scholarly journals Comparison of Salvage Autologous Hematopoietic Cell Transplantation with Outcomes Following Selinexor Combinations Among Double/Triple Refractory Myeloma Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4904-4904
Author(s):  
Guldane Cengiz ◽  
Bulent Karakaya ◽  
Hulya Yilmaz ◽  
Derya Koyun ◽  
Ekin Kircali ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Progression ◽  
Cell Transplantation ◽  
Treatment Options ◽  
Proteasome Inhibitors ◽  
Bridging Therapy ◽  
New Therapies ◽  
Expanded Access Program ◽  
Duration Of Response ◽  
Access Program

Abstract Introduction: A vast majority of multiple myeloma (MM) patients requires subsequent lines of therapy following relapses. The choice of regimen following relapse is influenced by response, tolerance to prior therapies, as well as by disease and patient features. Treatment options are limited for those who develop triple-class refractory disease. In this setting, the role of a salvage autologous stem cell transplantation (sAHCT) is controversial. This unmet need has driven the development of new therapies with novel mechanisms of action. Selinexor, an oral selective inhibitor of nuclear export (SINE) compound, was recently approved by the FDA and EMA for use in heavily pretreated relapse refractory (RRMM) patients, including triple-class refractory RRMM and FDA has also approved the agent in patients with first relapse. In the absence of head-to-head studies, comparison of treatment options among triple-class treated patients is based on real world experience. Here we performed a retrospective comparison between outcomes following sAHCT versus Selinexor combinations administered among RRMMs. Patients & Methods: Between January 2015 and April 2021, 22 patients at our center underwent sAHCT for treatment of refractory relapse. A transplant was defined as salvage if the patient had already received one prior AHCT and underwent a further AHCT after evidence of disease progression not responding to second generation proteasome inhibitors (PI), İmmunomodulating agents (IMID) or antiCD38 monoclonal antibody. We compared the outcomes of these patients with 10 RRMM patients who had exhausted their treatment options and were progressing on their last line of therapy to receive Selinexor, dexamethasone in combination with either bortezomib (n=7) (XVd) or carfilzomib (n=3) (XCd) as a part of a Karyopharm Expanded Access Program (KEAP). Selinexor was administered 80-100 mg po weekly in combination. Response and disease progression were assessed according to the IMWG criteria. Results: Patients' characteristics and the outcome of treatments are shown in Table. The median age of patients was similar in both groups. Patients were heavily treated with a median of 6 prior lines of therapy (4-9) and 2 out of 10 carried high-risk cytogenetics in SVd group. Seven (31.8%) patients with high-risk cytogenetics underwent sAHCT. All patients were treated with or refractory to immunomodulators and proteasome inhibitors. Five patients responded to DCEP bridging therapy prior to sAHCT. Five patients received Selinexor after sAHCT. One patient underwent sAHCT due to progression under Selinexor treatment. In sAHCT group, 68.2% of patients relapsed within a median of 6.3 months (Figure-1). Figure-2 shows the impact of the prior lines of therapy and selinoxor on PFS.Adverse events on selinexor regimens included fatigue, nausea, thrombocytopenia which were managed with Selinexor dose adjustment and supportive care. Two patients eventually transitioned to new therapies, while 4 still remain on SVd due to continued response. Conclusion: Our results based on a small number of patients, compared with outcomes post sAHCT reflects comparable duration of response and disease control rates with Selinexor-PI regimens among selected patients. Hospitalization and prolonged infusions are not required with the selinexor regimens, and prolonged treatment is possible with advance in lines of therapy duration of response lessens with any treatment modality. Despite of a DCEP bridging therapy prior to sAHCT, Selinexor combos have achieved similar PFS even among triple class refractory MM patients. For countries where CAR-T therapies are not accessible, sAHCT and Selinexor combinations may be considered as a valid clinical option after failing CD38 monoclonal antibodies, PI and IMIDs. These data support the use of selinexor-based regimens in the treatment of relapsed MM, and given the potency of the combinations, in earlier lines of therapy including in patients who have received anti-CD38 mAbs. Figure 1 Figure 1. Disclosures Kashyap: Karyopharm: Current Employment. Niblock: Karyopharm: Current Employment. Beksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau. OffLabel Disclosure: Selinexor has not been approved for myeloma patients in Turkey. It could be used as a part of Karyopharm Expanded Access program (KEAP).

Ipilimumab (Ipi) expanded access program (EAP) for patients (pts) with stage III/IV melanoma: 10 mg/kg cohort interim results.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8508-8508 ◽  
Author(s):  
Omid Hamid ◽  
Wen-Jen Hwu ◽  
Jon M. Richards ◽  
Jeffrey S. Weber ◽  
Jedd D. Wolchok ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Treatment Options ◽  
Stage Iii ◽  
Controlled Clinical Trials ◽  
Serious Adverse Events ◽  
Safety Database ◽  
Expanded Access Program ◽  
Unresectable Stage ◽  
The Us ◽  
Access Program

8508 Background: The EAP (CA184-045), begun in 8/07, currently provides the largest safety database for Ipi outside of controlled clinical trials (CCTs) and included pts with brain metastases (BM) and primary ocular (OM) and mucosal (MM) melanoma. The EAP was amended in 10/08 to administer a 3 mg/kg dose based on the current label (Hodi et al. NEJM 2010). We now report interim data from pts treated in the US at 10 mg/kg from 8/07-10/08. Methods: Pts with unresectable Stage III or IV melanoma who progressed on at least 1 systemic therapy or had no alternate treatment options were eligible. Pts received 10 mg/kg Ipi i.v. q 3 wks up to 4 doses (induction) followed by 10 mg/kg q 12 wks (maintenance) until no longer clinically benefiting or unacceptable/unmanageable toxicity occurred. All serious adverse events (SAEs) and on-study deaths were collected; overall survival (OS) was assessed retrospectively. Results: Of 906 treated pts, 830 were included in the analysis; 39 from prior Ipi trials + 37 from sites whose IRB did not agree to collect OS were excluded. Pts got a median of 4 doses; 31% got ≥5 doses. ECOG 0/1/2 was 53%/39%/8% (1 pt was ECOG 3); 27% had BM, 5% had OM, and 4% MM. Primary reasons for discontinuation were disease progression (67%) and drug toxicity (11%). Incidence of drug-related SAEs was 27% with diarrhea 10%, colitis 8%, endocrinopathies 4%, and dermatitis 0.8%. 2 pts (0.24%) had on-study hepatitis SAEs, both considered drug-related and resulted in discontinuation. There were 3 (0.36%) drug-related intestinal perforations. 2 deaths (0.24%) were the outcome of drug-related SAEs; 1 multi-organ failure and 1 acute respiratory distress syndrome (both ≤70 days from last induction dose). 72 (9%) pts currently remain on treatment (i.e. >3 years). Available OS data showed that 138 pts (17%) were still at risk after 3 years. For 27% of pts the last known alive date was >30 days before data cutoff (with most >2 yrs). Conclusions: Data from the US EAP must be interpreted with caution compared to CCTs. To date, incidence of SAEs for hepatitis and intestinal perforation, and drug-related death at 10 mg/kg Ipi monotherapy is consistent with that seen in BMS clinical trials. Durable OS (>3 yrs) was observed in at least 17% of pts.

Daratumumab Monotherapy for Heavily Pre-treated and Refractory Myeloma: Results from a UK Multicentre Real World Cohort

2021 ◽  
pp. 107815522110677
Author(s):  
Nadjoua Maouche ◽  
Anandagopal Srinivasan ◽  
Heather Leary ◽  
Freya Collings ◽  
Bing Tseu ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Real World ◽  
Median Overall Survival ◽  
Treatment Options ◽  
Single Agent ◽  
Objective Response ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
Real World Data

Daratumumab is the first anti-CD38 targeting monoclonal antibody approved as monotherapy in multiply relapsed myeloma patients who progressed following prior treatment with proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs). We present real world data on the efficacy of single agent daratumumab in a cohort of 55 multiply relapsed patients treated in the UK. The median age was 72 years, the majority (96%) received ≥ 3 previous lines of treatment; 54.5% were PI-refractory, 76.4% were IMiD-refractory and 47.2% were double refractory; 20% of patients had high-risk (HR) disease. The overall response rate was 49%. After a median follow up of 9.2 months, the median progression-free survival (PFS) for the total cohort was 5.1 months. Patients who achieved a partial response or better (≥PR) demonstrated a significantly longer PFS compared to those with <PR; 9.8 versus 2.7 months, p < 0.001. Double-refractory patients had an inferior PFS compared to single-refractory patients; 2.7 versus 7.4 months, p = 0.084. High-risk disease was associated with significantly shorter PFS compared to standard-risk (SR); 2.3 versus 6.7 months, p = 0.001. The median overall survival (OS) was 15.9 months. Despite a relatively short PFS seen in the double-refractory and high-risk patients; a favourable median overall survival of 12.9 months was achieved in these groups. Patients who achieved ≥PR, those with a previous objective response to PIs or IMiDs and those with SR disease, all benefited from a significantly longer OS which was not reached. A clear benefit in survival is encouraging in this setting of unmet clinical need and limited treatment options.

Cost-Effectiveness of Adding Imatinib to Chemotherapy in Adult Patients with Chromosom-Positive Acute Lymphoblastic Leukemia (Ph+ALL): A Canadian Perspective

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2401-2401 ◽  
Author(s):  
Khalid El Ouagari ◽  
Kimbach Tran ◽  
Jennifer Stephens ◽  
Marc Botteman
Keyword(s):  
Health Care ◽  
Cost Effectiveness ◽  
High Risk ◽  
Disease Progression ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Disease Free Survival ◽  
Model Framework ◽  
Health States ◽  
Life Years

Abstract BACKGROUND: Ph+ALL is a rare, high-risk, aggressive form of acute leukemia, affecting primarily adults and the elderly. Patients with high-risk forms of ALL typically have extremely poor prognosis and incur high disease-related costs. Successful use of imatinib in patients with Ph+CML has led to the administration of imatinib in recent clinical studies for patients with Ph+ALL. Given the changing treatment landscape of Ph+ALL and the recent development of additional targeted treatments for this disease, an appraisal of the economic burden associated with Ph+ALL is warranted for evaluation of appropriate treatment options and the potential value associated with novel therapies. This study explores the cost effectiveness of imatinib plus conventional chemotherapy (CC) regimens versus CC alone in adult Ph+ALL patients. METHODS: A Markov model simulated a hypothetical cohort of 1000 adult Ph+ALL patients receiving imatinib+CC or CC alone. Patients were distributed over time into three health states: alive without disease progression (DFS), alive with disease progression (DS), or dead. Probabilities of being in the states were derived from the published literature. In the absence of relevant data pertaining to Ph+ALL, assumptions about costs and utilities were derived from a cost analysis of CML. A Canadian health care payer perspective was considered, therefore only direct medical costs were included in the analysis. Patients were followed for a total of ten years in monthly intervals. All outcomes were discounted at a 5% rate per annum. RESULTS: Based on the model framework and assumptions, the total discounted survival was 1.09 years for CC and 4.13 years for imatinib+CC. Total discounted disease free survival was 0.76 year for CC and 2.69 years for imatinib+CC. Assuming utility weights of 0.854 and 0.596 for DFS and DS, respectively, the total discounted quality adjusted life years (QALY) were estimated to be 0.84 versus 3.16 for CC and imatinib+CC, respectively. Thus, the net incremental gain in discounted quality adjusted survival was 2.32 QALYs. The monthly costs of DFS and DS were estimated at $168 and $848, respectively. The net costs associated with imatinib were $101,929. The incremental cost per QALY of imatinib+CC v. CC alone was approximately $44,048 (i.e., $101,929 divided by 2.32 QALYs). CONCLUSIONS: Our results suggest that imatinib in the treatment of Ph+ALL is a cost-effective use of health-care resources, and should be considered in patients who are appropriate candidates for such therapy.

Treatment Outcomes with Pomalidomide (POM) in Combination with Low-Dose Dexamethasone (LoDex) in Patients with Relapsed and Refractory Multiple Myeloma (RRMM) and Del(17p13) and/or t(4;14)(p16;q32) Cytogenetic Abnormalities Who Have Received Prior Therapy with Lenalidomide (LEN) and Bortezomib (BORT)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4053-4053 ◽  
Author(s):  
Paul G. Richardson ◽  
Andrzej Jakubowiak ◽  
Nizar J. Bahlis ◽  
David S. Siegel ◽  
Christine I. Chen ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Progression ◽  
Risk Group ◽  
Advisory Board ◽  
Employment Equity ◽  
Cytogenetic Abnormalities ◽  
Duration Of Response ◽  
Equity Ownership ◽  
Grade 3 ◽  
Standard Risk

Abstract Abstract 4053 Background: Patients (pts) with MM who relapse and are refractory after therapy with bortezomib or immunomodulatory agents have overall survival (OS) and progression-free survival (PFS) of 9 mos and 5 mos, respectively (Kumar et al, Leukemia 2011). A number of cytogenetic abnormalities have also been associated with poor outcomes in MM, including t(4;14), and del(17p) (Avet-Loiseau et al, Blood 2007). In the multicenter, randomized, open-label MM-002 phase 1/2 study, the novel immunomodulatory agent POM, in combination with LoDEX, has demonstrated promising activity and favorable tolerability in pts with RRMM (Richardson PG, et al. Blood 2011;118:abs 634). Here we evaluated outcomes in pts participating in the study with high-risk cytogenetic profiles, with data as of 30 March 2012 presented. Methods: Eligible pts with MM who had received ≥2 prior therapies (including LEN and BORT) and had disease progression within 60 days of their last treatment were randomized to treatment with either POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle; LoDEX, 40 mg/week) or POM alone. At progression, patients receiving POM alone could receive POM+LoDEX at investigator's discretion. Thromboprophylaxis with daily low-dose aspirin was mandatory. The endpoints in this study were PFS, response rates (using European Bone Marrow Transplantation [EBMT] criteria), duration of response, time to response, OS, and safety. Efficacy outcomes and safety in pts with high-risk cytogenetics were compared with those of pts with standard-risk cytogenetics as well as with the overall population who received POM+LoDEX as part of an exploratory analysis. High-risk cytogenetics were defined based on modified criteria and included the presence of the following abnormalities: del(17p13) and/or t(4;14)(p16;q32), based on interphase FISH analysis from marrow aspirates collected at study entry. Results: The intention-to-treat population included 113 pts who were treated with POM+LoDex. At baseline, high-risk and standard-risk cytogenetic profiles were identified in 30 pts (27%) and 57 (50%) pts, respectively; 26 pts (23%) were inevaluable. Cytogenetic abnormalities included del(17p13) in 19 pts and t(4;14)(p16;q32) in 25 pts. Median follow-up time was 13.2 mos for the high-risk group and 17.7 mos for the standard-risk group. The median ORR (≥PR) for all pts was 34%; median ORR for high-risk pts was 23%, compared with 40% for standard-risk pts. The overall median duration of response (≥PR) was 8.3 mos for all pts, 4.9 mos for high-risk pts, and 10.1 mos for the standard-risk pts. The median PFS was 4.6 mos for all pts. The median PFS was 3.1 mos for pts with high-risk cytogenetics and 5.5 mos for pts with standard-risk cytogenetic profiles, respectively. Median OS for all pts was 16.5 mos and was 13.2 mos in the high-risk pts vs 21.7 mos in the standard-risk pts. The type and incidence of grade 3 or 4 adverse events (AEs) were similar in the high-risk pts (n=29) and those with standard-risk (n=57). The most common grade 3/4 AEs were neutropenia (48% vs 40%, respectively), thrombocytopenia (31% vs 16%), anemia (24% vs 25%), pneumonia (21% vs 28%), dyspnea (17% vs 11%), and fatigue (10% vs 18%). Febrile neutropenia developed in 2 pts (7%) with high-risk cytogenetics and in none with standard cytogenetics. There were no cases of grade 3/4 deep vein thrombosis in high-risk pts vs 2 pts (4%) in pts with standard-risk cytogenetics. There were no cases of grade 3/4 peripheral neuropathy in either group. Twenty-one (19%) of the POM+LoDex-treated subjects died during the study; 6 (21%) in the high-risk group (MM, n=3; disease progression, n=1; cardio-respiratory distress, n=1; not specified, n=1), and 10 (18%) in the standard-risk group (MM, n=4; disease progression, n=1; infection, n=3; cerebral/subarachnoid hemorrhage, n=2). Conclusions: POM+LoDex treatment appears to be effective in MM pts with high-risk cytogenetic profiles and advanced disease. Although this subgroup of pts has a shorter duration of response compared with RRMM pts without high-risk cytogenetic abnormalities, pts with high-risk demonstrated an ORR of 23%, which is comparable to that expected for the overall population treated in this study, and is therefore encouraging. Longer follow-up for PFS and OS is needed to better assess clinical benefit, with combination approaches (such as with bortezomib) in this high-risk population warranting further study. Disclosures: Richardson: Celgene, Millennium, Johnson & Johnson: Advisory Board Other. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Jakubowiak:Onyx: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Bahlis:Celgene: Honoraria; Johnson and Johnson: Honoraria, Research Funding. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Chen:Johnson & Johnson, Celgene, GlaxoSmithKline: Research Funding; Johnson & Johnson, Lundbeck, Celgene: Consultancy; Roche: Honoraria. Chen:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Larkins:Celgene Corporation: Employment, Equity Ownership. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

Expanded Access Program Of Ponatinib (AP24534) For Patients (Pts) With Refractory Chronic Myeloid Leukemia (CML) Or Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4044-4044
Author(s):  
Ghayathri Jeyakumar ◽  
Hagop M. Kantarjian ◽  
Kendra L. Sweet ◽  
Cecilia Y Arana Yi ◽  
Nitin Jain ◽  
...  
Keyword(s):  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Philadelphia Chromosome ◽  
Disease Stage ◽  
Clinical Activity ◽  
Expanded Access ◽  
Expanded Access Program ◽  
T315i Mutation ◽  
Access Program

Abstract Background Ponatinib is a pan-BCR-ABL inhibitor with activity against BCR-ABL, including the TKI resistant T315I and all other clinically relevant mutant. The efficacy and safety of ponatinib (45 mg orally once daily) in pts with CML in chronic (CP-CML), accelerated (AP-CML), or blastic (BP-CML) phase, or Ph+ ALL were evaluated in an expanded access program. Methods 49 pts, including 24 CP-CML, 5 AP-CML, 8 BP-CML (100% Myeloid Blasts), and 12 Ph+ ALL were registered at 2 institutions. Pts were resistant or intolerant (R/I) to dasatinib or nilotinib, or had the T315I mutation at baseline. For this analysis, pts were grouped in cohorts according to the disease stage and presence or not of T315I. Results The median age for CP-CML, AP-CML, BP-CML, and Ph+ ALL pts was 44, 36, 56, and 57 yrs, respectively. Median yrs from diagnosis to start of ponatinib were 7, 1, 3 and 2, respectively. 94% had received imatinib, 80% dasatinib, 59% nilotinib, 2% bosutinib, and 24% had undergone prior SCT. Among 37 pts evaluable for response to prior dasatinib or nilotinib, 84% had history of resistance to these agents, 16% were intolerant. 92% pts had received at least 2 prior TKI, and 45% had received at least 3. Reported response rates with the most recent TKI were 63% (15/24) MCyR for CP-CML, and CHR 60% AP-CML, 0% BP-CML, 33% Ph+ ALL. After a follow-up of 9 months on therapy, 49% of CP-CML, 60% of AP-CML, 25% of BP-CML, and 9% of Ph+ ALL pts remain on study. The reasons for discontinuation were progressive disease (38%, 40%, 75%, and 83%, respectively) and adverse events (13%, 0%, 0% and 8%, respectively). Among the 49 pts, 58% (14/24) pts in CP-CML have achieved MCyR (46% CCyR). 60% (3/5) AP-CML achieved MCyR (2 of them CCyR), and 35% (7/20) BP/Ph+ALL achieved MCyR (5 of them CCyR). MMR is available by IS only for 40 pts and 26% achieved MMR, and at 9 mos. MMR was achieved by 21% CP, 0% in AP, 0% in BP-CML and 38% Ph+ ALL. The median PFS for all pts was 5.8 mos. Estimated PFS at 9 mos. was 50% overall, and 71% in CP, and 75% in AP, 25% in BP-CML and 17% in Ph+ ALL. In CP-CML, AP- CML, BP-CML and Ph+ALL the median PFS was estimated as 12.5 mos., 13.3 mos., 3.5 mos. and 1.4 mos. respectively. Overall median OS was not reached. The probability of OS at 9 mos. for all pts was 80%.; in CP-CML it was 100%, in AP-CML was 75%, in BP-CML 58% and in Ph+ ALL was 53% at 9 mos. The most common AEs were thrombocytopenia (18%), G1-2 rash (14%), and neutropenia (12%) and the G3-4 AEs were thrombocytopenia (4%) and pancreatitis (6%) with G3-4 lipase elevation 8% and G3 amylase 8%. Conclusions Ponatinib has clinical activity in refractory CML and pretreated Ph+ leukemia patients who have limited treatment options. The results of this expanded access study match those of the pivotal PACE trial confirming the clinical benefit with ponatinib in this setting. Disclosures: Kantarjian: ARIAD: Research Funding. Jabbour:Ariad, BMS, Novartis, and Pfizer: Consultancy. O'Brien:ARIAD: Research Funding. Pinilla:Ariad: Advisory Board Other, Research Funding, Speakers Bureau. Cortes:Ariad, Pfizer and Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.

Sequential Azacitidine and High-Dose Lenalidomide for Relapsed and Refractory High-Risk MDS and AML: Interim Analysis of a Phase 2 Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3746-3746
Author(s):  
Daniel A Pollyea ◽  
Clayton A. Smith ◽  
Vu H. Nguyen ◽  
Aaron Fullerton ◽  
Derek Schatz ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Renal Insufficiency ◽  
Stem Cell Transplantation ◽  
Disease Progression ◽  
Cell Transplantation ◽  
Median Number ◽  
High Dose ◽  
Phase 2 ◽  
Phase 2 Study

Abstract Introduction: Relapsed/refractory high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have a dismal prognosis with few conventional treatment options. Intensive therapies are often intolerable or ineffective. Previously, Pollyea et al reported a phase 1/2 study for elderly, newly diagnosed AML patients (pts) who were administered sequential azacitidine with high-dose lenalidomide; the maximum tolerated dose of lenalidomide was 50 mg for 21 days of a 6-week cycle, and the ORR was 40% with a 28% CR/CRi rate (Leukemia 2012 893 and Haematologica 2013 591). Based on the efficacy and tolerability of this regimen, we designed a single-center phase 2 study for high-risk MDS and AML pts with relapsed/refractory disease. Methods: The primary objective was to evaluate the efficacy of this regimen in this population. Secondary objectives included safety, response duration, progression-free survival/overall survival, the number of eligible pts able to proceed to transplantation, and correlative outcomes. The schema involved azacitidine 75 mg/m2 d1-7 followed by lenalidomide 50 mg d8-28; d29-42 was a recovery period for a total 42-day cycle. Cycles could be repeated indefinitely in the absence of excessive toxicity or disease progression. Pts were ≥18 with relapsed/refractory high-risk MDS or AML. The study was designed to maximize inclusion to approximate a real-world clinical population, but pts with extensive organ dysfunction or hyperproliferative disease that was not controllable with hydroxyurea were excluded. Using a Simon two-stage minimax design, 37 pts are required to double the null hypothesis, a 15% CR/CRi rate. At least 2 of the first 18 pts must achieve a CR/CRi to justify proceeding to the second stage of the study; interim results are presented here. Results: Nineteen pts have been enrolled as of July 1 2014, with a median follow-up of 78 days. 16 are evaluable; 3 did not complete a full cycle, the protocol-defined minimum to be evaluable, due to disease progression. The median age was 73 (18-86). 16 were male; 16 had AML and 3 had high-risk MDS. The median number of prior therapies was 1 (range 1-5). All MDS patients had failed a hypomethylator. Three had relapsed after allogeneic stem cell transplantation. Using European LeukemiaNet cytogenetic and molecular prognostic data, 1 pt was considered favorable, 2 were intermediate-1, 4 were intermediate-2 and 12 were adverse. Five had a monosomal karyotype; 1 had a del(5q) as part of a complex karyotype. The median number of cycles received was 1 (0-4). Adverse events (AEs) were reported according to the NCI CTCAE v4.0. There were 114 independent possibly related AEs; the most common AEs (>25% of pts) were constipation (9/19, 47%), anemia (7/19, 37%), diarrhea (7/19, 37%), dizziness (7/19, 37%), abdominal pain (6/19, 32%), hypoxia (6/19, 32%), injection site reactions (6/19, 32%), anorexia (6/19, 32%), pruritus (6/19, 32%), pneumonia (5/19, 26%), nausea (5/19, 26%), thrombocytopenia (5/19, 26%) and hypotension (5/19, 26%). The possibly related ≥ grade 3 AEs (reported as total number of events) were: thrombocytopenia (n=9), febrile neutropenia (n=6), anemia (n=6), leukopenia (n=4), neutropenia (n=4), weakness (n=4), renal insufficiency (n=1) and pruritus (n=1). Three pts required a 50% dose reduction of lenalidomide for renal insufficiency (n=1), rash/GVHD flare (n=1) and fatigue (n=1), and 8 held lenalidomide for at least 2 days during at least 1 treatment cycle. The ORR was 50% (8/16) for evaluable patients and 42% (8/19) for all patients. 43% (7/16) of evaluable patients had a CR/CRi (n=2 CR, including 1 complete cytogenetic remission, n=5 CRi). There was 1 PR. 2/3 high-risk MDS patients responded (both CRi). The median time to achieve best response was 1.5 months. Lower baseline bone marrow blasts were predictive of response. Median OS was 91 days; 569 days for responders and 71 days for non-responders. 12 pts died; 1 was treatment related (renal failure) and 11 were disease related. Early death rate (death in the first 30 days) was 17% (2/12). 2/6 pts felt to be eligible for a stem cell transplantation were able to use this regimen as a bridge to this therapy. Conclusions: The requisite number of responders to proceed to the second phase of the study was reached. Sequential azacitidine and high-dose lenalidomide has activity in relapsed/refractory AML and high-risk MDS; updated clinical results and correlative studies will be presented. Disclosures Pollyea: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Lenalidomide for AML/non del-5q MDS.

Donor Lymphocyte Infusion after Haploidentical Transplantation with Post-Transplant Cyclophosphamide

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5863-5863 ◽  
Author(s):  
Clemence Roux ◽  
Samia Harbi ◽  
Raynier Devillier ◽  
Faezeh Legrand ◽  
Sabine Fürst ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Disease Progression ◽  
Cell Transplantation ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis

Abstract Background Although allogeneic hematopoietic stem cell transplantation (alloSCT) is a curative option to treat hematologic malignancies, disease recurrence remains a concern in the setting of high risk diseases. Thus, post alloSCT therapeutic strategies are needed to treat and/or prevent disease progression. In this setting, donor lymphocytes infusion (DLI) is an option as post alloSCT immunotherapy aiming to enhance graft versus leukemia (GVL) effect. Although DLI may induce persistent remission, graft versus host disease (GVHD) is a potential complication following DLI. Because of the suspected higher incidence of GVHD in the presence of HLA mismatches, few series focused on DLI following haploidentical stem cell transplantation (HaploSCT) so far. We therefore report our experience of DLI following HaploSCT using post-transplantation cyclophosphamide (PT-Cy) platform. Methods: We included in this single center study all consecutive adult patients with hematological malignancies who received DLI after HaploSCT with PT-Cy as part of GVHD prophylaxis from 2013 to 2016 (n=21). Conditioning regimens were non-myeloablative (low dose TBI-based) or with reduced toxicity (various dose of busulfan according to disease and patient characteristics). Ciclosporine A and mycophenolate mofetil were given as additional GVHD prophylaxis in all cases. DLI were given at escalating doses, expressed as CD3+cells/kg, without GVHD prophylaxis, and ranged from 1x105 to 5x107 cells/kg. Results: Eleven patients (52%) were transplanted for high risk disease according to the disease risk index (DRI, Armand et al., blood 2015). Twelve patients (57 %) received haploSCT in complete remission,.18 patients received first transplant and 3 patients their second transplant. After HaploSCT, 21 patients (median age: 56 years [range: 23-73]) received either therapeutic (treatment of hematological post transplantation relapse, n=6) or prophylactic (n=15) DLI. The median interval from HaploSCT to the first DLI was 128 days (range: 79-1011). The average number of DLI per patient was 1.8 (range, 1-3). Clinical characteristics are outlined in Table 1. Patients with AML and MDS received DLI alone (n = 13) or in association with azacytidine (n = 2). Patients with MM received DLI in association with Revlimid (n=3). Chimerism before first DLI was complete in 19 patients. 6 patients (33%) developed post DLI GVHD in a median time of 42 days (range: 30-210) with exclusively chronic features. 2 patients (9 %) had severe forms of chronic GVHD. GVHD-related death occurred in 1 patient No response was achieved when DLI were given as therapeutic and 4 of 6 patients died from disease progression. Otherwise, only 3 of 16 patients who received prophylactic DLI experienced relapse. With a median follow up of 129 days, overall survival was 63%. Conclusion Our study suggests that DLI following HaploSCT with PT-Cy is feasible. GVHD is frequent but with a relatively low incidence of severe forms. No response rate was achieved in the context of hematological relapse, underlining that preemptive or prophylactic strategy might be preferred. Indeed, the overall good outcome in patients receiving prophylactic DLI is promising taking into account the poor prognostic of the diseases indicated for alternative donor transplantation. Further prospective studies are needed in specific disease settings to assess the benefit for using such post alloHSCT immune-intervention. Table 1 Table 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Safety and Varicella Outcomes in In Utero–Exposed Newborns and Preterm Infants Treated With Varicella Zoster Immune Globulin (VARIZIG): A Subgroup Analysis of an Expanded-Access Program

2019 ◽  
Vol 9 (4) ◽  
pp. 449-453 ◽  
Author(s):  
Jennifer M Duchon ◽  
Myron J Levin ◽  
Anne A Gershon
Keyword(s):  
High Risk ◽  
Preterm Infants ◽  
Immune Globulin ◽  
In Utero ◽  
Open Label ◽  
Varicella Zoster ◽  
Expanded Access ◽  
Expanded Access Program ◽  
High Risk Infants ◽  
Access Program

Abstract Background Infants exposed to varicella zoster virus (VZV) in utero ≤5 days before or ≤48 hours after delivery and preterm infants are at high risk for varicella complications. An expanded-access program assessed varicella outcomes after administration of varicella zoster immune globulin (human) (VARIZIG) in a real-world setting. Methods In this open-label, expanded-access program, high-risk infants received ≤125 IU/10 kg of VARIZIG (NCT00338442). VZV outcomes and safety were assessed. Results There were 43 newborns exposed to VZV in utero and 80 preterm infants exposed to VZV; &gt;80% received VARIZIG within 96 hours of reported exposure. When varicella outcomes were available, varicella occurred in 7 of 38 (18%) in utero–exposed newborns and zero of 65 preterm infants. Varicella-related complications were reported in 3 in utero–exposed newborns (3 with &gt;100 lesions, 1 each with encephalitis and pneumonia). Adverse events were reported for 16% of in utero–exposed newborns and 25% of preterm infants, but few were considered related to VARIZIG. There were no deaths attributable to varicella or VARIZIG. Conclusions Varicella incidence and morbidity were low in in utero–exposed infants and zero in preterm infants who received prophylactic VARIZIG. There were few VARIZIG-related safety concerns.

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