Lenalidomide has tumoricidal and immunomodulatory activity against multiple myeloma. This double-blind, multicenter, randomized study compared melphalan-prednisone-lenalidomide induction followed by ...lenalidomide maintenance (MPR-R) with melphalan-prednisone-lenalidomide (MPR) or melphalan-prednisone (MP) followed by placebo in patients 65 years of age or older with newly diagnosed multiple myeloma.
We randomly assigned patients who were ineligible for transplantation to receive MPR-R (nine 4-week cycles of MPR followed by lenalidomide maintenance therapy until a relapse or disease progression occurred 152 patients) or to receive MPR (153 patients) or MP (154 patients) without maintenance therapy. The primary end point was progression-free survival.
The median follow-up period was 30 months. The median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months; hazard ratio, 0.49; P<0.001) or MP (13 months; hazard ratio, 0.40; P<0.001). Response rates were superior with MPR-R and MPR (77% and 68%, respectively, vs. 50% with MP; P<0.001 and P=0.002, respectively, for the comparison with MP). The progression-free survival benefit associated with MPR-R was noted in patients 65 to 75 years of age but not in those older than 75 years of age (P=0.001 for treatment-by-age interaction). After induction therapy, a landmark analysis showed a 66% reduction in the rate of progression with MPR-R (hazard ratio for the comparison with MPR, 0.34; P<0.001) that was age-independent. During induction therapy, the most frequent adverse events were hematologic; grade 4 neutropenia was reported in 35%, 32%, and 8% of the patients in the MPR-R, MPR, and MP groups, respectively. The 3-year rate of second primary tumors was 7% with MPR-R, 7% with MPR, and 3% with MP.
MPR-R significantly prolonged progression-free survival in patients with newly diagnosed multiple myeloma who were ineligible for transplantation, with the greatest benefit observed in patients 65 to 75 years of age. (Funded by Celgene; MM-015 ClinicalTrials.gov number, NCT00405756.).
Current treatment recommendations for patients with polycythemia vera call for maintaining a hematocrit of less than 45%, but this therapeutic strategy has not been tested in a randomized clinical ...trial.
We randomly assigned 365 adults with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both to receive either more intensive treatment (target hematocrit, <45%) (low-hematocrit group) or less intensive treatment (target hematocrit, 45 to 50%) (high-hematocrit group). The primary composite end point was the time until death from cardiovascular causes or major thrombotic events. The secondary end points were cardiovascular events, cardiovascular hospitalizations, incidence of cancer, progression to myelofibrosis, myelodysplasia or leukemic transformation, and hemorrhage. An intention-to-treat analysis was performed.
After a median follow-up of 31 months, the primary end point was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%) (hazard ratio in the high-hematocrit group, 3.91; 95% confidence interval CI, 1.45 to 10.53; P=0.007). The primary end point plus superficial-vein thrombosis occurred in 4.4% of patients in the low-hematocrit group, as compared with 10.9% in the high-hematocrit group (hazard ratio, 2.69; 95% CI, 1.19 to 6.12; P=0.02). Progression to myelofibrosis, myelodysplasia or leukemic transformation, and bleeding were observed in 6, 2, and 2 patients, respectively, in the low-hematocrit group, as compared with 2, 1, and 5 patients, respectively, in the high-hematocrit group. There was no significant between-group difference in the rate of adverse events.
In patients with polycythemia vera, those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with a hematocrit target of 45 to 50%. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT01645124, and EudraCT number, 2007-006694-91.).
The GIMEMA LAL1509 protocol, designed for adult (≥18-60 years) de novo Ph+ acute lymphoblastic leukemia patients, was based on a dasatinib plus steroids induction - with central nervous system ...prophylaxis - followed by dasatinib alone in patients in complete molecular response or chemotherapy and/or allogeneic transplantation in patients not reaching a complete molecular response. Sixty patients (median age 41.9 years) were enrolled: 33 were p190+, 18 p210+ and 9 p190/p210+. At the end of induction (day +85), 58 patients (97%) achieved a complete hematologic remission. No deaths in induction were recorded. Eleven patients (18.3%) obtained a complete molecular response. Among non-complete molecular responders (n=47), 22 underwent an allogeneic transplant. Seventeen hematologic relapses occurred (median 7 months, range 3-40.1), 13 during consolidation and 4 post-transplant. ABL1 mutations (5 T315I, 3 V299L, 1 E281K and 1 G254E) were found in 10/13 relapsed cases. With a median follow-up of 57.4 months (range: 4.2-75.6), overall survival and disease-free survival are 56.3% and 47.2%. A better diseasefree survival was observed in patients who obtained a molecular response at day +85 compared to cases who did not. The presence of additional copy number aberrations - IKZF1 plus CDKN2A/B and/or PAX5 deletions - was the most important unfavorable prognostic factor on overall and disease-free survival (p=0.005 and p=0.0008). This study shows that in adult Ph+ ALL long-term survivals can be achieved with a total-therapy strategy based on a chemo-free induction and, in complete molecular responders, also without further systemic chemotherapy. Finally, the screening of additional copy number aberrations should be included in the diagnostic work-up. EudraCT 2010-019119-39.
There is paucity of evidence-based data on health-related quality of life (HRQOL) outcomes of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). We performed a ...multicenter propensity-matched case-control study to compare HRQOL of newly diagnosed CML patients treated with front-line dasatinib (cases) or imatinib (controls). Patient-reported HRQOL was assessed with the EORTC QLQ-C30 and the EORTC QLQ-CML24 questionnaires. The impact on daily life scale of the EORTC QLQ-CML24 was selected a priori in the protocol as the primary HRQOL scale for the comparative analysis. Overall, 323 CML patients were enrolled of whom 223 in therapy with imatinib and 100 in therapy with dasatinib. Patients treated with dasatinib reported better disease-specific HRQOL outcomes in impact on daily life (Δ = 8.72, 95% confidence interval CI: 3.17-14.27, p = 0.002), satisfaction with social life (Δ = 13.45, 95% CI: 5.82-21.08, p = 0.001), and symptom burden (Δ = 7.69, 95% CI: 3.42-11.96, p = 0.001). Analysis by age groups showed that, in patients aged 60 years and over, differences favoring dasatinib were negligible across several cancer generic and disease-specific HRQOL domains. Our findings provide novel comparative HRQOL data that extends knowledge on safety and efficacy of these two TKIs and may help to facilitate first-line treatment decisions.
Extramedullary disease is relatively frequent in multiple myeloma, but our knowledge on the subject is limited and mainly relies on small case series or single center experiences. Little is known ...regarding the role of new drugs in this setting. We performed a meta-analysis of eight trials focused on the description of extramedullary disease characteristics, clinical outcome, and response to new drugs. A total of 2,332 newly diagnosed myeloma patients have been included; 267 (11.4%) had extramedullary disease, defined as paraosseous in 243 (10.4%), extramedullary plasmocytoma in 12 (0.5%), and not classified in 12 (0.5%) patients. Median progression-free survival was 25.3 months and 25.2 in extramedullary disease and non-extramedullary disease patients, respectively. In multivariate analysis the presence of extramedullary disease did not impact on progression-free survival (hazard ratio 1.15,
=0.06), while other known prognostic factors retained their significance. Patients treated with immunomodulatory drugs, mainly lenalidomide, or proteasome inhibitors had similar progression-free survival and progression-free survival-2 regardless of extramedullary disease presence. Median overall survival was 63.5 months and 79.9 months (
=0.01) in extramedullary and non-extramedullary disease patients, respectively, and in multivariate analysis the presence of extramedullary disease was associated with a reduced overall survival (hazard ratio 1.41,
<0.001), in line with other prognostic factors. With the limits of the use of low sensitivity imaging techniques, that lead to an underestimation of extramedullary disease, we conclude that in patients treated with new drugs the detrimental effect of extramedullary disease at diagnosis is limited, that lenalidomide is effective as are proteasome inhibitors, and that these patients tend to acquire a more aggressive disease in later stages. (EUDRACT2005-004714-32, NCT01063179 NCT00551928, NCT01091831, NCT01093196, NCT01190787, NCT01346787, NCT01857115).
To verify whether absolute monocyte count (AMC) and lymphocyte- monocyte ratio (LMR) at diagnosis are valid prognostic parameters in classical Hodgkin lymphoma (cHL).
Data were collected from 1450 ...patients with cHL treated in Israel and Italy from January 1, 1988, through December 31, 2007.
The median age of the patients was 33 years (range, 17-72 years), and 70% (1017) of the patients had nodular sclerosis (NS); the median follow-up duration was 87 months. The best cutoff value for AMC was 750 cells/mm3, and the best ratio for LMR was 2.1. The adverse prognostic impact of an AMC of more than 750 cells/mm3 was confirmed for the entire cohort, and its clinical significance was particularly evident in patients with NS histology. The progression-free survival (PFS) at 10 years for an AMC of more than 750 cells/mm3 was 65% (56%-72%), and the PFS at 10 years for an AMC of 750 cells/mm3 or less was 81% (76%-84%; P<.001). The overall survival (OS) at 10 years for an AMC of more than 750 cells/mm3 was 78% (70%-85%), and the OS at 10 years for an AMC of 750 cells/mm3 or less was 88% (84%-90%; P=.01). In multivariate analysis, both AMC and LMR maintained prognostic significance for PFS (hazard ratio HR, 1.54, P=.006, and HR, 1.50, P=.006) after adjusting for the international prognostic score, whereas the impact on OS was confirmed (HR, 1.56; P=.04) only in patients with NS and an AMC of more than 750 cells/mm3.
This study confirms that AMC has prognostic value in cHL that is particularly significant in patients with NS subtype histology. This finding links the known impact of macrophages and monocytes in Hodgkin lymphoma with routine clinical practice.
In the acute myeloid leukemia (AML) setting, research has extensively investigated the existence and relevance of molecular biomarkers, in order to better tailor therapy with newly developed agents ...and hence improve outcomes and/or save the patient from poorly effective therapies. In particular, in patients with AML, residual disease after therapy does reflect the sum of the contributions of all factors associated with diagnosis and post-diagnosis resistance. The evaluation of minimal/measurable residual disease (MRD) can be considered as a key tool to guide patient’s management and a promising endpoint for clinical trials. In this narrative review, we discuss MRD evaluation as biomarker for tailored therapy in AML patients; we briefly report current evidence on the use of MRD in clinical practice, and comment on the potential ability of MRD in the assessment of the efficacy of new molecules.
Carfilzomib, lenalidomide, and dexamethasone (KRd) have been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) based on ASPIRE clinical trial. However, its effectiveness ...and safety profile in real clinical practice should be further assessed. We retrospectively evaluated 130 consecutive RRMM patients treated with KRd between December 2015 and August 2018, in 9 Hematology Departments of Rete Ematologica Pugliese (REP). The overall response rate (ORR) was 79%, with 37% complete response (CR). Treatment with KRd led to an improvement in response regardless of age, refractory disease, and number and type of previous therapies. After a median follow-up of 18 months, median PFS was 24 months and 2y-PFS was 54%. PFS was longer in patients achieving a very good partial response (VGPR) with median PFS of 32.4 months. The relapses after prior autologous transplant (ASCT) positively impact median PFS. Several baseline disease characteristics, such as III ISS scoring or elevated LDH, and prior exposure to lenalidomide were found to negatively impact PFS. Primary refractory or relapsed myeloma patients have been treated with KRd as bridge to ASCT with a great benefit. Thirty-four (83%) reached at least a partial response after KRd and 21 (61%) performed ASCT. In transplanted patients, median PFS was not reached and 2y-PFS was 100%. The treatment discontinuation rate due to adverse events (AEs) was 18%, most commonly for lenalidomide (11%). Overall, in 10% of patients, a KRd dose reduction was necessary at least once (2.5% for carfilzomib and 8% for lenalidomide). The most frequent AE was neutropenia (44%) and anemia (41%). Infections occurred in 14% of patients. Cardiovascular events occurred in 11% of patients. Elderly patients have tolerated therapy very well, without additional side effects compared to younger patients, except for cardiac impairment. Our analysis confirmed that KRd is effective in RRMM patients. It is well tolerated and applicable to the majority of patients outside clinical trials. A longer PFS was shown in patients achieving VGPR, in those lenalidomide naïve and in patients relapsing after previous ASCT. Previous ASCT should not hamper the option for KRd therapy. Accordingly, KRd should be used as bridge regimen to ASCT with remarkable improvement in response and PFS rates. Further clinical studies are needed.
INTRODUCTION: Elderly patients with newly diagnosed multiple myeloma (NDMM) are highly heterogeneous and their outcome is influenced by many factors: beside age, also comorbidities, general physical ...fitness, and cognitive function play a crucial role. The IMWG frailty score combines age, functional status, and comorbidities, and it identifies fit, intermediate-fit and frail patients, with different risk of toxicity, treatment discontinuation, and mortality (Palumbo A et al. Blood 2015). Until now, evidence-based tailored treatments according to patients' frailty are still lacking. Therefore, this phase III study investigated the efficacy and feasibility of dose/schedule-adjusted lenalidomide-dexamethasone therapy followed by lenalidomide maintenance (Rd-R) versus continuous lenalidomide-dexamethasone (Rd) in elderly, intermediate-fit NDMM patients.
METHODS: Intermediate-fit NDMM patients, with a total frailty score (age, Charlson Index, ADL and IADL) of 1 (http://www.myelomafrailtyscorecalculator.net/), were enrolled and randomized to receive Rd-R or continuous Rd. To better approximate a real-world older population, patients usually excluded from clinical trials or with abnormal laboratory values could be included in the trial.
Rd-R treatment consisted of nine 28-day cycles of lenalidomide 25 mg/day for 21 days and dexamethasone 20 mg on days 1,8,15,22, followed by lenalidomide maintenance 10 mg/day for 21 days, until disease progression. Continuous Rd consisted of lenalidomide 25 mg/day for 21 days and dexamethasone 20 mg on days 1,8,15,22, until disease progression. The dose and schedule of continuous Rd was the one adopted in patients >75 years in the FIRST trial (Hulin C et al. JCO 2016).
The primary endpoint was event-free survival (EFS), defined as progression or death for any cause or discontinuation of lenalidomide or occurrence of any hematological grade 4 or non-hematological grade 3-4 adverse events (AEs), including Secondary Primary Malignancies (SPMs), whichever came first.
RESULTS: 199 patients (98 in Rd-R arm and 101 in continuous Rd arm) could be evaluated. Patients characteristics were well balanced between the 2 arms. Median age was 75 and 76 years (p=0.06); 47% in Rd-R vs 57% in continuous Rd were defined intermediate-fit for age (≥76 years), 53% vs 43% due to an impairment in Charlson Index, ADL or IADL (p=ns).
In intention-to-treat analysis, after a median follow-up of 25 months, EFS was 9.3 vs 6.6 months (HR 0.72, 95% CI 0.52-0.99, p=0.04), in Rd-R versus continuous Rd, respectively (Figure 1).
Best response rates were not significantly different between the 2 groups: ≥PR rates were 73% vs 63%, and ≥VGPR rates were 43% vs 35% in the Rd-R vs Rd continuous group, respectively (p=ns).
No difference in progression-free survival (PFS) and overall survival (OS) was observed. Median PFS was 18.3 vs 15.5 months (HR 0.93, 95% CI 0.64-1.34, p=ns) (Figure 1), 18 month-OS was 85% versus 81% (HR 0.73, 95% CI 0.40-1.33, p=ns).
Adverse events accounting for EFS (any hematologic grade 4, non-hematologic grade 3-4) were less frequent in the Rd-R group (30% vs 39%) than in the continuous Rd group (p=ns). The most frequent adverse events were neutropenia, infection and skin reactions (less than 10% in each arm). After 9 treatment cycles, these adverse events were less frequent in Rd-R vs continuous Rd group (3% vs 7%, p=ns).
Lenalidomide dose reduction after 9 treatment cycles was required in 1% of Rd-R patients and 21% of continuous Rd patients (p =0.06). Dexamethasone dose reduction was required in 17% vs 29% of patients, respectively (p=0.06).
CONCLUSION: This is the first prospective randomized phase III trial specifically designed for real-life intermediate-fit NDMM patients. A dose/schedule-adjusted Rd-R treatment was more feasible compared to full dose continuous Rd treatment in elderly intermediate-fit NDMM patients, with no negative impact but rather a comparable outcome. These results confirm the need for an appropriate definition of patient frailty, and pave the way to a frailty-adjusted treatment approach to better balance efficacy and safety in elderly NDMM patients.
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Larocca:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria. De Paoli:Amgen: Other: Advisory Board; Janssen: Other: Advisory Board; Celgene: Other: Advisory Board; Gilead: Other: Advisory Board. Galli:Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Sigma-Tau: Honoraria. Montefusco:Janssen: Other: Advisory Board; Amgen: Other: Advisory Board; Celgene: Other: Advisory Board. Caravita di Toritto:Johnson & Johnson: Other: Advisory Board, Travel and Accomodation EHA; Amgen: Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Travel and Accomodation EMN; Takeda: Other: Advisory Board; Celgene: Other: Advisory Board, Travel and Accomodation ASH, Research Funding. Giuliani:Celgene Italy: Other: Avisory Board, Research Funding; Takeda Pharmaceutical Co: Research Funding; Janssen Pharmaceutica: Other: Avisory Board, Research Funding. Patriarca:Jazz: Other: Travel, accommodations, expenses; Janssen: Other: Advisory role; Celgene: Other: Advisory Role; Travel, accommodations, expenses; Medac: Other: Travel, accommodations, expenses; MSD Italy: Other: Advisory Role. Offidani:Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board. Cavo:GlaxoSmithKline: 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; Takeda: 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, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: 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. Palumbo:Takeda: Employment. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding. Bringhen:Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria.
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