Lenalidomide Therapy in Nine Patients with POEMS Syndrome.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3872-3872 ◽  
Author(s):  
Arnaud Jaccard ◽  
Julie Abraham ◽  
Christian Recher ◽  
Remy Dulery ◽  
Isabelle Guichard ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Plasma Cells ◽  
High Dose Chemotherapy ◽  
Poems Syndrome ◽  
Bone Lesions ◽  
High Dose ◽  
Advisory Committees ◽  
Sclerotic Bone Lesions ◽  
Vegf Level

Abstract Abstract 3872 Poster Board III-808 Introduction POEMS syndrome is a rare disease characterized by peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cells, skin changes, papilledema, volume overload, sclerotic bone lesions, thrombocytosis, and high serum VEGF level. Efficient treatments consist in irradiation for patients with localized solitary plasmocytoma and high-dose chemotherapy with autologous stem cell transplantation for appropriate candidates without a focal lesion. Conventional myeloma chemotherapy can only control the disease in a limited number of patients. Results of monoclonal anti-VEGF antibodies, which seem to be attractive due to the role of VEGF in this disease, are controversy with efficacy in 3 patients but treatment related deaths in 2 other patients. Thalidomide effectiveness has been reported in Japanese patients but enthusiasm for its use is tempered by the high incidence of thalidomide-induced peripheral neuropathy. Lenalidomide, which efficacy has been described in one observation (Dispenzieri, Blood 2007 110: 1075-1076), has the advantage of being anti-angiogenic, cytotoxic to malignant plasma cells and with a much lower risk of peripheral neuropathy. We reported here a multicentric French experience with this drug in POEMS syndrome. Patients and Methods There were 3 women and 6 men treated with Lenalidomide in 7 French centres. Median age was 60 (41-76). All patients had sensitive polyneuropathy with motor deficiency in 5 patients. A monoclonal component was present in all cases (IgA lambda in 7 patients, IgG lambda and lambda light chain only in 1 patient each). Other manifestations of POEMS syndrome included sclerotic bone lesions in 6 patients, endocrinopathies in 7 patients, skin changes in 8 patients, oedema in 7 patients, organomegaly in 5 patients, papilledema in 5 patients, thrombocytosis in 3 patients. VEGF serum level was elevated in 4 among 5 patients with a dosage. Previous treatments were high-dose chemotherapy with autologous stem cell transplantation in 3 patients, Melphalan-Prednisone in 3 patients because of advanced age, and prolonged steroid treatment in 2 patients. One patient received Lenalidomide as primary treatment before high-dose therapy. Lenalidomide was given during 21 days each month and sequentially associated with dexamethasone, 5 patients received 25 mg/day and 4 patients received 10 or 15 mg, for a median of 5 cycles (1 to 11). Results Serious side effects were noted in 3 patients with 2 hematologic toxicities (grade III and IV) and a cutaneous allergy. Six patients could be evaluated for hematologic response and all responded, complete response in 3 patients and partial in 3 (>25%). Clinical responses occurred early, before 3 months of treatment, in 6 cases among 8 (1 patient is not yet evaluable), with a marked improvement in performance and in neurological syndrome. Other manifestations of POEMS syndrome improved, especially oedema in 5 cases among 6. VEGF level (normal value < 500 pg/ml) could be serially measured in 4 patients with a normalization in 1 patient and a significant decrease in 3 patients, median 7100 pg/ml (2100-10100) before treatment to 887 pg/ml (304-3270). In 1 of these 3 patients VEGF level increased to initial value while he was still taking Lenalidomide. A second patient experimented a relapse 5 months after ending Lenalidomide, he is still in good response after Lenalidomide reintroduction. With a median follow-up of 12 months (1-26) all patients are alive. Conclusion Lenalidomide seems to be a very promising therapy in POEMS syndrome. It should be tested in larger studies in patients with a systemic disease, who are not able to receive high dose therapy, in relapsing patients and before high dose treatment to avoid transplant related morbidity, particularly engraftment syndrome. Disclosures: Jaccard: Celgene: Membership on an entity's Board of Directors or advisory committees. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees and Speakers Bureau. Moreau:Celgene: Membership on an entity's Board of Directors or advisory committees. Fermand:Celgene: Speakers Bureau.

POEMS Syndrome

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 360-367 ◽  
Author(s):  
Angela Dispenzieri
Keyword(s):  
Peripheral Neuropathy ◽  
Chronic Inflammatory Demyelinating Polyneuropathy ◽  
Early Recognition ◽  
Correct Diagnosis ◽  
Bone Lesion ◽  
High Dose Chemotherapy ◽  
Poems Syndrome ◽  
Bone Lesions ◽  
High Dose ◽  
Sclerotic Bone

Abstract POEMS syndrome is defined by the presence of a peripheral neuropathy (P), a monoclonal plasma cell disorder (M), and other paraneoplastic features, the most common of which include organomegaly (O), endocrinopathy (E), skin changes (S), papilledema, edema, effusions, ascites, and thrombocytosis. Virtually all patients will have either sclerotic bone lesion(s) or co-existent Castleman’s disease. Not all features of the disease are required to make the diagnosis, and early recognition is important to reduce morbidity. Other names for the syndrome include osteosclerotic myeloma, Crow-Fukase syndrome, or Takatsuki syndrome. Because the peripheral neuropathy is frequently the overriding symptom and because the characteristics of the neuropathy are similar to that chronic inflammatory demyelinating polyneuropathy (CIDP), patients are frequently misdiagnosed with CIDP or monoclonal gammopathy of underdetermined significance (MGUS)-associated peripheral neuropathy. Not until additional features of the POEMS syndrome are recognized is the correct diagnosis made and effective therapies initiated. Clues to an early diagnosis include thrombocytosis and sclerotic bone lesions on plain skeletal radiographs. Therapies that may be effective in patients with CIDP and MGUS-associated peripheral neuropathy (intravenous gammaglobulin and plasmapheresis) are not effective in patients with POEMS. Instead, the mainstays of therapy for patients with POEMS include irradiation, corticosteroids, and alkylator-based therapy, including high-dose chemotherapy with peripheral blood stem cell transplantation.

Engraftment Syndrome Is Common in Patients with POEMS Syndrome Undergoing PBSCT.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2995-2995
Author(s):  
Angela Dispenzieri ◽  
Martha Q. Lacy ◽  
Suzanne R. Hayman ◽  
Shaji K. Kumar ◽  
Francis Buadi ◽  
...  
Keyword(s):  
Plasma Cells ◽  
Volume Overload ◽  
Poems Syndrome ◽  
Bone Lesions ◽  
Post Transplant ◽  
Gm Csf ◽  
Engraftment Syndrome ◽  
Sclerotic Bone Lesions ◽  
Definition Of ◽  
Discharge From Hospital

Abstract Background: POEMS syndrome is a devastating syndrome, characterized by peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cells, skin changes, papilledema, volume overload, sclerotic bone lesions, thrombocytosis, & high VEGF. We noted an unexpectedly high transplant related morbidity, which we have since postulated to be ES. Methods: 30 patients with POEMS were treated with PBSCT at Mayo Clinic Rochester. We retrospectively studied outcomes, with an emphasis on treatment related morbidity. Two definitions of ES were used: Spitzer (BMT 2001) and Maiolino (BMT 2003). Results: Two-thirds were male. Median age was 48, range 20–70. Time from first symptoms and diagnosis was 26 and 4 months, respectively. To mobilize stem cells, CTX/G-CSF was used in 5 & G-CSF in the remainder. Conditioning was Mel200 (n=19), Mel140 (n=10), and BEAM (n=1). Post-transplant 15 had GM-CSF begun day+6. Only 10% remained outpatient, and median time to discharge from hospital was transplant day 17 (range 0–175). Factors predicting for later dismissal included age (p=0.04), abnormal CXR 7 to 17 days post transplant (p<0.0001), & bolus corticosteroids (CS) beyond day 12 post-transplant (p=0.006). Ninety-three percent had fever, although only 9 had bacteremia. Eight satisfied criteria for ES according to Spitzer and 14 according to Maiolino. Another 3 patients received steroid bolus days 8, 12, and 11 for presumed ES but did not meet criteria because of delayed ANC recovery (days 16, 18, and 20, respectively). Of the 5 patients requiring endotracheal intubation, 3 satisfied Maiolino’s criteria for ES. Although these 3 received bolus CS during their course, administration was delayed at 18, 14, and 18 days. The patient whose CS bolus antedated intubation only received prednisone 30 mg/day. In toto, fourteen patients received bolus CS (daily doses between 20 and 1200 mg prednisone equivalents) commencing day 8 to 59. Those 7 patients who received CS before day 13 did better than the 7 who received them day 13 or later (Table). Conclusions: It is essential to recognize that nearly 50% of patients satisfied formal criteria for ES as defined by Maiolino. In these patients ES may run a self-limited course or lead to catastrophe. No Steroid (n=16) Steroid ≤ D12 (n=7) Steroid > D12 (n=7) P *Engraftment syndrome according to definition of Maiolino (M) or of Spitzer (S). ES M / S, n* 5 / 2 4 / 4 5 / 2 NA Wt change, % 0.6 (−.4.2–6.7) 6.7 (3.6–27.2) 11.2 (–2.1–23.2) 0.005 Rash, % 27 71 43 0.13 Diarrhea, % 73 86 86 0.71 Tmax, C 39 (37.8–41) 40.1 (39–41.1) 38.9 (38.7–40.8) 0.08 1st fever, day 10 (6–15) 8 (7–9) 12 (8–146) 0.007 Abn CXR1, % 13 71 71 0.03 Ventilator, % 0 14 71 0.004 First WBC, day 12 (8–21) 14 (12–14) 14 (12–17) 0.03 ANC500, day 15 (12–29) 16 (14–115) 18 (15–45) 0.08 PLT20, day 12 (8–41) 20 (11–115) 24 (9–170) 0.05 PLT50, day 15 (11–192) 32 (16–115) 56 (13–551) 0.03 RBCs, units 3 (2–8) 6 (4–31) 11 (6–64) 0.0008 PLTS, aph. units 2 (1–9) 9 (4–51) 18 (4–60) 0.0004 Hosp dsm, day 15 (13–36) 21 (15–69) 41 (16–175) 0.009

A Retrospective Study on Safety, Efficacy and Cost of the Chemo-Mobilization for Patients Planned to Undergo Autologous Hematopoietic Stem Cell Transplant: The Secom Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5903-5903
Author(s):  
Surapol Issaragrilsil ◽  
Yeow-Tee YT Goh ◽  
Anskar Y.H. Leung ◽  
S Fadilah S Abdul Wahid ◽  
Hwai Tzeng Cheng
Keyword(s):  
Stem Cell ◽  
Febrile Neutropenia ◽  
Board Of Directors ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Asian Countries ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Grade 3 ◽  
The Cost

Abstract Introduction: Failure of hematopoietic stem cell (HSC) mobilization occurs in 5 to 30% patients planning for high dose chemotherapy and autologous HSC transplantation worldwide. It has adverse impact on patient outcomes and significantly increases health care burden. Data regarding HSC mobilization based on chemotherapy + granulocyte colony stimulating factor (G-CSF) in Asia are currently limited. Objective: The primary objective was to determine the safety and efficacy of HSC chemo-mobilization protocols in Asia for patients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM) planning for autologous HSCT. The secondary objective was to provide an estimate of the cost of chemo-mobilization in Asian countries Study Design: This was a multicenter, multinational retrospective observational study. Patients with NHL or MM undergoing chemo-mobilization for planned autologous HSCT between 1 Jan 2009 to 31 Dec 2012 in five Asian countries including Thailand, Singapore, Malaysia, Hong Kong and Taiwan, were retrospectively included in the study. Patient demographics, disease diagnoses, previous treatment history as well as complete blood counts prior to chemo-mobilization and apheresis, were collected. Results: A total of 526 patients (male/female = 207/219) were analyzed (diagnoses: NHL=257; MM=269). 160 patients were recruited from Thailand, 98 from Malaysia, 161 from Taiwan, 59 from Singapore and 48 from HK. Median age for the overall group was 53 years (range: 15-82). The most common mobilization regimen was cyclophosphamide + G-CSF; 235 (87.4%) in MM and 72 (28%) in NHL patients. 448 (85.2%) patients had reached at least HSC yield of 2 x 106CD 34+ cells/kg in 1 or 2 apheresis days. During chemo-mobilization, 108 (20.5%) patients were without negative clinical events (grade 3/4 neutropenia, febrile neutropenia, prolonged hospitalization, bone pain, fever, gastrointestinal, line infections or others). Grade 3/4 neutropenia and febrile neutropenia occurred in 401 (76.2%) and 72 (13.7%) patients, respectively. Median number of apheresis sessions was 2 (range: 1-5). Median cost of mobilization was 6,200USD (9,000-48,000). The respective median costs in USD (range) was; 3,500 (1,500-28,500) in Thailand, 6,900 (2,300-29,600) in Malaysia, 7,700 (3,400-48,000) in Taiwan and 9,200 (900-45,400) in Singapore. 436 (82.9%) patients proceeded to receive high dose chemotherapy and HSCT but 94 (17.87%) patients did not, due to insufficient HSC yield (n=26, 4.94 %), progression of disease (n=18, 3.42 %), patient not fit/ withdrawal from study (n=19, 3.61 %), patient expiry (n=11, 2.09 %) and other reasons (n=20, 3.80 %). Conclusion: Cyclophosphamide and G-CSF is the most common mobilization regimen used in Asian countries. Current chemo mobilization regimens are associated with a satisfactory rate of successful stem cell collection but with a high rate of significant toxicity. More than three-quarter of patients suffered from grade 3/4 toxicity during chemo-mobilization, however, only 20% of them had febrile neutropenia. Variations exist in the cost of chemo-mobilization in Asia, both among and within countries. Disclosures Goh: Novartis Pte Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceuticals Inc: Research Funding; Bristol-Myres Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hospira Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals POEMS Syndrome: A Report of 14 Cases and Review of the Literature

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Zong Fei Ji ◽  
Dan Ying Zhang ◽  
Shu Qiang Weng ◽  
Xi Zhong Shen ◽  
Hou Yu Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cells ◽  
Clinical Manifestations ◽  
High Dose Chemotherapy ◽  
Castleman Disease ◽  
Response To Therapy ◽  
Poems Syndrome ◽  
Plasma Cell Dyscrasia ◽  
High Dose ◽  
Paraneoplastic Disorder

POEMS syndrome is a rare paraneoplastic disorder associated with an underlying plasma cell dyscrasia presenting polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes. This study reviewed the clinical characteristics of 14 POEMS patients in Zhongshan hospital. The ratio of male to female was 9 : 5, and the average age was 47.1 years. The clinical manifestations were various, including motorial symptoms (weakness), sensory symptoms (numbness), lymphadenopathy, edema, abdominal distention, and skin hyperpigmentation. Imaging studies and laboratory tests also exhibited hepatomegaly, splenomegaly, thrombocytosis, endocrinopathy, and positive serum immunofixation in most patients. In addition, increased plasma cells in bone marrow and Castleman Disease were found in bone marrow and lymph nodes biopsies. All the eight follow-up patients were treated with alkylator-based combination chemotherapy or corticosteroids and thalidomide, with or without autologous stem cell transplantation. Unfortunately, two patients died three or four years after diagnosis of POEMS syndrome. The others showed response to therapy to some extent, but not completely remission. Currently, treatments for POEMS include radiation to the plasmacytoma, and systemic therapy is indicated. Low-dose alkylators with or without corticosteroids are effective in some patients. However, high-dose chemotherapy with auto-SCT dramatically improved symptoms and outcomes for POEMS patients.

scholarly journals Long-Term Durable Responses after Autologous Stem Cell Transplantation in POEMS Syndrome

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4606-4606
Author(s):  
Neeraj Y Saini ◽  
Romil Patel ◽  
Ankur Varma ◽  
Qaiser Bashir ◽  
Omar Hasan ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Median Number ◽  
Castleman Disease ◽  
Poems Syndrome ◽  
Bone Lesions ◽  
Advisory Committees ◽  
Entire Cohort ◽  
The Mean

Abstract Abstract: Background: POEMS syndrome is a constellation of symptoms of polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. Other features often present in this syndrome include papilledema, extravascular volume overload, sclerotic bone lesions, Castleman disease, high vascular endothelial growth factor (VEGF) levels and thrombocytosis/polycythemia. The standard of care has not been established in the management of the disease. We had previously reported on the role of auto-HCT in a smaller cohort of POEMS patients at our institution1. Here, we present an updated analysis in a larger cohort of POEMS patients who underwent auto-HCT. Methods: We retrospectively reviewed the outcomes of POEMS patients who underwent auto-HCT at our institution from the period of January, 1999, through June, 2018. The Kaplan-Meier method was used to caculate progression-free survival (PFS) and overall survival (OS). Hematologic response was defined as per the International Myeloma Working Group (IMWG) criteria. OS was defined as the duration from the date of transplant to death or last date of follow-up in alive patients. PFS was defined as the duration from the date of transplant to either progressive disease or death, whichever occurred first. Results: 16 patients (13 males, 3 females) with POEMS syndrome received a total of 17 auto-HCTs. One patient underwent auto-HCT two times for multiple relapses. The median age at auto-HCT was 48 years (range: 18-75). The median time from diagnosis to auto-HCT was 15 months (2-141 months). All 16 (100%) patients had peripheral neuropathy and monoclonal gammopathy: IgG lambda in 7, IgA lambda in 6, IgG kappa in 2 and light chain in 1 patient. Other features were: osteosclerotic bone lesions in 13 (81%), endocrinopathy in 10 (69%), skin involvement in 8 (50%) and extravascular fluid overload in 7 (44%). Three (18%) patients had biopsy-proven co-existent Castleman disease. Among patients with available data (n=7), the mean serum VEGF level pre-transplant was 389 pg/ml (268-1622). The median HCT-CI (comorbidity index) score available for 15 patients was 2 (range 0-7). The median number of chemotherapies received before the transplant was 1 (range 1-3). Table 1 summarizes the prior systemic chemotherapies received before auto-HCT. Two patients also received plasmapheresis, and eight patients received radiation therapy for bone disease. The mobilization regimens used for collecting peripheral blood stem cells were granulocyte colony-stimulating factor (G-CSF) alone, cyclophosphamide+G-CSF and G-CSf+plerixafor in 16, 2 and one patient, respectively. The median number of CD34+ stem cells collected was 3.43 X 106 cells/kg (range 1.73 - 6.5). The overall response rate, as per the IMWG criteria, for the entire cohort was 94% (16/17): 5 (29.4%) CR, 4 (23.5%) nCR, 1 (5.8%) VGPR, and 6 (35.2%) PR. The mean serum VEGF levels improved from 389 pg/ml before transplant to a level of 35 pg/ml (31-86) post-transplant. Engraftment syndrome was seen only in 1 patient who required corticosteroid use. One-year transplant-related mortality was 0%. Median follow-up among surviving patients is 52 months (5-120 months). The median PFS and OS have not been reached yet. All 16 patients had a complete or partial resolution of their clinical symptoms after auto-HCT. 4-year PFS and OS rate for the entire cohort is 80.2% and 100% respectively. At ten years, PFS and OS rate is 59.4% and 80% respectively. Fourteen out of 16 patients were alive at the time of the last follow-up. One patient died six years after his auto-HCT secondary to gastrointestinal bleeding unrelated to his underlying disease, and the second patient died after 11 years post auto-HCT of unknown cause. Conclusions: Upfront Auto-HCT provides durable chemotherapy free remission and significant clinical improvement in patients with POEMS syndrome. References: Patel, K. et al. Durable responses with autologous hematopoietic SCT in patients with POEMS syndrome. Bone marrow transplantation49, 465-6 (2014). Figure. Figure. Disclosures Thomas: Acerta Pharma: Research Funding; Amgen Inc: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Celgene: Research Funding; Array Pharma: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Poseida: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy; Janssen Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioTheryX, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millenium Pharmaceuticals: Consultancy, Research Funding. Champlin:Sanofi: Research Funding; Otsuka: Research Funding. Patel:Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

Efficacy of Panobinostat in Phase II Study in Patients with Relapsed/Refractory Hodgkin Lymphoma (HL) After High-Dose Chemotherapy with Autologous Stem Cell Transplant.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 923-923 ◽  
Author(s):  
Anas Younes ◽  
Tee-Chuan Ong ◽  
Vincent Ribrag ◽  
Andreas Engert ◽  
Dina Ben-Yehuda ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
High Dose Chemotherapy ◽  
Tumor Burden ◽  
Clinical Activity ◽  
High Dose ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Dose Delay

Abstract Abstract 923 Introduction: Panobinostat (LBH589) is a pan-deacetylase inhibitor (pan-DACi), targeting epigenetic and non-epigenetic oncogenic pathways. In vitro, panobinostat decreases proliferation and induces apoptosis in Hodgkin lymphoma (HL) cell lines at low nanomolar concentrations. Encouraging clinical activity (objective response rate ∼40%) has been demonstrated in patients with HL who are enrolled in an ongoing Phase I study in hematologic malignancies (DeAngelo et al. EHA 2009, Abstract #1064). Methods: Utilizing a Simon two-stage design, the study will determine the efficacy of panobinostat in patients with HL with refractory/relapsed disease following high-dose chemotherapy and autologous hematopoietic stem cell transplant (AHSCT). Oral panobinostat is administered at a dose of 40 mg three times per week, every week in 21-day cycles. Treatment is continued until disease progression or intolerance. Dose delay and modification for toxicity is allowed. CT/MRI scans are conducted after every 2 cycles. Modified Cheson criteria are used to determine overall response. Results: As of July 10, 2009, 61 patients have been enrolled and treated: median age 31 years [range 18–70]; 29 male, 32 female; 48% Stage III/IV at initial diagnosis; 41% had ≥5 prior lines of therapy; median number of prior regimens is 4 (range 2–6). Of 61 patients, 53 have completed ≥2 cycles of therapy and have had ≥1 post baseline CT/MRI. Responses include one complete response (CR) and 10 partial responses (PR), with up to 92% decrease in tumor burden. Thirty-one patients had SD, of which 25 had reduction in tumor burden (up to 48%). The disease control rate (CR+PR+SD) is 79%. The CR was achieved after 4 cycles of therapy. The patient required dose reduction but continues on the study (>12 cycles) and has maintained CR with no signs of active disease on CT and PET. Another responder with mixed cellularity HL was refractory to prior systemic treatments but has maintained PR on panobinostat and continues on the study (>14 cycles). Median treatment duration is 89+ days (range 5–300+ days), and 27 of the 61 treated patients still continue on study. Common Grade 3/4 adverse events, which were suspected to be related, are thrombocytopenia (77%), anemia (20%), and neutropenia (16%). Thrombocytopenia was observed to be reversible with platelet recovery 7–8 days after drug hold (panobinostat T1/2 ∼16 hours). Conclusion: Panobinostat has demonstrated encouraging clinical activity in heavily pretreated patients with post-transplant, refractory/relapsed, classical HL. Panobinostat is generally well tolerated with reversible thrombocytopenia as the primary toxicity managed by dose delay/reduction. Stage 1 has been successfully completed with positive results. Enrollment to Stage 2 continues. Updated efficacy and safety data will be presented at the meeting. Disclosures: Younes: Novartis: Honoraria. Off Label Use: The data presented is related to investigational unapproved drug.. Ribrag:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; servier: Consultancy, Research Funding; celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Research Funding; J&J: Membership on an entity's Board of Directors or advisory committees; Biogene Idec: Membership on an entity's Board of Directors or advisory committees. McCabe:Novartis: Employment. Shen:Novartis: Employment. Le Corre:Novartis: Employment. Hirawat:Novartis: Employment. Sureda:Novartis: Consultancy, Honoraria.

Infusion of Ex Vivo Expanded Allogeneic Cord Blood-Derived Natural Killer Cells in Combination with Autologous Stem Cell Transplantation for Multiple Myeloma: Results of a Phase I Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 929-929 ◽  
Author(s):  
Nina Shah ◽  
Li Li ◽  
Indreshpal Kaur ◽  
Jessica McCarty ◽  
Eric Yvon ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Nk Cells ◽  
Board Of Directors ◽  
Research Funding ◽  
Ex Vivo ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background: Multiple myeloma (MM) is an incurable disease thought to be characterized by immune dysregulation and exhaustion, whereby proliferation of malignant plasma cells is not checked by the native immune system. Long term remissions in some patients after allogeneic stem cell transplant (SCT) suggest a graft versus myeloma effect; however the treatment-related toxicity limits the widespread use of this modality. Allogeneic natural killer (NK) cells are active in various hematologic malignancies and may have a role against MM, without concomitant graft versus host disease (GVHD). Umbilical cord blood is a potential source for allogeneic NK cells and ex vivo expanded umbilical cord blood-derived NK (CB-NK) cells demonstrate activity comparable to that of peripheral blood-derived NK cells. We describe here the results of a phase I, first-in-human study of ex vivo expanded allogeneic CB-NK cells in conjunction with high dose chemotherapy and autologous SCT. Methods: Patients with symptomatic MM who were appropriate candidates for high dose chemotherapy and autologous SCT were eligible. CB units with at least 4/6 match at HLA-A, B and DR were chosen for each patient. When possible, CB units with potential NK alloreactivity were prioritized. On day (-19) CB units were thawed and mononuclear cells (MNCs) were isolated by ficoll density gradient centrifugation. MNCs were cultured in a gas permeable bioreactor with irradiated (100 Gy) K562-based aAPCs expressing membrane bound IL-21 "Clone 9.mbIL21" (2:1 feeder cell:MNC ratio) and IL-2 (100 IU/mL). On day 7, cells were CD3-depleted via immunomagnetic depletion and remaining cells were re-stimulated with aAPC feeder cells and cultured for an additional 7 days. NK cell purity was determined after 14 days of culture. Due to pre-clinical data demonstrating synergy between lenalidomide and NK cells, patients received lenalidomide (10 mg orally daily) from days (-8) to day (-2). Melphalan 200 mg/m2 was given intravenously on day (-7). Freshly expanded CB-NK cells were infused on day (-5). Autologous peripheral blood progenitor cells (PBPC) were infused on day (0). Results: 12 patients have been enrolled thus far with 3 patients each on the following CB-NK cell dose levels: 5 e6 NK cells/kg, 1 e7 NK cells/kg, 5 e7 NK cells/kg and 1 e8 NK cells/kg. 11/12 patients had at least 1 high-risk feature of progressed/relapsed disease (n=7), high-risk cytogenetics (n=2) or International Staging System III disease (n=3). Successful NK expansion to target dose was achieved in all patients with median NK purity (CD56+/CD16+/CD3-) of 98.9% (96.8-99.7). Expanded cells demonstrated cytotoxicity against classic K562 and MM cell line targets. There were no infusional toxicities and no occurrence of GVHD. One patient (1 e8 NK cells/kg) failed to engraft due to a poor PBPC graft quality; this patient was rescued with a back-up autologous PBPC graft. There have been no other significant adverse events and no second primary malignancies. 11/12 patients are evaluable beyond day 100. Best response has been 8/12 nCR or better, 2/12 VGPR and 1/12 PR. 4/12 patients have progressed at a median of 330 days. By DNA microsatellite chimerism analysis, donor CB-NK cells were detected in 2 patients at the 1 e7 NK cells/kg dose and all 3 patients in the 1 e8 NK cells/kg dose, for at least 5 days after infusion. By a more sensitive flow cytometric chimerism assay using HLA class I-specific antibodies for donor or recipient, donor CB-NK cells were detected in 3 evaluable patients at doses of 1 e7 NK cells/kg, 5 e7 NK cells/kg and 1 e8 NK cells/kg for at least 12 days after infusion. Further analysis of these cells indicated persistence of an activated phenotype (NKG2D+/NKp30+) in vivo. Conclusion: CB-NK cells can be activated and expanded to clinical scale. This is the first clinical study of CB-NK cells for MM. When infused in the setting of myeloablative chemotherapy, up to 1 e8 allogeneic CB-NK cells/kg are well tolerated with no infusional toxicities or GVHD. These cells can persist for at least 12 days in vivo and demonstrate an active phenotype. Though clinical data are early, responses are encouraging in this high-risk patient population. Further updated data will be presented at the annual meeting. Disclosures Off Label Use: Lenalidomide with high dose chemotherapy and autologous stem cell transplantation. Kaur:UT MD Anderson Cancer Center: Employment. Orlowski:Millennium Pharmaceuticals: Consultancy, Research Funding; BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Onyx Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Acetylon: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Array BioPharma: Consultancy, Research Funding; Forma Therapeutics: Consultancy. Cooper:Intrexon: Equity Ownership, Patents & Royalties, Research Funding; ZIOPHARM Oncology: Employment, Equity Ownership, Patents & Royalties, Research Funding. Lee:Cyto-Sen: Equity Ownership; Ziopharm: Equity Ownership; Intrexon: Equity Ownership.

BEAM or BeEAM High-Dose Chemotherapy Followed By ASCT: A Single Center Comparative Analysis of Toxicity

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4648-4648
Author(s):  
Vincent Ribrag ◽  
Khalil Saleh ◽  
Alina Danu ◽  
Serge Koscielny ◽  
Sylvain Pilorge ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Hodgkin’S Lymphoma ◽  
Conditioning Regimen ◽  
Median Number ◽  
High Dose Chemotherapy ◽  
Case Control ◽  
Hodgkin's Lymphoma ◽  
High Dose ◽  
Advisory Committees

Abstract Introduction: The BEAM (carmustine (BCNU), etoposide, aracytin and melphalan) standard conditioning regimen in autologous stem-cell transplantation is widely used since 1990 in patients with relapsed/refractory non Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (HL) who remain sensitive to salvage therapy. Recently, a phase Ib-II feasibility study using bendamustine rather than BCNU in the same indication was reported, but was not really compared to BEAM concerning safety. We report herein a safety analysis of Bendamustine-EAM (BeEAM) with a control BEAM counterpart paired cohort (2/1). Methods: We performed a case control retrospective study of patients with NHL and HL who underwent high-dose chemotherapy (HDC) with BeEAM regimen between January 2015 and December 2015. We matched each BeEAM patient with two patients having the same age, sex and number of treatment lines who underwent BEAM and ASCT between January 2008 and December 2014. No patient presented significant comorbidity. The BEAM regimen consisted in BCNU on day -6 (300mg/m2) cytarabine daily from day -6 to day -3 (200mg/m2 every 12 hours), etoposide daily from day -6 to day -3 (100mg/m2 every 12 hours) and melphalan on day -2 (140mg/m2). A similar scheme was adopted in BeEAM arm with bendamustine on day -6 and -5 (100mg/m2/d) replacing BCNU. Autologous stem cells were reinfused on day 0. Unfractionated heparin was used with Bendamustine to prevent veno-occlusive disease. Pegfilgrastim 6mg was injected subcutaneously on day 4. Febrile neutropenia was treated according to ESMO guidelines. Results: One hundred and two patients (68 BEAM and 34 BeEAM) were analyzed. Median age was 48 years in both arms. 61.8% of patients were male and 38.2% female. A median number of 4.4 x106 CD34 were reinfused in the two groups. The median time to neutrophils recovery (> 0.5 x109) was similar between the two arms (9.06 vs 8.86 days, p=0.3). Grade 3 or greater diarrhea according to Commun Terminology Criteria for Adverse Events (CTCAE v4.03) classification was significantly more frequent in BeEAM patients (44 vs 13.2%, p=0.001). Median time to hospital discharge was significantly longer in BeEAM group (23 vs 20.8 days, p=0.0047). The median loss of weight during hospitalization was significantly greater in BeEAM patients (3.3 vs 1.9 kg, p=0.014). The median number of days with fever >38°C and with intravenous antibiotics was significantly higher in BeEAM group (6.06 vs 3.38, p<0.001; 10.76 vs 8.22, p=0.0012 respectively). Five patients in BeEAM arm (14.7%) and 3 patients in BEAM (4.4%) developed grade 2-3 liver cytolysis. Four patients in BeEAM arm developed grade 1 renal toxicity. Six patients presented bacteremia (17.6%) in BeEAM versus 8 patients (11.7%) in BEAM arm. Incidence of mucositis, nausea and vomiting was similar between the two groups. Four patients in the BeEAM arm were rehospitalized for recurrent fever three to five days after discharge. No death occurred in both groups during the ASCT procedure. Conclusion: Our results based on retrospective case-control study suggest that BeEAM conditioning regimen followed by ASCT seems to be more toxic than the standard BEAM regimen. Disclosures Ribrag: gilead: Membership on an entity's Board of Directors or advisory committees; infinity: Membership on an entity's Board of Directors or advisory committees; nanostring: Membership on an entity's Board of Directors or advisory committees; pharmamar: Membership on an entity's Board of Directors or advisory committees; nanostring: Membership on an entity's Board of Directors or advisory committees; ESAI: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; ESAI: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; servier: Consultancy; argenX: Research Funding. Michot:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Multi-Omic Analysis Identifies Epigenetic Evolution in Relapsed Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-14
Author(s):  
Kevin Nuno ◽  
Armon Azizi ◽  
Thomas Koehnke ◽  
M. Ryan Corces ◽  
Ravi Majeti
Keyword(s):  
Board Of Directors ◽  
Meta Analysis ◽  
Chemotherapy Resistance ◽  
Myeloid Cell ◽  
High Dose Chemotherapy ◽  
Chromatin Accessibility ◽  
High Dose ◽  
Genetic Evolution ◽  
Advisory Committees ◽  
Genetic Changes

Introduction: Acute myeloid leukemia (AML) is associated with a poor prognosis even with aggressive treatments including high dose chemotherapy. While most patients enter clinical remission, these remissions are often short-lived leading to chemotherapy-resistant relapsed disease that accounts for the majority of deaths. We undertook a meta-analysis of published datasets consisting of 142 genotyped paired diagnosis-relapse AML samples to understand the genetic evolution of AML between the two disease states. This analysis determined that a plurality of cases exhibited the same mutations at diagnosis and relapse, and that genetically stable clones were associated with an increased probability of relapse. The finding that many cases exhibited no clonal genetic evolution upon relapse, yet exhibited chemotherapy resistance, lead us to hypothesize that epigenetic evolution plays a significant role in AML relapse. Here, our objective was to investigate the epigenetic evolution and cis and trans regulatory elements that correlate with AML relapse. Methods: We identified 27 paired diagnosis and relapse specimens from patients treated at Stanford with high dose chemotherapy regimens. Leukemic blasts, and in some cases leukemia stem cell (LSC)-enriched fractions, were purified by FACS. Cells were then analyzed through a multi-omic platform including genotyping with a myeloid malignancy targeted panel, RNA-seq, and ATAC-seq to obtain a molecular and chromatin accessibility profile of each sample. The resulting data set was analyzed to investigate epigenetic evolution in relapsed AML. Results: Genotyping analysis of banked AML specimens identified a similar pattern of genetic evolution as our meta-analysis, with several samples exhibiting the same mutations at diagnosis and relapse. We used an epigenetic matrix of chromatin accessibility data obtained from purified cell populations within the hematopoietic hierarchy and implemented this with the CIBERSORT algorithm to map the regulatory programs active in diagnosis and relapsed AML blasts. This analysis revealed a general trend of epigenetic states associated with more primitive cells (such as hematopoietic stem and progenitor cells) active at relapse, as opposed to more differentiated myeloid cell programs active at diagnosis. Focusing further on samples with no genetic changes between the two disease states, we observed several samples with substantial epigenetic evolution at relapse, with AML blasts shifting from a more differentiated myeloid cell profile to that of stem and progenitor cells. These changes were associated with a loss of accessibility in PU.1 and CEBPα transcription factor motifs, with a corresponding increase in GATA and RUNX motifs, suggesting epigenetic remodeling contributes to relapse even in the absence of genetic changes. We have additionally identified various categories of relapse samples in our cohort that share similar epigenetic profiles relating to genotype; NPM1 and FLT3 double mutant samples, for example, shared active chromatin accessibility features. Given the key importance of LSCs in AML pathogenesis and their potential role in chemotherapy resistance, we further undertook an analysis of cellular subpopulations enriched for these cells in a subset of our sample cohort. ATAC-seq analysis of CD34+CD38- cell fractions revealed these cells share many epigenetic features between samples, yet also have distinct regulatory programs from those active in leukemia non-stem cells and exhibit similar epigenetic reprogramming between diagnosis and relapse. This analysis further indicates that epigenetic evolution at relapse occurs at the single cell level, rather than reflecting selection of cellular subpopulations at relapse. Ongoing work involves identifying the specific regulatory programs upregulated in relapse samples, and LSCs specifically, to understand how these programs contribute to relapse at the gene regulatory level. Conclusion: Our results indicate a substantial role for epigenetic evolution in AML, with the activation of more primitive stem and progenitor programs upon relapse. We have also identified epigenetic classifications for several relapse samples that correspond to genotype and characterized the regulatory programs associated with relapse. We hope this work will permit a deeper understanding of the evolutionary factors that guide AML relapse. Disclosures Majeti: Zenshine Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Coherus BioSciences: Membership on an entity's Board of Directors or advisory committees; CircBio Inc.: Research Funding; BeyondSpring Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Stanford University: Patents & Royalties: pending patent application on CD93 CAR ; Forty-Seven Inc.: Divested equity in a private or publicly-traded company in the past 24 months; Kodikaz Therapeutic Solutions Inc.: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Patents & Royalties: inventor on patents related to CD47 cancer immunotherapy.

Pharmacogenomic (PGx) Analysis of Bortezomib-Associated Peripheral Neuropathy in the Phase 3 VISTA Trial of Bortezomib Plus Melphalan–Prednisone Versus Melphalan–Prednisone in Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3875-3875 ◽  
Author(s):  
Deborah S Ricci ◽  
Reyna Favis ◽  
Yu Sun ◽  
Helgi van de Velde ◽  
Erin Broderick ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Immune Function ◽  
Board Of Directors ◽  
Multiple Testing ◽  
High Dose ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Time To Onset

Abstract Abstract 3875 Poster Board III-811 We investigated genotyping of 172 candidate gene loci (2016 SNPs) related to hereditary neuropathy, energy production and fast axonal transport, nociception and pain transmission, mitochondria, neurogenesis, neuroprotection, immune function, and bortezomib (Velcade®) mechanism of action. Our aim was to identify predictive classifiers for peripheral neuropathy (PN) in multiple myeloma (MM) following treatment with bortezomib in the phase 3 VISTA trial of bortezomib plus melphalan–prednisone (VMP, N=344) vs MP (N=338) in previously untreated MM patients ineligible for high-dose therapy (median age 71 years). We collected whole blood samples from 323 patients who provided consent for this analysis, from 99/151 participating clinical centers. Samples were transferred to a central laboratory for DNA extraction. After quality control for DNA integrity and quantity, DNA from 139 patients on the VMP arm (VISTA PGx subset) was included in this case-control candidate gene study. A custom array was developed by Illumina (San Diego, CA) for this analysis. Patient characteristics of the VISTA PGx subset were similar to those of the overall population. Of the PGx subset, 51.8% had reported PN events (36.0% grade ≥2). We sought to confirm VISTA findings in an independent cohort of patients in the IFM2005-01 phase 3 study of bortezomib–dexamethasone (Vel/Dex) vs VAD in previously untreated MM patients aged ≤65 years eligible for high-dose therapy (median age 57 years); 215 samples were collected from consenting patients on the Vel/Dex arm, of whom 46% had reported PN events (23.7% grade ≥2) including peripheral neuropathies, dysesthesia, and paresthesia. The VISTA analysis included cases and matched controls with result correlations to clinical adverse event descriptions of “peripheral sensory neuropathy”, “peripheral neuropathy NEC”, and/or “neuralgia”, or any occurrence of these three adverse events. Multiple covariates were included in single-marker association analyses using logistic regression in SAS (PROC LOGISTIC, SAS, v9.1) under three different genotypic models (additive, dominant, recessive) followed by FDR correction. No SNPs had significant associations with the terms above. However, analysis for time to onset of PN using Cox regression and the log rank test in SAS (PROC PHREG PROC TPHREG and PROC LIFETEST, SAS v9.1) using the same models and multiple testing corrections methods identified two SNPs significantly associated with shorter time to onset of any PN (rs4553808; CTLA4; FDR=0.002) and time to onset of grade ≥2 PN (rs1474642; PSMB1; FDR =0.014). Both of these associations were found in the recessive model so that 8.3% of patients with PN following bortezomib treatment have the homozygous recessive genotype of CTLA4 and 6% of patients with grade ≥2 PN have the recessive PSMB1 genotype. Both of these associations were also significant under Bonferroni's correction method. Two additional SNPs were identified that had significant association with grade ≥2 PN (rs12568757; CTSS, FDR=0.027) and with grade ≥3 PN (rs11974610; GJE1; FDR=0.041) but these were not significant under Bonferroni's method. These results suggest an immune-related influence for PN development involving genes associated with immune function (CTLA4, CTSS) and reflexive coupling within Schwann cells (GJE1). Mutations in the target (PSMB1) subunit suggest an influence with drug binding as well. When we investigated associations with these SNPs in the IFM2005-01 dataset, no significant associations were found in the analysis of time to onset of PN following multiple testing corrections; however, rs4553808 (CTLA4) had the same trend of association with time to onset of grade ≥2 PN in the recessive model (p=0.105). The differences in association were likely due to differences between the VISTA and IFM2005-01 study populations (e.g. neuropathy status at entry, rate of onset of PN, age, and baseline characteristics including β2-microglobulin, albumin, and diabetes status). This is the first report of an association between genes associated with immune function (e.g. CTLA4) and time to onset of bortezomib-associated PN. Although the clinical utility of this study is limited due to the low number of genes investigated and the exploratory nature of this analysis, further genome-wide studies may result in a predictive classifier for bortezomib-associated PN applicable to the clinic. This work is currently ongoing. Disclosures: Ricci: Johnson & Johnson: Employment, Equity Ownership. Favis:Johnson & Johnson: Employment, Equity Ownership, Research Funding. Sun:Johnson & Johnson: Employment. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Broderick:Johnson & Johnson: Employment. Meyers:Johnson & Johnson: Employment, Equity Ownership. Harousseau:Janssen Cilag: Honoraria; Celgene: Honoraria. Richardson:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. San Miguel:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; OrthoBiotech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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