Philip Campbell

Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma

BACKGROUND The combination of bortezomib, melphalan, and prednisone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem‐cell transplantation. Daratumumab has shown efficacy in combination with standard‐of‐care regimens in patients with relapsed or refractory multiple myeloma. METHODS In this phase 3 trial, we randomly assigned 706 patients with newly diagnosed multiple myeloma who were ineligible for stem‐cell transplantation to receive nine cycles of bortezomib, melphalan, and prednisone either alone (control group) or with daratumumab (daratumumab group) until disease progression. The primary end point was progression‐free survival. RESULTS At a median follow‐up of 16.5 months in a prespecified interim analysis, the 18‐month progression‐free survival rate was 71.6% (95% confidence interval [CI], 65.5 to 76.8) in the daratumumab group and 50.2% (95% CI, 43.2 to 56.7) in the control group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The overall response rate was 90.9% in the daratumumab group, as compared with 73.9% in the control group (P<0.001), and the rate of complete response or better (including stringent complete response) was 42.6%, versus 24.4% (P<0.001). In the daratumumab group, 22.3% of the patients were negative for minimal residual disease (at a threshold of 1 tumor cell per 105 white cells), as compared with 6.2% of those in the control group (P<0.001). The most common adverse events of grade 3 or 4 were hematologic: neutropenia (in 39.9% of the patients in the daratumumab group and in 38.7% of those in the control group), thrombocytopenia (in 34.4% and 37.6%, respectively), and anemia (in 15.9% and 19.8%, respectively). The rate of grade 3 or 4 infections was 23.1% in the daratumumab group and 14.7% in the control group; the rate of treatment discontinuation due to infections was 0.9% and 1.4%, respectively. Daratumumab‐associated infusion‐related reactions occurred in 27.7% of the patients. CONCLUSIONS Among patients with newly diagnosed multiple myeloma who were ineligible for stem‐cell transplantation, daratumumab combined with bortezomib, melphalan, and prednisone resulted in a lower risk of disease progression or death than the same regimen without daratumumab. The daratumumab‐containing regimen was associated with more grade 3 or 4 infections. (Funded by Janssen Research and Development; ALCYONE ClinicalTrials.gov number, NCT02195479.)

Autologous transplant vs oral chemotherapy and lenalidomide in newly diagnosed young myeloma patients: a pooled analysis

In newly diagnosed myeloma patients, upfront autologous transplant (ASCT) prolongs progression-free survival 1 (PFS1) compared with chemotherapy plus lenalidomide (CC+R). Salvage ASCT at first relapse may still effectively rescue patients who did not receive upfront ASCT. To evaluate the long-term benefit of upfront ASCT vs CC+R and the impact of salvage ASCT in patients who received upfront CC+R, we conducted a pooled analysis of 2 phase III trials (RV-MM-209 and EMN-441). Primary endpoints were PFS1, progression-free survival 2 (PFS2), overall survival (OS). A total of 268 patients were randomized to 2 courses of melphalan 200u2009mg/m2 and ASCT (MEL200-ASCT) and 261 to CC+R. Median follow-up was 46 months. MEL200-ASCT significantly improved PFS1 (median: 42 vs 24 months, HR 0.53; P<0.001), PFS2 (4 years: 71 vs 54%, HR 0.53, P<0.001) and OS (4 years: 84 vs 70%, HR 0.51, P<0.001) compared with CC+R. The advantage was noticed in good and bad prognosis patients. Only 53% of patients relapsing from CC+R received ASCT at first relapse. Upfront ASCT significantly reduced the risk of death (HR 0.51; P=0.007) in comparison with salvage ASCT. In conclusion, these data confirm the role of upfront ASCT as the standard approach for all young myeloma patients.

Fludarabine, cytarabine, granulocyte-colony stimulating factor and amsacrine: an effective salvage therapy option for acute myeloid leukemia at first relapse

Abstract Improved therapeutic options for relapsing patients with acute myeloid leukemia (AML) are urgently needed. Poor outcomes following salvage therapy have been reported in those with short initial remission duration, adverse risk karyotype, prior allograft, older age, FLT3-internal tandem duplication (ITD) AML and prior high-dose cytarabine (HiDAC) induction therapy. We present a cohort of 58 patients (aged 18–70) treated with fludarabine, cytarabine, granulocyte-colony stimulating factor (G-CSF) and amsacrine (FLAG-amsacrine) as salvage chemotherapy for AML at first relapse. 83% had received prior HiDAC-based therapy. The overall complete remission (CR/CR with incomplete blood count recovery [CRi]) rate was 59%, with median event-free survival (EFS) and overall survival (OS) of 6.9 and 10.6 months, respectively. FLAG-amsacrine was an effective bridge to allogeneic transplant with 38% successfully transplanted with excellent outcomes (median OS not reached). FLAG-amsacrine was also effective in elderly patients (≥60 years), with 61% achieving second remission. The regimen was well tolerated, with 30- and 42-day treatment-related mortality of 3.4% and 13.8%, respectively. Outcomes remained poor in those with short initial remission duration (<6 months). We conclude that FLAG-amsacrine is a useful salvage option for AML at first relapse.

The addition of dexamethasone to bortezomib for patients with relapsed multiple myeloma improves outcome but ongoing maintenance therapy has minimal benefit.

Despite the common practice of combining dexamethasone (Dex) with bortezomib (Bz) in patients with multiple myeloma (MM), until now there has been few prospective trials undertaken. We undertook a trial that recapitulated the original APEX study except that dexamethasone was incorporated from cycle 1. We also incorporated an exploratory maintenance component to the study. Twenty sites enrolled 100 relapsed/or refractory MM patients utilizing eight 21 day cycles of IV Bz [1.3 mg/m2; Day (D) 1, 4, 8, 11] and three 35 day cycles; Bz (1.3 mg/m2; Day (D) 1, 8, 15, 22). Our study was registered at www.clinicaltrials.gov (NCT00335348). Patients with stable disease or better received maintenance Bz (1.3 mg/m2) every 14 days until progression. Dexamethasone (20 mg) was given for 2 days with each Bz dose. A prospectively defined matched‐analysis of primary (overall response rate; ORR) and secondary endpoints [Complete Response (CR) and time to progression (TTP)] compared our cohort to those on the Bz arm of the APEX trial. The addition of Dex improved ORR by 20% (56% vs. 36%) [odds ratio 0.44 (0.24–0.80)]. The median TTP was also significantly longer (10.1 vs. 5.1 months) (hazard ratio 0.50, 95% CI: 0.35‐0.72, Pu2009=u20090.0002) and our landmark analysis demonstrated that this was largely due to the early use of dexamethasone, as we were unable to demonstrate any benefit of bortezomib/dexamethasone maintenance therapy. Am. J. Hematol. 90:E86–E91, 2015.

Impact of palifermin on mucosal toxicity in autologous stem cell transplants using busulfan–melphalan conditioning chemotherapy for Hodgkin and non-Hodgkin lymphoma

In Australia, busulfan and melphalan conditioning chemotherapy (bu-mel) is widely used in autologous stem cell transplant (ASCT) for patients with poor prognosis lymphoid malignancies, as previously reported in this journal [1,2]. Unpredictable mucosal toxicity has been associated with use of this preparative regimen, leading to considerable resource utilization in supportive care and prolonged hospital length of stay [3]. Palifermin (recombinant human keratinocyte growth factor) has been demonstrated to decrease the incidence and severity of oral and intestinal mucositis in ASCT using total body irradiation and chemotherapy-only conditioning [4 – 6]. To our knowledge the use of palifermin has never been studied in the setting of the bu-mel regimen. We conducted a retrospective analysis comparing the incidence of gastrointestinal mucosal toxicity and resource utilization between two cohorts of patients transplanted using bu-mel conditioning with and without palifermin. Nineteen patients included in this retrospective analysis underwent ASCT with bu-mel conditioning between April 2007 and May 2010 at the Geelong (GH) and Royal Melbourne (RMH) hospitals. Conditioning consisted of oral busulfan 4 mg/kg/day ( n 18) or intravenous (IV) busulfan 3.2 mg/kg/day ( n 1) for 4 days followed by IV melphalan 140 mg/m 2 on day 1 (where day 0 is day of stem cell infusion). All patients received oral cryotherapy around the time of melphalan infusion [7]. All GH patients ( n x02 9) received palifermin and pegfi lgrastim as supportive care, whereas neither growth factor was used in the RMH patient cohort ( n 10). Palifermin was administered as a single IV dose of 60 μ g/kg on days x03 9 to x03 7 and days 1 to x04 3, and pegfi lgrastim 6 mg was given on day 1. With the exception of growth factor use, supportive care protocols were otherwise identical between the two institutions. Oral mucositis and diarrhea as indicators of mucosal toxicity were assessed prospectively from the time of transplant by experienced nursing staff using World Health Organization criteria and Common Terminology Criteria, respectively. Other data collected and analyzed included days of IV narcotic, total parenteral nutrition (TPN) and IV antibiotic use, length of hospital stay, days of fever x05 38 ° C and days until neutrophil engraftment to 0.2 and 0.5 10 9 /L. Statistically signifi cant diff erences were assessed using independent t -tests for normally distributed continuous variables (Shapiro – Wilk test of normality x05 0.05) and independent sample Mann – Whitney tests for non-normal continuous variables (Shapiro – Wilk test of normality x07 0.05). All analyses were performed using SPSS version 18. Th e two cohorts were comparable with regard to age, gender, underlying disease, disease status prior to transplant, number of prior therapies and mean CD34 dose of cells infused (Table I). No patients had received prior ASCT or head and neck radiotherapy and no patients had experienced prior grade 3 or 4 mucositis with chemotherapy. Th e use of palifermin and pegfi lgrastim signifi cantly reduced the duration of grade 3 and 4 oral mucositis and grade 2 diarrhea, as well as the number of days of fever x05 38 ° C, IV narcotic use and TPN administration. Th ere was also a trend to less grade 3 and 4 diarrhea that did not reach statistical signifi cance. Th ere was no signifi cant diff erence in days of IV antibiotic use or hospital length of stay (Table I). Th ere was signifi cantly more rapid neutrophil engraftment in the GH cohort, refl ecting pegfi lgrastim use (mean days to neutrophil count 0.2 x06 10 9 /L [9 vs. 11.5 days; p 0.05] and 0.5 10 9 /L [10 vs. 12.5 days; p 0.05]). Th e obvious limitations of our study include the small size of the cohorts, its retrospective nature and the assessment of transplant outcomes across two institutions. Although granulocyte colony-stimulating factor use has never been conclusively shown to reduce rates of mucositis following intensive chemotherapy, the confounding eff ect of discordant pegfi lgrastim use between the two cohorts may potentially add to the benefi ts of palifermin use in this setting [8]. With these caveats in mind, the results suggest that use of palifermin with bu-mel conditioning and cryotherapy L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y M ic hi ga n U ni ve rs ity o n 11 /0 1/ 14