Background Although somatic mutations influence the pathogenesis, phenotype, and outcome of myeloproliferative neoplasms (MPN), little is known about their impact on molecular response to cytoreductive treatment. Methods We performed targeted next-generation sequencing (NGS) on 202 pre-treatment samples obtained from patients with MPN enrolled in the DALIAH trial (randomized controlled phase III clinical trial, NCT01387763) and 135 samples obtained after 24 months of therapy with recombinant interferon-alpha (IFNα) or hydroxyurea (HU). The primary aim was to evaluate the association between complete clinicohematologic response (CHR) at 24 months and molecular response through sequential assessment of 120 genes using NGS. Results Among JAK2-mutated patients treated with IFNα, those with CHR had a greater reduction in the JAK2 variant allele frequency (VAF) (median 0.29 to 0.07; p<0.0001) compared with those not achieving CHR (median 0.27 to 0.14; p<0.0001). In contrast, the CALR VAF did not significantly decline in neither those achieving CHR nor those not achieving CHR. Treatment-emergent mutations in DNMT3A were observed more commonly in patients treated with IFNα compared with HU, p=0.04. Furthermore, treatment-emergent DNMT3A-mutations were significantly enriched in IFNα treated patients not attaining CHR, p=0.02. A mutation in TET2, DNMT3A, or ASXL1 was significantly associated with prior stroke (age-adjusted OR=5.29 [95% CI, 1.59-17.54]; p=0.007) as was a mutation in TET2 alone (age-adjusted OR=3.03 [95% CI, 1.03-9.01]; p=0.044). Conclusion At 24 months, we found mutation-specific response patterns to IFNα: (1) JAK2- and CALR-mutated MPN demonstrated distinct molecular responses and (2) DNMT3A-mutated clones/subclones emerged on treatment.
Background The number of hematological malignancies is expected to increase as the Danish population ages within the next few decades. Despite this, data on the course of hematological cancers among the oldest patients are sparse with many intervention studies focusing on younger age groups. The aim of this study is to present Danish incidence and mortality rates among older patients with non-Hodgkin lymphomas (NHL), multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and acute myeloid leukemia (AML). Material and methods Nationwide population-based study presenting the incidence, prevalence and mortality rates of NHL, MM, and AML with a focus on the elderly population in Denmark during the last few decades. Data were drawn from the NORDCAN database. Results Incidence rates of NHL, MM, CLL and AML were 10-50 times higher among the population aged 70 years or more than among the younger population. An increasing incidence with stable or decreased mortality rates was seen mainly among elderly patients with NHL during the last few decades, leading to increased survival and a greater prevalence of patients with NHL. Increased relative survival and prevalence could also be seen among elderly patients with MM and CLL, while the trends of the incidence rates were inconclusive for these diseases. Survival among patients with AML improved most notably in those aged below 70 years leading to an increased prevalence of AML patients predominantly in this age group. Conclusion Improvements in diagnostics and treatment have led to increased survival and therefore prevalence of elderly patients with NHL, MM, CLL and AML during the past decades.
Background Recombinant Interferon Alpha-2a (r-IFNα) is a potent immunomodulating agent, which has been used off-label for the treatment of polycythemia vera (PV) for more than three decades and has been demonstrated to induce high rates of clinical, hematological and molecular responses. Only few studies have compared efficacy and safety of r-IFNα vs. hydroxyurea (HU), which is considered first line therapy for PV patients > 60 years in most parts of the world. However, recent studies have provided encouraging results for the treatment of PV with r-IFNα compared to HU irrespective of age (R. Hoffmann 2016; H. Gisslinger 2018). Aims To examine the difference in efficacy and safety of low-dose r-IFNα in PV patients ≤ 60 or > 60 years of age compared to HU > 60 years of age. Methods Ninety newly diagnosed or previously phlebotomized PV patients only (WHO 2008) were enrolled in the DALIAH trial (NCT01387763). All patients provided written informed consent. Patients ≤ 60 years were randomized (I:I) to r-IFNα-2a (Pegasys®) or to r-IFNα-2b (PegIntron®) whereas patients > 60 years were randomized (I:I:I) to either r-IFNα-2a, r-IFNα-2b or to HU. The starting dose of r-IFNα-2a and r-IFNα-2b was 45 or 35 µg/week, respectively. The HU dose was 500 to 2000 mg/day. Patients randomized to r-IFNα who presented with major thrombosis or platelets > 1500 109/L received HU from inclusion and until normalization of the platelet count. Efficacy assessment consisted of the clinicohematological and the molecular response rates by intention to treat analysis (ITT) using the European Leukemia Net (ELN) 2009 criteria. JAK2V617F analysis was performed by qPCR. Groups were compared by Fisher's Exact Test. Results Three-year analysis was available in all but five patients (n=85) at time of abstract submission (Table 1). The analysis was performed after a median of 36 months (range: 33-39 months). The median treatment dose was 684 mg/day (IQR: 131 - 942) for HU, 51 μg/week (IQR: 30-90 μg/week) and 54 μg/week (IQR: 30-66 μg/week) for r-IFNα-2a age ≤ 60 and > 60, respectively, and 41 μg/week (IQR: 29-45 μg/week) and 36 μg/week (IQR: 31-37 μg/week) for r-IFNα-2b age ≤ 60 and > 60. The overall clinicohematological response rate (ORR) was 68% (13/19) for HU, 42% (14/33) for r-IFNα ≤ 60 years and 39% (13/33) for r-IFNα > 60 years. The partial clinicohematological response rate (PHR) and the complete clinicohematological response rate (CHR) was 53% (10/19) and 16% (3/19) for HU, 9% (3/33) and 33% (11/33) for r-IFNα ≤ 60 years and 9% (3/33) and 30% (10/33) for r-IFNα > 60 years. Neither the ORR, CHR nor the PHR was significantly different between the three groups. Maintenance of CHR from first occurrence to data analysis after 36 months was 11% (2/19) for HU, 21% (7/33) for r-IFNα ≤ 60 years and 18% (6/33) for r-IFNα > 60 years. Forty-seven JAK2V617F positive patients were available for molecular response analysis after 36 months of therapy. A partial molecular response (PMR) was detected in 21% (4/19) of HU treated patients and in 24% (7/29) of r-IFNα treated patients ≤ 60 years and 18% (6/33) of r-IFNα > 60 years. Notably, 7% (2/29) of the r-IFNα treated patients ≤ 60 years obtained a complete molecular response (CMR). The median JAK2V617F reduction from baseline was 38% (IQR: 31-63%) for HU, 79% (IQR: 59-92%) for r-IFNα ≤ 60 years and 73% (IQR: 49-97%) for r-IFNα > 60 years. There was no statistically significant difference in the PMR between groups. Discontinuation of treatment for any reason after 36 months of therapy was 21% (4/19) for HU, 52% (17/33) for r-IFNα ≤ 60 years and 45% (15/33) for r-IFNα > 60 years. Toxicity related discontinuation was 5% (1/19) for HU and 30% (10/33) for both r-IFNα ≤ 60 and > 60 years. Grade 3-4 AEs occurred in 32% (6/19) of HU treated patients, 27% (9/33) in r-IFNα treated patients ≤ 60 years and in 42% (14/33) r-IFNα treated patients > 60 years. SAEs were reported in 21% (4/19) for HU, 9% (3/33) for r-IFNα ≤ 60 years and 24% (8/33) for r-IFNα > 60 years. The numbers of grade 3-4 AEs as well as SAEs were comparable between groups. Conclusion After 36 months of therapy CHR was non-significantly higher in PV patients treated with r-IFNα compared to HU by ITT, irrespective of age. Also, maintenance of CHR was longer for r-IFNα. However, ORR was non-significantly higher for HU. PMR was almost similar between the three groups but the median JAK2V617F reduction was greater for r-IFNα. Toxicity related discontinuation from study therapy was higher for r-IFNα compared to HU. Disclosures Stentoft: Bristol-Myers Squibb: Research Funding; Merck Sharp&Dohme: Research Funding. Hasselbalch:Novartis: Research Funding.
Background: Anemia is one clinically relevant symptom in patients (pts) with myelofibrosis (MF) which is not being addressed by treatment with ruxolitinib (RUX). Single treatment with pomalidomide (POM) improved cytopenia in 14% (POM 0.5 mg QD) and 29% (POM 2 mg QD) of MF pts in our previous MPNSG-0109 trial. Aims: Therefore, we sought to investigate the combination of RUX plus POM in MF with anemia. Methods: MPNSG-0212 (NCT01644110) is a multicenter, open-label, single-arm phase-Ib/II trial with a target population of 90 pts in a twostage design. Pts 1-40 (cohort 1 [co1]) are treated with RUX (10 mg BID) plus low-dose POM (0.5 mg QD), while pts 41-90 (cohort 2 [co2]) receive a step-wise dose increase of POM after 3 and 6 cycles (0.5 -> 1 -> 2 mg QD). Primary endpoints are safety of the combination therapy and anemia response after 12 28-day cycles (according to IWG-MRT and RBC transfusion independency [RBC-TI] criteria). Main inclusion criterion is MF with anemia (Hb <10 g/dL and/or RBC-TD). Pts suitable for allogeneic transplantation and pts with low platelets (<100/nL) are excluded.Results: Data from 59 pts were available for this analysis. Baseline characteristics were as following: Median age 72 yrs (range 49-84), 53% had prior treatment (RUX in 22%, POM in 4%), median Hb level was 8.5 g/dL (range 5.4-11.7), 27% fulfilled the RBC-TD criterion, median spleen size was 17.8 cm (range 12.6-36), 80% had constitutional symptoms, 93% were intermediate-2 (64%) or high-risk (29%) according to DIPSS, and 55% had 1 high molecular risk mutation (ASXL1, SRSF2, EZH2, and/or IDH1/2). Median number of treatment cycles was 12 (range 2-59) in co1 and 11 (range 1-16) in co2. 414 adverse events (AE) were recorded (mostly °I/II). Number or severity of AE were not increased in co2. Most common AE (°I/II) were anemia (34% of pts) and fatigue (29%) in the first weeks of treatment as well as musculoskeletal cramps (25%). Regarding serious AE (SAE), n = 77 were recorded in 64% of pts. No fatal (S)AE occurred in co2. Most common SAE were pneumonia (12%), leukemic transformation (10%), and worsening of general condition (7%). Interruption/termination of RUX and/or POM was rare in co1 and co2. In co1, 18/40 pts (45%) continued treatment beyond cycle 12 because of objective anemia response (7/40, 18%: CI-Hb [Hb increase 2 g/dL] n = 5, PR and RBC-TI n = 1 each) or stable disease in combination with clinical benefit (CB, 11/40, 28%) defined as: Hb increase 1 g/dL and/or doubling of RBC transfusion intervals [n = 4] or improvement of fatigue and/or overall quality of life >25% according to MPN-SAF [n = 7]. Notably, 16 pts of co1 (40%) were on treatment for more than 24 cycles, and mean Hb increased continuously from 8.7 g/dl at baseline to 9.8 g/dL at end of cycle 18 and sustained thereafter at 9.7 g/dL until end of cycle 30 (Figure 1). In co2, 6/19 pts (31%) reached cycle 12 and continued treatment afterwards: 1/6 (17%) experienced RBC-TI, whereas 5 had CB; 16/19 pts (84%) were still on treatment at the time of the analysis with 10/16 p...
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