Initial Results of the Phase I/II Panobidara Study of Panobinostat in Combination with Idarubicin and Cytarabine in Patients Aged 65 Years or Older with Newly Diagnosed Acute Myeloblastic Leukaemia (AML)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1512-1512
Author(s):  
Enrique M Ocio ◽  
Pilar Herrera ◽  
Teresa Olave ◽  
Salut Brunet ◽  
Albert Oriol ◽  
...  
Keyword(s):  
Overall Survival ◽  
Elderly Patients ◽  
Phase I ◽  
Research Funding ◽  
Maintenance Phase ◽  
Newly Diagnosed ◽  
Term Survival ◽  
Deacetylase Inhibitor

Abstract Abstract 1512 Introduction: Acute Myeloblastic Leukemia (AML) in elderly patients remains an unmet medical need with a long term survival rate inferior to 10% despite the use of novel drugs. Therefore, there is a need for new agents that could induce higher CR rates and, most importantly, that could prolong the relapse free survival (RFS) and the overall survival (OS) of these poor-prognosis patients. Agents targeting epigenetics such as the hypomethylating drug 5-Azacitidine, have emerged as a promising strategy for elderly patients with AML or MDS. A second group of drugs targeting the epigenome are deacetylase inhibitors. Panobinostat is a pan-deacetylase inhibitor, with clear in vitro activity in AML and which is synergistic with anthracyclines (Maiso et al. Leukemia 2009). Based on these data we designed a phase I/II trial of panobinostat in combination with idarubicine and cytarabine followed by panobinostat maintenance in newly diagnosed AML patients older than 65 years. Methods: The initial schema included one or two induction cycles with idarubicine (8 mg/m2 days 1–3) + cytarabine (100 mg/m2 days 1–7) followed by escalating doses of panobinostat three days per week, per 3 weeks starting at 20 mg. Patients achieving CR/CRi received a consolidation cycle with the same schema. Those patients remaining in CR/CRi started a maintenance phase with 40 mg oral panobinostat in monotherapy three days per week, for 3 weeks in 28-days cycles. This schedule was amended after the six first patients, to reduce the weeks of administration of panobinostat to two weeks in the cycles in combination and to every other week in the maintenance phase. Initially a dose-escalating phase I with the classical 3+3 schema was carried out to define the maximum tolerated dose (MTD) of panobinostat in this combination; and then a phase 2 expansion phase was started to determine the efficacy of this combination in terms of CR rate and RFS. Results: 21 patients have been included after the amendment. Median age was 71 (range 66–83). Median % blasts was 40 (20–93). 35% of patients had AML with dysplastic features while adverse cytogenetics were present in 24%. Two out of 6 evaluable patients in the first cohort developed DLTs with panobinostat 20 mg (G3 hyperbilirrubinaemia in both, and one of them also G3 oedema), accordingly the dose of panobinostat was reduced to 10 mg. No DLTs were observed at this dose level, so 10 mg panobinostat was defined as the MTD in this combination. Treatment was well tolerated in the intensive cycles with the toxicity proper of standard induction chemotherapy. The most common non-hematologic toxicities (occurring in ≥20% of patients) included: fever (90%), infections (62%), mucositis (52%), diarrhoea (62%), constipation (43%), vomiting (57%), skin rash (38%), hepatotoxicity (38%) and hypokalaemia (24%). Grade 3/4 AEs were fever, infection, diarrhoea and hepatotoxicity in 2 patients each (10%) and hypokalaemia in 5 (24%). The median duration of the aplasia was 32 days (range 26–51). Regarding the maintenance phase with panobinostat monotherapy, the most frequent AEs were gastrointestinal: diarrhoea (62%), vomiting (62%) or abdominal pain (25%); as well as asthenia (50%. One of them being G3) and hyporexia (25%). In terms of efficacy, 11 patients (52%) achieved CR plus 2 more (10%) achieving CR with incomplete blood recovery (CRi) (overall 62%). There were 2 deaths in induction (10%), one due to a tumoral lysis syndrome before starting panobinostat and the other secondary to a respiratory infection. From the remaining 6 patients, 2 achieved partial response (10%) and 4 showed refractory disease (19%). With a median follow up of 6 months (range 2–14), among the 11 patients that achieved CR, 10 of them remain in CR and only 1 has progressed (in the 9th maintenance cycle). Both patients that achieved CRi have progressed in the 2nd and 6thmaintenance cycles. The median overall survival for the whole population is 13 months (2.3–23.6), and has not been reached for patients achieving CR. Conclusion: To the best of our knowledge, this is the first report of the use of a histone deacetylase inhibitor with chemotherapy in elderly AML patients. This combination was shown to be safe at the MTD. Although preliminary results are encouraging, particularly for the potential benefit of the maintenance phase, longer follow up is needed to evaluate if panobinostat maintenance is able to prolong RFS and subsequently OS in this poor prognostic population. Disclosures: Ocio: Novartis: Consultancy, Research Funding. Off Label Use: Panobinostat in newly diagnosed AML. Aliseda:Novartis: Employment. Winiger:Novartis: Employment. Hardikar:Novartis: Employment. Mateos:Novartis: Consultancy. San-Miguel:Novartis: Consultancy, Research Funding.

Efficacy of Melphalan and Prednisone Plus Thalidomide in Patients Older Than 75 Years With Newly Diagnosed Multiple Myeloma: IFM 01/01 Trial

2009 ◽  
Vol 27 (22) ◽  
pp. 3664-3670 ◽  
Author(s):  
Cyrille Hulin ◽  
Thierry Facon ◽  
Philippe Rodon ◽  
Brigitte Pegourie ◽  
Lotfi Benboubker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Elderly Patients ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Standards Of Care ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
To Receive

Purpose Until recently, melphalan and prednisone were the standards of care in elderly patients with multiple myeloma. The addition of thalidomide to this combination demonstrated a survival benefit for patients age 65 to 75 years. This randomized, placebo-controlled, phase III trial investigated the efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed myeloma. Patients and Methods Between April 2002 and December 2006, 232 previously untreated patients with myeloma, age 75 years or older, were enrolled and 229 were randomly assigned to treatment. All patients received melphalan (0.2 mg/kg/d) plus prednisone (2 mg/kg/d) for 12 courses (day 1 to 4) every 6 weeks. Patients were randomly assigned to receive 100 mg/d of oral thalidomide (n = 113) or placebo (n = 116), continuously for 72 weeks. The primary end point was overall survival. Results After a median follow-up of 47.5 months, overall survival was significantly longer in patients who received melphalan and prednisone plus thalidomide compared with those who received melphalan and prednisone plus placebo (median, 44.0 v 29.1 months; P = .028). Progression-free survival was significantly prolonged in the melphalan and prednisone plus thalidomide group (median, 24.1 v 18.5 months; P = .001). Two adverse events were significantly increased in the melphalan and prednisone plus thalidomide group: grade 2 to 4 peripheral neuropathy (20% v 5% in the melphalan and prednisone plus placebo group; P < .001) and grade 3 to 4 neutropenia (23% v 9%; P = .003). Conclusion This trial confirms the superiority of the combination melphalan and prednisone plus thalidomide over melphalan and prednisone alone for prolonging survival in very elderly patients with newly diagnosed myeloma. Toxicity was acceptable.

Frontline Therapy for Older Patients (pts) with Acute Myeloid Leukemia (AML): Clofarabine Plus Low-Dose Cytarabine Induction Followed by Prolonged Consolidation with Clofarabine Plus Low-Dose Cytarabine Alternating with Decitabine

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 336-336 ◽  
Author(s):  
Stefan Faderl ◽  
Farhad Ravandi ◽  
Guillermo Garcia-Manero ◽  
Xuelin Huang ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Median Overall Survival ◽  
Low Dose ◽  
Response Rates ◽  
Newly Diagnosed ◽  
Secondary Aml ◽  
Prolonged Consolidation ◽  
Low Dose Cytarabine

Abstract Abstract 336 Standard therapy (e.g. “3+7”) of newly diagnosed older pts (≥ 60 yrs) with AML is characterized by low response rates, short response durations, and substantial toxicities. New approaches are therefore actively explored in clinical trials. Clofarabine is a second generation deoxyadenosine nucleoside analogue with activity in older pts with frontline AML and presence of unfavorable prognostic factors. In our experience, the combination of clofarabine with low-dose cytarabine achieved higher response rates at no increase of toxicity compared with clofarabine alone (Faderl S et al. Blood 2008). Based on the initial experience, we have designed a combination of lower-dose clofarabine plus low-dose cytarabine induction followed by a prolonged consolidation of these drugs alternating with decitabine to improve survival and maintain the high response rates from the earlier study. Pts were eligible if ≥ 60 yrs of age with newly diagnosed AML. Pts were excluded for ECOG PS > 2, creatinine > 1.5 mg/dL, cardiac ejection fraction < 40%, and prior therapy with clofarabine or decitabine. Induction therapy consisted of clofarabine 20mg/m2 i.v daily × 5 days plus cytarabine 20mg s.c. twice daily × 10 days. Responding pts could receive up to 17 courses of consolidation therapy of clofarabine plus cytarabine (over 3 and 7 days, respectively) during courses 1–2, 6–8, 12–14 alternating with decitabine 20mg/m2 i.v. daily for 5 days during courses 3–5, 9–11, and 15–17. All pts received antibiotic prophylaxis with levofloxacin, valacyclovir and itraconazole (or equivalent). Fifty-nine pts have been accrued with a median age of 70 yrs (range 60–81), of whom 17 pts (29%) were ≥ 75 yrs. Eleven pts (19%) had a PS of 2. Seven pts (12%) had a WBC of > 20,000/mcl at diagnosis. Thirty pts (51%) had abnormal cytogenetics. Molecular profile: FLT3/ITD 5 pts (9%), FLT3/D835 2 (4), NPM1 6 (13), Ras 2 (4). Thirteen pts (22%) had prior MDS (4 pts prior azacitidine; 2 pts prior lenalidomide) and 17 pts (29%) had secondary AML (Hx of prior chemo and/or XRT). Of 57 pts evaluable for response, 35 (61%) achieved CR and 4 (7%) CRp for an ORR of 68%. Six pts (11%) required more than one course to response. The ORR for pts with diploid vs abnormal cytogenetics was 79% vs 57%; for pts with prior MDS 46% vs 82% for pts with neither MDS nor secondary AML. All 7 pts with a FLT3 mutation responded. With a median follow up of 11.6 months (1.1-20.2+), 16 pts relapsed. Responses (CR) are ongoing in 19 pts. Median CR duration is 14.1 mos (1.8-16.4). Six pts (10%) died on study. Only one pt suffered an early death ≤ 28 days from induction (C1D26). Deaths were due to myelosuppression-associated infectious complications. Median overall survival for all 59 pts was 18.1 mos (0.8-20.2+). Median overall survival for responding patients has not been reached. The median number of consolidation cycles received by pts in CR/CRp was 4 (0-14). Fifteen of these pts have so far received at least 6 consolidation cycles. Most toxicities were ≤ grade 2 and included rash (64%), nausea (61%), transaminase elevations (58%), bilirubinemia (51%), diarrhea (32%), mucositis, creatinine evelations, and headache (12% each). Among toxicities > grade 2, transaminase elevations (14%) and bilirubinemia (5%) were most frequent. One pt (65 yr old female) experienced renal failure and pulmonary edema shortly following start of the induction. Myelosuppression and neutropenic fever were common, but prolonged myelosuppression in responders was rare. In summary, clofarabine plus low-dose cytarabine achieves high response rates with a manageable toxicity profile and low induction mortality in pts ≥ age 60 with previously untreated AML. Longer follow up and comparisons with conventional therapy will help establish whether or not this combination also has a survival advantage. Disclosures: Faderl: Genzyme: Honoraria, Research Funding; Eisai: Research Funding. Off Label Use: clofarabine and decitabine in AML. Kantarjian:Genzyme: Research Funding; Eisai: Research Funding.

Comparison Of Sequential Vs Alternating Administration Of Bortezomib, Melphalan and Prednisone (VMP) and Lenalidomide Plus Dexamethasone (Rd) In Elderly Patients With Newly Diagnosed Multiple Myeloma (MM) Patients: GEM2010MAS65 Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 403-403 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Joaquín Martínez-López ◽  
Miguel T. Hernandez ◽  
Rafael Martinez ◽  
Laura Rosiñol ◽  
...  
Keyword(s):  
High Risk ◽  
Elderly Patients ◽  
Research Funding ◽  
Risk Groups ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Sequential Scheme ◽  
To Receive

Abstract Background VMP and Rd are two of the most efficient and widely accepted regimens in the treatment of elderly newly diagnosed MM patients. In order to further improve the outcome of elderly patients, one possibility would be to use regimens including all these drugs simultaneously, but this may result into high toxicity. Alternatively, the use of these regimens (VMP and Rd) in a sequential or alternating scheme could improve the treatment of elderly patients. We hypothesized the alternating scheme would minimize the emergence of resistant clones, and would reduce the cumulative toxicity. In order to test this hypothesis we decided to compare VMP and RD in a sequential vs an alternating scheme. Patients and methods 241 patients were randomized to receive a sequential scheme consisting on 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd (half of the patients started by VMP and half by Rd) up to 18 cycles). VMP included the iv administration of bortezomib 1.3 mg/m2 twice weekly for 1 six-weeks cycle, followed by once weekly for 8 four-weeks cycles in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1–4 of each cycle. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. Results 121 patients were allocated to receive the sequential scheme and 120 the alternating regimen. Both arms were well balanced according to the baseline characteristics. 52% patients in the sequential arm and 55% in the alternating and had high risk cytogenetic abnormalities (t(4;14), t(14;16), del17p or 1q gains). After 9 cycles of treatment, in the sequential arm, 35 out of 66 (54%) achieved at least VGPR vs 51 out of 65 patients (78%) in the alternating arm (p=0.002), including sCR/CR rate of 28% vs 38% in the sequential and alternating arms, respectively (p=NS). Seven patients in each arm achieved immunophenotypic CR. Moreover, while four patients progressed in the sequential arm under treatment with VMP, no patients in the alternating scheme developed disease progression during the first 9 cycles, After a median follow up of 12 months, there was a trend for shorter TTP in the sequential as compared with the alternating scheme (18 m-TTP of 83% vs 89% (p=NS)). In terms of OS, 83% of patients in the sequential arm were alive at 18 m versus 93% in the alternating (p=NS). Patients who achieved sCR/CR had a significantly longer 18 m-TTP as compared with patients who didn’t achieve it in both sequential (100% vs 71%; p=0.006) and alternating arms (100% vs 79%; p=0.006) and this translated into a significant benefit in OS. No differences were observed in overall response rates and CR rates in standard and high risk patients. The 18 m-TTP was similar in standard and high risk groups in both sequential (86% vs 81%) and alternating arms (84% vs 94%), noting that 94% of patients receiving the alternating scheme were progression-free at 18 months. Regarding hematologic toxicity, the frequency of G3-4 neutropenia was slightly lower in the sequential than in the alternating arm (16% and 23%) and the same trend was observed for G3-4 thrombocytopenia (16% vs 20%). Concerning non-hematologic toxicity, 5% and 4% of the patients in the sequential and alternating arms developed G3-4 infections, respectively; the rate of G3-4 skin rash was 4% in the sequential and 3% in the alternating arm; 4% of patients in the sequential arm developed G3-4 peripheral neuropathy and 3% in the sequential arm. The rate of grade 3-4 thrombotic events was 2% in both arms. Nevertheless, the detailed evaluation of the toxicity will be done at the completion of the trial when all patients will have received the same amount of drugs in either a sequential or an alternating scheme (at the present time, 42 patients in the sequential arm were not yet at risk for the development of lenalidomide-related side effects). Conclusions The administration of melphalan, bortezomib, lenalidomide and steroids in elderly MM patients in a sequential or alternating scheme is feasible. Although longer follow-up is necessary, the alternating scheme may be superior in terms of response rate and outcome, as result of the early exposure of the plasma cell to different agents. Toxicity profile is acceptable. Aparently both schemes of therapy seems to overcome the poor prognosis of high risk cytogenetic. Disclosures: Mateos: Janssen, Celgene: Honoraria. Off Label Use: Lenalidomide plus dexamethasone is not approved for newly diagnosed MM patients. Ocio:Onyx: Consultancy, Research Funding; Novartis: Consultancy; Array Biopharma: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding. San Miguel:Janssen, Celgene: Membership on an entity’s Board of Directors or advisory committees.

Event-Free Survival at 12 Months and Subsequent Overall Survival in Patients with Peripheral T-Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1501-1501
Author(s):  
Matthew J Maurer ◽  
Fredrik Ellin ◽  
James Cerhan ◽  
Stephen Ansell ◽  
Brian K Link ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Free Survival ◽  
T Cell Lymphomas

Abstract Background: Peripheral T-Cell lymphomas (PTCLs) constitute approximately 10% of lymphoid malignancies and consist of several distinct entities based on pathologic and clinical characteristics. With the exception of a few subtypes (e.g., ALK-positive anaplastic large cell lymphoma (ALCL) and some primary cutaneous or leukemic forms of PTCL), a majority of PTCLs are aggressive as characterized by poor treatment response, rapid disease progression and poor overall survival. We have shown that landmark timepoints of event-free survival after diagnosis can stratify subsequent overall survival (OS) in diffuse large B-cell and follicular lymphoma. Here we evaluate this approach in newly diagnosed aggressive PTCLs treated with anthracyline-based or related chemotherapy. Methods. Newly diagnosed PTCL patients were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2012. Clinical data were abstracted from medical records using a standard protocol. For this analysis, we included patients receiving anthracycline-based or other multiagent chemotherapy for the following PTCL subtypes: ALK-negative ALCL (N=24); angioimmunoblastic T-cell lymphoma (AITL, N=34); PTCL, not otherwise specified (NOS; N=60); enteropathy-associated T-cell lymphoma (EATL, N=8); extranodal NK/T-cell lymphoma, nasal type (ENKTL, N=11); and hepatosplenic T-cell lymphoma (HSTCL, N=1). Patients were prospectively followed, and event-free survival (EFS) was defined as time from diagnosis to progression, re-treatment, or death due to any cause. Landmark EFS timepoints were assessed at 12 (EFS12) and 24 (EFS24) months after the date of diagnosis. Subsequent OS was defined as time from a specific endpoint (diagnosis, event or EFS landmark). Replication was performed in a population-based cohort of T-cell lymphomas diagnosed from 2000-2009 from the Swedish Lymphoma Registry. Results. 138 eligible patients were enrolled in the MER from 2002-2012, the median age at diagnosis was 58 years (range, 19-88), 66% were male, 73% had Stage III-IV disease, and 33% had IPI 0-1. At a median follow-up of 47 months (range 11-120), 87 patients (63%) had an event and 70 patients (51%) had died. From diagnosis, only 60 patients were event-free at 12 months (EFS12 45%). Patients who failed to achieve EFS12 had a poor subsequent OS from event (median OS = 6.8 months, 95% CI: 5.3-14.0, figure 1). In contrast, patients who achieved EFS12 had a favorable subsequent OS (median unreached, figure 2). Of the 427 eligible patients in the Swedish registry, the median age at diagnosis was 66 years (range, 18-88), 63% were male, 68% had Stage III-IV disease, and 25% had IPI 0-1. PTCL subtypes were: ALK-negative ALCL (N=89); AITL (N=80); PTCL, NOS (N=183); EATL (N=44); ENKTL (N=24); and HSTCL (N=7). At a median follow-up of 86 months (range 40-158), 333 patients (79%) had an event and 316 patients (74%) had died. From diagnosis, 183 patients were event-free at 12 months (EFS12 44%). Similar to the MER cohort, Swedish patients failing EFS12 had poor subsequent survival (median OS = 3.7 months, 95% CI: 2.9-5.3, figure 1). Swedish patients achieving EFS12 had a favorable subsequent OS (median OS = 89 months, figure 2). Similar results were obtained when conducting landmark analysis at 24 months after diagnosis (EFS24). Conclusion. Relapse and re-treatment events within the first 12 months of diagnosis are associated with very poor OS in PTCL treated with anthracyclines or related chemotherapy, while patients achieving EFS12 have encouraging subsequent OS. Stratifying patients into prognostically distinct subsets using EFS12 may help focus biologic and biomarker studies. EFS12 has potential as an early endpoint for studies of newly diagnosed PTCL. Further investigation of determinants related to post-EFS12 survival is needed. Disclosures Maurer: Kite Pharma: Research Funding. Cerhan:Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding. Relander:Respiratorius: Patents & Royalties: valproate for DLBCL.

A Phase I Study of Selinexor in Combination with Daunorubicin and Cytarabine in Patients with Newly Diagnosed Poor-Risk Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4040-4040 ◽  
Author(s):  
Kendra L. Sweet ◽  
Rami S. Komrokji ◽  
Eric Padron ◽  
Christopher L Cubitt ◽  
Leyla Khavarian ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Poor Risk

Abstract Background: Induction chemotherapy for older adults with poor-risk AML has remained largely unchanged over the past 40 years, with complete remission (CR) rates ranging from 20-50%. Five-year overall survival (OS) ranges from 2-15%, illustrating the need for novel treatment strategies. Selinexor is an oral selective inhibitor of nuclear export (SINE) that has shown promising single agent activity in AML (NCT01607892). By inhibiting the primary export protein, XPO1, selinexor localizes tumor suppressor proteins to the nucleus leading to their activation. Furthermore, selinexor inhibits DNA damage repair, rationalizing its use in combination with DNA damaging agents. Preclinical data from our institution suggest Selinexor synergizes with daunorubicin when used in CD34+ AML cells. Here we report early results from a phase I clinical trial with selinexor plus cytarabine and daunorubicin in patients (pts) with newly diagnosed, poor-risk AML. Methods: This is a single institution phase I clinical trial with a 3+3 design and an expansion phase at the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary endpoint was to determine the MTD/RP2D of selinexor. Secondary endpoints included rate of CR/CRi, overall survival (OS), relapse free survival (RFS) and toxicity assessment. Eligible pts had a diagnosis of previously untreated AML (non-M3), with poor-risk features based on karyotype, mutational profile, secondary AML (sAML) arising from an antecedent hematologic disorder (AHD) or prior chemotherapy, or age ≥60 years. Prior treatment for an AHD was allowed. Induction included daunorubicin 60 mg/m2/day on days 1-3 and cytarabine 100 mg/m2/day CIVI days 1-7 (7+3) with two dose cohorts of selinexor: 60 mg and 80 mg PO. Selinexor was given on days 1, 3, 8, 10, 15 and 17. Re-induction with 5+2 plus selinexor was allowed if indicated. Once in CR, pts received 1-2 cycles of consolidation with 5+2 plus selinexor followed by maintenance selinexor on days 1 and 8 of a 21 day cycle for up 12 months. Selinexor was given at the same dose for all phases of the study. Pts could proceed to hematopoietic stem cell transplant (HCT) at any time after achieving CR. Results: 21 pts (14 (67%) M / 7 (33%) F) were enrolled from June 2015 to June 2016. Median age was 68 years (range 37-77); 18 (86%) were age ≥60 and 9 (43%) were age ≥70. Nineteen (90%) pts were considered poor-risk (unrelated to age), and two (10%) were eligible due to age ≥60 only. Each cohort enrolled 4 pts, and 13 pts were enrolled in the expansion. One pt in each cohort was replaced before completing the 28-day DLT period; one withdrew consent and the second died on day 23 from acute renal failure related to antibiotics. At data cutoff, 18 pts were included in the safety and efficacy assessment. Three additional patients have not completed induction. The early death rate (≤60 days) was 4.8%. No DLTs occurred in the dose-escalation cohorts. The MTD of selinexor was not reached and the RP2D was 80 mg twice weekly. The most common grade 3/4 non-hematologic, treatment emergent AEs in all pts were febrile neutropenia (56%), diarrhea (22%), hyponatremia (22%) and sepsis (17%). Nine patients (50%) achieved CR/CRi. Of the 14 pts treated at the RP2D (selinexor 80 mg), 6 (43%) achieved CR/CRi. In the entire cohort, the median age of the responders was 69 (61-77) and 4 (44%) were age ≥70. Seven (78%) were considered high-risk. Four (44%) had sAML. Two (22%) required a second induction. The median time to response was 47 days (range 28-77) At a median follow up of 8.7 months in the 9 responding pts, 7 (78%) remain in remission. Overall, 4 pts (44%) underwent HCT, and 1 (11%) relapsed just prior to HCT. Conclusion: Results from this phase I trial suggest that selinexor 80mg PO twice weekly can be safely administered in combination with induction chemotherapy using cytarabine and daunorubicin to pts with poor-risk AML, including older pts. The most prominent AEs were febrile neutropenia, diarrhea and hyponatremia. Response rates are encouraging and many elderly pts proceeded to transplant, suggesting this regimen warrants further investigation in this challenging population. Disclosures Sweet: Karyopharm: Honoraria, Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sullivan:Karyopharm: Research Funding. Shah:Incyte: Research Funding; Rosetta Genomics: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria; Pfizer: Honoraria.

Disease-Management of Low- and Intermediate-1 Risk Myelodysplastic Syndromes: Report on 800 Newly Diagnosed MDS Patients From the European LeukemiaNet MDS Registry

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2917-2917 ◽  
Author(s):  
Louise de Swart ◽  
Alex Smith ◽  
Pierre Fenaux ◽  
Argyris Symeonidis ◽  
Eva Hellström-Lindberg ◽  
...  
Keyword(s):  
Overall Survival ◽  
Disease Management ◽  
Serum Ferritin ◽  
Research Funding ◽  
Iron Chelation ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Free Survival ◽  
The Mean

Abstract Abstract 2917 Background: The European LeukemiaNet MDS (EUMDS) registry is designed to collect information about the demographics and disease-management of newly diagnosed low-risk and intermediate-1 risk MDS patients. From April 2008 until July 2010, 828 patients have been registered in eleven participating countries through a web-based reporting system. Objectives: This report describes the disease-management of the first 800 registered patients, including transfusion-related issues like secondary iron overload and its treatment. Results: 159 of 800 patients (20%) started MDS specific treatment within three months before registration; this percentage increased to 50% at 18 months of follow-up. Most patients received erythroid-stimulating agents (ESA), like erythropoietin (Table 1). In patients with a clinical indication for ESA, the percentage of transfusion-independency was similar to the transfusion-independent group without indication for ESA at 18 months of follow-up (Table 1). Overall, 27% of the patients received blood transfusions at registration. This percentage remained stable during follow-up, probably due to the therapeutic effect of ESA (Table 1). The number of units transfused, per 6 months, in these patients increased from 5 to 13 units at 18 months of follow-up, with a mean pre-transfusion Hb level of 7.6 g/dL. The serum ferritin levels of the transfusion-dependent patients at registration were available in 159 patients. The serum ferritin level at registration was ≥2000 μg/L in 4% of the patients who received a mean number of 10 units (SD 7). This increased to 28% of the patients who received a mean number of 20 units (SD 11) at 18 months of follow-up. The percentage of patients on iron chelation therapy increased from 1% to 9% during follow-up (Table 1). In these patients the mean serum ferritin levels remained stable: 1913 μg/L (SD 1183) at registration and 1626 μg/L (SD 1232) at 18 months of follow-up. In contrast, transfusion-dependent patients not treated with iron chelation or ESA had increasing ferritin levels, with a mean ferritin of 630 μg/L (SD 597) at registration and 1586 μg/L (SD 1017) at 18 months of follow-up. 37 patients (5%) progressed to high-risk MDS or acute myeloblastic leukemia at a median of 155 days from registration. 62 patients (8%) have died within a median of 269 days from registration, 32 deaths were MDS related. The overall survival was 93% at 18 months of follow-up, with a progression-free survival of 90%. Differences in overall survival between transfusion-independent and transfusion-dependent patients were significant: 97% versus 85%, respectively (p<0.0001; Table 2). In the multivariate analysis transfusion-dependency, ferritin levels and IPSS score predicted survival (Table 2). The IPSS score had a significant prognostic impact on overall survival and progression-free survival in contrast to the WHO classification (Data not shown). Conclusions: Despite a high transfusion load the mean serum ferritin levels remained stable during treatment with iron chelation. Transfusion-dependent patients had a worse overall survival and progression-free survival with higher ferritin levels and higher IPSS score as compared to transfusion-independent patients. This report demonstrates the importance of detailed disease-management in low- and intermediate-1 risk MDS patients. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding. Bowen:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Honoraria; Celgene: Honoraria, Research Funding; Chugai: Honoraria, Research Funding.

Bosutinib Versus Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia – BELA Trial: 24-Month Follow-up

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 455-455 ◽  
Author(s):  
Jorge E Cortes ◽  
Anish Maru ◽  
Carmino Antonio Antonio De Souza ◽  
François Guilhot ◽  
Ladan Duvillie ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Primary Reason ◽  
Newly Diagnosed ◽  
Function Test ◽  
Grade 3

Abstract Abstract 455 Introduction: Bosutinib (SKI-606) is an orally active, dual competitive inhibitor of the Src and Abl tyrosine kinases. The phase 3 BELA study compared bosutinib with imatinib in patients (pts) with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML). Methods: Pts were randomized 1:1 to open-label oral bosutinib 500 mg/d (n = 250) or imatinib 400 mg/d (n = 252) and stratified by Sokal score risk group (low, medium, high) and geographical region. The primary efficacy endpoint was complete cytogenetic response (CCyR) at 12 mo in the intent-to-treat population. Key secondary and exploratory efficacy endpoints included major molecular response (MMR) at 12 mo, time to CCyR and MMR, duration of CCyR and MMR, time to and incidence of transformation to accelerated/blast phase (AP/BP) CML, event-free survival (EFS), and overall survival. Safety analyses included all treated pts. Results: The median treatment duration was 19.3 mo for bosutinib and 19.5 mo for imatinib; 67% and 74% of pts, respectively, are still receiving therapy. The primary reason for discontinuation of bosutinib was toxicity (23%), while the primary reason for discontinuation of imatinib was disease progression (13%). Rates of CCyR and MMR are shown in the table. The rate of cumulative CCyR by 18 mo was 79% in both arms, and the cumulative rate of MMR by 18 mo was 55% in the bosutinib arm versus 45% in the imatinib arm. Median time to CCyR was faster for bosutinib versus imatinib (12.7 vs 24.6 wk); median time to MMR was also faster for bosutinib versus imatinib (36.9 vs 72.3 wk). Transformation to AP/BP CML while on treatment occurred in 4 (2%) pts on bosutinib and 13 (5%) pts on imatinib. On-study deaths from any cause occurred in 6 (2%) pts receiving bosutinib versus 13 (5%) pts receiving imatinib, and included 5 (2%) and 9 (4%) pts, respectively, who died due to CML progression. Median on-treatment EFS and overall survival were not yet reached for either arm. At 18 mo, the Kaplan-Meier estimates of EFS were 95% for bosutinib versus 91% for imatinib, and the estimates of overall survival were 99% versus 95%, respectively. Bosutinib was associated with higher incidences compared with imatinib of gastrointestinal events (diarrhea [69% vs 22%, respectively], vomiting [32% vs 14%], pyrexia [18% vs 10%], and abdominal pain [13% vs 7%]). In contrast, bosutinib was associated with lower incidences of edema (peripheral edema [4% vs 11%] and periorbital edema [1% vs 14%]) and musculoskeletal events (myalgia [5% vs 11%], muscle cramps [4% vs 22%], and bone pain [4% vs 10%]). Fewer pts on bosutinib experienced grade 3/4 laboratory abnormalities of neutropenia (11% vs 24% with imatinib), while the incidences of grade 3/4 anemia and thrombocytopenia were similar between treatment arms (8% with anemia and 14% with thrombocytopenia). Grade 3/4 liver function test abnormalities occurred more frequently with bosutinib versus imatinib (increased alanine aminotransferase [23% vs 4%] and aspartate aminotransferase [12% vs 3%]). Although common with bosutinib, gastrointestinal events and liver function test abnormalities were typically transient, managed with dose modifications, and not life threatening. Conclusions: The study did not meet the primary endpoint (CCyR at 12 mo); early discontinuation of bosutinib due to adverse events may have contributed to this observed lack of difference. However, bosutinib did result in a higher rate of MMR at 12 mo, faster times to MMR and CCyR, fewer events of transformation to AP/BP CML, and fewer overall and CML-related deaths compared with imatinib, suggesting superiority of bosutinib in pts with newly diagnosed CP CML. In addition, the 18-mo estimates for both EFS and OS currently favor bosutinib. Bosutinib and imatinib were each associated with acceptable but distinct toxicity profiles. Based on these results, bosutinib may offer a new therapeutic option for pts with newly diagnosed CP CML. Minimum of 24 mo of follow-up will be presented for all pts. Disclosures: Cortes: Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Guilhot:CHU de Poitiers: Employment; Pfizer Inc: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria. Duvillie:Pfizer Inc: Employment. Powell:Pfizer Inc: Employment, Equity Ownership. Countouriotis:Pfizer Inc: Employment. Gambacorti-Passerini:Pfizer Inc: Honoraria, Research Funding; BMS: Research Funding; Novartis: Honoraria; Biodiversity: Honoraria.

Continued Improvement in Survival in Multiple Myeloma and the Impact of Novel Agents

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3972-3972 ◽  
Author(s):  
Shaji K. Kumar ◽  
Angela Dispenzieri ◽  
Morie A Gertz ◽  
Martha Q Lacy ◽  
John A Lust ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Initial Therapy ◽  
Novel Agents ◽  
The Novel ◽  
Newly Diagnosed ◽  
Entire Cohort ◽  
The Past ◽  
The Impact

Abstract Abstract 3972 Background: The treatment paradigm for myeloma has undergone a dramatic shift in the past decade with the introduction of the novel agents and their application at every stage of the treatment. We and others had previously shown that survival of patients with myeloma had improved in the earlier half of the last decade and attributed this to a combination of novel therapies as well as increased use of stem cell transplant. It is not clear if this momentum in improving survival has been maintained. We examined the survival trends of patients with newly diagnosed myeloma seen within the past decade to examine this question. Patients and Methods: We studied 1056 patients with newly diagnosed myeloma, who were seen at Mayo Clinic between January 1, 2001 and December 31, 2010; who were seen within 30 days of their diagnosis. For examination of the time trends, we grouped the time interval into two five year periods, 2001–2005 and 2006–2010. Survival was estimated using Kaplan Meier method and survival curves were compared by log rank test. Impact of various prognostic factors was evaluated using Cox proportional hazards test. Results: The median age at diagnosis was 65 (range; 22–92), and 59% were male. The median estimated follow up for the entire cohort was 4.6 years (95% CI; 4.4, 4.9) and 57% of the patients were alive at last follow up. The median overall survival (OS) for the entire cohort was 5.4 years (95% CI; 5, 6.3). The overall survival for patients in the 2001–2005 group was 4.6 years compared with not reached for the 2006–2010 cohort (P< 0.001). The five-year estimated OS was 48% for the earlier group compared with 66% for the latter group. The estimated 1-year survival was 90% for the recent cohort compared with 83% for the earlier cohort, suggesting improvements in the early mortality. Interestingly, the improvement was predominantly seen in the older age group (>65 years; 49%). The 5-year survival of the older patients improved significantly from 31% (2001–2005) to 56% (2006–2010) (P<0.001). In contrast, among younger patients (≤65 years of age), the 5-year survival improved only marginally from 63% (2001–2005) to 73% (2006–2010) (P=NS). One or more novel agents (Lenalidomide, thalidomide or bortezomib) were used as part of initial therapy in 631 (62% of 1021 in whom treatment data was available). The OS among of this group was 7.3 years (95% CI; 5.9, NR) compared with 3.8 years (95% CI; 3.1, 4.6). In a multivariate model that included both use of novel agent and the year group, only the novel agent use was associated with improved survival suggesting that the improvement in the survival is related to the increased use of novel agents in the initial therapy. No significant differences were observed between the groups in terms of conventional prognostic factors. Conclusions: The current results confirm continued improvement in the overall survival of patients, even within the last 10 year period, and highlight the impact of initial therapy with novel agents. Most importantly, we demonstrate that the improved survival has primarily benefited older patients. Our study highlights that urgent need for additional new agents to provide further survival improvement for younger patients, and in order achieve a cure for this disease. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Research Funding; Millennium: Research Funding; Novartis: Research Funding; Cephalon: Research Funding; Genzyme: Research Funding. Dispenzieri:Celgene: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Janssen Research & Development: Research Funding. Gertz:Binding Site: Honoraria.

No Improvement Of Overall Survival After Extended Follow-Up Of Donor Versus No Donor Analysis Of Newly Diagnosed Myeloma Patients Included In The HOVON 50/54 Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2132-2132 ◽  
Author(s):  
Henk Lokhorst ◽  
Bronno van der Holt ◽  
Jan Cornelissen ◽  
Marie José Kersten ◽  
Marinus H.J. Van Oers ◽  
...  
Keyword(s):  
Overall Survival ◽  
Maintenance Therapy ◽  
Survival Benefit ◽  
Research Funding ◽  
Phase Iii ◽  
High Dose ◽  
Newly Diagnosed ◽  
Donor Group ◽  
No Donor

Abstract Background The value of Allo-SCT in myeloma is heavily disputed. In our previous Donor versus No Donor (DvND) comparison we found no survival benefit of Allo-RIC in newly diagnosed myeloma. (Lokhorst et al:Blood 2012119: 6219-6225). However, a recent update of the EBMT-NMA 2000 trial (Gahrton el al:Blood 2013121: 5055-506) suggested that extended follow-up (> 5 years) may be necessary for a correct interpretation of a potential survival benefit for Allo-RIC. Here we present the extended follow-up of our trial, in which the median follow-up of patients now exceeds over 7.5 years since the first autologous SCT. Methods Patients with an HLA–identical sibling donor included in the phase III HOVON-50 study, that was designed to assess the role of thalidomide in induction treatment and maintenance after high-dose therapy (HDM 200 mg/m2), could proceed to the Hovon 54 study in which an Allo-SCT was performed after conditioning with low dose TBI only, between 2-6 months after HDM. Among the 536 eligible patients randomized in the HOVON-50 trial, ultimately 260 patients were eligible to be included into the DvND analysis: 122 patients with a donor, of whom 99 patients received an Allo-RIC and 138 without a donor, of whom 115 patients started maintenance therapy with thalidomide. Groups were comparable with regard to age, myeloma stage, and prognostic factors including cytogenetics and ISS stage. Results 93% of the patients in the no donor group achieved at least a PR (38% CR, 71% at least VGPR ), versus 96% of the patients in the donor group (43% CR, 73% at least VGPR). After a median follow-up of 91 months after HDM, PFS and OS were comparable between the two groups. In the intention to treat analysis median PFS was 29 months for the no donor group and 30 months the no donor group (P=0.25). Median OS was 76 for the donor group and 81 months for the no donor group (P=0.61). For the patients who actually received their allocated treatment (Allo-RIC or maintenance), PFS curves started to diverge after 3 years, however no statistical difference was observed (P=0.07). Allo-RIC improved the median overall survival from 73 to 94 months compared to patients receiving maintenance. However, due to frequent late mortality (> after 96 months) in the Allo-RIC group the benefit was not statistically significant (P=0.54). No subgroup including those achieving CR or those with high risk features (ISS, deletion of chromosome 13) did benefit from Allo-RIC. Conclusion This analysis failed to show improvement of tandem Auto Allo-RIC as part of first line therapy in myeloma as compared to Auto-SCT followed by maintenance therapy, even after extended follow-up. Disclosures: Lokhorst: Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. Minnema:Janssen Cilag: Consultancy, Honoraria. Sonneveld:Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding.

Fludarabine, Cyclophosphamide, Rituximab (FCR) and Vorinostat Followed By Rituximab and Vorinostat Maintenance Therapy in Patients with Previously Untreated Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Leukemia (SLL) - Final Results of a Phase I/II Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4396-4396
Author(s):  
Mazyar Shadman ◽  
Ajay K Gopal ◽  
Oliver Press ◽  
David G. Maloney ◽  
Raya Mawad ◽  
...  
Keyword(s):  
Phase I ◽  
Disease Progression ◽  
Median Time ◽  
Patient Preference ◽  
Research Funding ◽  
Maintenance Treatment ◽  
Progressive Disease ◽  
Maintenance Phase ◽  
Lymphocytic Leukemia

Abstract Background: Chemoimmunotherapy regimens remain the preferred first-line treatment for most of patients with CLL/SLL. Recent studies have demonstrated the efficacy of maintenance regimens by improving progression-free survival (PFS). We studied safety and efficacy of a treatment protocol that included induction and maintenance components using vorinostat, a histone deacetylase inhibitor, in combination with FCR for induction and with rituximab for the maintenance. Methods: Previously untreated CLL/SLL patients with indication for treatment were eligible. Primary objective of the Phase I part was the maximum tolerated dose (MTD) of vorinostat that could be combined with FCR and PFS was the primary endpoint for phase II. In the induction phase, FCR (fludarabine 25 mg/m2 days 1-3, cyclophosphamide 250 mg/m2 days 1-3 and rituximab 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of subsequent cycles) was given every 28 days for 6 cycles. In addition to FCR, patients received vorinostat orally on days 1-5 and days 8-12 of each treatment cycle. In the dose finding phase, vorinostat was given at 3 dose levels: 200 mg, 300 mg and 400 mg PO daily. There was no dose limiting toxicity and 400 mg was chosen as the MTD for phase II. Patients who received at least 4 cycles of induction were eligible to receive maintenance beginning within 3 months of the last cycle of FCR. In the maintenance phase, given every 3 months for 8 cycles, rituximab was given at dose of 500 mg/m2 on day 1 and vorinostat was given at 400 mg PO daily on days 1-14 of each cycle. Results: 40 patients (CLL 32, SLL 8) were treated. Median age was 58 years (36-72). Median time from diagnosis to treatment was 27 months (0 -102). Rai stage at the time of treatment was I/II in 23 (60%) and III/IV in 17 (40%) patients. Cytogenetic (CG) abnormalities included del17p in 2 (5%), del11q in 2 (5%), trisomy 12 in 4 (10%), del13q in 3 (7.5%), normal CG in 14 (35%) and other abnormalities in 6 (15%) patients. Median number of induction cycles was 6 (1-6) and 33 patients (83%) patients finished at least 4 cycles of induction and were eligible for maintenance. Reasons for delivery of less than 4 induction cycles were patient preference (2), GI toxicity (1), thrombocytopenia (1), pulmonary emboli (1), progressive disease (1) and sepsis (1). Twenty-six patients (65%) received at least 1 cycle of maintenance treatment (median 8; range, 1-8) and 15 patients (40%) finished all 8 planned maintenance cycles. Eleven patients started maintenance treatment but did not receive all 8 maintenance courses due to neutropenia (3), patient preference (3), infections (1), insurance issues (1) or other reasons (3). Six patients (15%) were eligible for maintenance but did not receive it because of hematologic toxicities (3), infection (1) or patient preference (2). Overall response rate after induction was 91% with CR in 26 (74%), PR in 4 (11%), nPR in 2 (6%) and stable disease (SD) in 1 (3%). One patient (3%) had progressive disease during the induction and 1 (3%) was not evaluable. Twenty-one of 23 (88%) patients who achieved CR after induction, were tested for minimal residual disease (MRD) by flow cytometry and cytogenetics and 21 (91%) had negative MRD status. One of 2 CR patients who was MRD positive after induction converted to MRD negative after maintenance. After median follow-up of 42 months, 5-year estimate of overall survival was 90% (95% CI 75%-96%) and 5-year estimate of PFS was 72% (95% CI 51%-85%). None of the patients who achieved CR after induction (n=26; 74%) had disease progression after median 46 months of follow-up while 3 of 6 patients with PR or nPR had disease progression which occurred median of 40 months (29-51). Most common grade 3-4 toxicities were hematologic (36%), electrolyte abnormalities (9%), gastrointestinal (8%) and cardiovascular (6%). 4 patients (10%) died during the follow-up because of disease progression (1), sepsis (1), fungal infection (1) and suicide (1). Median time to death was 9.5 months (5 -20). Conclusion: Combination of vorinostat with FCR for induction and with rituximab for maintenance was feasible and effective with a high ORR and long OS and PFS with no relapses observed among patients who achieved CR after induction. Cytopenias and infections were main reasons for treatment discontinuation especially during the maintenance phase. Combination of novel agents with conventional induction and maintenance regimens is a promising strategy for treatment of CLL/SLL. Disclosures Shadman: Gilead: Honoraria, Research Funding; Emergent: Research Funding; Acerta: Research Funding; Pharmacyclics: Honoraria, Research Funding. Gopal:Paid Consultancy- Gilead, Janssen, Seattle Genetics, Spectrum, Research funding- Gilead, Janssen, Pfizer, BMS, Merck, Teva, Takeda, Spectrum, Seattle Genetics: Consultancy, Honoraria, Research Funding. Press:Roche / Genentech: Consultancy, Research Funding. Maloney:Juno Therapeutics: Research Funding; Genentech/Roche: Consultancy, Honoraria.

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