle A. Fanale ◽  
Jason R. Westin ◽  
Nathan Fowler ◽  
Sattva S. Neelapu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase I ◽  
Research Funding ◽  
Phase I Study ◽  
Complete Response ◽  
Advisory Board ◽  
Hematologic Toxicity ◽  
Scientific Advisory Board ◽  
Scientific Advisory ◽  
Grade 3

Abstract The standard approach to patients with refractory or recurrent cHL is treatment with an effective salvage chemotherapy followed by stem cell transplantation. The best outcome from the transplant is expected in patients who achieve complete response (CR) after the salvage chemotherapy. The commonly used regimen, ICE produces CR rate ranging from 26% (response evaluation by CT, Moskowitz CH et al. Blood 2001) to 61% (by augmented ICE, response evaluation by PET, Moskowitz CH et al. Blood 2012). Panobinostat is a potent oral pan-deacetylase inhibitor that has shown activity against refractory or recurrent cHL after transplant with acceptable toxicity profile with a dose limiting toxicity of reversible thrombocytopenia (Younes A et al. JCO 2012). We conducted a phase I study of oral panobinostat in combination with standard ICE for patients who had recurrent or refractory disease after ABVD based chemotherapy. The treatment consisted of oral panobinostat on Monday/Wednesday/Friday starting from 1 week before first ICE, and to be continued during ICE through the second cycle. Third cycle was administered without panobinostat concerning the potential adverse impact on stem cell collection. The starting dose of panobinostat was 20mg, and the target dose was 30mg based on 3+3 design, with planned expansion at the highest dose. As the time of data cut off (July 2013), a total of 23 patients were registered and 21 were assessable for toxicity and response. The median age of patients were 31 (range 19-60), male/female 14/7 patients, primary refractory disease in 9 patients. At 20mg, dose limiting toxicity (DLT, febrile neutropenia) was observed in one of the 6 patients. At 30mg, 3 patients were enrolled without DLT. Thus, we expanded the cohort at 30mg in two different schedules (A: panobinostat to be started one week before first ICE, then 1st and 2nd week of ICE [n=10], B: panobinostat to be started one week before ICE, then only 1st week of ICE of each cycle [n=2, ongoing]). Overall, there was no grade 3/4 non-hematologic toxicity observed. The common non-hematologic toxicity of grade 1/2 (>10%) was fatigue (43%), nausea (43%), and vomit (29%). Hematologic toxicity included anemia (grade 1/2 in 24%, grade 3 in 5%), neutropenia (grade 1/2 in 5%, grade 3 in 10%, grade 4 in 57%), thrombocytopenia (grade 1/2 in 5%, grade 2 in 10%, grade 4 in 81%) and febrile neutropenia (grade 3 in 10%). All 21 patients were assessed for response and overall response rate was 86%, with complete response rate of 71%. All responding patients (86%) proceeded to autologous stem cell transplant after this regimen. Patients who did not have a stem cell collection after 3rd cycle of ICE received stem cell mobilizing chemotherapy. There were no issues with stem cell harvest and engraftment in any of patients. In conclusion, panobinostat plus ICE is an effective first salvage regimen for recurrent or refractory cHL. We are currently evaluating schedule B, which is with shorter treatment with panobinostat, in an expansion cohort in this phase I study. Disclosures: Oki: Novartis: Research Funding. Fowler:pharmacyclics: Research Funding, Scientific advisory board Other; Jannsen: Scientific advisory board, Scientific advisory board Other; Roche: Honoraria, Research Funding, Scientific advisory board, Scientific advisory board Other; Celgene: Research Funding, Scientific advisory board, Scientific advisory board Other; gillead: Research Funding, Scientific advisory board Other, Scietific advisory board. Younes:Novartis: Research Funding.

The Combination of Brentuximab Vedotin (Bv) and Bendamustine (B) Demonstrates Marked Activity in Heavily Treated Patients with Relapsed or Refractory Hodgkin Lymphoma (HL) and Anaplastic Large T-Cell Lymphoma (ALCL): Results of an International Multi Center Phase I/II Experience

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 586-586 ◽  
Author(s):  
Ahmed Sawas ◽  
Joseph M. Connors ◽  
John G. Kuruvilla ◽  
Celeste Rojas ◽  
Renee Lichtenstein ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Complete Response ◽  
Brentuximab Vedotin ◽  
Dose Cohort ◽  
Genetics Research ◽  
Grade 3

Abstract Introduction Patients with HL or ALCL who have relapsed post or are ineligible for autologous stem cell transplant (ASCT) remain incurable with standard therapies. The CD30 immunoconjugate Brentuximab vedotin has become the preferred treatment for such patients. Bendamustine has also demonstrated good activity and tolerability in several lymphoma subtypes including HL. This ongoing phase I/II study was designed to evaluate the safety and efficacy of the combination of brentuximab vedotin with bendamustine for the treatment of patients with relapsed or refractory HL or ALCL. We provide the phase I and II data. (ClinicalTrials.gov #NCT01657331). Methods Patients received an outpatient IV infusion of brentuximab vedotin on Day 1 with bendamustine on Days 1 and 2 of a 3-week cycle for up to 6 cycles. In the Phase 1 portion 4 dose levels were evaluated: (1) Bv = 1.2mg/kg; B = 70mg/m2; (2) Bv = 1.2mg/kg; B = 80mg/m2; (3) Bv = 1.8mg/kg; B = 80mg/m2; and (4) Bv = 1.8mg/kg; B = 90. Accrual followed a classic Fibonacci dose escalation, with 3 patients being treated at each dose level. Dose Limiting Toxicity (DLT), defined as any CTC version 4 Grade 3 or 4 toxicity led to expansion of the dose cohort. The recommended phase II dose was Bv 1.8 mg/kg on Day 1 and B 90 mg/m2 on Days 1 and 2. Response was assessed by the investigator per Cheson 2007 after cycles 2 and 6. Enrollment is ongoing of the Phase 2 portion of the study, where an additional 24 patients will be accrued. In addition, plasma and serum biomarkers are being prospectively collected for correlation with toxicity and response. Results Forty-two patients (55% male) with a median age of 37 years (range, 30-70) were enrolled. Forty-one patients had HL and 1 ALCL; the median number of prior systemic therapies was 5 (range 1-16); with 26 patients having had prior ASCT and 14 patients receiving prior radiation therapy. The predominant all grade toxicity observed with the combination was nausea (62%, grade 1-2). The observed grade 3-4 toxicities in the phase I were: neutropenia (19%), thrombocytopenia (19%), anemia (15%) and rash (11%). The observed phase II grade 3-4 toxicities were neutropenia (14%) and pneumonia (14%). No DLT was observed at dose level 4 (Bv 1.8 mg/m2 and B 90 mg/m2). The maximum tolerated dose (MTD) was not reached. A decision was made not to explore further doses that exceeded the standard single agent doses of both drugs. Patient's received a median of 6 cycles (range, 1-6). To date, 36/39 patients are evaluable for response. The overall response rate was 67%, with 7 patients (19%) attaining a complete response (CR). Eight patients had stable disease. Among the 11 patients who received prior Bv, 6 responded (55%) (CR= 2, PR=4, SD=3, PD=2), and of the 4 patients who had prior B, 2 responded (50%) (PR=2, SD=1, PD=1). Two patients had received both Bv and B as single agents prior to initiation of study; one patient achieved a PR and the other experienced PD. The ALCL patient achieved a PR. Conclusion In this heavily treated population of HL and ALCL, the combination of brentuximab vedotin 1.8 mg/kg on Day 1 with bendamustine 90 mg/m2 on Days 1 and 2 of 3-week cycles represents a very effective and tolerable outpatient regimen. The regimen has an ORR of 67% with responses ≥ 50% in patients who had received either agent separately supporting the potential clinical synergy of the combination. Table. Dose Cohort No. Patients Responses Complete Response Dose Cohort 1Bv = 1.2 mg/kg B = 70 mg/m2 7 4 1 Dose Cohort 2Bv = 1.2 mg/kg B = 80 mg/m2 3 3 0 Dose Cohort 3Bv = 1.8 mg/kg B = 80 mg/m2 7 5 1 Dose Cohort 4Bv = 1.8 mg/kg B = 90 mg/m2 11 5 1 Phase IIBv = 1.8 mg/kg B = 90 mg/m2 11 7 4 Total 39 (36 evaluable) 24 (67%) 7 (19%) Disclosures Sawas: Seattle Genetics: Research Funding; Gilead Sciences: Honoraria. Off Label Use: Bendamustine is not approved for the treatment of Hodgkin lymphoma or anaplastic large T- cell lymphoma. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Kuruvilla:Karyopharm: Honoraria, Research Funding; Roche Canada: Honoraria; Seattle Genetics: Honoraria, Research Funding. Neylon:Genentech: Speakers Bureau; Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau; Gilead: Speakers Bureau. Deng:TG Therapeutics, Inc.: Honoraria, Research Funding; Seattle Genetics: Research Funding. Amengual:Acetylon Pharmaceuticals, INC: Consultancy, Research Funding. Villa:Roche: Research Funding. Crump:Sanofi: Honoraria; Celgene: Honoraria; Seattle Genetics: Honoraria. O'Connor:Spectrum: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding; Seattle Genetics: Research Funding.

A phase I-II study to assess the safety, pharmacokinetics, and potential efficacy of intravenous SB-743921 on days 1 and 15 of a 28-day cycle in patients with non-Hodgkin lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18516-18516
Author(s):  
A. Goy ◽  
T. Feldman ◽  
M. Dessanti ◽  
J. Hainsworth ◽  
C. Weaver ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Phase I ◽  
Mitotic Spindle ◽  
Cell Cycle Progression ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Grade 3 ◽  
Dose Limiting Toxicity

18516 Background: Kinesin spindle protein (KSP) is required for mitotic spindle bipolarity and cell cycle progression. SB-743921 (SB- 921), a selective KSP inhibitor, blocks mitotic spindle assembly, causing cell cycle arrest in mitosis and subsequent cell death. Neutropenia was the dose-limiting toxicity (DLT) in the first-in-humans study of SB-921 given Q21 days. Methods: Cohort 1 of the Phase I portion of a study determining the safety, pharmacokinetics and MTD of SB-921 without prophylactic GCSF in patients (pts) with Non-Hodgkin’s Lymphoma (NHL) or Hodgkin’s Disease is reported. Pts with relapsed or refractory disease were eligible if they had received at least one prior chemotherapy regimen, had failed high-dose therapy with autologous stem cell transplant (ASCT), or were not candidates for ASCT. SB-921 is given to dose-escalating cohorts of 3 pts as a 1 hr IV infusion, Q14 days. Dosing began at 2 mg/m2 and escalated in 1 mg/m2 increments after 3 pts tolerated 1 cycle. Pts without dose-limiting toxicity (DLT) not completing Cycle 1 are replaced. Cohort expansion to 6 pts occurs if 1/3 pts experiences DLT, defined as any drug-related toxicity = grade 3 or drug-related grade 4 hematologic toxicity. Results: Cohort 1 (2 mg/m2) enrolled 6 NHL pts (5 indolent, 1 aggressive). 4 were female; median age = 59 (52–73); 5 Caucasian, 1 African-American; median no. of cycles = 2 (1–6). 5/6 pts were evaluable; 1 dropped out before dosing. The most common Grade 1–2 AEs, in decreasing order, were fatigue, dysgeusia, paresthesia, leukopenia, and diarrhea. Grade 3 AEs of note were 1 each of hemolytic anemia, leukopenia, thrombocytopenia and dyspnea; 1 Grade 4 anemia was reported. Conclusions: SB-921 was well tolerated without prophylactic GCSF in Cohort 1 of the Phase I portion of this study, which continues to dose-escalate. If neutropenia is the DLT, dose escalation will continue with prophylactic GCSF. No significant financial relationships to disclose.

scholarly journals Brentuximab Vedotin Plus ESHAP (BRESHAP) Is a Highly Effective Combination for Inducing Remission in Refractory and Relapsed Hodgkin Lymphoma Patients Prior to Autologous Stem Cell Transplant: A Trial of the Spanish Group of Lymphoma and Bone Marrow Transplantation (GELTAMO)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1109-1109 ◽  
Author(s):  
Ramon Garcia-Sanz ◽  
Anna Sureda ◽  
Ana Pilar Gonzalez ◽  
Fatima De la Cruz ◽  
Blanca Sanchez-Gonzalez ◽  
...  
Keyword(s):  
Stem Cell ◽  
Adverse Events ◽  
Hodgkin Lymphoma ◽  
Abdominal Sepsis ◽  
Brentuximab Vedotin ◽  
High Dose ◽  
Line Therapy ◽  
Grade 3 ◽  
One Year

Abstract Introduction: 30% of Hodgkin Lymphoma (HL) patients are refractory or relapse (RR) after first line therapy. Salvage chemotherapy followed by high-dose chemotherapy and with Autologous Peripheral Blood Stem Cell Transplantation (APBSCT) can cure many patients, but those who are transplanted with active disease detectable by PET-CT have a very poor prognosis. Therefore, the current challenge in HL is to improve the results of the pre-transplant chemotherapy. We and others have demonstrated that the addition of Brentuximab Vedotin (BV) to chemotherapy can produce very good results. Objectives: We conducted a phase II trial to assess response rate with combined Brentuximab vedotin and ESHAP chemotherapy [BRESHAP] as 2nd line therapy for RRHL prior to APBSCT (ClinicalTrials.gov #NCT02243436). Methods: Primary efficacy endpoint was the proportion of complete responses (CR) pre-APBSCT. A prior phase I step was carried out to establish the appropriate dosis. Final treatment consisted of Brentuximab Vedotin (1.8 mg/m2/day IV, D1), Etoposide (40 mg/m2/day IV, D1-4), Solumedrol (250 mg/day IV, D1-4), High dose AraC (2 g/m2 IV, D5) and cisPlatin (25 mg/m2/day IV, D1-4). Results: Patients with relapsed or refractory classical HL (cHL) after one prior line of therapy were eligible. 66 patients were included in the trial. There were 35 females and 31 males, with a median age of 36 years (18-66). At inclusion, 40 patients were considered primary refractory, 16 as early relapses (complete remission -CR- shorter than 1 year) and 10 as late relapses. Currently, all patients have completed the pre-transplant therapy. During that period, there were 22 Severe Adverse Events (SAEs) reported in 15 patients: Fever in 13 occasions (neutropenic in seven, and non-neutropenic in six), hypomagnesemia and gastrointestinal alterations (n=2) and pneumothorax, skin lesions, left ventricular function reduction and pulmonary embolism [PE](n=1). There were 2 deaths: non-neutropenic abdominal sepsis and PE. Grade 3-4 hematologic toxicity presented in 22 cases: neutropenia (n=18), thrombocytopenia (n=12), and anemia (n=5). Grade 3-4 extrahematologic adverse events present in ≥5% of cases were non-neutropenic fever (n=8) and hypomagnesemia (n=3). All patients except three underwent stem cell mobilization after the 1st (n=15), 2nd (n=36) or 3rd (n=12) cycle using subcutaneous G-CSF 5 mcg/Kg/12 h. for 5 days. All patients collected >2·10e6/Kg peripheral blood CD34+ cells in all cases (median 5.75, range 2.12-33.4). The number of harvesting procedures was one in 47 patients, two in 13, three in 2 and four in 1. The transplant has been done in 61 patients, with data are available from 47: all engrafted with a median of 9&10 days for neutrophil and platelet recovery, respectively. No major events were registered during transplant period, except for one patient who died at day +110 due to pneumonia. Overall pre-transplant response was 96%, including a 70% and 26% complete and partial remission rates, respectively. Of these forty-seven patients, 37 (80%) were in metabolic CR after transplant and 3 (7%) in PR; six patients were considered as non-responders (13%) and went out of the trial. At a mean follow-up of 11 months, 7 patients have progressed, rendering a projected progression free survival of 87% at one year. Six patients have already died: three due to progression, and the three already mentioned above (PE, abdominal sepsis and pneumonia). With a mean follow-up of 11 months, the projected overall survival was 90% at one year (cause specific, 96%). Conclusions: BRESHAP is a highly effective regimen for remission induction prior to transplant in patients with refractory or relapsed Hodgkin lymphoma. The addition of BV to the conventional chemotherapy did not resulted in a higher toxicity for the pre- and post-transplant periods and it did not hamper the collection of PBSC. Disclosures No relevant conflicts of interest to declare.

Phase I study of repeated cycles of high-dose cyclophosphamide, etoposide, and cisplatin administered without bone marrow transplantation.

1990 ◽  
Vol 8 (10) ◽  
pp. 1728-1738 ◽  
Author(s):  
J A Neidhart ◽  
W Kohler ◽  
C Stidley ◽  
A Mangalik ◽  
A Plauche ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Performance Status ◽  
Complete Response ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Tumor Type ◽  
Advanced Malignancy ◽  
Prior Therapy ◽  
And Performance

Forty-two patients with advanced malignancy judged unlikely to respond to standard treatment received high-dose combination chemotherapy with cyclophosphamide, etoposide, and cisplatin in a phase I trial. Twenty-two of these patients who had at least a partial response (PR) to the first cycle of therapy received a second cycle, and eight patients received three or more cycles of therapy. Bone marrow replacement was not used. The maximum-tolerated doses (MTDs) were cyclophosphamide 2.5 g/m2 on days 1 and 2; etoposide 500 mg/m2 on days 1, 2, and 3; and cisplatin 50 mg/m2 on days 1, 2, and 3. Hematologic toxicity was not dose-limiting by study design. Recovery to an absolute granulocyte count above 100/microL occurred at a median of 9 days from onset (range, 3 to 23 days) at the MTD. Recovery was delayed after the third cycle. Only one patient on his third cycle failed to recover peripheral blood counts and died of sepsis an day 43. Hematologic toxicity was not dose-dependent. Nonhematologic toxicities included emesis, fatigue, alopecia, diarrhea, and anorexia and were generally well tolerated. The dose-limiting toxicities were fatal pulmonary or cardiac toxicities in five of nine patients treated at the highest dose level. Patients likely to do well can be selected by tumor type, response to prior therapy, and performance status. Nine of 36 assessable patients had a complete response (CR) and 13 a PR for a response rate of 61%. Five patients (12%) remain alive and free of disease at 15 to 32 months. Repeated cycles of dose-intensive combination therapy can produce long-term disease-free remissions in patients with refractory tumor types. The toxicity of the regimen is acceptable if patients are carefully selected.

A Pilot Study of Acalabrutinib with Bendamustine/Rituximab Followed By Cytarabine/Rituximab (R-ABC) for Untreated Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
Daniel Guy ◽  
Marcus Watkins ◽  
Fei Wan ◽  
Nancy L. Bartlett ◽  
Amanda F Cashen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Complete Response ◽  
High Dose ◽  
Advisory Committees ◽  
Mantle Cell ◽  
Grade 3 ◽  
Stem Cell Collection

Introduction The management of younger fit patients with mantle cell lymphoma (MCL) varies widely with no consensus on an optimal induction therapy. To date, the treatments with the longest progression-free survival incorporate a chemotherapy backbone that includes high dose cytarabine, followed by consolidation with an autologous stem-cell transplantation (ASCT) (Hermine et al. Lancet 2016, Eskelund et al. Br J Haematol 2016). Recent data showed that a regimen of bendamustine/rituximab followed by cytarabine/rituximab achieved high complete response rates with high minimal residual disease (MRD) negativity (Merryman RW et al. Blood Adv 2020). We hypothesized that adding the Bruton tyrosine kinase inhibitor acalabrutinib to the same chemotherapeutic backbone would be safe and increase complete response rates as well as minimal residual disease (MRD) negativity pre-transplant, and potentially improve clinical outcomes. Methods We conducted a single arm, single institution pilot study registered at clinicaltrials.gov (NCT03623373). Patients with untreated MCL, who were between ages 18-70 and were candidates for ASCT, were eligible. Patients received six 28-day cycles of treatment. Cycles 1-3 consisted of bendamustine 90 mg/m2 on days 1 and 2, rituximab 375 mg/m2 on day 1 and acalabrutinib 100mg BID on days 1 through 28. Cycles 4-6 consisted of rituximab 375 mg/m2 on day 1, cytarabine 2 g/m2 (1.5 g/m2 if age>60) q12 hours on days 1 and 2, and acalabrutinib 100mg BID on days 1 through 7 and 22 through 28. Restaging PET/CT and response assessment based on the Lugano classification were obtained following cycles 3 and 6. After cycle 6 patients underwent leukapheresis and stem-cell collection as preparation for ASCT. Blood for MRD status was collected after cycles 2, 4 and 6 and will be evaluated using the ClonoSeq assay (Adaptive Biotechnologies). The primary objective was to determine the stem cell mobilization success rate. Secondary objectives included safety and tolerability, overall response rate (ORR), pre-transplant complete response rate (CR), and the MRD negativity rate during and after completion of therapy. Results The trial enrolled 14 patients from December 2018 to February 2020. One patient withdrew consent prior to start of treatment and another was found to have an undiagnosed adenocarcinoma shortly after starting MCL treatment. Both are excluded from the analysis. The median age was 57 years (range 52-66). 11 patients were males (92%), all patients had an ECOG performance status of 0-1. 11 patients (92%) presented with stage IV disease. The mean MCL International Prognostic Index (MIPI) score was 6.3 (25% high-risk, 42% intermediate-risk and 33% low-risk). Of the 12 patients who began treatment, 9 completed all 6 cycles. Three patients did not complete therapy due to: insurance issues (n = 1), and thrombocytopenia (n = 2) following cycle 5 and 4. The side effect profile showed expected hematologic toxicities with grade 3-4 cytopenias in all patients, mostly during cytarabine cycles. In total, 100% of patients developed grade 3-4 thrombocytopenia and 83% of patients developed grade 3-4 neutropenia. Three episodes of febrile neutropenia were observed. One patient had a grade 3 transaminase increase, and one patient had grade 3 diarrhea. No bleeding events or treatment related deaths occurred. The remainder of the side effects were low grade and the treatment was generally well tolerated. Of the 12 evaluable patients, 10 responded (ORR 83%) with 9 achieving CR (75%). One patient achieved PR prior to being removed from the study due to thrombocytopenia and then achieved CR off study. Two patients experienced PD during induction. With a median follow up of 9 months, no responding patients have relapsed. The median CD34+ stem cell collection was 3.84x106 cells/kg (range 2.77 - 5.9). MRD results will be presented at the meeting. Conclusions This is the first study attempting to combine BTK inhibition with a high dose cytarabine containing regimen. The addition of acalabrutinib to a regimen of bendamustine/rituximab followed by cytarabine/rituximab appears to be safe. The R-ABC combination will be further tested in the recently activated intergroup trial EA4181. Disclosures Bartlett: Autolus: Research Funding; BMS/Celgene: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BTG: Consultancy; Acerta: Consultancy; Affimed Therapeutics: Research Funding; ADC Therapeutics: Consultancy. Fehniger:ImmunityBio: Research Funding; HCW Biologics: Research Funding; Kiadis: Consultancy; Nkarta: Consultancy; Indapta: Consultancy; Wugen: Consultancy; Orca Biosystems: Consultancy; Compass Therapeutics: Research Funding. Ghobadi:Amgen: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; EUSA: Consultancy; WuGen: Consultancy. Mehta-Shah:Bristol Myers-Squibb: Research Funding; C4 Therapeutics: Consultancy; Celgene: Research Funding; Genetech/Roche: Research Funding; Innate Pharmaceuticals: Research Funding; Kyowa Hakko Kirin: Consultancy; Verastem: Research Funding; Karyopharm Therapeutics: Consultancy; Corvus: Research Funding. Kahl:Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy.

A Prospective, Randomized, Phase III Study of Melphalan 200 mg/m2 (MEL200) Versus Melphalan 100 mg/m2 (MEL100) in Newly Diagnosed Myeloma Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 55-55 ◽  
Author(s):  
Antonio Palumbo ◽  
Sara Bringhen ◽  
Maria Teresa Petrucci ◽  
Antonietta Falcone ◽  
Anna Marina Liberati ◽  
...  
Keyword(s):  
Stem Cell ◽  
Adverse Events ◽  
Response Rate ◽  
Complete Response Rate ◽  
Complete Response ◽  
Phase Iii ◽  
Psychiatric Disease ◽  
High Dose ◽  
Free Survival ◽  
Grade 3

Abstract Several trials have shown the superior impact of high-dose melphalan (usually 200 mg/m2, MEL200) versus standard therapy in myeloma patients. Intermediate-dose melphalan (100 mg/m2, MEL100) was also superior to the standard dose, but MEL100 has not been clinically compared with MEL200 in a randomized study. In a case-matched study, response rate and event-free survival of MEL200 were superior to MEL100, but overall survival (OS) was similar. In this prospective, randomized, phase III trial, we compared the efficacy and toxicity of MEL200 and MEL100. Between January 2002 and July 2006, 299 patients were enrolled. Inclusion criteria were previously untreated myeloma, aged < 65 and Durie and Salmon stage II or III. Exclusion criteria were abnormal cardiac function, respiratory disease, abnormal liver function, abnormal renal function, HBV, HCV, or HIV positivity, concomitant cancer or psychiatric disease. The institutional review board approved the protocol and written informed consent was obtained from all patients. All patients received: 2 dexamethasone-doxorubicin-vincristine debulking courses (doxorubicin 50 mg/m2 day 1, vincristine 1 mg day 1, dexamethasone 40 mg days 1, 2, 3, 4, each course repeated every 28 days), 2 cycles of cyclophosphamide (4 g/m2, day 1) plus G-CSF followed by stem cell harvest. The MEL200 group was conditioned with 2 cycles of melphalan 200 mg/m2 followed by stem cell reinfusion; the MEL100 group was conditioned with 2 courses of melphalan 100 mg/m2 followed by stem cell reinfusion. At the present, 246 patients, median age 57 (range 32–65), completed the assigned therapy and were evaluated for response, progression-free survival (PFS) and OS. One-hundred and twenty-four patients were randomized to MEL200 and 122 to MEL100. Patient characteristics were similar in both groups. Abnormal cytogenetics (13q deletion, t(4;14), t(11;14), p53) were 75% in MEL200 patients and 56% in MEL100 patients (p=0.05). Forty-six patients did not complete tandem MEL200; 36 patients did not complete tandem MEL100. The near complete response rate of MEL200 was superior to MEL100 (32% versus 18%, p=0.011), but partial response was 80% versus 71%, respectively (p=0.079). The median follow-up for censored patients was 26.5 months. The 3 years PFS was 51% in the MEL200 arm and 33% in the MEL100 arm (HR=0.81, 95% CI 0.55–1.21, p=0.31). The 3 years OS was 86% in the MEL200 group and 71% in the MEL100 group (HR=0.82, 95 CI 0.45–1.48, p=0.51). Duration of grade 4 neutropenia and thrombocytopenia was comparable in two arms, but MEL200 patients required more platelet transfusions (p=0.03). Grade 3–4 non-hematological adverse events were reported in 49% of the MEL200 patients and in 38% of the MEL100 patients (P=0.07). The most frequent grade 3–4 adverse events were infections (54% of MEL200 patients versus 45% of MEL100 patients, p=0.25), mucositis (31% of MEL200 patients versus 7% of MEL100 patients, p=0.002) and gastrointestinal toxicities (20% of MEL200 patients versus 14% of MEL100 patients, p=0.3). In conclusion, MEL200 resulted in a significantly higher near complete response rate but this did not translate in a superior PFS and OS.

A Phase I Study Of Myeloablative Radioimmunotherapy Using Iodine-131 Anti-CD45 Antibody Followed By Autologous Stem Cell Transplantation For High-Risk B-Cell and T-Cell Non-Hodgkin Lymphoma and Hodgkin Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3333-3333 ◽  
Author(s):  
Ryan D. Cassaday ◽  
Oliver W. Press ◽  
John M. Pagel ◽  
Joseph G. Rajendran ◽  
Theodore A. Gooley ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
High Risk ◽  
Phase I ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Absorbed Dose ◽  
High Dose ◽  
Normal Organ

Abstract Background High-dose therapy and autologous stem cell transplant (ASCT) remains the standard of care for many high-risk/relapsed B-cell non-Hodgkin lymphomas (B-NHL), T-cell NHL (T-NHL) and classical Hodgkin lymphoma (HL), yet most will not achieve sustained remissions. High-dose anti-CD20 radioimmunotherapy (RIT) and ASCT has been successfully employed to address this challenge in B-NHL, yet relapse still occurs potentially due to blockade of target sites by circulating rituximab (R). RIT options are limited for patients with T-NHL and HL. Preclinical data indicate that targeting the panhematopoietic antigen CD45 with RIT can successfully circumvent R blocking in B-NHL and target a variety of T-NHL histologies (Gopal, 2008 & 2009). We thus performed a phase I trial using high-dose anti-CD45 RIT and ASCT for B-NHL, T-NHL, and HL. Methods Patients were ≥18 years old with relapsed, refractory, or high-risk B-NHL, T-NHL, or HL and had acceptable organ function with an ECOG performance status of 0-1 and no detectible human anti-mouse antibodies. They could not have received ≥20 Gy of prior radiation (RT) to critical organs or prior ASCT within 1 year, or prior allogeneic transplant at any time. All patients first received anti-CD45 antibody (BC8) trace-labeled with 131I followed by gamma camera imaging to evaluate biodistribution and estimate organ-specific absorbed doses. Patients then received 131I-BC8 at an absorbed dose determined by the following: Patients with prior RT >20 Gy or prior ASCT started at 10 Gy to the dose-limiting normal organ (Arm A), while others started dose escalation at 20 Gy (Arm B). Subsequent dose escalation/de-escalation followed a two-stage approach (Storer, 2001). ASCT occurred after sufficient radiation decay, and G-CSF was started on day 1. Dose limiting toxicity (DLT) was determined by Bearman grade III/IV events. The primary objective was to estimate the maximum tolerated dose, defined as that yielding a DLT rate of 25%. Responses were scored using standard criteria (Cheson, 2007). Results Between August 2009 and March 2013, 15 patients were treated. Median age was 62 years (range 20-71); stage III/IV = 11 (73%); median prior regimens = 3 (range 2-12), including 1 prior ASCT; chemorefractory disease (i.e., <PR to the most recent chemotherapy) = 8 (53%); histologies were HL (n = 6), B-NHL (n = 6), and T-NHL (n = 3; see Table). The mean administered 131I activity was 646 mCi (range 344-1064 mCi; 23.9 GBq, range 12.7-39.4 GBq). The liver was the dose-limiting normal organ in 12 patients (2.41-3.98 cGy/mCi). The absorbed dose was escalated to 14 Gy for patients in Arm A (n = 3) and 30 Gy in Arm B (n = 12). Neutrophil (>500/μl) and platelet (>20 K/μl) engraftment occurred a median of 8 (range 10-20) and 12 (range 8-26) days after ASCT, respectively. No DLTs, non-relapse deaths, or non-hematologic toxicities > NCI-CTCAE v3 grade 3 have been observed. Currently, 11 (73%) patients are alive and 7 (47%) are progression-free with a median follow-up of 12 months. Seven (54%) of 13 patients with measurable disease at enrollment had objective disease responses, including 3 of 3 with T-NHL, 3 of 6 with HL, and 1 of 1 with follicular lymphoma (FL; see Table). Conclusion Myeloablative doses of 131I targeted to CD45 are safe and feasible in patients with lymphoma, with no DLTs observed after delivery of up to 30 Gy to the liver. Objective disease responses in heavily-treated B-NHL, T-NHL, and HL were observed. This work has led to current studies using yttrium-90 as the therapeutic radionuclide (given its longer beta pathlength and absence of gamma emission) in anti-CD45 RIT for lymphoma. Disclosures: No relevant conflicts of interest to declare.

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