High Response Rate to Lenalidomide in Relapsed/Refractory Aggressive Non-Hodgkin’s Lymphoma with Prior Stem Cell Transplant.

Abstract Background: High dose chemotherapy with stem cell transplant is currently employed in relapsed/refractory aggressive Non-Hodgkin’s Lymphoma (NHL). Lenalidomide (Revlimid®), an immunomodulatory drug, has shown activity in hematological malignancies including relapsed/refractory multiple myeloma, chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Aim: To determine the activity and safety of lenalidomide monotherapy in relapsed/refractory aggressive NHL following stem cell transplant (SCT). Methods: Patients with relapsed/refractory aggressive NHL with measurable disease ≥ 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: Fourteen (29%) of the 49 patients enrolled into the study had a prior SCT. Median age was 61 (23–76) and 5 were female. Histology was diffuse large B-cell lymphoma [DLBCL] (n=5), follicular center lymphoma grade 3 [FL] (n=2), mantle cell lymphoma [MCL] (n=5) and transformed [TSF] (n=2). Median time from diagnosis to lenalidomide was 3.9 (1.1–31.4) years and median time from SCT to study entry was 1.9 (0.5–11.7) years. The median number of prior treatment regimens was 5 (2–8). Seven patients (50%) exhibited an objective response (1 complete response unconfirmed (CRu), and 6 partial responses (PR)), 5 had stable disease (SD) and 2 patients had progressive disease (PD). Six responses were in eight patients having a tumor burden < 50 cm2 and a time since last rituximab therapy of ≥ 230 days. One response was achieved in six patients having a tumor burden ≥ 50 cm2 or a time since last rituximab therapy of < 230 days. Four of 6 (67%) patients who had SCT as their last treatment prior to lenalidomide [median time from SCT to lenalidomide = 0.8 (0.5–4.8) years] responded. Progression free survival [PFS] is 4.5 months and ongoing. Six patients (43%) required at least one dose reduction with a median time to first dose reduction of 1.6 months (0.4–4.9). Two patients each (14%) had Grade 4 adverse events of neutropenia and thrombocytopenia. The most common Grade 3 adverse events were neutropenia (36%), thrombocytopenia (21%), and leukopenia (14%). Conclusion: Lenalidomide produced a 50% response rate with manageable side effects in relapsed/refractory aggressive NHL following stem cell transplant.

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Lenalidomide Oral Monotherapy Produces a 53% Response Rate in Patients with Relapsed/Refractory Mantle-Cell Non-Hodgkin’s Lymphoma.

Blood ◽

10.1182/blood.v110.11.2563.2563 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2563-2563 ◽

Cited By ~ 4

Author(s):

Joseph M. Tuscano ◽

Izidore S. Lossos ◽

Glen Justice ◽

Julie M. Vose ◽

Kenichi Takeshita ◽

...

Keyword(s):

Adverse Events ◽

Dose Reduction ◽

Median Time ◽

Response Rate ◽

Cell Lymphoma ◽

Progression Free Survival ◽

Complete Response ◽

Tumor Burden ◽

Free Survival ◽

Mantle Cell

Abstract Background: Mantle cell lymphoma (MCL) is a distinct type of non-Hodgkin’s Lymphoma characterized by being incurable with a low response rate and short progression free survival when treated with conventional chemotherapy agents. Lenalidomide (Revlimid®), an immunomodulatory drug, is approved for the treatment of relapsed/refractory multiple myeloma and myelodysplastic syndromes associated with a del(q5) cytogenetic abnormality. Lenalidomide has also shown activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Aim: To determine the activity and safety of lenalidomide in relapsed/refractory MCL. Methods: Patients with relapsed/refractory MCL and measurable disease ≥ 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: Fifteen patients with MCL were enrolled. Median age was 67 (45–84) and 7 were female. Median time from diagnosis to lenalidomide was 5.1 (0.7–12.7) years and median number of prior treatment regimens was 4 (2–6). Eight patients (53%) exhibited an objective response (1 complete response (CR), 1 complete response unconfirmed (CRu) and 6 partial responses (PR)), 2 had stable disease (SD) and 5 had progressive disease (PD). All eight responses were in eleven patients having a tumor burden < 50 cm2 and a time since last rituximab therapy of ≥ 230 days. No responses were achieved in four patients having a tumor burden ≥ 50 cm2 or a time since last rituximab therapy of < 230 days. Four of 5 patients (80%) with a prior stem cell transplant responded. Progression free survival [PFS] is 5.7 months and ongoing. Seven patients (47%) required at least one dose reduction with a median time to first dose reduction of 2.3 months (1.2–4.9). Grade 4 adverse events were neutropenia (13%), thrombocytopenia (13%), and thromboembolism (13%). Most common Grade 3 adverse events were neutropenia (33%) and leukopenia (20%). Conclusion: Lenalidomide oral monotherapy produced a 53% response rate in relapsed/refractory MCL with manageable side effects.

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A Phase II Study of Sepantronium Bromide (YM155) Plus Rituximab in Previously Treated Subjects with Aggressive CD20-Positive B Cell Non-Hodgkin's Lymphoma Who Are Ineligible for or Have Previously Received an Autologous Stem Cell Transplant - Stage I Results.

Blood ◽

10.1182/blood.v120.21.2731.2731 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2731-2731 ◽

Cited By ~ 2

Author(s):

Kyriakos P Papadopoulos ◽

Scott E. Smith ◽

Joyce Steinberg ◽

Renelle Papa ◽

Javier Lopez-Jimenez ◽

...

Keyword(s):

Stem Cell ◽

Adverse Events ◽

B Cell ◽

Overall Response Rate ◽

Stem Cell Transplant ◽

Response Rate ◽

Median Number ◽

Autologous Stem Cell Transplant ◽

Stage I ◽

Cell Transplant

Abstract Abstract 2731 Background: Survivin is responsible for preservation of cell viability and regulation of mitosis in tumor cells. Survivin is overexpressed in the majority of aggressive B-cell lymphomas and thus is an attractive target in subjects with relapsed lymphoma. YM155 is a survivin suppressant that in vitro, when combined with rituximab, synergistically enhances the induction of apoptosis in lymphoma cells. In human DLBCL xenograft models, this combination significantly inhibits tumor growth and prolongs survival. Based on these preclinical combination data and single agent clinical data, a Phase 2 study utilizing YM155 rituximab was initiated. Methods: The study employs a two-stage group sequential method, designed to enroll a total of 40 subjects with an interim futility assessment (Stage I). Eligible patients have histologically confirmed relapsed CD20-positive primary or transformed diffuse large B cell lymphoma (DLBCL) or grade 3 follicular lymphoma (FL) and are either not candidates or previously had an autologous stem cell transplant (ASCT). Subjects had received ≥ 1 prior anthracycline containing regimen with a documented response to the last regimen prior to study entry. Induction, ASCT and maintenance therapy were considered as one regimen. The dosing regimen was YM155 5 mg/m2/day as a 168 hour (7-day) continuous infusion in a 14 day cycle and rituximab 375 mg/m22 Days 1 and 8 cycles 1 – 4 and then repeated every 10 cycles. The primary endpoint of the study is objective response rate (ORR) per modified IWG 2007. Imaging studies are performed every 8 weeks (4 cycles) after initiation of therapy. In order to continue enrolling in the study, an overall response rate of 4/16 (25%) must be achieved. Results from the completed Stage I are reported here. Results: Sixteen subjects, the majority of whom were male 13/16 (81%), were enrolled in Stage I. The median age was 62.9 (range: 32 – 78) with a majority of subjects 15/16 (93.8%) with DLBCL. IPI/FLIPI scores were intermediate in 10 subjects (62.5%) and high in 3 subjects (18.8%). The median number of prior therapies was 2 (range: 1 – 5), 16/16 (100%) of patients received rituximab in 1st or subsequent lines of therapy. Seven patients (43.7%) had prior ASCT. The median number of cycles of YM155 administered was 11 (1–37). The overall response rate was 9/16 (56.3%) with 2/16 (12.5%) CR, 7/16 (43.8%) PR and 4/16 (25%) SD. The median time to response was 53 days (range: 52 – 109). Median duration of response and median PFS has not been achieved. Clinical benefit rate was 13/16 (81.3%). The most common adverse events reported, regardless of relationship, were pyrexia 8/16 (50%), cough 7/16 (43.8%), asthenia 5/16 (31%) and fatigue, back pain, vomiting, neutropenia and thrombocytopenia each 4/16 (25%). Five subjects (31.3%) experience Grade 4 adverse events and 2 (12.5%) had Grade 5 adverse events (disease progression and respiratory failure), neither of which was considered related to therapy. The most common Grade 4 event was neutropenia 4/16 (25%), with all other Grade 4 events occurring in only 1 subject (febrile neutropenia, thrombocytopenia, general physical health deterioration, infusion site extravasation, central line infection, infective thrombosis, mediastinitis, dyspnoea, pleural effusion). Conclusion: In subjects with relapsed aggressive NHL receiving combination YM155 and rituximab, the ORR for Stage I was 56.3%, which exceeds the requirement to continue to Stage II. Overall the combination regimen was well tolerated with limited hematologic toxicities. Stage II enrollment is ongoing. Disclosures: Papadopoulos: Astellas: Consultancy, Research Funding. Steinberg:Astellas Pharma: Employment. Papa:Astellas Pharma: Employment. Keating:Astellas Pharma: Employment.

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Results From the Phase II Dose Expansion of Cyclophosphamide, Carfilzomib, Thalidomide and Dexamethasone (CYCLONE) in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.445.445 ◽

2012 ◽

Vol 120 (21) ◽

pp. 445-445 ◽

Cited By ~ 4

Author(s):

Joseph R. Mikhael ◽

Craig B. Reeder ◽

Edward N. Libby ◽

Luciano J. Costa ◽

P. Leif Bergsagel ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Phase Ii ◽

Initial Phase ◽

Stem Cell Transplant ◽

Response Rate ◽

Phase Ii Trial ◽

Cell Transplant ◽

Newly Diagnosed ◽

Grade 3

Abstract Abstract 445 Background: Carfilzomib is a proteasome inhibitor that irreversibly binds its target and has a favorable toxicity profile that has shown significant activity in relapsed multiple myeloma (MM), leading to recent FDA accelerated approval. To achieve rapid and deep response in patients eligible for stem cell transplant, we combined carfilzomib with the regimen of cyclophosphamide-thalidomide-dexamethasone (CTD). We recently reported the results of the Phase I component of the trial (in which no MTD was reached) followed by the initial Phase II trial; however, with increasing evidence for the safe and effective use of higher doses of carfilzomib, we now report results from dose escalation extension of the Phase II trial. Methods: Newly diagnosed myeloma patients intended for stem cell transplant were eligible. All patients were treated on a 28 day cycle with Carfilzomib IV Days 1,2,8,9,15,16 (see Table 1 below for dosing per cohort) along with Cyclophosphamide 300 mg/m2 PO Days 1,8,15, Thalidomide 100 mg PO Days 1–28 and Dexamethasone 40 mg PO Days 1,8,15,22. We initially conducted a Phase I run in trial of 6 patients with no DLT observed before expanding to the Phase II portion of the study. The initial phase II regimen is shown below – as no DLTs were observed, we have now fully accrued to the Phase II dose level +1. Treatment was for 4 cycles with expected SCT post induction. The primary endpoint of the trial is the proportion of patients who have ≥very good partial response (VGPR) to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results: A total of 38 patients have been accrued to the trial, 6 in the initial Phase 1, 21 in the initial Phase II, and the remaining at dose escalated cohorts. We are reporting the 27 patients who have completed therapy and will update with the dose escalated cohorts. Median age was 65 (range 27–74) and 52% were female. ISS Stage was advanced (II-III) in 56%. Best overall response rate during 4 cycles of CYCLONE at dose level 0 is 96%: CR 29%, VGPR 46%, PR 21% (1 pt achieved MR). Adverse events of grade 3 or higher at least possibly related to CYCLONE occurred in 12 (44%). Most commonly reported non hematological toxicities (all grades) included fatigue (67%), constipation (56%), lethargy (41%) somnolence (37%), malaise (30%) depressed level of consciousness (22%); however, grade 3/4 toxicities occurring in >5% were uncommon: thromboembolic event 11%) and muscle weakness (7%). Two cases of pneumonia required hospitalization. Eight patients (30%) developed grade 1 sensory neuropathy; no higher grade or painful neuropathy was evident. There were no cardiac events seen in greater than 5% of patients. Grade 3/4 hematological toxicities included neutropenia (15%) and lymphopenia (7%). All patients advancing to SCT successfully collected stem cells. One patient died on study from pneumonia. Conclusion: The 4 drug CYCLONE regimen is highly efficaceous with a response rate after only 4 cycles of 96% (75% ≥VGPR, 29% CR) at the current dosing level of carfilzomib IV 20/27 mg/m2 in newly diagnosed myeloma. Toxicities are manageable, with only grade 1 neuropathy and minimal cardiac or pulmonary toxicity. Increasing the dose of carfilzomib is feasible and updated results of dose escalated cohorts will be reported at 20/36 and 20/45 mg/m2. Disclosures: Bergsagel: onyx: Membership on an entity's Board of Directors or advisory committees. Stewart:Millennium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.

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Efficacy and Safety of YM155 in Relapsed/Refractory Non-Hodgkin’s Lymphoma Patients Enrolled in a Phase I Study.

Blood ◽

10.1182/blood.v110.11.3422.3422 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3422-3422 ◽

Cited By ~ 1

Author(s):

Kyriakos Papadopoulos ◽

Alain Mita ◽

Scott Antonio ◽

Lionel D. Lewis ◽

N.J. Reddy ◽

...

Keyword(s):

Stem Cell ◽

Adverse Events ◽

Phase I ◽

Tumor Cells ◽

Phase I Study ◽

Stem Cell Transplant ◽

Cell Lymphoma ◽

Large Cell ◽

Cell Transplant ◽

To Receive

Abstract Background: YM155 is a member of a novel class of compounds called survivin suppressants that target survivin. Survivin is a member of the inhibitor of apoptosis proteins (IAPs) family which is responsible for preservation of cell viability and regulation of mitosis in tumor cells. Survivin over-expression has been reported in a variety of tumor cells including lymphoma. A Phase I dose escalation study of YM155 was conducted to evaluate safety, tolerability and antitumor activity in patients with solid tumors or non-Hodgkin’s lymphoma (NHL). Methods: Patients with solid tumors or NHL with no other treatments options were eligible for this Phase I study and received YM155 in escalating doses ranging from 1.8 – 6 mg/m2/day as a 168 hour (7 day) continuous infusion in a 21 day cycle. Patients could continue to receive YM155 until either disease progression or toxicity. 41 patients were enrolled into the study including 5 patients with NHL (2 diffuse large B-cell lymphoma [DLBCL], 1 each small lymphocytic B-cell, follicular [FL] and anaplastic large cell lymphoma). This report focuses solely on the patients with NHL. All 5 NHL patients had at least 2 prior treatment regimens (range: 2 – 7) including stem cell transplant in two patients (DLBCL, FL) and one patient who received 2 investigational therapies. Three patients were considered refractory to the treatment regimen given just prior to study entry (DLBCL, anaplastic large cell, FL). Results: All 5 NHL patients were male with a mean age of 56 (range: 46 – 64). They were all dosed at the maximum tolerated dose (MTD) of 4.8 mg/m2/day. The most common adverse events reported, regardless of relationship to YM155, were URI (3/5) and arthralgia, fever, hypomagnesemia, mucositis peripheral edema and rash (2/5). The majority of adverse events were Grade 1 or 2 with 3 events reported as Grade 4: Klebsiella bacteremia, neutropenia and hypokalemia. Three patients (60%) (2 DLBCL and FL) had partial response (PR) to YM155 as assessed by independent review using both RECIST and 1999 Cheson criteria. One responder (DLBCL) had a PR after 2 cycles, completed a total of 5 cycles and proceeded to stem cell transplant. This patient has no evidence of disease at 3 years. A second responder (DLBCL) had a PR after 12 cycles and received a total of 26 cycles (∼ 1.5yrs) before disease progression. The third responder (FL) had a PR after 14 cycles, has maintained a prolonged PR for ∼ 2 years and continues to receive YM155 in a long-term extension study. Conclusion: Based upon the objective responses, the tolerability and safety profile observed in this Phase I study in 5 NHL patients, a Phase II study in refractory DLBCL has been initiated.

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Final Analysis of the Front-Line Phase III Randomized ACT-1 Trial in Younger Patients with Systemic Peripheral T-Cell Lymphoma Treated with CHOP Chemotherapy with or without Alemtuzumab and Consolidated By Autologous Hematopoietic Stem Cell Transplant

Blood ◽

10.1182/blood-2018-99-110429 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 998-998 ◽

Cited By ~ 4

Author(s):

Francesco d'Amore ◽

Sirpa Leppä ◽

Maria Gomes da Silva ◽

Thomas Relander ◽

Grete Fossum Lauritzsen ◽

...

Keyword(s):

Stem Cell ◽

Research Funding ◽

Stem Cell Transplant ◽

Cell Lymphoma ◽

Fungal Infections ◽

Final Analysis ◽

Cell Transplant ◽

Peripheral T Cell Lymphoma ◽

Advisory Committees ◽

Grade 3

Abstract [§ share last authorship] Background: In 2000-2010, the first large prospective trials in peripheral T-cell lymphoma (PTCL) showed outcomes burdened by high failure rates during induction. Concurrently, trials with the anti-CD52 monoclonal antibody alemtuzumab (ALZ) yielded promising responses in PTCL while demonstrating the feasibility of combining ALZ with CHOP. Hence, the Nordic Lymphoma Group initiated the randomized ACT-1 trial to test, in younger patients (pts) (18-65yrs), the addition of ALZ to CHOP + autologous stem cell transplant (ASCT). Primary endpoint was the 3 years event-free survival (EFS). Here, we present the final analysis of the ACT-1 trial (ClinicalTrials.gov: NCT00646854). Patients and Methods: Overall, 136 pts were randomized (43% of planned sample size due to slow accrual), five did not receive study treatment, and 131 were analyzed (ALZ-CHOP: 65; CHOP: 66). Due to lack of tumoral CD52 expression, anaplastic large cell lymphomas (ALCL) were not included in the ACT-1 trial. An amendment tapering ALZ dose from 360 mg (30 mg on days 1+2 of each CHOP course) to 120 mg (30 mg on day 1 of CHOP courses 1-4) was introduced early on due to systemic fungal infections in 2 pts. Of the 65 pts treated with ALZ-CHOP, 4 received the pre- and 61 (94%) the post-amendment dose. Monitoring for CMV- and EBV-DNA and antimicrobial prophylaxis were mandatory. Results: The median observation time for the Full Analysis Set was 66 months and the median age 51 yrs. The ALZ-CHOP and CHOP cohorts were well balanced with regard to classical prognostic factors and histological subtypes (PTCL-NOS 58% vs 54%, AILT 21% vs 25%, other 21% vs 21%). Feasibility: Neither CHOP nor ALZ-CHOP pts experienced substantial treatment delay. ALZ exposure did not affect stem cell harvest nor hematopoietic recovery. Grade 4 leucopenia was more frequent in ALZ-CHOP pts (73% vs 35%; p=0.001), whereas the occurrence of grade 3-4 anemia and thrombocytopenia did not differ significantly. After ALZ dose amendment, the frequency of bacterial and fungal infections of grade ≥3 was similar in both treatment arms. ALZ treated pts had more viral events (22/57=42% vs 4/23=17%), mainly due to asymptomatic CMV reactivations. The ratio of serious adverse events per ALZ-CHOP treated patient dropped markedly (from 3.25 to 0.86, comparable with 0.46 for CHOP) after dose amendment. Additional toxicity was mild and similar in both arms. Treatment related mortality was 4% (5% vs 3%). Efficacy: Complete remission (CR) was 52% in ALZ-CHOP vs 42% in CHOP. Primary refractory disease occurred for ALZ-CHOP and CHOP in 23% and 38% of pts, respectively. Overall, females had a significantly better outcome than males (p=0.004), also after adjustment for classical prognostic factors. Analyzing time-related endpoints without knowledge of CD52 expression, 3-years EFS, progression-free, and overall survival (PFS, OS) did not differ significantly between ALZ-CHOP and CHOP (EFS 35% vs 26%, PFS 37% vs 26%, OS 52% vs 50%). Fig.1A shows EFS by treatment arm, by gender, and by gender and treatment arm. Although not significantly different, EFS, PFS and OS values of ALZ-CHOP treated females in the ACT-1 trial were consistently higher than those of non-ALZ treated females or of males regardless of treatment group. RNA sequencing from evaluable pre-therapeutic tumor biopsies defined a signature of differentially expressed genes to be predictive of clinical outcome in ALZ-CHOP but not CHOP treated pts (n=33). Tumor microenvironment genes were prominent in determining response to ALZ. Tumors rich in B-cell milieu showed good responses, while the opposite was observed in tumors with signatures enriched with high endothelial cell genes (p<0.001) (Fig.1B). The good risk signature was associated with a higher frequency of X-linked and the bad risk with a higher frequency of Y-linked transcripts (Fig.1B). Conclusion: In previously untreated younger non-anaplastic PTCL pts, the addition of ALZ to CHOP + ASCT was feasible. Overall, we did not find a significant outcome benefit. However, a gene expression signature predictive of ALZ response was identified and found predominantly in female patients. Carriers of this signature had an outcome benefit only if exposed to ALZ. A validation of this predictor of ALZ response is ongoing. Due to the limited sample size of the ACT-1 study cohort, both the negative and the positive findings of the trial should be interpreted with caution. Disclosures Leppä: Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Bayer: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy. Silva:Gilead Sciences: Research Funding; Abbvie, Gilead Sciences, Janssen, BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche, Janssen, Celgene: Other: Travel Support; Roche, Janssen: Other: Institution's payment for consultancy. Hagberg:Roche: Honoraria. Lugtenburg:takeda: Consultancy, Research Funding; servier: Consultancy, Research Funding; roche: Consultancy; BMS: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; GenMab: Research Funding. Walewski:Roche, GSK/Novartis, Takeda, and Janssen-Cilag: Research Funding; Roche, Celgene, Takeda, Janssen-Cilag, and Servier: Honoraria; Roche, Celegene, Takeda, Janssen-Cilag, and Servier: Membership on an entity's Board of Directors or advisory committees. Hopfinger:Janssen: Honoraria; Gilead: Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Jantunen:Amgen: Honoraria; Genzyme/Sanofi: Honoraria; Takeda: Honoraria. Steidl:Seattle Genetics: Consultancy; Juno Therapeutics: Consultancy; Tioma: Research Funding; Bristol-Myers Squibb: Research Funding; Nanostring: Patents & Royalties: patent holding; Roche: Consultancy. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Scott:Celgene: Consultancy, Honoraria; Janssen: Research Funding; Roche: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding.

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First Interim Safety Analysis of a Phase III Randomized Trial in Newly Diagnosed Systemic Peripheral T-Cell Lymphoma Treated with CHOP Chemotherapy with or without Alemtuzumab and Consolidated by Autologous Hematopoietic Stem Cell Transplant,

Blood ◽

10.1182/blood.v118.21.4110.4110 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4110-4110 ◽

Cited By ~ 1

Author(s):

Francesco d'Amore ◽

Maria Gomes da Silva ◽

Sirpa Leppa ◽

Thomas Relander ◽

Antonio Pezzutto ◽

...

Keyword(s):

Stem Cell ◽

Dose Reduction ◽

Dose Level ◽

Stem Cell Transplant ◽

De Novo ◽

Cell Lymphoma ◽

Cell Transplant ◽

Newly Diagnosed ◽

Peripheral T Cell Lymphoma ◽

Dose Dense

Abstract Abstract 4110 Background: The ACT trial (ACT-1 and −2) tests the addition of alemtuzumab (ALZ) to 6 courses of bi-weekly CHOP (A-CHOP-14) followed, in younger patients (ACT-1), by high-dose therapy with autologous stem cell transplant (HDT/ASCT) in newly diagnosed primary systemic peripheral T-cell lymphoma (PTCL). To date, the trial has accrued a total of 131 patients (ACT-1 n=72; ACT-2 n=59). Here, we present the first planned interim safety analysis of the ACT-1 trial based on the first 51 randomized patients. Aims: The aim of the present analysis is to report on the feasibility of a dose-dense chemo-immunotherapy schedule combining ALZ and bi-weekly CHOP followed by HDT/ASCT in ‘de novo' PTCL patients. Results: Results contain two data subsets corresponding to ALZ dose levels prior and subsequent to a dose-reduction amendment tapering ALZ dose from 360 mg (30 mg on days 1 and 2 of each CHOP course) to 120 mg (30 mg on day 1 of CHOP courses 1–4), respectively. Of the 51 randomized patients, 43 had a complete set of evaluable data and represent the background for the present set of results. Of these, 5 received the higher ALZ dose, 17 the lower and 21 belonged to the antibody-void control arm. Treatment arms were well balanced with regard to histological subtypes, IPI sub-groups, and single prognostic factors. Neither of the two treatment cohorts, and for the experimental one irrespective of ALZ dose level, showed significant treatment delay. The median duration of chemotherapy (calculated for 5 bi-weekly cycles of an expected cumulative duration of 70 days) for non-ALZ vs. ALZ-treated patients was 73 vs. 81 days, respectively. No suspected unexpected serious adverse reactions (SUSARs) were reported. Grade 3–4 leucopenia and anemia were more frequent in ALZ-treated patients (71% vs 29% and 47% vs 14%, respectively), whereas no difference was seen in terms of thrombocytopenia (17% vs 18%). Non-hematological toxicity unrelated to infectious complications was similar in the two groups. At the higher ALZ dose level, two cases of systemic fungal infection were reported, of which one (verified as being aspergillosis) with fatal outcome in a patient with pre-existing type II diabetes and steroid-requiring chronic obstructive pulmonary disease. These two events prompted the ALZ dose-reduction amendment, which led to a significant drop in the number of serious adverse events (SAEs) for ALZ-treated patients (SAE/patient pre-amendment: 2.6, post-amendment: 0.76) to a level comparable with the control arm (SAE/patient pre-amendment: 0.67, post-amendment: 0.44). With regard to the types of infection (≥grade 2), there was a similar frequency in reported fungal infections between the two treatment cohorts, bacterial infections were more often reported in the standard treatment arm (55% vs 46%), while the opposite was observed for viral infections (29% vs. 35%). Among the latter, there were 8 cases of cytomegalovirus reactivation among ALZ-treated patients, of which only two were clinically symptomatic and regressed upon specific treatment. Conclusion: In conclusion, the early-on impression of a SAE decrease subsequent to the ALZ dose-reduction amendment (applied on both ACT-1 and ACT-2) has been further confirmed by a larger cohort of patients treated at the lower ALZ dose level. The number of adverse events in the two study arms is now fairly comparable and adds further useful information to the previous reports on feasibility of stem cell harvest (Blood 2010;116: 2395) and hematopoietic recovery (Ann Oncol 2011;22(s4): 476) in ‘de novo' PTCL patients treated with a dose-dense ALZ-CHOP regimen followed by HDT/ASCT. Disclosures: Walewski: 4SC AG: Consultancy. Jantunen:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Comparison of Outcomes between the Cellex and Uvar-Xts Closed-System Extracorporeal Photopheresis (ECP) Devices When Used for Graft-Versus-Host Disease; A Single Center Experience

Blood ◽

10.1182/blood-2018-99-115122 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4686-4686

Author(s):

Amber Afzal ◽

Maryna Tarbunova ◽

George Despotis ◽

Brenda J. Grossman

Keyword(s):

Stem Cell ◽

Adverse Events ◽

Dose Reduction ◽

Stem Cell Transplant ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Buffy Coat ◽

Cell Transplant ◽

Allogeneic Stem Cell Transplant ◽

Steroid Dose

Abstract BACKGROUND: Graft versus host disease (GVHD) is a significant contributor to non-relapse mortality after allogeneic stem cell transplant (SCT). Steroids are first line therapy and extracorporeal photopheresis (ECP) is used as second line therapy for steroid refractory or intolerant patients. ECP has immunomodulatory effects rather than immunosuppressive effect which decreases the risk of infection, and may decreases the risk of disease relapse. There are two ECP instruments approved in the US for the treatment of Cutaneous T Cell Lymphoma (CTLC), however both have been used "off-label" to prevent or treat solid organ transplant rejection, acute and chronic GVHD, and other autoimmune diseases. Until recently the UVAR-XTS instrument has been the most commonly used closed system in the US until the CELLEX was approved in 2009. The CELLEX and the UVAR-XTS procedures are similar in that buffy coat is collected, exposed to methoxsalen (UVADEX®) ex vivo and then UVA light before returning the treated cells back to the patient in a closed looped system. The instruments differ in the collection of the buffy coat; collection is continuous by the CELLEX, and it is intermittent by UVAR-XTS. In addition CELLEX has been shown to be more efficient in collecting mononuclear cells when compared to the UVAR -XTS. Little clinical data is available comparing the clinical efficacy of the two instruments in the setting of GVHD. We designed a single institution retrospective study to compare the efficacy and safety of the two instruments. The primary outcomes analyzed were >/=50% reduction of steroid dose between the initial and final dose during the study period, and the number and type of adverse events that occurred during the ECP procedures. METHODS: Study Population: We reviewed charts of allogeneic stem cell transplant patients who received ECP for the treatment of acute or chronic GVHD between 1/2009 and 12/2015. The patients were divided into two groups based on the type of ECP instrument that was used. One group was exclusively treated with UVAR-XTS while the second group with CELLEX. Patients who received treatments with both instruments were excluded. The frequency of steroid dose reduction by >/=50%, and toxicity was compared between the two instruments while adjusting for age, gender, GVHD severity, number of organs involved by GVHD, type of allogeneic stem cell transplant, conditioning regimen, number of other immunosuppressants, type of anticoagulants (ACDA vs heparin), type of access line, and baseline blood counts. Statistical Analysis: The baseline characteristics of the patients in the two groups were compared using Chi square, Fischer's exact test for categorical variables and one-way analysis of variance (ANOVA) for continuous variables. Chi square analysis was used to determine the difference in frequency of >/=50% steroid dose reduction and adverse events between the two groups. Logistic multivariate regression was used to evaluate the potential interactions of all significant covariates. A p value of less than 0.05 was considered to be statistically significant. Statistical analyses were performed using STATA14 software (StataCorp, College Station, TX). RESULTS: We identified 242 allogeneic SCT recipients who received ECP for acute or chronic GVHD in the study period, 146 of whom met the selection criteria. 69 patients had all procedure performed with UVAR-XTS and 77 patients had all procedures performed with CELLEX. There was no significant difference in age, gender, percent of acute GVHD, anticoagulant used, type of transplant, number of organs involved, number of immunosuppressants, vascular access and baseline blood counts between the two treatment cohorts as shown in table 1. Although year of transplant and conditioning regimen were different between the two cohorts, neither of these covariates influenced the impact of instrument on the primary outcome. In multivariate analysis, the patients who underwent ECP with CELLEX were 3 times more likely to have >/=50% steroid dose reduction (p =0.01). The total number of adverse events was similar between the instruments (p = 0.73). (Table 2) CONCLUSION: More than twice as many patients with GVHD treated with the CELLEX had a steroid dose reduction by >/=50% reflecting clinical improvement when compared to the patients treated with the UVAR-XTS. Similar safety profile was observed between the two instruments based on a similar number of adverse events. Disclosures No relevant conflicts of interest to declare.

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