Kooperativer Bibliotheksverbund

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15 ( 2017-05-20), p. 1678-1685

Abstract: Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m 2 daily for 5 days, etoposide 75 mg/m 2 daily for 5 days, and idarubicin 9 mg/m 2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3–internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation ( P 〈 .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%] ; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm ( P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3–internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2016.70.6374

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2017

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 338-338

Abstract: Background: Anthracylines are one of the major classes of drugs active against acute myeloid leukemia (AML). Increased doses of daunorubicin during induction therapy for AML have been shown to improve remission rates and survival. The ALLG used idarubicin in induction therapy at a dose of 9 mg/m2 x 3 days (total dose 27 mg/m2) in combination with high-dose cytarabine and etoposide (Blood 2005, 105:481), but showed that a total idarubicin dose of 36 mg/m2 was too toxic in this context (Leukemia 2001, 15:1331). In order to further improve outcomes in adult AML by anthracycline dose escalation, we conducted a phase 3 trial comparing standard to an increased idarubicin dose during consolidation therapy. Methods: Patients achieving complete remission after 1 or 2 cycles of intensive induction therapy (idarubicin 9 mg/m2 daily x3, cytarabine 3 g/m2 twice daily on days 1,3,5 and 7, and etoposide 75 mg/m2 daily x7; ICE protocol) were randomized to receive 2 cycles of consolidation therapy with cytarabine 100 mg/m2 per day for 5 days, etoposide 75 mg/m2 for 5 days, and idarubicin 9mg/m2 daily for either 2 or 3 days (standard and intensive arms respectively). No further protocol therapy was given. The primary endpoint was leukemia-free survival from randomization to consolidation therapy (LFS) with overall survival (OS) as secondary endpoint. Results: A total of 422 patients with AML (excluding cases with CBF rearrangements or APL) aged 16 to 60 years were enrolled between 2003-10, with 345 (82%) achieving complete remission, and 293 being randomized to standard (n=146) or intensive (n=147) consolidation arms. The median age was 45 years in both arms (range 16- 60), and both groups were balanced for intermediate versus unfavorable karyotypes and for frequency of mutations involving FLT3-ITD and NPM1 genes. Of the randomized patients, 120 in the standard arm (82%) and 95 in the intensive arm (65%) received the second consolidation cycle (p 〈 0.001). The median total dose of idarubicin received in the 2 consolidation courses was 36 mg/m2 (range 17-45), or 99% (47-125%) of the protocol dose in the standard arm, versus 53 mg/m2 (18-73), or 98% (33-136%) of the protocol dose in the intensive arm. The durations of grades 3-4 neutropenia and thrombocytopenia were significantly longer in the intensive arm, but there were no differences in grade 3 or 4 non-hematological toxicities. There were no non-relapse deaths during consolidation on the standard arm and 2 in the intensive (0% vs 1%; p =0.50). Subsequently, 41 patients in the standard arm and 37 in the intensive arm underwent elective allogeneic BMT during first remission. On intention to-treat analysis uncensored for transplant and with a median follow-up time of 5.3 years (range 0.6 - 9.9), there was improvement in LFS in the intensive arm compared with the standard arm (3 year LFS 47% (95% CI 40-56%) versus 35% (28-44%); HR 0.74 (95% CI 0.55-0.99); p=0.045) (Figure 1). The 3 year OS for the intensive arm was 61% (95% CI 54-70%) and 50% (95% CI 43-59%) for the standard arm; HR 0.75 (95% CI 0.54-1.05); p=0.092). Although adverse cytogenetics, presence of FLT3-ITD mutation, and absence of NPM1 mutation were all associated with poorer outcomes, there was no evidence of a benefit of intensive consolidation being confined to specific cytogenetic or gene mutation sub-groups. Conclusion: We conclude that in adult patients in complete remission after intensive induction chemotherapy an increased dose of idarubicin delivered during consolidation therapy results in improved LFS, without increased non-hematologic toxicity. Figure 1. Figure 1. Disclosures Szer: Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees. Marlton:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wei:Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Abbvie: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Cartwright:ROCHE: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roberts:Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Mills:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Meeting attendance sponsorship. Gill:Janssen: Membership on an entity's Board of Directors or advisory committees. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.338.338

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: The Lancet Haematology, Elsevier BV, Vol. 2, No. 9 ( 2015-09), p. e357-e366

Type of Medium: Online Resource

ISSN: 2352-3026

URL: Article

DOI: 10.1016/S2352-3026(15)00115-5

Language: English

Publisher: Elsevier BV

Publication Date: 2015

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 436-436

Abstract: Abstract 436 Background: Combination immunochemotherapy with fludarabine (F), cyclophosphamide (C) and rituximab (R) gave superior progression free and overall survival compared to FC in the CLL8 Study. The median age in CLL8 was 61 years compared to a median age for overall CLL patients of 72 years. There is ongoing debate regarding the tolerability and safety of FCR in elderly patients, and what are the most appropriate criteria for selection of therapy. Methods: Previously untreated patients with progressive CLL aged ≥65 were randomised to one of three treatment regimens FR5, FCR3 and FCR5 as follows: (i) F 24mg/m2 po D1-5 + R (375 mg/m2 C1, 500mg/m2 C2-6) iv D1 (FR5), (ii) F 24mg/m2 po and C 150mg/m2 po D1-3 + R iv D1 (FCR3) or (iii) F 24mg/m2 po + C 150mg/m2po D1-5 + R iv D1 (FCR5), all given at 4 weekly intervals for an intended 6 cycles. The dosage of FCR5 is equivalent to standard 3 day IV FCR in the CLL8 Study. Patients were administered their therapy arm with no dose reduction but fludarabine dose was reduced if the eGFR was 50–69ml/min. Therapy was delayed up to 2 weeks if there was grade 3 or 4 toxicity, and if unresolved after 2 weeks, patients were taken off study. If toxicity resolved to grade 2 or less, therapy proceeded. Results: Recruitment of all 120 randomised patients was completed in July 2012. An analysis was performed with a cut-off date of 5 May, 2012 at which time there were 117 of 120 recruited from 29 centres in Australia and New Zealand. Median age was 71.7 (range 65–83) years. Binet stage at registration was progressive A – 20 (17.1%), B – 55 (47.0%) and C – 42 (35.9%). Response data are shown in table 1 for the total patient cohort - no analysis has been performed to date by treatment arm. Analysis of grade 3 and 4 toxicity events by Cumulative Illness Rating Scale (CIRS) score and age are shown in Tables 2 and 3 with data available at the cut-off date. Conclusions: Oral F(C)R therapy appears generally safe and well tolerated in CLL patients aged ≥65 years requiring first-line treatment according to data available at end of recruitment. Using stringent stopping criteria with delay of 2 weeks for recovery of grade 3 or 4 toxicity but no dose reduction, ∼40% of patients stop early due to toxicity, intercurrent illness or patient choice. Based on the 66 patients with completed Final Pathological Staging 2 months after end of therapy, response rates appear high with an overall response rate (ORR) of 92.3%. For this relatively fit elderly patient cohort, neither a CIRS score of 0 to 6, nor age predicted for grade 3 and 4 toxicity. Disclosures: Mulligan: Roche: Consultancy, Research Funding, Speakers Bureau; Genzyme: Consultancy, Research Funding, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.436.436

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4247-4247

Abstract: Introduction: 5'-Azacitidine (AZA), a DNA demethylating agent, is the primary drug for the treatment of high-risk Myelodysplastic Syndrome (MDS) and Chronic Myelomonocytic Leukaemia (CMML). Response is associated with improved survival. However, only half of patients respond, and these responses are rarely durable. We recently reported that primary AZA resistance is associated with a molecular signature of cell cycle quiescence within bone marrow (BM) hematopoietic progenitor cells (Unnikrishnan et al, Cell Reports, 20:572-585 (2017)). As DNA incorporation of the deoxyribonucleic form of AZA (5-aza-2′-deoxycytidine, DAC) occurs during DNA replication, cell cycle quiescence is predicted to lead to less DAC in DNA and concomitantly less DNA demethylation. We recently developed a quantitative multi-parameter assay, AZA-MS (Unnikrishnan, Vo et al, Leukemia 32:900-910 (2018)), to measure the intracellular dynamics of AZA in patients. Using AZA-MS, we reported data supporting the predicted resistance model. CC486 is an oral formulation of AZA. A 28-day cycle of CC486 involves 21 continuous days (21/28) versus the standard 7/28 subcutaneous (SC) injection AZA scheme. Whether levels of in vivo DAC incorporation into DNA during a cycle of CC486 are comparable with that of SC AZA is unknown. AZA-MS provides us with a unique opportunity to empirically assess the in vivo intracellular dynamics of SC versus oral AZA. Study Design and Methods: To directly assess in vivo DAC incorporation and concomitant DNA demethylation with SC AZA and CC486 in the same patient, we initiated a phase II clinical trial (NCT03493646; Fig A). MDS (IPSS; intermediate-2 or high-risk), CMML (bone marrow [BM] blasts 10-29%) and AML (20-30%) patients were recruited for six cycles of SC AZA (75mg/m^2/day for 7/28 days) followed by six cycles of CC486 (100mg bid for 21/28 days in C7-C8 and 150mg bid for 21/28 in C9-C12). Clinical response was assessed at the end of C6 and C12 using International Working Group criteria. Clinical responders and non-responders to SC AZA at C6 received CC486 from C7 onwards. From each patient, 36 peripheral blood (PB) samples and five BM samples were collected over the study period. DNA, RNA and intracellular fractions were isolated from the PB MNCs, for intracellular DAC/AZA measurements by AZA-MS (primary endpoint; Fig A). BM MNCs were utilised for AZA-MS as well as flow cytometry-based cell cycle measurements (secondary endpoint). Results: 31 of 42 consented patients have commenced treatment since trial opening (Fig B-C). We applied the AZA-MS assay on the longitudinal PB and BM samples collected from the seven patients who had completed six months AZA and commenced CC486 as at 26th June 2019 (Fig D). DAC incorporation into DNA and DNA methylation levels were quantified within the same cells, in addition to measuring other parameters (Fig E). As represented by patient 61213-005 (Fig F) who had a complete response (CR) at cycle 6, after 7 days of injection AZA we observed robust incorporation of DAC within PB MNCs (left panel, Fig F) together with concomitant DNA demethylation (right panel, Fig F). DAC levels diminished upon cessation of AZA within a cycle, with corresponding increases in DNA methylation. There were quantitatively higher levels of DAC incorporated in DNA during SC AZA cycles versus CC486. The trend observed is also appreciated from 2.3x higher area under the curve (AUC) measurements in 61213-005 during the SC AZA cycle. DAC incorporation was higher at C9/10 (CC486 150mg bid 21/28) than at C7/8 (CC486 100mg bid 21/28) without appreciable changes in DNA demethylation. During SC AZA cycles, higher DAC levels (top panel, Fig G) and greater DNA methylation (lower panel, Fig G) were seen in the BM MNCs. In a non-responding patient at cycle 6 (61290-002, SD), we saw less DAC incorporation and DNA demethylation (Fig H). We also observed a positive correlation between baseline proportions of cycling BM cells (LIN-CD34+CD38+) and the amount of DAC incorporated in BM MNCs at C1 day 8 (Fig I). Conclusion: AZA-MS can be used to reliably measure in vivo DAC incorporation and concomitant DNA demethylation in PB MNCs and inform appropriate CC486 dosing. Figure Disclosures Unnikrishnan: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fong:Astellas: Consultancy; Novartis: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau. Roncolato:St. George Hospital: Employment. Enjeti:Roche: Honoraria, Speakers Bureau; Bayer and Sanofi: Honoraria, Speakers Bureau; Astellas: Consultancy; Novartis: Consultancy; Abbvie: Consultancy. Hertzberg:BMS: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Polizzotto:Janssen: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; ViiV: Research Funding. Pimanda:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123921

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: European Journal of Clinical Pharmacology, Springer Science and Business Media LLC, Vol. 78, No. 12 ( 2022-12), p. 1911-1921

Abstract: To evaluate the accuracy of melphalan test dose pharmacokinetic (PK) predictions of the subsequent high dose (HDM) area under the concentration-versus-time curve (AUC) and to identify sources of prediction error (PE). Methods A prospective multicentre PK study was conducted in 40 myeloma patients of median age 60 (range:35–71) years using a 20 mg/m 2 test dose administered 1–3 days prior to HDM (predominantly 180 mg/m 2 ). PK data were collected post the test and high doses to compare predicted versus actual AUCs determined using the trapezoidal rule. Test and high dose infusion concentration, volume and duration and the time from preparation to infusion were compared using the paired Wilcoxin rank sign test. The impact of Melphalan administration parameters on PE was evaluated using the Mann–Whitney test. The predictive capacity of a previously published population PK (PopPK) model was also examined. Results Predicted HDM AUC was within 15% of the observed values in only 63% of patients when analysed using the trapezoidal rule and 70% of patients using PopPK. Test dose infusion concentration, volume, duration and time from preparation to infusion were significantly lower than for HDM ( p   〈  0.005). Test dose administration within 15 min of reconstitution ( n  = 5) was associated with significantly lower PE than administration times of 16–60 min ( n  = 22), p   〈  0.05. Test and HDM infusion concentrations were lower in patients with large PE ( 〉  ± 15%), but the differences were not significant ( p  = 0.078, 0.228, respectively). Conclusion Test dose PK has the potential to predict subsequent HDM exposure to achieve a target AUC once melphalan administration parameters are optimised to account for stability issues in the formulation.

Type of Medium: Online Resource

ISSN: 0031-6970 , 1432-1041

URL: Article

DOI: 10.1007/s00228-022-03396-x

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 1459058-X

SSG: 15,3

In: Cancers, MDPI AG, Vol. 14, No. 11 ( 2022-05-30), p. 2710-

Abstract: The association between smoking and alcohol consumption and follicular lymphoma (FL) incidence and clinical outcome is uncertain. We conducted a population-based family case-control study (709 cases: 490 controls) in Australia. We assessed lifetime history of smoking and recent alcohol consumption and followed-up cases (median = 83 months). We examined associations with FL risk using unconditional logistic regression and with all-cause and FL-specific mortality of cases using Cox regression. FL risk was associated with ever smoking (OR = 1.38, 95%CI = 1.08–1.74), former smoking (OR = 1.36, 95%CI = 1.05–1.77), smoking initiation before age 17 (OR = 1.47, 95%CI = 1.06–2.05), the highest categories of cigarettes smoked per day (OR = 1.44, 95%CI = 1.04–2.01), smoking duration (OR = 1.53, 95%CI = 1.07–2.18) and pack-years (OR = 1.56, 95%CI = 1.10–2.22). For never smokers, FL risk increased for those exposed indoors to 〉 2 smokers during childhood (OR = 1.84, 95%CI = 1.11–3.04). For cases, current smoking and the highest categories of smoking duration and lifetime cigarette exposure were associated with elevated all-cause mortality. The hazard ratio for current smoking and FL-specific mortality was 2.97 (95%CI = 0.91–9.72). We found no association between recent alcohol consumption and FL risk, all-cause or FL-specific mortality. Our study showed consistent evidence of an association between smoking and increased FL risk and possibly also FL-specific mortality. Strengthening anti-smoking policies and interventions may reduce the population burden of FL.

Type of Medium: Online Resource

ISSN: 2072-6694

URL: Article

DOI: 10.3390/cancers14112710

Language: English

Publisher: MDPI AG

Publication Date: 2022

detail.hit.zdb_id: 2527080-1

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 6927-6929

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-157634

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 8 ( 2012-08-23), p. 1570-1580

Abstract: The treatment of acute promyelocytic leukemia has improved considerably after recognition of the effectiveness of all-trans-retinoic acid (ATRA), anthracycline-based chemotherapy, and arsenic trioxide (ATO). Here we report the use of all 3 agents in combination in an APML4 phase 2 protocol. For induction, ATO was superimposed on an ATRA and idarubicin backbone, with scheduling designed to exploit antileukemic synergy while minimizing cardiotoxicity and the severity of differentiation syndrome. Consolidation comprised 2 cycles of ATRA and ATO without chemotherapy, followed by 2 years of maintenance with ATRA, oral methotrexate, and 6-mercaptopurine. Of 124 evaluable patients, there were 4 (3.2%) early deaths, 118 (95%) hematologic complete remissions, and all 112 patients who commenced consolidation attained molecular complete remission. The 2-year rate for freedom from relapse is 97.5%, failure-free survival 88.1%, and overall survival 93.2%. These outcomes were not influenced by FLT3 mutation status, whereas failure-free survival was correlated with Sanz risk stratification (P[trend] = .03). Compared with our previously reported ATRA/idarubicin-based protocol (APML3), APML4 patients had statistically significantly improved freedom from relapse (P = .006) and failure-free survival (P = .01). In conclusion, the use of ATO in both induction and consolidation achieved excellent outcomes despite a substantial reduction in anthracycline exposure. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12605000070639.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2012-02-410746

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4314-4314

Abstract: Introduction and aims: High-dose melphalan (HDM) is the commonest conditioning regimen used in autologous transplantation for multiple myeloma (MM), with 〉 10,000 transplants performed annually. The standard dosing algorithm of 200mg/m2, with reduction to 140mg/m2 for renal impairment, has been based upon empiric dose selection, rather than pharmacokinetic (PK) and pharmacodynamic (PD) studies. We have previously examined PK and clinical outcome in 114 patients receiving HDM and shown that exposure (area under the concentration versus time curve: AUC) above the median (12.8 mg/L.h) was associated with increases in ≥ grade 3 mucositis (HR 1.2, p 〈 0.005), and a median overall survival of 8.5 years vs. 5.4 years for AUC below the median (HR 0.40, p 〈 0.001) [1]. The aims of this pilot study were to (1) test the feasibility of real-time PK in patients with MM and (2) evaluate whether a test dose reliably predicted exposure to a full dose. Methods: Thirty three patients (age range: 35 to 71 years) scheduled to receive HDM followed by ASCT were recruited from six Australian hospitals situated within 16-860km from the PK laboratory. A test dose (20 mg/m2) was administered one to three days prior to the remaining 180 mg/m2, n=29, or another dose (n = 4, 186- 200mg/m2) chosen by the treating physician. Melphalan infusion duration ranged from 9 to 36 min for the test dose and from 15 to 45 min for the remaining dose. Blood samples were collected after both doses at: 5 min, 15 min, 30 min, 40 min, 1.25 h and 2.5 h after completion of the infusion, stored immediately on ice and centrifuged within 40 minutes at 3000 rpm for 10 minutes at 4o C to collect plasma, then stored at -40°C until transported on dry ice. Melphalan concentrations were determined by HPLC with UV detection. Test dose AUC was calculated using the trapezoidal rule (Kinetica software) and used to predict what the AUC would be for the 180mg/m2 (or modified) dose, assuming linear PK. Percent deviation of actual-from-predicted AUC was calculated as % deviation = (actual AUC - predicted AUC) / predicted AUC*100. Comparison of % deviation between the first patient recruited at each institution and the remaining patients was performed using the Mann-Whitney test. Results: The predicted and actual melphalan AUC values for all 33 patients are charted (Figure 1). AUC values following the test dose were median (range): 1.34 (0.83-1.88 mg/L.h). Predicted AUC values (adjusted for subsequent dose) were median (range): 11.8 (8.3-15.8) mg/L.h, whilst actual values were 10.5 (6.3-16.0) mg/L.h. Median % deviation of actual from predicted values was -8%, (range -43 to 11%), with predictions for 23 patients (70%), being within ± 15%. The median % deviation for the first patient in each centre was -22.1%, and for subsequent patients was -7%, (p=0.046), for whom 21/27 (78%) had full dose AUC values within ± 15%. Conclusions: Test-dose PK predictions of melphalan exposure were accurate to within ± 15% for 70% of patients in this pilot study. The significantly improved AUC predictions with subsequent dosing suggest that meticulous care is required in dose administration and blood sampling. Other factors such as duration of infusion, concomitant medications and renal function are being examined in a larger cohort to identify any impact on melphalan exposure and subsequently whether PK directed dosing of HDM to achieve a desirable AUC is sufficiently reliable to implement for patients undergoing ASCT. [1] Shaw PJ et al. Biol Blood Marrow Transplant (2012): 18 (2), S207 Abs13. Figure 1. Figure 1. Disclosures Grigg: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.4314.4314

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7