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Background: Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine (ara‐C) and anthracyclines. Five‐year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that the addition of hydroxyurea potentiates cytarabine efficacy by increasing ara‐C triphosphate (ara‐CTP) levels through targeted inhibition of SAMHD1. Objectives: In this phase 1 trial, we evaluated the feasibility, safety and efficacy of the addition of hydroxyurea to standard chemotherapy with cytarabine/daunorubicin in newly diagnosed AML patients. Methods: Nine patients were enrolled and received at least two courses of ara‐C (1 g/m2/2 h b.i.d. d1‐5, i.e., a total of 10 g/m2 per course), hydroxyurea (1–2 g d1‐5) and daunorubicin (60 mg/m2 d1‐3). The primary endpoint was safety; secondary endpoints were complete remission rate and measurable residual disease (MRD). Additionally, pharmacokinetic studies of ara‐CTP and exvivo drug sensitivity assays were performed. Results: The most common grade 3‐4 toxicity was febrile neutropenia (100%). No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in median ara‐CTP levels (1.5‐fold; p = 0.04) in patients receiving doses of 1 g hydroxyurea. Ex vivo, diagnostic leukaemic bone marrow blasts from study patients were significantly sensitised to ara‐C by a median factor of 2.1 (p = 0.0047). All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow cytometry or real‐time quantitative polymerase chain reaction [RT‐qPCR]) had an MRD level <0.1% after two cycles of chemotherapy. Treatment was well‐tolerated, and median time to neutrophil recovery >1.0 × 109/L and to platelet recovery >50 × 109/L after the start of cycle 1 was 19 days and 22 days, respectively. Six of nine patients underwent allogeneic haematopoietic stem‐cell transplantation (allo‐HSCT). With a median follow‐up of 18.0 (range 14.9–20.5) months, one patient with adverse risk not fit for HSCT experienced a relapse after 11.9 months but is now in second complete remission. Conclusion: Targeted inhibition of SAMHD1 by the addition of hydroxyurea to conventional AML therapy is safe and appears efficacious within the limitations of the small phase 1 patient cohort. These results need to be corroborated in a larger study. [ABSTRACT FROM AUTHOR]

Objectives: The use of patient‐reported outcome (PRO) measured outside clinical trials is not well defined. We report the first analysis of the prospective PRO study within the Swedish acute myeloid leukemia (AML) and the acute lymphoblastic leukemia (ALL) registries. Methods: PRO was requested 6 months after diagnosis. The EORTC Quality of life Questionnaire Core 30‐item, the Patient Health Questionnaire‐8 (PHQ‐8), and questions from a Swedish National Cancer Questionnaire were used. Results: An invitation letter was sent to 398 patients; 255 (64%) responded, 60% web‐based, and 40% on paper. The ALL cohort had lower physical, role and social functioning, higher symptom burden, and more financial difficulties compared to the AML cohort. A PHQ‐8 score ≥ 10p, which indicates depression, was reported in 18% of the patients; 33% of these patients reported being prescribed antidepressants. The patients' overall experience of care was satisfying, but more psychological and practical support was desired. There was no difference in survival between patients who reported their PRO and those who did not. Follow‐up at 2 and 4 years is ongoing. Conclusions: PRO collected in a registry‐based setting is feasible, but the selection of time points and questionnaires are delicate in a diverse patient population. [ABSTRACT FROM AUTHOR]

Objective: We describe survival in patients with oligo‐ and non‐secretory multiple myeloma (MM). We refer to the whole group as non‐measurable MM and compare it with secretory MM. Methods: Oligo‐secretory MM was defined as M protein in serum <10 g/L and M protein in urine <200 measured as mg/day, mg/liter or mg/mmol creatinine. If patients had no M protein, they were defined as non‐secretory. The groups were also subdivided by Free Light Chains (SFLC) level and ratio. Results: Out of 4325 patients with symptomatic MM in the Swedish Myeloma Registry during 2008‐2016 eligible for the study, 389 patients (9%) had non‐measurable MM. Out of these, 253 patients (6%) had oligo‐secretory and 136 (3%) had non‐secretory MM. Median survival for secretory MM was 42.7 months, non‐measurable MM 40.2 months, oligo‐secretory MM 38.6 months, and non‐secretory MM 44.6 months. Difference in overall observed survival was non‐significant for all groups when compared with secretory MM. Within non‐secretory MM, stem cell transplantation (SCT), 95% being auto‐SCT, was significant for superior survival in multivariate analysis (HR 0.048. P =.0015). Conclusion: In this population‐based study, we found no difference in survival between oligo‐ or non‐secretory MM when compared with secretory MM. SCT appears to be important also for patients with non‐secretory disease. [ABSTRACT FROM AUTHOR]

Real-world data on treatment patterns and outcomes of hypomethylating therapy in patients with newly diagnosed acute myeloid leukaemia aged >= 60 years Hypomethylating agents (HMAs) are increasingly used in patients with acute myeloid leukaemia (AML). PC patients had poorer World Health Organization Performance Status (WHO PS 2-4 in 75%) compared to HMA and IC patients (WHO PS 0-1 in 76% and 82%, respectively) and cytogenetically high-risk patients were equally frequent between treatment regimens. [Extracted from the article]

Decreasing early mortality in acute myeloid leukaemia in Sweden 1997-2014: improving performance status is a major contributing factor The early mortality (EM) in acute myeloid leukaemia (AML) is a significant clinical problem in AML management. Palliative patients were to a larger extent female, older, with more secondary AML, higher cytogenetic high risk and higher PS compared to induction patients ( I P i -values: 0-003, <0-001, <0-001, <0-001 and <0-001 respectively) (see Table). Again, when applying the adjusted model the improving trend of EM was abrogated among the intensively treated patients [RR = 1-00(95% CI: 0-97-1-02), I P i = 0-807] (Fig C), while for palliative patients the adjusted EM risk actually increased from the reference year 1997 [RR = 1-02(95% CI: 1-01-1-03), I P i = 0-001] (Fig B). [Extracted from the article]

Solitary plasmacytoma ( SP) and plasma cell leukemia ( PCL) are uncommon (3-6%) types of plasma cell disease. The risk of progression to symptomatic multiple myeloma ( MM) is probably important for the outcome of SP. PCL is rare and has a dismal outcome. In this study, we report on incidence and survival in PCL/ SP, and progression to MM in SP, using the prospective observational Swedish Multiple Myeloma Register designed to document all newly diagnosed plasma cell diseases in Sweden since 2008. Both solitary bone plasmacytoma ( SBP) ( n=124) and extramedullary plasmacytoma ( EMP) ( n=67) have better overall survival ( OS) than MM ( n=3549). Progression to MM was higher in SBP than in EMP (35% and 7% at 2 years, respectively), but this did not translate into better survival in EMP. In spite of treatment developments, the OS of primary PCL is still dismal (median of 11 months, 0% at 5 years). Hence, there is a great need for diagnostic and treatment guidelines as well as prospective studies addressing the role for alternative treatment options, such as allogeneic stem cell transplantation and monoclonal antibodies in the treatment of PCL. [ABSTRACT FROM AUTHOR]

Objectives and Methods To ascertain the incidence/clinical implications of isolated autosomal trisomies in adult acute myeloid leukemia (AML), all such cases were retrieved from the Swedish AML Registry. Results Of the 3179 cytogenetically informative AMLs diagnosed January 1997-May 2015, 246 (7.7%) had isolated trisomies. The frequency increased by age (2.4% at age 18-60 years vs. 23% at >60 years; P<.0001); the median age was 69 years. The five most common were +8 (4.0%), +13 (0.9%), +11 (0.8%), +21 (0.7%), and +4 (0.5%). Age and gender, types of AML and treatment, and complete remission and early death rates did not differ between the single trisomy and the intermediate risk (IR) groups or among cases with isolated gains of chromosomes 4, 8, 11, 13, or 21. The overall survival (OS) was similar in the single trisomy (median 1.6 years) and IR groups (1.7 years; P=.251). The OS differed among the most frequent isolated trisomies; the median OS was 2.5 years for +4, 1.9 years for +21, 1.5 years for +8, 1.1 years for +11, and 0.8 years for +13 ( P=.013). Conclusion AML with single trisomies, with the exception of +13, should be grouped as IR. [ABSTRACT FROM AUTHOR]

The article discusses research which examined the function ex vivo of acute myeloid leukaemia-initiating cells (AML-IC). Topics discussed include the poor AML prognosis on older people, factors that limit the understanding of AML physiopathology and use of a co-culture system to evaluate the effect of various drugs approved by the U.S. Food and Drug Administration of primary human AML-ICs.

Unsuccessful cytogenetics ( UC) in patients with acute myeloid leukaemia ( AML) treated on different SWOG trials was recently reported to be associated with increased age and dismal outcome. To ascertain whether this holds true also in unselected patients with AML, we retrieved all cytogenetic reports in cases from the population-based Swedish AML Registry. Between 1997 and 2006, 1737 patients below 80 yr of age without myelosarcoma or acute promyelocytic leukaemia received intensive treatment. The frequencies of UC and unperformed cytogenetics ( UPC) were 2.1% and 20%, respectively. The early death rates differed between the cytogenetic subgroups ( P = 0.006) with the highest rates in patients with UC (14%) and UPC (12%) followed by high-risk ( HR) AML, intermediate risk ( IR) and standard risk ( SR) cases successfully karyotyped (8.6%, 5.9%, and 5.8%, respectively). The complete remission rate was lower in UC and UPC and HR compared with the other risk groups ( P < 0.001). The overall five-year survival rates were 25% for UC and 22% for UPC, whereas the corresponding frequencies for SR, IR and HR AML patients without UC and UPC were 64%, 31% and 15%, respectively. In conclusion, lack of cytogenetic data translates into a poor prognosis. [ABSTRACT FROM AUTHOR]

Recent multi-stage genome-wide association studies ( GWAS) have identified single nucleotide polymorphisms ( SNPs) that are robustly associated with chronic lymphocytic leukaemia ( CLL) risk. Given that most of these SNPs map to non-coding regions of the genome, it suggests that the functional basis of many GWAS signals will be through differential gene expression. By referencing publically accessible expression quantitative trait loci ( eQTL) data on lymphoblastoid cells lines ( LCLs) we have globally demonstrated an association between GWAS P-values and eQTLs, consistent with much of the variation in CLL risk being defined by variants impacting on gene expression. To explore using eQTL data to select GWAS SNPs for replication, we genotyped rs2072135 ( GWAS P-value = 0·0024, eQTL P-value = 1·510−19) in five independent case-control series totalling 1968 cases and 3538 controls. While not attaining statistical significance (combined P-value = 1 × 10−4), rs2072135 defines a promising risk locus for CLL. Incorporating eQTL information offers an attractive strategy for selecting SNPs from GWAS for validation. [ABSTRACT FROM AUTHOR]

The efficacy of bendamustine versus chlorambucil in a phase III trial of previously untreated patients with Binet stage B/C chronic lymphocytic leukaemia ( CLL) was re-evaluated after a median observation time of 54 months in May 2010. Overall survival ( OS) was analysed for the first time. At follow-up, investigator-assessed complete response ( CR) rate (21·0% vs 10·8%), median progression-free survival (21·2 vs 8·8 months; P < 0·0001; hazard ratio 2·83) and time to next treatment (31·7 vs 10·1 months; P < 0·0001) were improved for bendamustine over chlorambucil. OS was not different between groups for all patients or those ≤65 years, >65 years, responders and non-responders. However, patients with objective response or a CR experienced a significantly longer OS than non-responders or those without a CR. Significantly more patients on chlorambucil progressed to second/further lines of treatment compared with those on bendamustine (78·3% vs 63·6%; P = 0·004). The benefits of bendamustine over chlorambucil were achieved without reducing quality of life. In conclusion, bendamustine is significantly more effective than chlorambucil in previously untreated CLL patients, with the achievement of a CR or objective response appearing to prolong OS. Bendamustine should be considered as a preferred first-line option over chlorambucil for CLL patients ineligible for fludarabine, cyclophosphamide and rituximab. [ABSTRACT FROM AUTHOR]

BACKGROUND: Allogeneic stem cell transplantation (alloSCT) reduces relapse rates in acute leukemia, but outcome is hampered by toxicity. Population-based data avoid patient selection and may therefore substitute for lack of randomized trials. METHODS: We evaluated alloSCT rates within the Swedish Acute Leukemia Registry, including 3899 adult patients diagnosed from 1997 through 2006 with a coverage of 98% and a median follow-up of 6.2 years. RESULTS: AlloSCT rates and survival decreased rapidly with age >55 years. The 8-year overall survival (OS) was 65% in patients <30 years and 38% in patients <60 years and was similar for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Among 1073 patients <60 years, alloSCT was performed in 42% and 49% of patients with AML and ALL, respectively. Two-thirds of the alloSCTs were performed in first complete remission, and half used unrelated donors, the same in AML and ALL. Regional differences in management and outcome were found: 60% of AML patients <40 years received alloSCT in all parts of Sweden, but two-thirds of AML patients 40-59 years had alloSCT in one region compared with one-third in other regions ( P<.001), with improved 8-year OS among all AML patients in this age cohort (51% vs 30%; P = .005). CONCLUSIONS: More Swedish AML patients received alloSCT, and long-term survival was better than in recently published large international studies, despite our lack of selection bias. There was no correlation between alloSCT rate and survival in ALL. In adult AML patients <60 years of age, a high alloSCT rate was associated with better long-term survival, but there was no such correlation in ALL. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

A recent genome wide association study of chronic lymphocytic leukaemia (CLL) provided evidence that common variation at 2q13 (rs17483466), 2q37.1 (rs13397985), 6p25.3 (rs872071), 11q24.1 (rs735665), 15q23 (rs7176508) and 19q13.32 (rs11083846) affects CLL risk. To verify and further explore the relationship between these variants and CLL risk we genotyped case-control datasets from Spain and Sweden (824 cases, 850 controls). Combined data provided statistically significant support for an association between genotypes at rs13397985, rs872071, rs735665, rs7176508 and rs11083846 and CLL risk. CLL risk increased with increasing numbers of risk alleles ( Ptrend = 1·40 × 10−15), consistent with a polygenic model of disease susceptibility. These data validate the relationship between common variation and risk of CLL. [ABSTRACT FROM AUTHOR]

The article focuses on a randomized trial conducted in 2001 by the Nordic Myeloma Study Group, in an attempt to bring a larger portion of patients to autologous stem cell transplantation (ASCT) more quickly. Under the trial, patients were randomized to receive either 3 cycles of vincristine, doxorubicin and dexamethasone (VAD) or 2 courses of cylcophosphamide plus dexamethasone. The study observed no significant difference in the proportion of patients undergoing ASCT.

BACKGROUND: Effective T-cell depletion is a prerequisite for haploidentical peripheral blood progenitor cell (PBPC) transplantation. This study was performed to investigate the performance of magnetic cell sorting–based direct large-scale T-cell depletion, which is an attractive alternative to standard PBPC enrichment procedures. STUDY DESIGN AND METHODS: PBPCs were harvested from 11 human leukocyte antigen (HLA)-haploidentical donors. T cells labeled with anti-CD3–coated beads were depleted with a commercially available magnetic separation unit (CliniMACS, Miltenyi Biotec) with either the Depletion 2.1 (D2.1, n = 11) or the novel Depletion 3.1 (D3.1, n = 12) program. If indicated, additional CD34+ selections were performed (n = 6). Eleven patients received T-cell-depleted grafts after reduced-intensity conditioning. RESULTS: The median log T-cell depletion was better with the D2.1 compared to the D3.1 (log 3.6 vs. log 2.3, p < 0.05) and was further improved by introducing an immunoglobulin G (IgG)-blocking step (log 4.5 and log 3.4, respectively). The D3.1 was superior to the D2.1 (p < 0.05) in median recovery of CD34+ cells (90% vs. 78%) and in median recovery of CD3– cells (87% vs. 76%). The median processing times per 1010 total cells were 0.90 hours (D2.1) and 0.35 hours (D3.1). The transplanted grafts (directly T-cell–depleted products with or without positively selected CD34+ cells) contained a median of 10.5 × 106 per kg CD34+, 0.93 × 105 per kg CD3+, and 11.6 × 106 per kg CD56+. Rapid engraftment was achieved in 10 patients. The incidences of acute graft-versus-host disease were less than 10 percent (Grade I/II) and 0 percent (Grade III/IV). CONCLUSION: The novel D3.1 program with IgG blocking enables highly effective, time-saving large-scale T-cell depletion. Combining direct depletion techniques with standard CD34+ selection enables the composition of grafts optimized to the specific requirements of the patients. [ABSTRACT FROM AUTHOR]

The value of intensive therapy, including autologous stem cell transplantation, in newly diagnosed myeloma patients >60 years is not clear. We evaluated the impact of age (<60 years vs. 60–64 years) on survival in a prospective, population-based setting and compared survival with conventionally treated historic controls. The prospective population comprised 452 patients registered between 1998 and 2000. Of these, 414 received intensive therapy. The historic population, derived from our most recent population-based study on conventional therapy, comprised 281 patients. Of these, 243 fulfilled our eligibility criteria for intensive therapy. For patients undergoing intensive therapy it was found that two factors, beta-2-microglobulin and age <60 years vs. 60–64 years, had independent prognostic impact on survival. However, compared with the historic controls a survival advantage was found both for patients <60 (median 66 months vs. 43 months, P < 0·001) and 60–64 years (median 50 months vs. 27 months; P = 0·001). We conclude that in a population-based setting higher age adversely influences outcome after intensive therapy. Our results indicate that intensive therapy prolongs survival also at age 60–64 years but with less superiority than in younger patients. [ABSTRACT FROM AUTHOR]

Sixty-five patients who were primary or secondary refractory to melphalan/prednisone or other type of chemotherapy, or relapsed within 6 months after high dose chemotherapy with stem cell support, were given thalidomide at a dose of 200 mg/d escalating to 800 mg. The patients were followed for a median of 2 years and 22 weeks. Response was evaluated according to M-protein reduction combined with improvement of haemoglobin (Hb) concentration, renal function and pain. Altogether, 14% of patients had a minor response, 14% partial response and 6% complete response. Median survival was 12 months and 29% were alive at last contact. Decline of M protein started early and a minimum 25% reduction of M protein was detected in 14 of 20 responders (70%) after 3 weeks, and in 20 of 22 responders (91%) after 5 weeks of treatment. Reduction of M protein continued for 3 months and further decline was observed in only four patients. The Hb concentration showed a different time course, with a significant increase after 3 months and further increases continued for up to 12 months. Blood concentration levels of thalidomide from 40 patients were used to evaluate the pharmacokinetics of the drug. Rate of absorption, rate of elimination, volume of distribution, clearance and elimination half-life were calculated to be 0·200/h, 0·140/h, 0·886 l/kg, 0·126 l/h/kg and 4·98 h respectively. We found no relationship between thalidomide concentration and effect after 12 weeks. [ABSTRACT FROM AUTHOR]

Cladribine has single-drug activity in acute myeloid leukaemia (AML), and may enhance the formation of the active metabolite (ara-CTP) of cytosine arabinoside (ara-C). To evaluate the feasibility of adding intermittent cladribine to intermediate-dose ara-C (1 g/m2/2 h) b.i.d. for 4 d with idarubicin (CCI), we performed a 2:1 randomized phase II trial in AML patients aged over 60 years. Primary endpoints were time to recovery from cytopenia and need for supportive care following the first course. Sixty-three patients (median 71 years, range 60–84 years) were included, constituting 72% of all eligible patients. Toxicity was limited, with no differences between the treatment arms. The early toxic death rate was 11%. The median time to recovery from neutropenia and thrombocytopenia was 22 and 17 d from the start of course no. 1, respectively, and the requirement for platelet and red cell transfusions was four and eight units respectively. Patients had a median of 8 d with fever over 38°C, and 17 d with intravenous antibiotic treatment. The overall complete remission (CR) rate was 62%, with 51% CR from one course of CCI in comparison with 35% for the two-drug therapy ( P = 0·014). The median survival with a 2-year follow-up was 14 months, and the 2-year survival was over 30%, with no differences between the treatment arms. Considering the median age and our population-based approach, the overall results are encouraging. [ABSTRACT FROM AUTHOR]

Summary. A phase II study was undertaken to evaluate the efficacy and toxicity of a new schedule of cladribine administration (10 mg/m2 orally daily for 3 d every 3 weeks) in 107 patients with B-cell chronic lymphocytic leukaemia (CLL). To minimize toxicity, treatment withdrawal criteria were defined. The results of the 63 previously untreated patients were retrospectively compared with 63 from an earlier study using a 5-d monthly schedule. The compiled data were analysed for prognostic factors for survival. No significant difference regarding response were seen in the two cohorts of the 126 previously untreated patients. The complete response (CR), nodular partial response (nPR) and partial response (PR) rates were 15%, 21% and 41%. Quality of response had no impact on survival. The 3- and 5-year overall survival for previously untreated patients was 73% and 58%, respectively, with a median follow-up of 54 months. Pretreatment haemoglobin < 11·0 g/dl and elevated beta-2-microglobulin had a negative influence on survival. Major infections occurred in 21% of patients in the 3-d study compared with 35% in the 5-d study. The overall response (OR) and CR rates in the 40 previously treated patients were 34% and 5% respectively. Median overall survival was 24 months and median progression-free survival for responding patients was 14 months. Cladribine used as a single agent is an effective treatment with an acceptable safety profile for pretreated and untreated B-CLL. The achievement of complete remission was not a prerequisite for long-term survival. [ABSTRACT FROM AUTHOR]

Summary. Twenty-three patients with advanced and heavily pretreated myeloma were treated with thalidomide. Starting dose was 200 mg/d, and 20 patients had dose escalations up to 400 (n = 5), 600 (n = 12) or 800 mg/d (n = 3), usually in divided doses. Nineteen patients were refractory to recent chemotherapy, and four had untreated relapse after prior intensive therapy. Ten out of 23 patients (43%) achieved partial response (PR; nine with refractory and one with relapsed disease), six patients had minor response or stabilization of the disease and four had disease progression. Another three patients died early from advanced myeloma at less than 3 weeks of thalidomide therapy. Of the 10 patients with PR, seven had a better response than after any prior therapy, despite vincristine-doxorubicin-dexamethasone (VAD)-based treatment in all but one and high-dose melphalan with autologous stem cell support in four. Time to achieve PR was rapid in patients receiving thalidomide in divided doses (median 31 d). Responses also included reduced bone marrow plasma cell infiltration and improved general status. Normalized polyclonal gammaglobulin levels were seen in four cases. Six out of 10 patients with PR remained in remission with a median time on treatment of 23 weeks (range 15-50 weeks). Sedation was common but usually tolerable, and some patients continued full-or part-time work. Four patients had skin problems, three patients had pneumonia, one hypothyrosis, one sinus bradycardia and one minor sensory neuropathy. Thalidomide may induce good partial remissions in advanced refractory myeloma with tolerable toxicity, and should be evaluated in other settings for myeloma patients. Divided thalidomide doses seem to reduce time to achieve remission and may improve response rate. [ABSTRACT FROM AUTHOR]