Safety and efficacy of nelarabine in children and young adults with relapsed or refractory T‐lineage acute lymphoblastic leukaemia or T‐lineage lymphoblastic lymphoma: results of a phase 4 study

Nelarabine is an antineoplastic agent approved for the treatment of relapsed/refractory T‐lineage acute lymphoblastic leukaemia (T‐ALL) or T‐lineage acute lymphoblastic lymphoma (T‐LBL). The purpose of this phase 4, multicentre, single‐arm, observational, open‐label trial was to provide additional data on the safety and efficacy of nelarabine under licensed conditions of use in children and young adults ≤21 years of age. Patients (N = 28) had a mean ± standard deviation age of 11·5 ± 4·6 years; 71% were male and 61% had a diagnosis of T‐ALL. Adverse events (AEs) and treatment‐related AEs were experienced by 46% and 21%, respectively, and included few haematological AEs and no haematological serious AEs. Neurological AEs from one of four predefined categories (peripheral and central nervous systems, mental status change and uncategorized) were reported in four patients. There were no AE‐related treatment discontinuations/withdrawals. The overall response rate was 39.3%: complete response (CR), 35.7%; CR without full haematological recovery (CR*), 3.6%. Post‐treatment stem cell transplantation was performed for 46% of the cohort. Median overall survival (OS) was 3·35 months for non‐responders and not reached for responders (CR + CR*). The response rate, median OS, and safety profile of nelarabine in this disease setting and population were consistent with those reported previously.     

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.     

Secondary acute lymphoblastic leukaemia is constitutional and probably not related to prior therapy

Very little is known about secondary acute lymphoblastic leukaemia (s‐ALL). This retrospective analysis studied a cohort of s‐ALL patients treated at a single centre between 1994 and 2013, while comparing therapy‐associated ALL (t‐ALL) and antecedent malignancy ALL (am‐ALL) patients. Thirty‐two patients with s‐ALL were identified. The overall incidence was 9·4% among ALL adults while T‐cell s‐ALL was rare (12% of s‐ALLs). The median time interval between two malignant diagnoses was 5·3 years (range: 0·1–28). In contrast to previous reports, most of the s‐ALLs were CD10 +  and without KMT2A (MLL) abnormalities. The overall survival (OS) rates of the entire cohort at 12 and 24 months from ALL diagnosis was 49% and 25%, respectively. Most patients (n = 23, 72%) received prior chemo‐/radio‐therapy for their first malignancy (t‐ALL) and only 9 (28%) did not (am‐ALL). No significant difference was found in the incidence of B‐/T‐ lineage ALL, extramedullary disease, blood count, and the rate of Philadelphia‐positive ALL, nor in the rates of complete remission (P = 0·55) and OS (P = 0·97). This similarity, together with high incidence of family malignancy in both groups, raise the possibility that s‐ALL patients may have an inherent predisposition to malignancies and a history of previous therapy may be of lesser importance in the pathogenesis of s‐ALL.     

NOTCH1 mutations are associated with favourable long‐term prognosis in paediatric T‐cell acute lymphoblastic leukaemia: a retrospective study of patients treated on BCH‐2003 and CCLG‐2008 protocol in China

Activating mutations of NOTCH1 are a common occurrence in T‐cell acute lymphoblastic leukaemia (T‐ALL), but its impact on T‐ALL treatment is still controversial. In this study, the incidence, clinical features, and prognosis of 92 Chinese children with T‐ALL treated using the Beijing Children's Hospital‐2003 and Chinese Childhood Leukaemia Group‐2008 protocols were analysed. NOTCH1 mutations were found in 42% of T‐ALL patients and were not associated with clinical features, prednisone response, and minimal residual disease (MRD) at day 33 and 78. However, proline, glutamate, serine, threonine (PEST)/transactivation domain (TAD) mutations were associated with younger age (15/16 mutant vs. 48/76 wild‐type, P = 0·018) and more central nervous system involvement (4/16 mutant vs. 3/76 wild‐type, P = 0·016); while heterodimerization domain (HD) mutations were associated with KMT2A‐MLLT1 (MLL‐ENL; 4/30 mutant vs. 1/62 wild‐type, P = 0·037). Furthermore, prognosis was better in patients with NOTCH1 mutations than in those with wild‐type NOTCH1 (5‐year event‐free survival [EFS] 92·0 ± 4·5% vs. 64·0 ± 7·1%; P = 0·003). Long‐term outcome was better in patients carrying HD mutations than in patients with wild‐type HD (5‐year EFS 89·7 ± 5·6% vs. 69·3 ± 6·2%; P = 0·034). NOTCH1 mutations and MRD at day 78 were independent prognostic factors. These findings indicate that NOTCH1 mutation predicts a favourable outcome in Chinese paediatric patients with T‐ALL on the BCH‐2003 and CCLG‐2008 protocols, and may be considered a prognostic stratification factor.     

Donor‐derived CD19‐targeted T cell infusion induces minimal residual disease‐negative remission in relapsed B‐cell acute lymphoblastic leukaemia with no response to donor lymphocyte infusions after haploidentical haematopoietic stem cell transplantation

Relapse is a common cause of failure in patients with B‐cell acute lymphoblastic leukaemia (B‐ALL) after haploidentical haematopoietic stem cell transplantation (haplo‐HSCT), and non‐responders to donor lymphoblastic infusion after HSCT have a very poor prognosis. Although donor‐derived CD19‐directed chimeric antigen receptor‐modified (CAR) T cells can potentially cure leukaemia, their effectiveness and safety have not been confirmed in relapsed B‐ALL cases after haplo‐HSCT. Between January 2015 and January 2017, two and four patients each received one and two infusions of CAR T cells from haplo‐HSCT donors. Five (83·33%) achieved minimal residual disease (MRD)‐negative remission; one patient was discharged automatically without evaluation after developing severe thrombotic microangiopathies. Four of five responsive patients relapsed after 2–7 months, and one died of sepsis following MRD‐negative remission after a second infusion. None of the other second infusion recipients achieved a second complete remission. Five patients (83·33%) experienced eight courses of grade 1–3 cytokine release syndrome; two were treated with tocilizumab. Two (33·3%) and one patient developed grade 2 and 3 acute graft‐versus‐host disease (aGVHD), respectively; the former was controlled with glucocorticoids. Donor‐derived CAR T‐cell infusion seems be effective and safe for relapsed B‐ALL after haplo‐HSCT, although larger clinical studies are needed.     

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.     

Improved outcome for children with non‐high risk acute lymphoblastic leukaemia after using an ALL IC‐BFM 2002‐based protocol in Shanghai,China

We report the outcome of 92 non‐high risk children with acute lymphoblastic leukaemia (ALL) following a Berlin‐Frankfürt‐Münster (BFM) Intercontinental ALL ‐based protocol. Compared with a matched historical control group, we found a lower incidence of treatment‐related early death (1·2% vs. 10·9%, P = 0·015), a higher 6‐year event‐free survival (75·4 ± 4·9% vs. 58·2 ± 6·7%, P = 0·02), reduced total in‐hospital costs per person (US $) (10267·0 vs. 18331·0, P < 0·001) and fewer total in‐hospital days (164 vs. 296, P < 0·001). This ALL‐BFM based protocol was quite tolerable in our institution and will be extended to high‐risk patients.     

Paediatric lymphoblastic T‐cell leukaemia and lymphoma: one or two diseases?

There is ongoing discussion on whether paediatric acute T‐cell lymphoblastic leukaemia (T‐ALL) and paediatric lymphoblastic T‐cell lymphoma (T‐LBL) are two distinct entities or whether they represent two variant manifestations of one and the same disease and the distinction is arbitrary. Both show overlapping clinical, morphological and immunophenotypic features. Many clinical trials use the amount of blast infiltration of the bone marrow as the sole criterion to distinguish between T‐ALL and T‐LBL. The current World Health Organization classification designates both malignancies as T lymphoblastic leukaemia/lymphoma. However, subtle immunophenotypic, molecular and cytogenetic differences suggest that T‐ALL and T‐LBL might be biologically different in certain aspects. The current review summarizes and discusses the recent advances and understanding of the molecular profile of paediatric T‐ALL and T‐LBL.     

Increased post‐induction intensification improves outcome in children and adolescents with a markedly elevated white blood cell count (≥200 × 109/l) with T cell acute lymphoblastic leukaemia but not B cell disease: a report from the Children's Oncology Group

Children and adolescents presenting with a markedly elevated white blood cell (ME WBC) count (WBC ≥200 × 10⁹/l) comprise a unique subset of high‐risk patients with acute lymphoblastic leukaemia (ALL). We evaluated the outcomes of the 251 patients (12% of the study population) with ME WBC treated on the Children's Cancer Group‐1961 protocol. Patients were evaluated for early response to treatment by bone marrow morphology; those with a rapid early response were randomized to treatment regimens testing longer and stronger post‐induction therapy. We found that ME WBC patients have a poorer outcome compared to those patients presenting with a WBC <200 × 10⁹/l (5‐year event‐free survival 62% vs. 73%, P = 0·0005). Longer duration of therapy worsened outcome for T cell ME WBC with a trend to poorer outcome in B‐ALL ME WBC patients. Augmented therapy benefits T cell ME WBC patients, similar to the entire study cohort, however, there appeared to be no impact on survival for B‐ALL ME WBC patients. ME WBC was not a prognostic factor for T cell patients. In patients with high risk features, B lineage disease in association with ME WBC has a negative impact on survival.     

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 .     

Allogeneic haematopoietic stem cell transplantation for infant acute lymphoblastic leukaemia with KMT2A (MLL) rearrangements: a retrospective study from the paediatric acute lymphoblastic leukaemia working group of the Japan Society for Haematopoietic Cell Transplantation

Allogeneic haematopoietic stem cell transplantation (HSCT) is still considered to play an important role as a consolidation therapy for high‐risk infants with acute lymphoblastic leukaemia (ALL). Here, we retrospectively analysed outcomes of HSCT in infants with ALL based on nationwide registry data of the Japan Society for Haematopoietic Cell Transplantation. A total of 132 allogeneic HSCT for infant ALL with KMT2A (MLL) gene rearrangements, which were performed in first complete remission (CR1), were analysed. The 5‐year overall survival rate after transplantation was 67·4 ± 4·5%). Although recent HSCT (after 2004) had a trend toward better survival, no statistical correlation was observed between outcomes and each factor, including age at diagnosis, initial leucocyte count, cytogenetics, donor types or conditioning of HSCT. Myeloablative conditioning with total body irradiation did not provide a better survival (60·7 ± 9·2%) over that with busulfan (BU; 67·8 ± 5·7%). Two of the 28 patients treated with irradiation, but none of the 90 BU‐treated patients, developed a secondary malignant neoplasm. In conclusion, allogeneic HSCT using BU was a valuable option for infant ALL with KMT2A rearrangements in CR1.     

Disturbed CXCR4/CXCL12 axis in paediatric precursor B‐cell acute lymphoblastic leukaemia

Malignant cells infiltrating the bone marrow (BM) interfere with normal cellular behaviour of supporting cells, thereby creating a malignant niche. We found that CXCR4‐receptor expression was increased in paediatric precursor B‐cell acute lymphoblastic leukaemia (BCP‐ALL) cells compared with normal mononuclear haematopoietic cells (P < 0·0001). Furthermore, high CXCR4‐expression correlated with an unfavourable outcome in BCP‐ALL (5‐year cumulative incidence of relapse ± standard error: 38·4% ± 6·9% in CXCR4‐high versus 12% ± 4·6% in CXCR4‐low expressing cases, P < 0·0001). Interestingly, BM levels of the CXCR4‐ligand (CXCL12) were 2·7‐fold lower (P = 0·005) in diagnostic BCP‐ALL samples compared with non‐leukaemic controls. Induction chemotherapy restored CXCL12 levels to normal. Blocking the CXCR4‐receptor with Plerixafor showed that the lower CXCL12 serum levels at diagnosis could not be explained by consumption by the leukaemic cells, nor did we observe an altered CXCL12‐production capacity of BM‐mesenchymal stromal cells (BM‐MSC) at this time‐point. We rather observed that a very high density of leukaemic cells negatively affected CXCL12‐production by the BM‐MSC while stimulating the secretion levels of granulocyte colony‐stimulating factor (G‐CSF). These results suggest that highly proliferative leukaemic cells are able to down‐regulate secretion of cytokines involved in homing (CXCL12), while simultaneously up‐regulating those involved in haematopoietic mobilization (G‐CSF). Therefore, interference with the CXCR4/CXCL12 axis may be an effective way to mobilize BCP‐ALL cells.     

Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia

Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment‐related mortality of 8%. Leukaemia‐free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre‐HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre‐HSCT (LFS 41%, OS 64%, P < 0·0001) or post‐HSCT (LFS 35%, OS 55%, P < 0·0001). Patients with B‐other ALL had more relapses (CIR 50%, LFS 41%) than T‐ALL and the main precursor‐B subtypes including BCR‐ABL1, KMT2A (MLL), ETV6‐RUNX1 (TEL‐AML1) and hyperdiploidy >50. A Cox multivariate regression model for LFS retained both B‐other ALL subtype (hazard ratio 4·1, P = 0·0062) and MRD persistence post‐HSCT (hazard ratio 3·9, P = 0·0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post‐HSCT therapy.     

Outcome of Down syndrome associated acute lymphoblastic leukaemia treated on a contemporary protocol

We report the outcome for children and young people with Down syndrome‐associated acute lymphoblastic leukaemia (DS‐ALL) treated on a contemporary protocol. Compared with non‐DS ALL, patients with DS‐ALL had an inferior event‐free survival (65·6% vs. 87·7% at 5 years; P < 0·00005) and overall survival (70·0% vs. 92·2%; P < 0·00005). Excess treatment‐related mortality – was primarily responsible for the worse outcomes for DS‐ALL (21·6% at 5 years, vs. 3·3%, P < 0·00005). Minimal residual disease (MRD) risk status was highly discriminant for relapse in DS patients with 0/28 relapses in the MRD low risk group.     

Haploidentical transplantation compared with matched sibling and unrelated donor transplantation for adults with standard‐risk acute lymphoblastic leukaemia in first complete remission

We retrospectively investigated outcomes of haploidentical donor (HID) transplant for adults with standard‐risk acute lymphoblastic leukaemia (ALL) in first complete remission (CR1) compared with human leucocyte antigen (HLA)‐matched sibling donor (MSD) and HLA‐matched unrelated donor (MUD) transplants. A total of 348 adult patients were enrolled, including 127 HID, 144 MSD and 77 MUD recipients. The cumulative incidence of grade II–IV acute graft‐versus‐host disease (aGVHD) was 39·5%, 24·0% and 40·3% for HID, MSD and MUD, respectively (P = 0·020). However, there was no difference in grade III–IV aGVHD (11·4%, 7·7%, 13·5%, respectively, P = 0·468). The 5‐year cumulative transplant‐related mortality was 16·4%, 11·6% and 19·6% (P = 0·162), the 5‐year relapse rate post‐transplantation was 14·8%, 21·1% and 16·7% (P = 0·231), the 5‐year overall survival was 70·1%, 73·7% and 69·8% (P = 0·525), and the 5‐year disease‐free survival was 68·7%, 67·3% and 63·7%, respectively (P = 0·606). Furthermore, the 3‐year GVHD‐free, relapse‐free survival was not different (50·8%, 54·9% and 52·2%, respectively, P = 0·847). Our results indicate that the outcomes of HID transplants are equivalent to those of MSD and MUD, and that HID transplantation is a valid alternative for standard‐risk adults with ALL in CR1 who lack matched donors.     

Outcomes of treatment for relapsed acute lymphoblastic leukaemia in children with Down syndrome

Children with Down syndrome (DS) have a greater risk for developing both acute lymphoblastic leukaemia (ALL) and significant adverse effects of chemotherapy. We investigated their outcome with, and tolerance of, treatment protocols for relapsed ALL optimized in the paediatric population without DS. Probability of survival and causes of treatment failure were determined for 49 children with DS and a matched cohort of 98 children without DS among 2160 children treated for relapsed ALL in clinical trials conducted by the Berlin‐Frankfurt‐Münster ALL Relapse Study Group between 1983 and 2012. Despite more favourable ALL relapse characteristics, children with DS experienced lower event‐free (EFS) and overall survival (OS) than the control group without DS (EFS 17 ± 08% vs. non‐DS 41 ± 06%, P = 0·006; OS 17 ± 09% vs. non‐DS 51 ± 06%, P < 0·001). Children with DS developed more frequently fatal complications of treatment (34 ± 07% vs. non‐DS 10 ± 04%, P < 0·001). During the last decade, EFS and OS were no longer significantly different in children with and without DS (EFS 31 ± 09% vs. 36 ± 09%, P = 0·399; OS 31 ± 12% vs. 53 ± 09%, P = 0·151). DS proved an independent prognostic factor of outcome after ALL relapse. Induction deaths and treatment‐related mortality but not subsequent relapse were the main barrier to successful outcomes of relapse therapy in children with DS.     

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.     

Disseminated lymphoblastic lymphoma in children and adolescents: results of the COG A5971 trial: a report from the Children's Oncology Group

The Children's Oncology Group's A5971 trial examined central nervous system (CNS) prophylaxis and early intensification in paediatric patients diagnosed with CNS‐negative Stage III and IV lymphoblastic lymphoma. Using a 2 × 2 factorial design, the study randomized patients to Children's Cancer Group (CCG) modified Berlin‐Frankfurt‐Muenster (BFM) acute lymphoblastic leukaemia (ALL) regimen with intensified intrathecal (IT) methotrexate (MTX) (Arm A1) or an adapted non‐Hodgkin lymphoma/BFM‐95 therapy with high dose MTX in interim maintenance but no IT‐MTX in maintenance (Arm B1) . Each cohort was randomized ± intensification (cyclophosphamide/anthracycline) (Arms A2/B2). For the 254 randomized patients, there was no difference in 5‐year event‐free survival (EFS) for the four arms: Arm A1 , 80% [95% confidence interval (CI) 67–89%] and Arm A2 , 81% (95% CI 69–89%); Arm B1 , 80% (95% CI 68–88%) and Arm B2 , 84% (95% CI 72–91%). The cumulative incidence of CNS relapse was 1·2%. Age <10 years and institutional imaging response at 2 weeks was associated with improved outcomes (P < 0·001 and P = 0·014 for overall survival). CNS positive patients (n = 12) did poorly [5‐year EFS of 63% (95% CI 29–85%)]. For CNS‐negative patients, there was no difference in outcome based on CNS prophylaxis (IT‐MTX versus HD‐MTX) or with intensification.     

Clinical utility of next‐generation sequencing‐based minimal residual disease in paediatric B‐cell acute lymphoblastic leukaemia

We assessed the clinical utility of next‐generation sequencing (NGS)‐based monitoring of minimal residual disease (MRD) in a uniformly treated cohort of 79 patients with paediatric B‐cell acute lymphoblastic leukaemia. Bone marrow samples were collected at the time of diagnosis, days 33 and 80, pre‐ (4–5 months) and post‐ (24 months) maintenance therapy time points, and at relapse. We identified leukaemia‐specific CDR3 sequences in 72 of 79 patients (91%) and detected MRD in 59 of 232 samples. Although MRD was detected in 28 of 55 samples (51%) on day 33, the frequencies of MRD detection decreased to 25% (16/65) at day 80, 19% (11/58) at 4–5 months and 7·4% (4/54) at 24 months. In a univariate analysis, positive MRD results on day 80 [relative risk (RR) 95% confidence interval (CI) = 7·438 (2·561–21·6), P < 0·001], at 4–5 months [RR (95% CI) = 10·24 (3·374–31·06), P < 0·001], and at 24 months [RR (95% CI) = 19·26 (4·974–74·59), P < 0·001] exhibited statistically significant associations with inferior leukaemia‐free survival; this was confirmed using a Cox proportional hazard model. Our study suggests the promising potential of NGS‐MRD for patients with B‐cell ALL.     

Rescue of genomic information in adult acute lymphoblastic leukaemia (ALL) with normal/failed cytogenetics: a GIMEMA centralized biological study

Metaphase (M‐) and array (A‐) Comparative Genomic Hybridization (CGH) were used to investigate 40 cases of T‐ and 32 of B‐cell acute lymphoblastic leukaemia (ALL) with normal/failed cytogenetics. M‐CGH was performed in all cases and A–CGH in 10/12 T‐ALL cases with uncertain/normal M‐CGH results. M‐CGH was abnormal in 38/72 cases, with a total of 110 imbalances (60 gains, 50 losses). 25/40 patients with T‐ALL (62·5%) showed 77 imbalances, with at least 1 genomic imbalance and a mean of 3 aberrations/patient (range 1–12). 13/32 patients with B‐ALL (40·6%) presented 34 imbalances, with a mean of 2·6 imbalances (range 1–8). A‐CGH detected 4 more T‐ALL cases with genomic imbalances. A‐CGH identified NF1/17q11·2 deletion and interphase fluorescence in situ hybridization provided a 10·8% estimated overall incidence of NF1/17q11·2 deletion in T‐ALL. In all but one case (6/7) with NF1 deletion, denaturing high‐performance liquid chromatography and direct sequencing detected NOTCH1 gene mutations. Three or more imbalances in CGH‐positive cases were significantly associated with resistance to treatment and death during or after induction therapy. We suggest that the work‐up for ALL at diagnosis should include CGH investigations, particularly when cytogenetics is uninformative, because they may provide potentially valuable information with prognostic and therapeutic implications.