Efficacy and toxicity of a paediatric protocol in teenagers and young adults with Philadelphia chromosome negative acute lymphoblastic leukaemia: results from UKALL 2003

Despite the substantial outcome improvements achieved in paediatric acute lymphoblastic leukaemia (ALL), survival in teenage and young adult (TYA) patients has remained inferior. We report the treatment outcomes and toxicity profiles observed in TYA patients treated on the UK paediatric ALL trial, UKALL2003. UKALL2003 was a multi‐centre, prospective, randomized phase III trial, investigating treatment intensification or de‐escalation according to minimal residual disease (MRD) kinetics at the end of induction. Of 3126 patients recruited to UKALL2003, 229 (7·3%) were aged 16–24 years. These patients were significantly more likely to have high risk MRD compared to 10–15 year olds (47·9% vs. 36·6%, P = 0·004). Nonetheless, 5‐year event‐free survival for the TYA cohort (aged 16–24 years) was 72·3% [95% confidence interval (CI): 66·2–78·4] overall and 92·6% (95% CI: 85·5–99·7) for MRD low risk patients. The risk of serious adverse events was higher in patients aged ≥10 years compared to those aged 9 or younger (P < 0·0001) and novel age‐specific patterns of treatment‐related toxicity were observed. TYA patients obtain excellent outcomes with a risk‐ and response‐adapted paediatric chemotherapy protocol. Whilst those aged 10 years and older have excess toxicity compared with younger patients, the age association is specific to individual toxicities.     

Asparaginase‐associated pancreatitis in children with acute lymphoblastic leukaemia in the NOPHO ALL2008 protocol

L‐asparaginase is an important drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Treatment is associated with several toxicities, including acute pancreatitis. Clinical course, presentation, re‐exposure to L‐asparginase after pancreatitis and risk of recurrent pancreatitis within an asparaginase‐intensive protocol has been poorly reported. Children (1–17 years) on the ongoing Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol with asparaginase‐associated pancreatitis (AAP) diagnosed between 2008 and 2012 were identified through the online NOPHO ALL toxicity registry. NOPHO ALL2008 includes eight or 15 doses of intramuscular pegylated L‐asparginase (PEG‐asparaginase) 1000 iu/m²/dose at 2–6 weeks intervals, with a total of 30 weeks of exposure to PEG‐asparaginase (clinicaltrials.gov no: NCT00819351). Of 786 children, 45 were diagnosed with AAP with a cumulative risk of AAP of 5·9%. AAP occurred after a median of five doses (range 1–13), and 11 d (median) from the latest administration of PEG‐Asparaginase. Thirteen patients developed pseudocysts (30%) and 11 patients developed necrosis (25%). One patient died from pancreatitis. Twelve AAP patients were re‐exposed to L‐asparginase, two of whom developed mild AAP once more, after four and six doses respectively. In conclusion, re‐exposure to PEG‐asparaginase in ALL patients with mild AAP seems safe.     

Survival of childhood acute lymphoid leukaemia in Yorkshire by clinical trial era, 1990–2011

Gender‐specific differences in survival by clinical trial era in Yorkshire were assessed for children with acute lymphoid leukaemia (ALL) enrolled onto UKALLXI, ALL97/99 or UKALL2003 (n = 630; 1990–2011). For males, there was a non‐significant improvement in survival for ALL97/99 [hazard ratio (HR) = 0·77; 95% confidence interval (CI) 0·43–1·42) and a significant improvement for UKALL2003 (HR = 0·50; 95%CI 0·25–0·99) compared to UKALLXI. For females, survival was significantly improved for ALL97/99 (HR = 0·33; 95%CI 0·14–0·78), and non‐significantly improved for UKALL2003 (HR = 0·51; 95%CI 0·25–1·08) compared to UKALLXI. Modest overall survival improvements masked clinically important gender‐specific changes over time by trial era, requiring confirmation in larger population‐based studies.     

The combination of bortezomib with chemotherapy to treat relapsed/refractory acute lymphoblastic leukaemia of childhood

Achieving complete remission (CR ) in childhood relapsed/refractory acute lymphoblastic leukaemia (ALL ) is a difficult task. Bortezomib, a proteasome inhibitor, has in vitro activity against ALL blasts. A phase I‐II trial, reported by the Therapeutic Advances in Childhood Leukaemia and Lymphoma (TACL ) consortium, demonstrated that bortezomib with chemotherapy has acceptable toxicity and remarkable activity in patients with relapsed ALL failing 2–3 previous regimens. We evaluated bortezomib in combination with chemotherapy in 30 and 7 children with B‐cell precursor (BCP ) and T‐cell ALL , respectively. Bortezomib (1·3 mg/m²/dose) was administered intravenously on days 1, 4, 8, and 11. Chemotherapy agents were the same as those used in the TACL trial, consisting of dexamethasone, doxorubicin, vincristine and pegylated asparaginase. Three patients (8·1%) died due to infections. Twenty‐seven patients (72·9%) achieved CR or CR with incomplete platelet recovery (CR p). Fourteen had minimal residual disease (MRD ) lower than 0·1%. Twenty‐two of 30 BCP ‐ALL patients (73·3%) and 5/7 patients (71%) with T‐cell ALL achieved CR /CR p. The 2‐year overall survival (OS ) is 31·3%; CR /CR p patients with an MRD response had a remarkable 2‐year OS of 68·4%. These data confirm that the combination of bortezomib with chemotherapy is a suitable/effective option for childhood relapsed/refractory ALL .     

Anthracyclines during induction therapy in acute myeloid leukaemia: a systematic review and meta‐analysis

This systematic review and meta‐analysis compared the efficacy of different anthracyclines and anthracycline dosing schedules for induction therapy in acute myeloid leukaemia in children and adults younger than 60 years of age. Twenty‐nine randomized controlled trials were eligible for inclusion in the review. Idarubicin (IDA), in comparison to daunorubicin (DNR), reduced remission failure rates (risk ratio (RR) 0·81; 95% confidence interval (CI), 0·66–0·99; P = 0·04), but did not alter rates of early death or overall mortality. Superiority of IDA for remission induction was limited to studies with a DNR/IDA dose ratio <5 (ratio <5: RR 0·65; 95% CI, 0·51–0·81; P < 0·001; ratio ≥5: RR 1·03; 95% CI, 0·91–1·16; P = 0·63). Higher‐dose DNR, compared to lower‐dose DNR, was associated with reduced rates for remission failure (RR 0·75; 95% CI, 0·60–0·94; P = 0·003) and overall mortality (RR 0·83; 95% CI, 0·75–0·93; P < 0·001), but not for early death. Comparisons of several other anthracycline derivates did not reveal significant differences in outcomes. Survival estimates in adults suggest that both high‐dose DNR (90 mg/m² daily × 3 or 50 mg/m² daily × 5) and IDA (12 mg/m² daily × 3) can achieve 5‐year survival rates of between 40 and 50 percent.     

No impact of high‐dose cytarabine and asparaginase as early intensification with intermediate‐risk paediatric acute lymphoblastic leukaemia: results of randomized trial TCCSG study L99‐15

The Tokyo Children's Cancer Study Group conducted a randomized controlled study to evaluate the effect of experimental early intensification using high‐dose cytarabine and L‐asparaginase in paediatric intermediate‐risk (IR) acute lymphoblastic leukaemia (ALL). A total of 310 IR ALL patients were randomized to receive either experimental early intensification (n = 156) or standard early intensification including standard‐dose cytarabine arm (n = 154) after induction therapy. The experimental arm consisted of high‐dose cytarabine and L‐asparaginase, while the standard arm consisted of standard‐dose cytarabine, oral 6‐mercaptopurine and cyclophosphamide. The probabilities of event‐free survival at 8 years in the experimental and standard arms were 72·3 ± 3·7% and 77·5 ± 3·5%, respectively (P = 0·32). The 8‐year overall survival rates for these two arms were 85·0 ± 3·0% and 86·9 ± 2·8%, respectively (P = 0·72). The frequency of infectious events was significantly higher in the experimental arm (66·4%) than in the standard arm (24·6%) (P < 0·001). In conclusion, experimental early intensification including high‐dose cytarabine followed by L‐asparaginase had no advantage over standard early intensification in paediatric IR ALL patients.     

Outcome for children and young people with Early T‐cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol,UKALL 2003

We investigated the outcome for children and young people with Early T‐precursor acute lymphoblastic leukaemia (ETP‐ALL), a recently described poor prognosis sub‐group of T‐ALL, treated on a contemporary protocol, UKALL 2003. After a median follow‐up of 4 years and 10 months, the ETP sub‐group, representing 16% of T‐ALL patients, had non‐significantly inferior 5‐year event‐free survival (76·7% vs. 84·6%, P = 0·2) and overall survival (82·4% vs. 90·9%, P = 0·1), and a higher relapse rate (18·6% vs. 9·6%, P = 0·1) compared to typical T‐ALL. ETP‐ALL has an intermediate risk outcome, which does not warrant experimental treatment or first remission allogeneic transplant for the group universally.     

Susceptibility to 6‐MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia

Genotyping of TPMT prior to 6‐mercaptopurine (6‐MP) administration in acute lymphoblastic leukaemia (ALL) patients has been integrated into clinical practice in some populations of European ancestry. However, the comparable rates of 6‐MP myelotoxicity, but rarity of TPMT variants, in Asians suggest that major determinants have yet to be discovered in this population. We genotyped 92 Japanese paediatric ALL patients for NUDT15 rs116855232, a 6‐MP toxicity‐related locus discovered in Asians. Logistic regression and survival analysis were used to evaluate its association with leucopenia, hepatotoxicity, 6‐MP dose reduction, therapy interruption and event‐free survival. The allele frequency of rs116855232 was 0·16, and leucopenia was more common in carriers of the T allele (odds ratio, 7·20; 95% confidence interval, 2·49–20·80; P = 2·7 × 10^?4). As leucopenia results in 6‐MP dose reduction, we observed average doses during maintenance therapy of 40·7, 29·3 and 8·8 mg/m² for patients with CC, CT and TT genotypes, respectively (P < 0·001). Hepatotoxicity was observed only in CC genotype patients. Event‐free survival did not significantly differ by NUDT15 genotype. rs116855232 is an important determinant of 6‐MP myelotoxicity in Japanese children with ALL and may represent the most robust toxicity‐related locus in Asians to date. Considerations for clinical application may be warranted.     

A phase 1, open‐label,dose‐escalation study of pralatrexate in combination with bortezomib in patients with relapsed/refractory multiple myeloma

Pralatrexate inhibits folic acid metabolism, and preclinical studies have shown that it is cytotoxic to multiple myeloma cells. This phase 1 study investigated the safety and efficacy of pralatrexate in combination with bortezomib in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous pralatrexate at doses ranging from 10 to 30 mg/m² and intravenous bortezomib at a dose of 1·3 mg/m² on days 1, 8 and 15 of each 4‐week cycle. Eleven patients were enrolled and completed a median of two cycles. The maximum tolerated dose was 20 mg/m². Two patients experienced dose‐limiting toxicity of mucositis. The most frequent non‐haematological toxicities were fatigue (55%) and mucositis (45%). There were three serious adverse events in three patients: rash, sepsis and hypotension. One patient (9%) had a very good partial response, 1 (9%) had a partial response, 1 (9%) had minimal response and two (18%) had progressive disease. The median duration of response was 4 months, the median time to next treatment was 3·4 months and the median time to progression was 4 months. Pralatrexate, in combination with bortezomib, was generally safe and demonstrated modest activity in relapsed or refractory multiple myeloma. Clinicaltrials.gov identifier: NCT01114282.     

Toxicity profile of repeated doses of PEG‐asparaginase incorporated into a pediatric‐type regimen for adult acute lymphoblastic leukemia

Despite having been long regarded as too toxic for adult patients, pediatric‐like regimens containing L‐asparaginase have resulted in improved outcomes for adults with acute lymphoblastic leukemia (ALL). To characterize the spectrum of toxicity of repeated doses of polyethylene glycolated‐asparaginase (PEG‐asp) in adults, we reviewed all doses (2000 IU/m²) administered as part of a pediatric‐inspired regimen in adult ALL at our center. Subjects aged 18–60 yr with ALL (n = 152, 69.1% male) contributed 522 dose cycles to the study. Hepatotoxicity was the most common adverse event: grades 3–4 transaminitis and hyperbilirubinemia occurred in 53.9% and 23.7% of subjects, respectively. Hepatotoxicity was reversible; no cases of fulminate hepatic failure were observed. Other toxicities affecting at least 5% of subjects were grades 3–4 triglyceridemia in 50.9%, hypofibrinogenemia (<100 mg/dL) in 47.9%, clinical pancreatitis in 12.6%, venous thromboembolism in 11.2%, allergic reaction in 7.2%, and any grade bleeding in 5.3%. PEG‐asp was always discontinued after grades 3–4 pancreatitis or allergic reaction. Otherwise, toxicities did not preclude administration of additional cycles of the drug. Our results suggest that repeated PEG‐asp dosing is safe in adults aged 18–60 yr, even after occurrence of a drug‐related toxicity.     

Bendamustine,thalidomide and dexamethasone combination therapy for relapsed/refractory myeloma patients: results of the MUKone randomized dose selection trial

There is a significant unmet need in effective therapy for relapsed myeloma patients once they become refractory to bortezomib and lenalidomide. While data from the front line setting suggest bendamustine is superior to melphalan, there is no information defining optimal bendamustine dose in multiply‐treated patients. We report a multi‐centre randomized two‐stage phase 2 trial simultaneously assessing deliverability and activity of two doses of bendamustine (60 mg/m² vs. 100 mg/m²) days 1 and 8, thalidomide (100 mg) days 1–21 and low dose dexamethasone (20 mg) days 1, 8, 15 and 22 of a 28‐d cycle. Ninety‐four relapsing patients were treated on trial, with a median three prior treatment lines. A pre‐planned interim deliverability and activity assessment led to closure of the 100 mg/m² arm due to excess cytopenias, and led to amendment of entry criteria for cytopenias. Non‐haematological toxicities including thromboembolism and neurotoxicity were infrequent. In the 60 mg/m² arm, treatment was deliverable in 61·1% subjects and the partial response rate was 46·3% in the study eligible population, with 7·5 months progression‐free survival. This study demonstrates bendamustine at 60 mg/m² twice per month with thalidomide and dexamethasone is deliverable for repeated cycles in heavily pre‐treated myeloma patients and has substantial clinical activity.     

Low‐dose anti‐CD20 veltuzumab given intravenously or subcutaneously is active in relapsed immune thrombocytopenia: a phase I study

Low doses of the humanized anti‐CD20 monoclonal antibody, veltuzumab, were evaluated in 41 patients with immune thrombocytopenia (ITP), including 9 with ITP ≤1 year duration previously treated with steroids and/or immunoglobulins, and 32 with ITP >1 year and additional prior therapies. They received two doses of 80–320 mg veltuzumab 2 weeks apart, initially by intravenous (IV) infusion (N = 7), or later by subcutaneous (SC) injections (N = 34), with only one Grade 3 infusion reaction and no other safety issues. Thirty‐eight response‐assessable patients had 21 (55%) objective responses (platelet count ≥30 × 10⁹/l and ≥2 × baseline), including 11 (29%) complete responses (CRs) (platelet count ≥100 × 10⁹/l). Responses (including CRs) occurred with both IV and SC administration, at all veltuzumab dose levels, and regardless of ITP duration. Responders with ITP ≤1 year had a longer median time to relapse (14·4 months) than those with ITP >1 year (5·8 months). Three patients have maintained a response for up to 4·3 years. SC injections resulted in delayed and lower peak serum levels of veltuzumab, but B‐cell depletion occurred after first administration even at the lowest doses. Eight patients, including 6 responders, developed anti‐veltuzumab antibodies following treatment (human anti‐veltuzumab antibody, 19·5%). Low‐dose SC veltuzumab appears convenient, well‐tolerated, and with promising clinical activity in relapsed ITP.( Clinicaltrials.gov identifier: NCT00547066.)     

Combination therapy with bortezomib,continuous low‐dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients

Combination therapy for longer periods but at low dose might be an effective and tolerable manner to treat patients with relapsed multiple myeloma (MM). We used bortezomib, dexamethasone and low‐dose oral cyclophosphamide as an induction regimen, followed by 1 year of maintenance consisting of bortezomib and cyclophosphamide. Relapsed MM patients were treated with six cycles of bortezomib twice weekly, cyclophosphamide 50 mg daily and dexamethasone. Maintenance therapy was given for 1 year. Primary endpoints were toxicity during re‐induction and maintenance therapy. Secondary endpoints were response to treatment and progression‐free (PFS) and overall survival (OS). This study included 59 patients. Myelosuppression and neuropathy were the most common side effects. Median follow‐up was 27·1 (0·46–54·4) months with an overall response of 71%, and a very good partial response or more of 33%. During maintenance, improved responsiveness was observed in 19% of the patients. The median PFS was 18·4 months (range 0·13–43·5) and the median OS was 28·1 months (range 0·13–54·4). In conclusion, our study demonstrates that treatment with bortezomib, dexamethasone and low‐dose cyclophosphamide is an effective and manageable regimen. Adding 1 year of maintenance was feasible, with limited side effects and an increased response rate.     

A phase II study of dose‐dense and dose‐intense ABVD (ABVDDD‐DI) without consolidation radiotherapy in patients with advanced Hodgkin lymphoma

We explored activity and safety of a dose‐dense/dose‐intense adriamycin, bleomycin, vinblastine and dacarbazine regimen (ABVD_DD‐DI) in 82 patients with advanced Hodgkin Lymphoma. Patients entered a two‐stage Bryant‐Day Phase II study to receive six cycles of ABVD_DD‐DI without consolidation radiotherapy. Cycles were supported with granulocyte colony‐stimulating factor and delivered every 21 d; drugs were administered on days 1 and 11 at the same doses of standard ABVD except for doxorubicin (35 mg/m²; first four cycles only). Co‐primary endpoints were complete response (CR) rate and severe acute cardiopulmonary toxicity; secondary endpoints were event‐free (EFS) and disease‐free survival (DFS). All patients received the four doxorubicin‐intensified courses and 96% concluded all six cycles (82·3% within the intended 18 weeks). This translated into a 66·9% increase of received dose‐intensity for doxorubicin and 31·8% for the other agents over standard ABVD. The CR rate was 95·1% (78/82) and 87·8% (72/82) achieved a metabolic CR after two cycles. Cardiopulmonary toxicity never exceeded grade 2 and affected 14·6% of patients. Most frequent toxicities were grade 4 neutropenia (10%) and anaemia (9%), grade 3 infection (17%) and grade 2 mucocutaneous changes (30%). Five‐year EFS and DFS was 88·3% and 93·7%, respectively. ABVD_DD‐DI regimen was well‐tolerated and ensured substantial CR and EFS rates without radiotherapy.     

Phase I‐II trial of oral cyclophosphamide,prednisone and lenalidomide for the treatment of patients with relapsed and refractory multiple myeloma

This single institution, open label Phase I‐II dose escalation trial evaluated the safety and efficacy of the combination of lenalidomide (Revlimid®), cyclophosphamide and prednisone (CPR) in patients with relapsed/refractory multiple myeloma. The maximal administered dose of CPR consisted of cyclophosphamide 300 mg/m² on day 1, 8, and 15, lenalidomide 25 mg on d 1–21 and prednisone 100 mg every other day in a 28‐d cycle. Between November 2007 and June 2009, 32 patients were entered in cohorts of three at three dose levels. The median age was 64 years, 59% were male, with a median two prior regimens. Responding patients could stay on treatment until progression. The full‐dose CPR regimen produced no dose‐limiting toxicity and was delivered for a median of 16 months (3·5–65 months) with acceptable safety and tolerance. The overall response rate (≥ partial response) was 94% at a median follow up of 28 months. The median progression‐free survival was 16·1 months [95% confidence interval (CI); 10·9–22·5 months], while the median overall survival was 27·6 months (95% CI; 16·8–36·6 months). Only the beta‐2 microglobulin level at protocol entry correlated with a better survival (P = 0·047). These observations compare favourably with other 2‐ and 3‐ drug combinations for relapsed/refractory myeloma, and suggest that CPR should be evaluated further in the setting of relapsed/refractory disease, or in newly diagnosed patients.     

Intermediate dose of imatinib in combination with chemotherapy followed by allogeneic stem cell transplantation improves early outcome in paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL): results of the Spanish Cooperative Group SHOP studies ALL-94, ALL-99 and ALL-2005

Philadelphia‐chromosome acute lymphoblastic leukaemia (Ph+ ALL) is a subgroup of ALL with very high risk of treatment failure. We report here the results of the Sociedad Española de Hematología y Oncología Pediátricas (SEHOP/SHOP) in paediatric Ph+ ALL treated with intermediate‐dose imatinib concurrent with intensive chemotherapy. The toxicities and outcome of these patients were compared with historical controls not receiving imatinib. Patients with Ph+ ALL aged 1–18 years were enrolled in three consecutive ALL/SHOP trials (SHOP‐94/SHOP‐99/SHOP‐2005). In the SHOP‐2005 trial, imatinib (260 mg/m² per day) was given on day‐15 of induction. Allogeneic haematopoietic stem‐cell transplantation (HSCT) from a matched related or unrelated donor was scheduled in first complete remission (CR1). Forty‐three patients were evaluable (22 boys, median age 6·8 years, range, 1·2–15). Sixteen received imatinib whereas 27 received similar chemotherapy without imatinib. Seventeen of 27 and 15 of 16 patients in the non‐imatinib and imatinib cohort, respectively, underwent HSCT in CR1. With a median follow‐up of 109 and 39 months for the non‐imatinib and imatinib cohorts, the 3‐year event‐free survival (EFS) was 29·6% and 78·7%, respectively (P = 0·01). These results show that, compared to historical controls, intermediate dose of imatinib given concomitantly with chemotherapy and followed by allogeneic HSCT markedly improved early EFS in paediatric Ph+ ALL.     

Effective Response Metric: a novel tool to predict relapse in childhood acute lymphoblastic leukaemia using time‐series gene expression profiling

Accurate risk assignment in childhood acute lymphoblastic leukaemia is essential to avoid under‐ or over‐treatment. We hypothesized that time‐series gene expression profiles (GEPs) of bone marrow samples during remission‐induction therapy can measure the response and be used for relapse prediction. We computed the time‐series changes from diagnosis to Day 8 of remission‐induction, termed Effective Response Metric (ERM‐D8) and tested its ability to predict relapse against contemporary risk assignment methods, including National Cancer Institutes (NCI) criteria, genetics and minimal residual disease (MRD). ERM‐D8 was trained on a set of 131 patients and validated on an independent set of 79 patients. In the independent blinded test set, unfavourable ERM‐D8 patients had >3‐fold increased risk of relapse compared to favourable ERM‐D8 (5‐year cumulative incidence of relapse 38·1% vs. 10·6%; P = 2·5 × 10⁻³). ERM‐D8 remained predictive of relapse [P = 0·05; Hazard ratio 4·09, 95% confidence interval (CI) 1·03–16·23] after adjusting for NCI criteria, genetics, Day 8 peripheral response and Day 33 MRD. ERM‐D8 improved risk stratification in favourable genetics subgroups (P = 0·01) and Day 33 MRD positive patients (P = 1·7 × 10⁻³). We conclude that our novel metric – ERM‐D8 – based on time‐series GEP after 8 days of remission‐induction therapy can independently predict relapse even after adjusting for NCI risk, genetics, Day 8 peripheral blood response and MRD.     

Mammalian‐target of rapamycin inhibition with temsirolimus in myelodysplastic syndromes (MDS) patients is associated with considerable toxicity: results of the temsirolimus pilot trial by the German MDS Study Group (D‐MDS)

The mammalian‐target of rapamycin (also termed mechanistic target of rapamycin, mTOR) pathway integrates various pro‐proliferative and anti‐apoptotic stimuli and is involved in regulatory T‐cell (TREG) development. As these processes contribute to the pathogenesis of myelodysplastic syndromes (MDS), we hypothesized that mTOR modulation with temsirolimus (TEM) might show activity in MDS. This prospective multicentre trial enrolled lower and higher risk MDS patients, provided that they were transfusion‐dependent/neutropenic or relapsed/refractory to 5‐azacitidine, respectively. All patients received TEM at a weekly dose of 25 mg. Of the 9 lower‐ and 11 higher‐risk patients included, only 4 (20%) reached the response assessment after 4 months of treatment and showed stable disease without haematological improvement. The remaining patients discontinued TEM prematurely due to adverse events. Median overall survival (OS) was not reached in the lower‐risk group and 296 days in the higher‐risk group. We observed a significant decline of bone marrow (BM) vascularisation (P = 0·006) but were unable to demonstrate a significant impact of TEM on the balance between TREG and pro‐inflammatory T‐helper‐cell subsets within the peripheral blood or BM. We conclude that mTOR‐modulation with TEM at a dose of 25 mg per week is accompanied by considerable toxicity and has no beneficial effects in elderly MDS patients.     

Kinetics of T-cell subset reconstitution following treatment with bendamustine and rituximab for low-grade lymphoproliferative disease: a population-based analysis

Delayed lymphocyte and T-cell immune reconstitution following bendamustine-rituximab (BR) for indolent non-Hodgkin lymphoma (iNHL) has been described, but no information is available for chronic lymphocytic leukaemia (CLL). We present a population-based retrospective analysis of immune reconstitution and risk of infection following BR. Outcomes included timing/correlates of CD4+ recovery and risk of ≥grade 3 infections. Consecutively treated patients (1 April 2014 to 31 January 2017) were included (n = 295),with a median age of 65 years (range 33–92); 57% were 1st line treatments. Median cumulative bendamustine dose was 1080 mg/m² (range 140–1440 mg/m²). CD4/CD8/CD19/NK subsets were available for 148 patients. Median follow-up was 24 months. Median times to lymphocyte count (ALC) recovery (≥1 × 10⁹/l) and CD4+ recovery (≥0·2 × 10⁹/l) were 26 and 24 months, respectively. Bendamustine total dose >1080 mg/m² (hazard ratio [HR] 0·4; 95% confidence interval [CI]: 0·2–0·8), end-of-treatment ALC ≤0·4 × 10⁹/l (HR 0·53; 95% CI: 0·3–0·9) and CD4+ <0·1 × 10⁹/l 1-year post-BR (HR 0·03; 95% CI: 0·008–0·15) were covariables for delayed CD4+ recovery. ALC-recovery ≥1 × 10⁹/l was an unreliable predictor of CD4+ recovery (negative predictive vale 74%, positive predictive value 86%, likelihood ratio 3·3). CD4+ lymphopenia >3 years was a significant risk factor for ≥grade 3 infections (Odds ratio 3·4; 95% CI: 1·4–6·9). CD4+ recovery after BR is unexpectedly delayed and late recovery is associated with risk of serious infections. Monitoring CD4+ following BR could identify patients at high risk of delayed infections.     

Escalated daunorubicin dosing as an induction treatment for Philadelphia-negative adult acute lymphoblastic leukemia

The dose intensity of daunorubicin (DNR) delivered during the induction period represented the major prognostic factor for the outcome of adult acute lymphoblastic leukemia (ALL). The aim of this study was to determine the survival or toxicity of escalated doses of DNR in induction treatment of adult patients with acute lymphoblastic leukemia who are at least 15 years of age. For induction chemotherapy, all patients were given 90 mg/m²/day of DNR by continuous intravenous (IV) infusion over 24 h daily on days 1–3, 2 mg of vincristine IV push on days 1 and 8, and 60 mg/m²/day of prednisolone per oral (PO) on days 1–14 in conjunction with 4,000 units/m²/day of l-asparaginase intramuscular or subcutaneous on days 17–28. The median patient age was 32 years (range, 15–69). Complete remission (CR) was achieved in 169 (88.5 %) patients, while 4 died before CR was reached. Additionally, 11 patients died from leukemia progression, 4 had refractory disease, and 3 had follow-up loss. The median follow-up time was 697 days (range, 12–2,270). The 3-year cumulative incidence of relapse was 49.3 %. The probabilities of disease-free survival and overall survival at 3 years were 46.1 and 43.1 %, respectively. The dose of DNR was 100 % of the target dose, and there were no additional specific toxicities. The results show that escalated doses of DNR in induction chemotherapy are similar with the standard dose in response and toxicities. Our study indicates that a more effective regimen or better chemotherapy agents are needed to improve the CR rate and prolong survival in Philadelphia-negative adult ALL.