Final results of a phase I study of daily PI-88 as a single agent and in combination with dacarbazine (D) in patients with metastatic melanoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8532-8532 ◽  
Author(s):  
M. Millward ◽  
A. Hamilton ◽  
D. Thomson ◽  
A. Gautam ◽  
E. Wilson
Keyword(s):  
Metastatic Melanoma ◽  
Sinus Thrombosis ◽  
Single Agent ◽  
Cerebral Venous Sinus Thrombosis ◽  
Randomised Study ◽  
Concurrent Use ◽  
Group 2 ◽  
Recommended Phase Ii Dose ◽  
Pet Scans ◽  
Group 1

8532 Background: PI-88 is a heparan sulfate mimetic that inhibits angiogenesis and metastasis directly and via release of tissue factor pathway inhibitor (TFPI). PI-88 has shown some efficacy in an intermittent dosage regimen (250 mg/day 4 days/week) in melanoma (Thomson et al, ASCO 2005). This study tested PI-88 7 days per week alone (group 1) and in combination with 3 weekly D (group 2). Methods: Eligibility included inoperable metastatic melanoma, no prior chemotherapy, PS 0–1, adequate organ function, no recent use of heparin, negative anti-heparin antibody (AHA), no concurrent use of anti-coagulants or anti-platelet agents, no history of GI bleeding. Group 1 cohorts received daily PI-88 in doses of 140 mg, 190 mg and 250 mg. Group 2 received PI-88 commencing at the level below the single agent MTD plus D 1,000 mg/m2 every 21 days. Group 1 pts who had PD could continue PI-88 with the addition of D. FDG-PET scans were performed prior to and after 6 weeks PI-88 in Group 1. Free TFPI was measured in serum prior to and up to 2hr post first dose PI-88 in group 1. Results: Group 1 - DLT occurred in 0/3 (140 mg), 0/3 (190 mg) and 2/3 (250 mg) pts. Group 2 - DLT occurred in 1/6 (140 mg) and 0/4 (190 mg) pts. All DLTs were AHA positive grade III/IV thrombocytopenia with in 1 pt (250 mg) cerebral venous sinus thrombosis. No other major toxicities and no increase in expected DTIC toxicities were observed. 4 group 1 pts had pre/post PET scans. One pt had 50% fall in SUVmax with radiologic SD for 4 months. No radiologic responses occurred with PI-88 alone. 3/9 pts in group 2 had radiologic PR. 2/5 group1 pts who had D added to PI-88 had PR. Free TFPI increased from 6.9 ± 1.9 ng/ml just prior PI-88 to 56.1 ± 19.4 30 min post PI-88. The elevated levels were maintained at 60 and 120 min. Elevation of free TFPI did not correlate with PI-88 dose. Conclusion: The recommended phase II dose of continuous daily PI-88 is 190mg alone and in combination with D 1,000 mg/m2 every 3 weeks. An ongoing randomised study is comparing D 1,000 mg/m2 plus PI-88 190mg/day to single-agent D. No significant financial relationships to disclose.

Thromboembolic Complications of Elective Coil Embolization of Unruptured Aneurysms

Neurosurgery ◽  
2010 ◽  
Vol 67 (3) ◽  
pp. 743-748 ◽  
Author(s):  
Gyojun Hwang ◽  
Chulkyu Jung ◽  
Sukh Que Park ◽  
Hyun Sung Kang ◽  
Sang Hyung Lee ◽  
...  
Keyword(s):  
Complication Rate ◽  
Coil Embolization ◽  
Single Agent ◽  
Thromboembolic Complication ◽  
Thromboembolic Complications ◽  
Unruptured Aneurysms ◽  
Complication Risk ◽  
Group 2 ◽  
Risk Of Hemorrhage ◽  
Group 1

Abstract OBJECTIVE We retrospectively evaluated whether antiplatelet preparation lowered the thromboembolic complication rate during the perioperative period. METHODS We reviewed 328 elective coil embolization procedures in which only microcatheters were used for coiling. No antiplatelet medication was prescribed before the procedure in 95 cases (29%, group 1), whereas antiplatelet therapy was used in 233 cases (71%, group 2; 61 [18.6%] with a single agent [aspirin or clopidogrel] and 172 [52.4%] with both agents). Antiplatelet agents were not given after coiling unless atherosclerosis, severe coil protrusion, or a thromboembolic complication occurred during the procedure. A thromboembolic complication was defined as a procedural thromboembolic event or transient ischemic attack or stroke occurring within 2 days of embolization. RESULTS Thromboembolic complications occurred in 11 cases (3.4%): 6 (6.3%) in group 1 and 5 (2.1%) in group 2 (P = .085). In 195 cases (59.5%) treated by the single microcatheter technique, the risk of thromboembolic complications was low and not affected by antiplatelet preparation (1.8% [no preparation] vs 2.2% [preparation]; P = 1.000). However, in 133 cases (40.5%) treated by the multiple microcatheter technique, antiplatelet preparation significantly reduced the thromboembolic complication risk by 85.2% (12.8% [no preparation] vs 2.1% [preparation]; odds ratio, 0.148; 95% confidence interval, 0.027–0.798; P = .023). The aneurysms treated by the multiple microcatheter technique had more complex configurations for coiling (P < .001). The risk of hemorrhage was not increased by antiplatelet preparation (P = .171). CONCLUSION Antiplatelet preparation lowered the periprocedural thromboembolic complication rate in unruptured aneurysms treated by the multiple microcatheter technique and did not increase the risk of hemorrhage. Therefore, antiplatelet preparation can help to reduce complications in patients in whom technical difficulties are expected without the risk of hemorrhage.

scholarly journals Preoperative lanreotide treatment in acromegalic patients with macroadenomas increases short-term postoperative cure rates: a prospective, randomised trial

2010 ◽  
Vol 162 (4) ◽  
pp. 661-666 ◽  
Author(s):  
Zhi-gang Mao ◽  
Yong-hong Zhu ◽  
Hai-liang Tang ◽  
Dao-yuan Wang ◽  
Jing Zhou ◽  
...  
Keyword(s):  
Hospital Stay ◽  
Transsphenoidal Surgery ◽  
Randomised Trial ◽  
Preoperative Treatment ◽  
Surgical Morbidity ◽  
Randomised Study ◽  
Surgical Cure ◽  
Group 2 ◽  
Cure Rates ◽  
Group 1

ObjectiveTo investigate whether 4-month preoperative lanreotide treatment would improve the surgical cure rate of newly diagnosed acromegalic patients with macroadenomas.DesignA prospective, randomised study.MethodsAfter a baseline evaluation, patients were randomly assigned to 4-month preoperative treatment with lanreotide (starting with 30 mg/2 weeks i.m. and increasing to 30 mg/week i.m. at week 8 if mean GH >2.5 μg/l on GH day curves; pretreatment group, Group 1) or to transsphenoidal surgery (direct surgery group, Group 2). Cure was evaluated 4 months postoperatively primarily by fasting IGF1 less than or equal to age-adjusted upper limit of normal.ResultsA pool of 108 patients was randomly divided into two groups. Five patients in each group were lost to follow-up during the study period, so 49 patients in each group were analysed. At baseline, no difference was observed between the two groups. Cure was established in 24 of 49 (49.0%, 95% confidence interval (CI), 35.0–63.0%) pretreated patients (Group 1) versus 9 of 49 (18.4%, 95% CI, 7.6–29.2%) direct surgery patients (Group 2;P=0.001). Surgical morbidity was recorded in 12 patients (12.2%) and was similar in Group 1 and 2 patients (14.3 and 10.2% respectively;P=0.538). The postoperative hospital stay was similar between groups: being 4.5±1.6 days in Group 1 vs 4.8±1.9 days in Group 2 (P=0.328).ConclusionsPretreatment with lanreotide before transsphenoidal surgery improves surgical cure rates in patients with GH-secreting pituitary macroadenomas. Pretreatment does not affect surgical complications or duration of hospital stay (ClinicalTrials.gov number, NCT00993356).

ITCC phase I study of erlotinib as single agent in children with refractory and relapsed malignant brain tumors and in combination with irradiation in newly diagnosed brain stem glioma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9556-9556 ◽  
Author(s):  
B. Geoerger ◽  
D. Hargrave ◽  
A. Ndiaye ◽  
D. Frappaz ◽  
F. Doz ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Phase I ◽  
Brain Stem ◽  
Phase I Study ◽  
Single Agent ◽  
Glioneuronal Tumor ◽  
Brain Stem Glioma ◽  
Newly Diagnosed ◽  
Group 2 ◽  
Group 1

9556 Background: Erlotinib hydrochloride (OSI-774), a selective inhibitor of the EGFR tyrosine kinase, may be active in childhood brain tumors, particularly in combination with irradiation. Methods: Multicenter, non-randomized phase I study with separate dose findings for erlotinib as single agent in children with refractory or relapsing brain tumors (group 1), and combined to irradiation in newly diagnosed brain stem glioma (group 2). Erlotinib was administered orally daily at 75, 100, 125 or 150 mg/m2. Dose escalation was performed in a classical 3+3 methodology for group 1 and according to the continuous reassessment method for group 2; dose-limiting toxicity (DLT) was evaluated at 3 and 6 weeks, respectively. Results: In total, 31 patients have been entered to date, 30 received treatment, 17 in group 1 (3 relapsing brain stem glioma, 4 ependymoma, 4 oligodendroglioma, 6 other) and 13 in group 2 with a median age of 9 and 6 years (range 4–16 and 2–12), respectively. Median treatment duration was 1.5 and >5 months, respectively. In group 1, 3 patients each were treated at 75 mg/m2 and 100 mg/m2, 7 at 125 mg/m2, 4 at 150 mg/m2. One patient with a glioneuronal tumor treated at 125 mg/m2 experienced G5 intra-tumoral hemorrhage at day 4 which was considered as DLT; at 150 mg/m2, 1 patient with an oligodendroglioma experienced G3 asthenia at day 18 and G3 intratumoral hemorrhage at day 29, and 1 patient with an ependymoma experienced G5 intra-tumoral hemorrhage at day 49. In group 2, 1/6 patients treated with erlotinib 75 mg/m2 and irradiation experienced seizures and died, no DLT occurred in 6 patients at 100 mg/m2. Non-hematological toxicities included G1-G2 erythema, folliculitis, dry skin, trichomegaly, G1 transaminitis, bilirubinemia, G1–3 asthenia, G1–5 intra-tumoral hemorrhage. Minor tumor response was observed in an oligodendroglioma. Pharmacokinetic and biological evaluations are ongoing. Conclusions: Erlotinib was well tolerated in children with cutaneous symptoms being the most frequent treatment toxicity. However, neurological toxicity and intra-tumoral hemorrhage was notable in these children with brain tumors. Inclusion at 125 mg/m2 is ongoing to confirm the MTD. No significant financial relationships to disclose.

Phase I-II open label multicenter study of PD0332991 in BRAFV600mut metastatic melanoma patients harboring CDKN2A loss and RB1 expression and treated with vemurafenib.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9545-9545
Author(s):  
Baptiste Louveau ◽  
Matthieu Resche-Rigon ◽  
Thierry Lesimple ◽  
Marc Pracht ◽  
Barouyr Baroudjian ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Phase I ◽  
Clinical Response ◽  
Metastatic Melanoma ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Open Label ◽  
Melanoma Patients ◽  
Group 2 ◽  
Group 1

9545 Background: Among mechanisms of resistance to BRAF inhibitors (BRAFi), cell cycle effectors including CDK4 have been involved in ERK reactivation. In this phase I-II open label study, we aimed to establish the Maximum Tolerated Dose (MTD) of PD0332991, an inhibitor of CDK4/6, when added to vemurafenib (VM) in metastatic melanoma patients. Methods: Patients with BRAFV600E/K mutated metastatic melanoma harbouring CDKN2A loss and RB1 expression were included. Patients were treated with a 14 days followed by 7 days rest daily dosing schedule of PD0332991 + continuous BID dosing of VM, and stratified into 2 groups according to previous BRAFi treatment (no group 1, yes group 2). Dose levels (PD0332991 (mg/QD)/VM (mg/BID) ranged from 25/720 to 200/960. The primary endpoint was the occurrence of a DLT within the first 2 cycles of therapy. Secondary endpoints included best response (RECIST), OS, PFS, pharmacokinetics parameters, tumour molecular profiling on baseline lesions using transcriptomic and NGS analysis. Results: Nineteen patients were enrolled, among them 16 (84%) in group 2, with 18.5 months median follow-up. Characteristics at baseline were: male 11 (58%), median age 54.4 years, unresectable stage IIIC 2 (11%), stage IV 17 (89%), M1C 12 (67%), high LDH 9 (47%), median time from advanced melanoma diagnosis to inclusion 26.8 months, ≥ 2 lines therapy 13 (68%). A DLT was observed for 1 and 5 patients in group 1 and 2 respectively, defining the MTD at PD0332991 25mg and VM 960mg in group 2. No significant evidence for drug-drug interaction between PD0332991 and VM was highlighted. In group 2, ORR was estimated to 4 (25%), SD to 8 (50%), median PFS to 9.3 months and median OS to 13.2 months. Baseline transcriptomic analysis revealed high alteration rate associated with clinical response and enrichment in genes related to MAPK, cell cycle and apoptosis pathways. Conclusions: While combination of fixed dose of PD0332991 + VM did not allow us to increase PD0332991 dosage above 25mg, significant clinical benefit was achieved in heavily pretreated patients; baseline molecular analysis revealed an association between transcriptomic data and clinical response. Clinical trial information: NCT02202200.

Effect of vitamin D supplementation during pregnancy on neonatal mineral homeostasis and anthropometry of the newborn and infant

2012 ◽  
Vol 108 (6) ◽  
pp. 1052-1058 ◽  
Author(s):  
Pramila Kalra ◽  
Vinita Das ◽  
Anjoo Agarwal ◽  
Mala Kumar ◽  
V. Ramesh ◽  
...  
Keyword(s):  
Vitamin D ◽  
Usual Care ◽  
Head Circumference ◽  
Usual Care Group ◽  
Hypovitaminosis D ◽  
Vitamin D Supplementation ◽  
Care Group ◽  
Randomised Study ◽  
Group 2 ◽  
Group 1

Hypovitaminosis D is common in India. In the present prospective partially randomised study of vitamin D (D3) supplementation during pregnancy, subjects were randomised in the second trimester to receive either one oral dose of 1500 μg vitamin D3(group 1,n48) or two doses of 3000 μg vitamin D3each in the second and third trimesters (group 2,n49). Maternal 25-hydroxyvitamin D (25(OH)D) at term, cord blood (CB) alkaline phosphatase (ALP), neonatal serum Ca and anthropometry were measured in these subjects and in forty-three non-supplemented mother–infant pairs (usual care). Median maternal 25(OH)D at term was higher in group 2 (58·7, interquartile range (IQR) 38·4–89·4 nmol/l)v. group 1 (26·2, IQR 17·7–57·7 nmol/l) and usual-care group (39·2, IQR 21·2–73·4 nmol/l) (P = 0·000). CB ALP was increased (>8.02 μkat/l or >480 IU/l) in 66·7 % of the usual-care groupv. 41·9 % of group 1 and 38·9 % of group 2 (P = 0·03). Neonatal Ca and CB 25(OH)D did not differ significantly in the three groups. Birth weight, length and head circumference were greater and the anterior fontanelle was smaller in groups 1 and 2 (3·08 and 3·03 kg, 50·3 and 50·1 cm, 34·5 and 34·4 cm, 2·6 and 2·5 cm, respectively)v. usual care (2·77 kg, 49·4, 33·6, 3·3 cm;P = 0·000 for length, head circumference and fontanelle andP = 0·003 for weight). These differences were still evident at 9 months. We conclude that both 1500 μg and two doses of 3000 μg vitamin D3had a beneficial effect on infant anthropometry, the larger dose also improving CB ALP and maternal 25(OH)D.

scholarly journals Comparative study of pharmacological and combined pharmaco-mechanical method of induction of labour: a randomised study

2021 ◽  
Vol 10 (5) ◽  
pp. 1977
Author(s):  
Anshu Kumari ◽  
Mahantappa A. Chiniwar ◽  
Sharada B. Menasinkai
Keyword(s):  
Comparative Study ◽  
Active Phase ◽  
Induction Of Labour ◽  
Research Centre ◽  
Cervical Canal ◽  
Mechanical Method ◽  
Randomised Study ◽  
Group 2 ◽  
Foley’S Catheter ◽  
Group 1

Background: Comparative study of Pharmacological and Pharmaco- Mechanical method of induction of labour- A Randomised study. The objective of the study was to compare efficacy of pharmacological and combined pharmaco-mechanical method of induction of labour.Methods: A study was conducted in the department of Obstetrics and gynaecology, Adichunchanagiri Institute of Medical Sciences and Research Centre for a period of 18 months. 200 pregnant women requiring induction of labour were included in the study.  In group 1 Dinoprostone 0.5 mg gel was inserted into cervical canal. In group 2 Foley’s catheter No 18 F was inserted within the cervix. The balloon of the catheter was filled with 30 ml normal saline and at the same time Dinoprostone 0.5 mg gel was inserted into posterior vaginal fornix. The Excel and SPSS (SPSS Inc, Chicago V 18.5) software packages were used for data entry and analysis. The results were averaged (mean ± Std Deviation) for each parameter for continuous data in tables.Results: Mean induction to active phase interval in group 1 was 8.43±4.11 hrs, in group 26.82±3.01 hrs (p =0.001). The rate of vaginal delivery in group 1 and group 2 was 55% and 66% respectively, difference was statistically significant (p=0.026).Conclusions: Synchronous use of intracervical Foley’s catheter and Dinoprostone 0.5 mg resulted in a shorter time for progress to active phase and also shortened induction to delivery interval as compared to Dinoprostone 0.5 mg alone. Higher risk of caesarean delivery was associated with single method as compared to combined methods. 

scholarly journals Tolerance and Effectiveness of Targeted Therapies in Aged Patients with Metastatic Melanoma

2021 ◽  
Author(s):  
Ondine Becquart ◽  
Bastien Oriano ◽  
Stéphane Dalle ◽  
Laurent Mortier ◽  
Marie Thérèse Leccia ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Elderly People ◽  
Targeted Therapies ◽  
Objective Response ◽  
Real Life ◽  
Standard Regimen ◽  
Aged Patients ◽  
Group 2 ◽  
Group 1

Purpose: Melanoma’s incidence is increasing, and elderly people could be significantly impacted since the majority occurs in people over 65 years of age. Combined targeted therapies (TT) are current standard regimen for BRAF mutated metastatic melanoma (MM). Except for subgroups of pivotal trials, little data are available for TT in this population. Materials and Methods: Outcomes were explored in real life patients from MelBase, a French multicentric biobank dedicated to the prospective follow-up of unresectable stage III or IV melanoma. Patients treated by BRAF TT and/or MEK TT combined or not, were included from 2013 to 2017 in 2 groups: group 1 <65-year-old (yo), group 2 >65 yo, analyzed for tolerance and efficacy. Results: 353 patients were included: 231 in group 1, 122 in group 2. Median follow-up was 12 months (M). Median time of treatment was 6.9 M. A total of 80% had at least one Adverse Effect (AE). Most frequent AE (all grades) were mainly skin and subcutaneous, general, and gastrointestinal disorders. A total of 31% of AE were grade 3–4: 28% in group 1 and 39% in group 2 (p = 0.05). No differences were observed in all AE grades proportion, dose modifications, interruptions, and discontinuations. For each group, median overall survival was 20.3 M (CI 95%: 15.5–27.9) and 16.3 M (CI: 14.5–26.9), respectively (p = 0.8). Median progression free survival was 7.8 M (6.4–9.9) and 7.7 M (CI: 5.8–11.3) (p = 0.4). Objective response rate was 59% and 50% (p = 0.6). Conclusion: This study on a large multicentric cohort is the first to assess that TT is well tolerated in elderly BRAF-mutated patients such as in patients younger than 65. Efficacy was similar between groups with outcomes reaching those from pivotal studies. There is thus no argument against using TT in elderly people, although an onco-geriatric opinion is welcome for the most vulnerable.

Single-agent docetaxel (TXT) as first-line treatment in metastatic breast cancer (MBC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 11515-11515
Author(s):  
D. Guarneri ◽  
R. Ratti ◽  
A. Venturino ◽  
G. Addamo ◽  
Z. Coccorullo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Single Agent ◽  
Metastatic Breast ◽  
Line Treatment ◽  
First Line ◽  
Group 2 ◽  
Agent Treatment ◽  
First Line Treatment ◽  
Group 1

11515 Background: Historically anthracyclines have been considered the most active agents in metastatic breast cancer (MBC). Docetaxel (TXT) has challenged this belief. Aims: Evaluate response rates, toxicity and time to progression in patients with MBC receiving single agent TXT as first line treatment. Methods: MBC patients received first line single agent treatment according to one of the following schedules: TXT 35 mg/m2 iv weekly for 6 wks q 8 wks (Group 1) or TXT 100 mg/m2 iv day 1 q 3 weeks (Group 2). Adjuvant chemotherapy was FAC (600,50,600) day 1 q 21 days for 6 courses in all cases so treated. Results: Conclusions: It appears that results with single agent TXT obtained in clinical practice are comparable to those reported in Phase II-III trials (Group 1 and Group 2, respectively ) using the same regimens. [Table: see text] No significant financial relationships to disclose.

Bevacizumab and its impact on survival for patients receiving subsequent anti-EGFR therapy: Updated results from the SA metastatic CRC registry.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3569-3569
Author(s):  
Timothy Jay Price ◽  
Christos Stelios Karapetis ◽  
Robert Padbury ◽  
Matthew E. Burge ◽  
Amitesh Chandra Roy ◽  
...  
Keyword(s):  
Single Agent ◽  
Acquired Resistance ◽  
Patient Characteristics ◽  
First Line ◽  
Test Analysis ◽  
First Line Therapy ◽  
Line Therapy ◽  
Impact On Survival ◽  
Group 2 ◽  
Group 1

3569 Background: Debate exists as to whether first line bevacizumab effects subsequent sensitivity to anti-EGFR therapy. Authors hypothesize that initial anti-VEGF therapy may induce biological changes that then increase the risk of acquired resistance to subsequent EGFR inhibitors. Methods: A retrospective cohort study was performed to compare the characteristics and survival of patients who were treated with an anti-EGFR therapy 2nd line and beyond by two groups defined by the first line therapy; 1. chemotherapy (chemo) plus bevacizumab (bev) and 2. chemo alone. Survival for this analysis is from the time of commencing first line chemotherapy and secondly from anti-EGFR therapy. Pearson chi test analysis was performed to determine whether receiving first line bev was associated with worse overall survival (OS). Results: 348 mCRC patients who received chemo with or without bev and then an anti-EGFR therapy were studied. Patient characteristics are summarised in the table below. The significant differences between group 1. Vs. 2. were as follows; median age 63.8 years v 67.9 years (p = 0.005), lower use of single agent FU 6.4% v 19.2%, KRAS status not tested (reflecting the practice changes over time) 19.3% v 39.2%, KRAS MT 2% v 4%, and where BRAF MT status was known (11%); BRAF MT rate 23% v 0. Median OS for the 2 groups was 34.2 months, and 28.2 months respectively (p = 0.12) from first line therapy. Median OS for patients who underwent single agent anti-EGFR as subsequent therapy was also not significantly different, 31.1 months group 1 (n = 60) versus 27.7 months group 2 (n = 85), p = 0.52. Results based on commencement of anti-EGFR therapy are under way. Conclusions: Survival was not significantly different between the two groups, and the trend was towards higher OS with chemo plus bev suggesting that in our registry population, bev administration in first line therapy with chemo did not lead to a worse outcome overall for those patients subsequently receiving anti-EGFR therapy, either with chemotherapy or as a single agent. Updated results from commencement of anti-EGFR therapy will give further insights and will be presented at the meeting.

Bortezomib (VEL) Based Regimens in Multiple Myeloma (MM) Patients with Renal Impairment (RI): A Preliminary Retrospective Italian Multicenter Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3681-3681 ◽  
Author(s):  
Massimo Gentile ◽  
Stefania Ciolli ◽  
Maria Teresa Petrucci ◽  
Sara Galimberti ◽  
Giuseppe Mele ◽  
...  
Keyword(s):  
Liposomal Doxorubicin ◽  
Treatment Options ◽  
Single Agent ◽  
Median Number ◽  
Who Grade ◽  
Prior Therapy ◽  
Highly Active ◽  
Appropriate Treatment ◽  
Group 2 ◽  
Group 1

Abstract RI is a common and severe complication throughout the course of MM. Vel, either as single agent or combined with other drugs, has been shown to be highly active in MM pts with varying degrees of RI. We retrospectively analyzed the outcome of 105 pts with RI (CrCl<80 ml/min), who were treated with Vel-based regimens between November 2003 and June 2008. Of these 105 pts, 26 were previously untreated, while the remaining 79 were either relapsed (49 pts) or refractory (30 pts) to a median single line of prior therapy (range 1–5). Median age was 64 years (range 39–82); 43% were female. Isotypes were IgG in 37%, light chain only in 32%, IgA in 29%, IgD in 2%. Vel-based regimens were the following: Vel alone in 10 patients, Vel plus Dex (Vel/Dex) in 41, Vel/Dex plus Thal in 13, Vel/Dex plus liposomal doxorubicin (either Caelyx® or Myocet®) in 11 patients, Vel/Dex plus liposomal doxorubicin plus Thal in 8, Vel plus Mel plus Pdn (VMP) in 14, Vel plus Mel plus Pdn plus Thal (VMPT) in 3, and Vel/Dex plus cyclophosfamide in 5. The median Vel dosage was 1.3 mg/m2 (range 0.8–1.3) for 4 doses per cycle, administered on days 1, 4, 8 and 11 every 3 weeks in all schedules but VMPT and VMP (Vel on days 1, 8, 15 and 22 every 5 weeks). For the purpose of this analysis pts were pooled into 2 major groups: (group 1, 51 pts treated with Vel or Vel/Dex) (group 2, 54 pts who received Vel/Dex or Vel/Pdn combined with other agents). RI was evaluated by CrCl, using the Cockcroft–Gault formula; pts were clustered into 3 subgroups based on CrCl values of 51–80, 30–50 and <30 ml/min, corresponding to mild (12 pts, 11.4%), moderate (22 pts, 21%) and severe (71 pts, 67.6%) RI, respectively. Twelve patients required dialysis. A total of 532 cycles of Vel were administered, with a median number of 5 cycles/pt. 10 pts (9.5%, 7 refractory, 2 relapsed and 1 previously untreated) necessitated early discontinuation of therapy due to WHO grade 4 neuropathy (5 pts), diarrhoea (1), pneumonia (1), cardiotoxicity (1) and stroke (1), while the last pt due to sepsis. The rate of Vel discontinuation in pts with severe, moderate and mild RI was 13%, 5% and 0%, respectively (p=ns). Twenty patients (19%, of whom 12 with severe, 6 with moderate and 2 with mild RI) required Vel dose reduction. Overall, 85 episodes of WHO grade III/IV toxicity were observed: 25 were non-hematological (stroke in 1 case, neuropathy in 6 cases, gastrointestinal in 5, infections in 11 and cardiotoxicity in 2), and 68 were haematological (anemia in 21 pts, neutropenia in 16 and thrombocytopenia in 31). A higher rate of hematological SAEs were observed in pts with severe RI as compared to those with moderate and mild RI (72% vs 50% vs 50%; p=0.035). At least a PR was documented 74/101 evaluable pts (74%), including CR (19%), nCR (10%) and VGPR (15%). The ORR was similar across both renal subgroups (severe vs moderate vs mild RI: 67.5% vs 77% vs 75%; p=ns) and treatment subgroups (group 1 vs group 2: 74.5% vs 76% p=ns). Reversal of RI was documented in 43% of pts after a median of 2.2 months (range 0.5–7.9) and occurred more frequently among previously untreated pts (61.5% vs 37% refractory/relapsed pts; p=0.039) and those with mild to moderate RI (67% and 77%, respectively, vs 28% for pts with severe RI; p<0.0001). No differences in terms of RI recovery rate were observed across treatment subgroups (group 1 vs group 2: 40% vs 60%; p=ns). In 3/12 pts on dialysis, renal replacement therapy was discontinued after 1, 1 and 4 months of Vel-including therapy. After a median follow-up of 12 months, 27 patients died. 2-year estimate of PFS and OS was 51% and 56%, respectively. In conclusion, Vel-based regimens are safe and highly active in MM pts with RI, effecting a high ≥PR rate (74%, including 44% ≥VGPR) and prompt reversal of RI in approximately 50% of cases. Thus, Vel-based regimens should be considered appropriate treatment options for MM pts with any RI degree, including those requiring dialysis.

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