Hematological Improvement in AML/RAEB Elderly Patients Treated with Valproic Acid and Low-Dose ARA-C

Abstract Histone deacetilase inhibitors (HDCAi) have been shown to modulate gene expression with pro-differentiative effects. Valproic acid (VPA) has HDCAi activity and synergizes with Ara-C to differentiate AML blasts in vitro. VPA is orally applicable and has a low toxicity prophile. We tried to assess the therapeutic activity of VPA in combination with low-dose Ara-C in elderly/frail AML/RAEB patients. We enrolled in this study 31 patients with Myeloid Pathologies. Fifteen pts had diagnosis of oligoblastic AML (M0:2, M1: 7, M2: 1, M4:1, M5: 4); 13 patients had RAEB (RAEB 1: 2, RAEB 2: 11) with the following IPSS: int-1=2, int-2= 2, high= 6. Three other patients had progression from previous MPS (1 from ET, 2 from LMMC). Median age was 70 yrs (range: 53 to 84). Median time from Diagnosis to treatment was 15 months (range 1 to 79). Clinical status at start of protocol was: at Diagnosis = 13 pts, Resistant after induction =6 pts, Relapsed after CR =11 pts, Relapsed after allogeneic transplant =1 pt). All patients were excluded from conventional chemotherapy for age and multiple comorbidities. In 27 out of 31, these comorbidities required therapy or periodic controls (grade 3), other 2 pts had one of G4 grade (life-threatening). Thirteen patients were defined “frail” because they presented 3 of G3 comorbidities or at least a G4 one. Twenty-nine pts were evaluated for autosufficiency with ADL score, 5 of them didn’t reach the score of 6, showing impairment in their autosufficiency. Assessing functional autonomy, IADL score showed deficiency in 17 of 29 patients. In our protocol, VPA was administered in continuum to reach serum concentration of 50–100μg/ml. Ara-C was given in cycles of 8 days, 40 mg/day. Ammonium and valproic acid serum level was routinely checked. Bone marrow examination was done at the enrollement in the study, after sixth cycle of Ara-C and/or if improvement of blood counts were observed. In two patients that were in CR at the end of sixth cycle, VPA was maintained; other six cycles of Ara-C were given monthly and thereafter every third month until relapse. Six patients received the treatment for at least 6 cycles, the other patients had a median of 2 cycles, (range 1 to 4). Ten patients are still in treatment, 17 dropped out for progression/death, one patient underwent reduced intensity allotransplant while in remission. From the start of protocol, median overall survival was 4 mths, range 1 to 33 mths. Fifteen pts are alive now. Overall, 11 of 31 patients (35%) had hematological improvement (according to IWG, 2008), including 7 CR (22%) with clearing of blasts in the marrow and normalization of blood counts. The median cycle of improvement was 2 (range 1 to 4) and the median duration of improvement was 2 months (range 1 to 23 months), including two pts that lasted in CR for 10 and 23 months; 3 pts are still in CR at 5,8 and 10 mths from the starting of response, one patient is in Hematological Improvenment at 2 mths. Hematological toxicity requiring platelet transfusion was seen in 17 patients, while 10 pts required red cell transfusion. Transient hyperammoniemia was seen in one patient; liver toxicity in another patient. Neutropenia-related infections were seen in 3 pts. Adding VPA to low-dose Ara-C, some complete responses and some improvements in peripheral cytopenias can be achieved without a significant increase in toxicity. Therefore this therapeutic protocol is feasible for elderly/frail oligoblastic AML/RAEB patients who cannot have aggressive therapy.

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CTNI-18. PHASE I AND PRELIMINARY PHASE 0 RESULTS OF ABTC 1801: A MULTI-ARM CLINICAL TRIAL OF THE PARP INHIBITOR PAMIPARIB (BGB290) WITH VERY LOW DOSE METRONOMIC TEMOZOLOMIDE IN RECURRENT IDH MUTANT GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noab196.243 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi63-vi63

Author(s):

David Schiff ◽

Ranjit Bindra ◽

Jing Li ◽

Xiaobu Ye ◽

Benjamin Ellingson ◽

...

Keyword(s):

Phase I ◽

Low Dose ◽

Parp Inhibitor ◽

Parp Inhibition ◽

Hematological Toxicity ◽

Phase 0 ◽

Grade 3 ◽

Pharmacologically Active ◽

Preliminary Phase

Abstract BACKGROUND Preclinical studies have demonstrated that IDH1-mutant (IDHmt) gliomas harbor a BRCAness phenotype with a defect in homologous recombination that confers PARP inhibitor sensitivity. Pamiparib (BeiGene BGB-290) is an effective PARP-trapping PARP inhibitor with demonstrated favorable brain penetration in animal models. METHODS ABTC 1801 is a study examining the safety, pharmacokinetics, and efficacy of the combination of pamiparib with low dose metronomic temozolomide in recurrent IDHmt gliomas. The Phase I component utilized a 3 + 3 design with a target DLT rate ≤ 33%. Pamiparib dose was 60 mg BID and temozolomide dose 20 mg daily, with dose de-escalation levels for anticipated hematological toxicity. RESULTS Seven patients were enrolled on the Phase I portion at dose level 1; one patient was replaced for inadequate dosing secondary to non-compliance. All patients had prior radiotherapy and temozolomide; 4/7 had received multiple lines of alkylator therapy including nitrosoureas. Median age was 45, KPS 90, and number of prior relapses 3. Four patients had anaplastic astrocytoma, 2 anaplastic oligodendroglioma, and 1 glioblastoma. One of 6 patients (16.7%) experienced DLT during the first cycle (grade 3 neutropenia and thrombocytopenia). Two additional patients had grade 2 neutropenia. Two patients remain on study treatment at 12+ and 10+ months, while a third progressed at 10.1 months (PFS-6 43%). Tumor tissue was collected from two patients in the surgical arm. In enhancing and non-enhancing tumors, the mean unbound pamiparib concentrations were 198 and 160 nmol/L (or nmol/kg), respectively, which were > 20-fold the in vitro IC50 for PARP inhibition; mean unbound tumor-to-plasma ratios were 0.65 and 0.38. CONCLUSIONS Phase I results support pamiparib 60 mg BID with temozolomide 20 mg daily as the dosages for the Phase II study. Preliminary Phase 0 data suggest that pamiparib likely achieves sufficient pharmacologically active concentrations in both enhancing and non-enhancing brain tumors.

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Phase II trial of carboplatin in the management of malignant mesothelioma.

Journal of Clinical Oncology ◽

10.1200/jco.1990.8.1.151 ◽

1990 ◽

Vol 8 (1) ◽

pp. 151-154 ◽

Cited By ~ 65

Author(s):

D Raghavan ◽

P Gianoutsos ◽

J Bishop ◽

J Lee ◽

I Young ◽

...

Keyword(s):

Phase Ii ◽

Malignant Mesothelioma ◽

Phase Ii Trial ◽

Objective Response ◽

World Health ◽

Hematological Toxicity ◽

Who Grade ◽

Life Threatening ◽

Grade 3 ◽

Health Organization

Thirty-one patients with advanced malignant mesothelioma, previously untreated or having received only one prior cytotoxic regimen, were treated in a prospective, single-arm phase II trial with carboplatin (NSC 241240) at a dose of 150 mg/m2 per day intravenously (IV) for 3 days (450 mg/m2/course). One complete remission and four partial remissions were achieved, yielding an overall objective response rate of 16% (95% confidence interval [CI], 5.4% to 34%). The median duration of remission was 8 months (range, 5 to 17). Nonhematological toxicity was mild (only 12% with World Health Organization [WHO] grade 3 vomiting); 16% suffered WHO grade 3 to 4 hematological toxicity, but there were no life-threatening episodes and no treatment-related deaths. Carboplatin has modest activity against malignant mesothelioma and, because of its low toxicity, has a role in the management of this disease.

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Low-Dose Docetaxel Combined with Dexamethasone Is Feasible for Patients with Castration-Resistant Prostate Cancer

Chemotherapy ◽

10.1159/000440942 ◽

2015 ◽

Vol 61 (1) ◽

pp. 23-31 ◽

Cited By ~ 4

Author(s):

Noriyoshi Miura ◽

Nozomu Tanji ◽

Yutaka Yanagihara ◽

Terutaka Noda ◽

Seiji Asai ◽

...

Keyword(s):

Prostate Cancer ◽

Low Dose ◽

Specific Antigen ◽

Progression Free Survival ◽

Hematological Toxicity ◽

Castration Resistant Prostate Cancer ◽

Gastric Bleeding ◽

Castration Resistant ◽

Analgesic Agents ◽

Grade 3

Aim: Docetaxel-based chemotherapy against castration-resistant prostate cancer (CRPC) has recently been shown to be effective and tolerable. The objective of this study was to retrospectively evaluate the efficacy and toxicity of low-dose docetaxel in combination with dexamethasone. Methods: Thirty-seven CRPC patients were administered a treatment regimen consisting of 50 mg/m2 docetaxel once every 3-4 weeks and 1 mg dexamethasone daily at our institution, between November 2004 and April 2014. Results: Twenty-four patients (65%) had a decrease in serum prostate-specific antigen (PSA) >50%. The median overall survival (OS) and PSA progression-free survival were 26.2 and 10.0 months, respectively. Ten of 12 patients (83%) taking analgesic agents reduced their intake because of decreased pain levels. Grade 3 febrile neutropenia occurred in 2 patients (5%). Nonhematological toxicities were less frequent but sometimes severe. Treatment-related death occurred in 2 octogenarian patients, 1 due to gastric bleeding and the other due to infective endocarditis. Conclusion: Low-dose docetaxel in combination with dexamethasone is feasible in Japanese CRPC patients. Hematological toxicity is less than that seen with standard docetaxel therapy, but it is necessary to monitor patients for severe nonhematological toxicities, particularly very elderly patients.

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Phase II of Single-Agent Ibrutinib in Recurrent/Refractory Primary (PCNSL) and Secondary CNS Lymphoma (SCNSL)

Blood ◽

10.1182/blood-2018-99-118538 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2965-2965 ◽

Cited By ~ 3

Author(s):

Christian Grommes ◽

Julia Wolfe ◽

Igor Gavrilovic ◽

Thomas Kaley ◽

Jacqueline Stone ◽

...

Keyword(s):

Adverse Events ◽

Drug Treatment ◽

Clinical Response ◽

Liver Toxicity ◽

Conflicts Of Interest ◽

Systemic Disease ◽

Clinical Status ◽

Single Agent ◽

Cns Lymphoma ◽

Grade 3

Abstract BACKGROUND: PCNSL is an aggressive primary brain tumor with median progression free survival (PFS) after upfront methotrexate-based chemotherapy of 2-3 years. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Ibrutinib has shown promising clinical response in various B-cell malignancies. This trial investigates Ibrutinib in patients with r/r PCNSL and SCNSL. METHODS: Eligible patients had r/r PCNSL or SCNSL, age≥18, ECOG≤2, normal end-organ function, and unrestricted number of CNS directed prior therapies. In patients with SCNSL, systemic disease needed to be absent. All patients needed to have at least one prior CNS directed therapy. RESULTS: Forty-four patients were enrolled; 3 received ibrutinib at 560mg and 41 at 840mg. Median age was 68 years (range 21-90); 20 were women. Median ECOG was 1 (0: 11, 1: 22, 2: 11); 29 had PCNSL and 15 SCNSL; 61% had recurrent disease. Twenty-four had isolated parenchymal disease, 4 isolated cerebrospinal fluid (CSF) involvement and 16 both. No grade 5 event has been observed. Eleven patients experienced 12 grade 4 adverse events: neutropenia (in 5 patients), lymphopenia (2), ALT elevation (1), combined ALT/AST elevation (1), sepsis (1), and pneumonitis (1). Seventeen patients experienced 35 grade 3 adverse events (most common: lymphopenia in 4, ALT elevation (3), hyperglycemia (3), urinary tract infection (3), decreased WBC (2), lung infection (2), and thrombocytopenia (2)). Treatment was stopped due to adverse events in 3 patients (grade 4 pulmonitis, grade 4 liver toxicity, grade 3 infectious encephalitis). Twenty-four patients did not experience ≥3 grade adverse events. The most common toxicities at any grade were thrombocytopenia (73%), hyperglycemia (55%), anemia (43%), hypercholesterolemia (43%) and hypertriglyceridemia (43%) of which most were grade 1/2. Only 1 Aspergillus infection has been observed in a patient with chronic steroid use. After a median follow-up of 22 months (range 1.5-39), 40/44 patients were evaluated for response (4 did not complete at least 15 days of drug treatment due to deteriorating clinical status or withdrawal from study). Overall response was 78% (31/40; 81% (22/27) in PCNSL; 69% (9/13) in SCNSL) with 17 CR, 14 PR, 4 SD and 5 PD as best response. The median PFS is 4 months (5.4 months in patients that completed at least 15 days of drug treatment; longest: 16.5 months). The median overall survival is 19.5 months. CONCLUSION: Patients with CNS lymphoma tolerate Ibrutinib with manageable adverse events. Clinical response was seen in 78% of CNS lymphoma patients. Disclosures No relevant conflicts of interest to declare.

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Efficacy and Tolerability of Ixazomib, Daratumumab and Low Dose Dexamethasone (IDd) in Unfit and Frail Newly Diagnosed Multiple Myeloma (NDMM) Patients; First Interim Safety Analysis of the Phase II HOVON 143 Study

Blood ◽

10.1182/blood-2018-99-114668 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 596-596 ◽

Cited By ~ 9

Author(s):

Claudia A.M. Stege ◽

Kazem Nasserinejad ◽

Mark-David Levin ◽

Noortje Thielen ◽

Saskia K. Klein ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Frailty Index ◽

Safety Analysis ◽

Hematological Toxicity ◽

Newly Diagnosed ◽

Advisory Committees ◽

Frail Patients ◽

Grade 3

Abstract Introduction Data from clinical trials indicate that elderly non-transplant eligible newly diagnosed multiple myeloma (nte-NDMM) patients also benefit from novel therapies. However, overall survival is inferior in unfit and frail compared to fit patients as defined by the International Myeloma Working Group (IMWG) frailty index, caused by a high discontinuation rate due to toxicity. Therefore, there is a need for less toxic treatment for unfit and frail patients. In view of the favorable safety profile of ixazomib and daratumumab, we investigated the efficacy and feasibility of treatment with ixazomib, daratumumab and low dose dexamethasone (IDd) in unfit and frail patients. This trial was registered at www.trialregister.nl as NTR6297. Methods In this prospective multicenter phase II trial treatment consisted of 9 28 day-induction cycles consisting of ixazomib (I) 4 mg (days 1, 8, 15), daratumumab (D) 16 mg/kg (cycle 1-2: days 1, 8, 15, 22; cycle 3-6: days 1, 15; cycle 7-9: day 1) and dexamethasone (in combination with daratumumab (d); cycle 1-2: 20 mg; subsequent cycles 10 mg) followed by maintenance therapy with I (days 1, 8, 15, 29, 36, 43) and D (day 1) of 8-week cycles, until progression for a maximum of 2 years. The primary objective is to determine the overall response rate (ORR) on induction therapy. Aiming for an ORR of at least 65% and considering 50% as a too low ORR, with an optimal Simon 2-Stage design, α = 0.10 and β = 0.20, 60 unfit and 60 frail patients should be included, increased to 66 for both populations to account for ineligibility. A pre-specified safety analysis was planned when for the first 10 unfit and 10 frail patients separately the data of the first 4 cycles of induction therapy are available. Inclusion criteria were NDMM, either being unfit or frail according to the IMWG frailty index. Main exclusion criteria were severe cardiac dysfunction, chronic obstructive pulmonary disease with an FEV1 <50% of expected and a creatinine clearance of <20 ml/minute. We here report the results of the planned safety interim analysis of the first 10/32 included frail patients who completed the first 4 induction cycles. The safety interim analysis of the first 10 unfit patients is planned in September, of which the results will be available at the ASH meeting. In addition, we here report the severe adverse events (SAE) for 58 eligible patients (26 unfit, 32 frail) who were included in the study until July 16, 2018. Results The demographic data of the first 10 frail patients are described in Table 1. Median FU of the first 10 frail patients is 5.2 months (range 0.6-9) and of the 58 included patients 1.6 months (range 0-9). Toxicity is described in Table 2. Hematological toxicity was limited, being mainly thrombocytopenia; 3/10 grade 3, 1/10 grade 4, the latter being disease-related. Non-hematological toxicity was manageable, with only 2 grade 3 gastro-intestinal events and 1 pulmonary embolism. No infusion related reactions and neuropathy were reported. There were minor dose reductions only. The median and inter-quartile range of relative dose intensity (RDI) were 1.0 (0.9, 1.0) for ixazomib, 0.9 (0.9, 1.0) for daratumumab and 1.0 (0.9, 1.0) for dexamethasone. SAEs occurred in 9/26 unfit and 14/32 frail patients, mainly caused by prolongation of hospitalization (82% and 88% respectively). Two patients died during cycle 1, both not related to therapy. One 81-year old patient unexpectedly died at home at day 35 of cycle 1 (delay due to low platelet count) after having recovered from thrombocytopenia and a decreased renal function, grade 3, probably caused by cotrimoxazole and valaciclovir. The second 81-year old patient had a thrombocytopenia of 18x109/l related to MM and died of gastrointestinal bleeding for which he declined therapy at day 15 of cycle 1. In the first included 58 patients a total of 4 patients died (6.9%, 4/32 frail (12.5%) and 0/26 unfit (0%)), of whom 2 not related to therapy (see above) and 2 possibly therapy-related; 1 due to Influenza B and 1 acute pre-renal failure due to vomiting and diarrhea. Preliminary response during the first 4 cycles of therapy is promising is; ORR 70% of which 20% VGPR, 10% MR, 10% SD and 10% not evaluable. Conclusion This planned safety analysis of frail patients in the HOVON 143 showed that Ixazomib-Daratumumab-low dose dexamethasone is feasible with a low rate of therapy-related toxicity and mortality. Preliminary response rates are promising. Disclosures Levin: Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. van de Donk:Janssen Pharmceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Sonneveld:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A phase II study of weekly low-dose paclitaxel plus 24-hour infusion of cisplatin as first-line chemotherapy for metastatic breast cancer (MBC)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.1100 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 1100-1100

Author(s):

Y. Shen ◽

C. Hsu ◽

S. Kuo ◽

Y. Lu ◽

C. Lin ◽

...

Keyword(s):

Low Dose ◽

Liver Toxicity ◽

Performance Status ◽

Metastatic Breast ◽

Complete Response ◽

Stage Design ◽

Conventional Dose ◽

Her 2 ◽

Grade 3

1100 Background: The dose and schedule of paclitaxel have been evolving in the past 15 years. However, the lowest effective dose of weekly paclitaxel remains unclear. In this study, we examined if a very low dose of paclitaxel can be effective in MBC. Except for the dose of paclitaxel, the chemotherapy regimen and the patient population of this study were very similar to one of our previous report (Cancer 2002; 95:2044–50). Methods: Women with chemotherapy-naïve metastatic BC, adequate performance status and organ functions were eligible. All patients received paclitaxel, 50 mg/m2 iv 1 hr on D1, 8 and 15, and cisplatin, 40 mg/m2 iv 24 hrs on D1 and 8, every 4 weeks. Patients continued this low-dose regimen until progressive disease (PD) or prohibitive toxicities occurred. Patients who had PD or stable disease (SD) without clinical benefit were shifted to paclitaxel 80 mg/m2 iv 1 hr on D1, 8 and 15, and cisplatin, 40 mg/m2 iv 24 hrs on D1 and 8, every 4 weeks. The primary endpoint was overall response rate (ORR). Simon’s optimal two-stage design (P0, P1,a, and βare 20%, 40%, 0.05, and 0.2, respectively) was adopted. More than 4 objective responses were needed in the first 13 patients, and a total of 43 patients will be enrolled. Results: After a median follow-up duration of 16.5 months, 27 patients were evaluable for response and toxicity. Their median age was 52.7 years (range: 30.1∼69.4). Twenty patients were hormone receptor (+), while 6 patients were Her-2/neu (+). A total of 121 cycles of protocol treatment were administered as of Dec. 2006. There were 0 complete response and 14 partial responses, for an ORR of 51.9%. Nine of 14 responders remain progression-free. The PFS was 9.6 months (95% of CI: 5.53∼13.67%) and the OS not reached. Grade 3–4 anemia, neutropenia, liver toxicity, thrombocytopenia, and skin toxicities were reported in 8, 6, 2, 1, and 1 patients, respectively. Neurotoxicity was common (22/27), but all were grade 1 or 2. Conclusions: The preliminary results of this study suggest that weekly low-dose paclitaxel is as effective as conventional-dose paclitaxel, and the treatment-related toxicities were more acceptable. No significant financial relationships to disclose.

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Activity of fractionated radioimmunotherapy with clivatuzumab tetraxetan combined with low-dose gemcitabine (Gem) in advanced pancreatic cancer (APC).

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.240 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 240-240 ◽

Cited By ~ 6

Author(s):

A. J. Ocean ◽

M. J. Guarino ◽

K. L. Pennington ◽

A. J. Montero ◽

T. Bekaii-Saab ◽

...

Keyword(s):

Low Dose ◽

Advanced Pancreatic Cancer ◽

Hematological Toxicity ◽

Bleeding Events ◽

Best Response ◽

Stage 4 ◽

Grade 3 ◽

Ecog Ps ◽

Unacceptable Toxicity

240 Background: The90Y-labeled anti-mucin humanized mAb, clivatuzumab tetraxetan (90Y-hPAM4), is in clinical development in APC. A phase I/II trial of 90Y-hPAM4 with low-dose radiosensitizing Gem has now concluded 90Y-dose escalation. Methods: Pts with untreated, inoperable, stage 3-4 APC received 200 mg/m2 Gem once-weekly x 4 with 90Y-hPAM4 on wks 2-4, and with 90Y escalated in cohorts by 3+3 design. Tumor responses were assessed by CT, FDG/PET and serum CA19.9, with cycles repeated until progression or unacceptable toxicity. Results: Of 42 pts (40-87 yrs, ECOG PS 0-1, 36 stage 4), 4 withdrew early while 38 received weekly x 3 90Y doses of 6.5 (N=4), 9 (N=12), 12 (N=17) and 15 (N=5) mCi/m2. Treatment was well-tolerated with few non-hematologic side-effects, including 13 pts retreated with 1-3 additional cycles. CTCv3 grade 3-4 plts or ANC developed in 21/38 (55%) pts after cycle 1 and all (100%) retreated pts after last cycle. Escalation reached limits on radiation doses to the marrow, but hematologic suppression was reversible without major infections or bleeding events, except for 3 pts after repeated cycles, one with extensive marrow tumor infiltration. By CT, the overall disease control rate was 55%, including 6 pts (16%) with partial responses (PRs) by RECIST criteria and 15 pts (39%) with stabilization as best response. After cycle 1, 43% (10/23) improved by PET studies (negative or >25% reduced uptake), and 36% (9/25) with elevated CA19.9 levels had >50 decreases. With 26% (10/38) of pts still in follow-up, 55% (21/38) have now achieved survival of ≥ 6 months [18% (7/38) ≥ 1 yr]. Treatment outcome may increase with 90Y dose, since pts treated at 3 x ≥12 mCi/m2 vs ≤9 mCi/m2 had 19% vs 6% PRs by CT, 47% vs 22% CA19.9 decreases, 63% vs 25% PET improvement, and 64% vs. 44% survival ≥ 6 months. Anecdotally, PS and pain level improved, which needs validation. Updated survival will be presented at the meeting. Conclusions: Fractionated 90Y-hPAM4 plus low-dose Gem showed encouraging therapeutic activity with manageable hematological toxicity. The 12-mCi/m2 dose level was selected for continued dose exploration now underway, involving standard Gem doses and adding maintenance Gem. [Table: see text]

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Lenalidomide and Low Dose Dexamethasone As First Line Therapy for Newly Diagnosed Patients with Primary Plasma Cell Leukemia

Blood ◽

10.1182/blood.v120.21.729.729 ◽

2012 ◽

Vol 120 (21) ◽

pp. 729-729 ◽

Cited By ~ 1

Author(s):

Pellegrino Musto ◽

Vittorio Simeon ◽

Giovanni D'Arena ◽

Maria Carmen Martorelli ◽

Maria Teresa Petrucci ◽

...

Keyword(s):

Plasma Cell ◽

Low Dose ◽

Response Rate ◽

Plasma Cell Leukemia ◽

Hematological Toxicity ◽

Cell Leukemia ◽

First Line ◽

First Line Therapy ◽

Primary Plasma Cell Leukemia ◽

Grade 3

Abstract Abstract 729 Introduction: The prognosis of primary plasma cell leukemia (PPCL) remains poor. The “novel agents” have recently shown promising results in PPCL patients in case reports or small retrospective series. Here we describe the first prospective, multicenter, phase II clinical trial of PPCL, where lenalidomide in combination with low dose dexamethasone (Ld) was tested as initial therapy in newly diagnosed patients fulfilling the IMWG diagnostic criteria of PPCL. Patients and methods: Ld regimen consisted of lenalidomide 25 mg/d for 21 days and oral dexamethasone 40 mg on days 1, 8, 15, and 22 for each 28-day cycle. After 4 cycles, responding patients not eligible for stem cell transplantation (SCT) continued until 8 cycles of full-dose Ld, followed by a maintenance dose of single agent lenalidomide equal to 10 mg/d on days 1–21 of each 28-day cycle. Patients responding after 4 cycles and eligible for SCT proceeded according to the treatment centre's transplant policy. Patients not responding after 4 cycles or progressing during this treatment were considered off-study. Appropriate dose reductions (in particular for patients with reduced renal function at baseline), double contraception methods and anti-thrombotic/anti-infective prophylaxis were recommended. The primary end-point was early response rate according to IMWG uniform response criteria. Secondary end-points were PFS, OS, feasibility and efficacy of SCT, safety. Results: According to the Simon optimal two-stage adaptive design, twenty-three patients were enrolled in between March 2009 and May 2011. The male/female ratio was 1.1, and median age was 60 years (range 44–80). The median absolute number and percentage of circulating plasma cells were 4.280/μl (range 1.500–114.660) and 34% (range 21–90) respectively. Fifteen patients (65.2%) had abnormal renal function at presentation. Twenty-one patients (91.3%) were tested by FISH analysis and cytogenetic abnormalities were detected in all of them, del13q being the most frequently found (16 patients). Seventeen patients showed multiple chromosomal lesions. Involvement of chromosome 14 was observed in 18 patients, three of whom showed t(4;14). Chromosome 1q gain and del17p were detected in 10 and 7 patients, respectively. In the intention-to-treat (ITT) population, overall response rate (ORR) after at least one Ld cycle was 73.9% (17/23), with 8 patients (34.7%) achieving partial remission (PR), 5 (21.7%) very good PR (VGPR), 3 (13%) complete response (CR), and 1(4.3%) near CR (nCR) (VGPR or better: 39%). In the efficacy-evaluable (EE) population, 14 out of 15 patients who received the initially planned 4 Ld cycles (65.2% of the ITT population) responded (ORR 93.3%), achieving 5 PR (33.3%), 5 VGPR (33.3%), 1 near-CR (6.6%) and 3 CR (20%) (VGPR or better: 59.9%). The maintenance phase was reached and safely performed in 4 responding patients not eligible for SCT, 3 of whom relapsed after 2, 8 and 22 months, respectively. After Ld induction therapy, 8 patients received single (n. 4) or double (n. 4) autologous SCT (ASCT); another patient underwent a sequence of ASCT followed by non-myeloablative allogeneic SCT (AlloSCT). Six eligible patients did not receive ASCT frontline, due to initial Ld failure or adverse events; three of them underwent single ASCT (n. 2) or tandem ASCT/non-myeloablative AlloSCT (n. 1) after a bortezomib-based salvage therapy, achieving 2 CR and 1 PR. After a median follow-up of 23 months, median OS and PFS in ITT population were not reached and 22 months, respectively. All transplanted patients remained alive, although three of them relapsed and started salvage treatments; OS was 12 months in the 11 patients who did not receive ASCT (p < 0.001). The correspondent figures for PFS were 29 and 16 months, respectively (p < 0.01). Considering ITT population, multivariate analyses showed that SCT was positively correlated to both OS and PFS. There were 17 episodes of grade 3/4 non hematological toxicity, which occurred in 13 patients (5 infections, 3 renal, 3 metabolic, 2 gastro-intestinal, 2 skin, 1 fatigue, 1 thromboembolic), causing early interruption of Ld treatment in 4 patients. Grade 3/4 hematological toxicity (mainly neutropenia) occurred in 11 patients (47.8%). Conclusions: Ld may be a feasible and effective initial therapeutic option for PPCL, particularly in patients who receive ASCT after a short course of induction treatment. Disclosures: Musto: Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide as first line therapy of plasma cell leukemia. Petrucci:Celgene: Honoraria. Cascavilla:Celgene: Honoraria. Di Raimondo:Celgene: Honoraria. Caravita:Celgene: Honoraria. Morabito:Celgene: Honoraria. Offidani:Celgene: Honoraria. Bringhen:Celgene: Honoraria. Boccadoro:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Palumbo:Celgene: Consultancy, Honoraria.

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Pomalidomide (CC4047) Plus Low-Dose Dexamethasone As Therapy for Relapsed Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2009.23.6802 ◽

2009 ◽

Vol 27 (30) ◽

pp. 5008-5014 ◽

Cited By ~ 225

Author(s):

Martha Q. Lacy ◽

Suzanne R. Hayman ◽

Morie A. Gertz ◽

Angela Dispenzieri ◽

Francis Buadi ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Partial Response ◽

Low Dose ◽

Progression Free Survival ◽

Complete Response ◽

Hematologic Toxicity ◽

High Risk Disease ◽

Grade 3

Purpose Thalidomide and lenalidomide are immunomodulatory drugs (IMiDs) that produce high remission rates in the treatment of multiple myeloma. Pomalidomide is a new IMiD with high in vitro potency. We report, to our knowledge, the first phase II trial of pomalidomide administered in combination with low-dose dexamethasone for the treatment of relapsed or refractory multiple myeloma. Patients and Methods Pomalidomide was administered orally at a dose of 2 mg daily on days 1 through 28 of a 28-day cycle. Dexamethasone 40 mg daily was administered orally on days 1, 8, 15, and 22 of each cycle. Responses were recorded using the criteria of the International Myeloma Working Group. Results Sixty patients were enrolled. Thirty-eight patients (63%) achieved confirmed response including complete response in three patients (5%), very good partial response in 17 patients (28%), and partial response in 18 patients (30%). Responses were seen in 40% of lenalidomide-refractory patients, 37% of thalidomide-refractory patients, and 60% of bortezomib-refractory patients. Responses were seen in 74% of patients with high-risk cytogenetic or molecular markers. Toxicity consisted primarily of myelosuppression. Grade 3 or 4 hematologic toxicity consisted of anemia (5%), thrombocytopenia (3%), and neutropenia (32%). One patient (1.6%) had a thromboembolic event. The median progression-free survival time was 11.6 months and was not significantly different in patients with high-risk disease compared with patients with standard-risk disease. Conclusion The combination of pomalidomide and low-dose dexamethasone is extremely active in the treatment of relapsed multiple myeloma, including high response rates in patients refractory to other novel agents.

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A Prospective, Observational Study on the Safety and Effectiveness of Rituximab Plus Chemotherapy As the First-Line Treatment of Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v124.21.5475.5475 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5475-5475

Author(s):

Jifeng Feng ◽

Jianqiu Wu ◽

Yongping Song ◽

Liping Su ◽

Mingzhi Zhang ◽

...

Keyword(s):

Observational Study ◽

Real World ◽

Liver Toxicity ◽

B Cell Lymphoma ◽

Hematological Toxicity ◽

Hbv Reactivation ◽

Concomitant Disease ◽

Line Treatment ◽

Large B Cell Lymphoma ◽

Grade 3

Abstract Background: The efficacy and safety of rituximab(R)-based immunochemotherapy, the standard regimens for patients (pts) with diffuse large B-cell lymphoma (DLBCL) which is more common in Asia than in Western countries, are well confirmed in RCT studies. However, the safety and effectiveness of R+chemo for DLBCL in real world use is not widely reported, especially population are normally excluded in RCT studies. The objective of this observational study is to investigate the safety and effectiveness of R+chemo as 1st line treatment for Chinese DLBCL in routine clinical practice. Methods: This study was a multicenter, prospective, single-arm observational study conducted in China. DLBCL pts eligible to receive R+chemo (CHOP or non-CHOP) as 1st line treatment were enrolled with no specific exclusion criteria. The primary endpoint was safety. Data on safety and effectiveness were collected from medical records 120 d after the last R dose was administered. This study was registered in clincialtrials.gov (NCT01340443). Results: In total, 279 pts (162male/117femal) with a median age of 57 yrs (range 13 to 88 yrs) were included in the safety analysis set. By IPI criteria, 50.2% of pts were low risk, 25.4% low-intermediate risk, 16.5% intermediate-high risk, 7.2% high risk and 0.7% with unknown risk. The most common concomitant diseases observed are liver (44,15.8%), heart (23, 8.2%), kidney (9, 3.2%) or lung (7, 2.5%) disease. Pts received R+chemo treatment with a median cycle of 6 and a median interval of 24 d. In total, 52.7% pts had grade 3-4 AEs and 16.8% pts had SAE (Table 1). AE related death was 1.1% (n=3). 67.0% pts had any grade hematologic toxicity and the most common grade 3/4 hematologic toxicities were leukocytopenia (29.7%), erythrocytopenia (3.9%), and thrombocytopenia (5.7%). Infection (46.2%), gastrointestinal toxicity (45.2%), and liver toxicity (12.5%) were common non-hematologic toxicities. The AEs of special population (with common concomitant and very young/older DLBCL) are listed in Table 2. For HBV management, the incidence of HBV reactivation in HBsAg+, HBsAg-/HBcAb+, HBsAg-/HBcAb-, and undefined pts was 12.5% (3/24), 4.3% (3/69), 0.7% (1/149), and 2.7% (1/37), respectively, no death due to HBV reactivation 120 d after the last R dose was administered. The detail outcomes of HBV reactivation management in this study was reported in EHA 2014. For ITT population (n=258), the overall response rate was 93.7%. Rates of complete response (CR), unconfirmed CR (CRu) and partial response (PR) were 55.0%, 18.2% and 20.9%, respectively. Summary and Conclusions: During this observation study, the incidence of adverse events of R+chemo as 1st line for DLBCL in real world were tolerable and consistent to previous reports. The AEs in special DLBCL sup-population (very younger, older or with common concomitant disease) are well tolerated too. R+chemo treatment brought more than 90% response rate in these Chinese pts might due to the pts with relative low IPI score. More education on standard management of HBV is needed. Accordingly, this real world study further validates the safety and effectiveness of using R+chemo to treat pts with DLBCL. Table 1: The Hamatologist and common non-hematologist AEs ¡¡ Any grade, n (%) Grade 3/4, n (%) SAE, n (%) Death, n (%) Any toxicity 267 (95.7) 147 (52.7) 47 (16.8) 3 (1.1) Hematological toxicity 187 (67.0) 104 (37.3) 6 (2.2) 0 (0.0) Bone Marrow Failure 23 (12.3) 14 (7.5) 2 (1.1) 0 (0.0) Leukocytopenia 167 (59.9) 83 (29.7) 4 (1.4) 0 (0.0) Erythrocytopenia 62 (22.2) 11 (3.9) 0 (0.0) 0 (0.0) Thrombocytopenia 24 (8.6) 16 (5.7) 1 (0.4) 0 (0.0) Common Non-hematological toxicity Infection 129 (46.2) 48 (17.2) 34 (12.2) 2 (0.7) Gastrointestinal toxicity 126 (45.2) 7 (2.5) 2 (0.7) 0 (0.0) Liver toxicity(SMQ) 663(22.6) 10 (3.6) 2 () 0 (0.07) Cardiac toxicity(SMQ) 29 (10.4) 4 (1.4) 3 (1.1) 1 (0.4) Kidney toxicity 9 (3.2) 1 (0.4) 0 (0.0) 0 (0.0) Table 2: The AEs of special population (with common concomitant and very young/older DLBCL) ¡¡ Total common concomitant disease ¡¡ Age ¡¡ Cardiac History Liver History ¡¡ <=18 or >=80 19-79 ¡¡ (N=279) (N=23) (N=44) ¡¡ (N=10) (N=269) ¡¡ No.% No.% No.% ¡¡ No.% No.% AE 267 (95.7) 22 (95.7) 42 (95.5) ¡¡ 10 (100) 257 (95.5) SAE 47 (16.8) 7 (30.4) 11 (25.0) ¡¡ 3 (30.0) 44 (16.4) AESI 46 (16.5) 6 (26.1) 9 (20.5) ¡¡ 2 (20.0) 44 (16.4) ADR 226 (81.0) 21 (91.3) 36 (81.8) ¡¡ 10 (100) 216 (80.3) Disclosures No relevant conflicts of interest to declare.

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