Front‐line,dose‐escalated immunochemotherapy is associated with a significant progression‐free survival advantage in patients with double‐hit lymphomas: a systematic review and meta‐analysis

‘Double‐hit lymphomas’ (DHL), defined by concurrent MYC and BCL2 (or, alternatively, BCL6) rearrangements, have a very poor outcome compared to standard‐risk, diffuse large B‐cell lymphomas (DLBCL). Consequently, dose‐intensive (DI) therapies and/or consolidation with high‐dose therapy and transplant have been explored in DHL, although benefit has been debated. This meta‐analysis compared survival outcomes in DHL patients receiving dose‐escalated regimens [DI: R‐Hyper‐CVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) or R‐CODOX‐M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high dose cytarabine); or intermediate‐dose: R‐EPOCH (rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone)] versus standard‐dose regimens (R‐CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in the first‐line setting. Data were synthesized to estimate hazard ratios of dose‐escalated treatments versus R‐CHOP using a Weibull proportional hazards model within a Bayesian meta‐analysis framework. Eleven studies examining 394 patients were included. Patients were treated with either front‐line R‐CHOP (n = 180), R‐EPOCH (n = 91), or R‐Hyper‐CVAD/rituximab, methotrexate, cytarabine (R‐M/C), R‐CODOX‐M/R‐IVAC (DI) (n = 123). Our meta‐analysis revealed that median progression‐free survival (n = 350) for the R‐CHOP, R‐EPOCH and DI groups was 12·1, 22·2, and 18·9 months, respectively. First‐line treatment with R‐EPOCH significantly reduced the risk of a progression compared with R‐CHOP (relative risk reduction of 34%; P = 0·032); however, overall survival (n = 374) was not significantly different across treatment approaches. A subset of patients might benefit from intensive induction with/without transplant. Further investigation into the role of transplant and novel therapy combinations is necessary.     

Prospective phase II study of rituximab with alternating cycles of hyper‐CVAD and high‐dose methotrexate with cytarabine for young patients with high‐risk diffuse large B‐cell lymphoma

We conducted a prospective randomized phase II study to evaluate two chemotherapy regimens: (i) rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (R‐HCVAD) alternating with rituximab, high‐dose methotrexate, and cytarabine (R‐MA) and (ii) rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP) in diffuse large B‐cell lymphoma (DLBCL). This study randomized patients aged ≤60 years with DLBCL and an age‐adjusted international prognostic index ≥2 to R‐HCVAD/R‐MA or R‐CHOP based on a Bayesian adaptive algorithm. Interim analysis of the first 26 eligible patients showed that the complete response rate (CRR) was higher with R‐HCVAD/R‐MA than R‐CHOP (P = 0·03); thus, R‐CHOP arm was closed. In the final analysis, 49 and 10 eligible patients were treated in R‐HCVAD/R‐MA and R‐CHOP arms respectively; CRR were 82% and 60% respectively (P = 0·13); 3‐year progression‐free survival (PFS) rates were 75·7% and 77·8% respectively (P = 0·53). In the R‐HCVAD/R‐MA arm, 3‐year PFS rates in patients aged 46–60 years and ≤45 years were 70·3% and 87·1% respectively (P = 0·13), and the treatment‐associated early mortality rate in patients >45 years was 12%. In conclusion, R‐HCVAD/R‐MA is associated with excellent outcome in patients ≤45 years old. However, in patients >45 years old, R‐HCVAD/R‐MA is associated with unacceptable mortality rates.     

Clinical activity of a new regimen combining gemcitabine and alemtuzumab in high‐risk relapsed/refractory chronic lymphocytic leukemia patients

Optimal treatment strategies are lacking in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Gemcitabine has shown activity and acceptable safety profile in B‐cell lymphomas. We present a retrospective case review of gemcitabine and alemtuzumab, every 21 d (for up to six courses) in 27 community‐based patients with high‐risk R/R CLL. Median age was 70 yr (44–83 yr), 55% patients had Binet stage C, deletion 17p (del(17p)) and/or deletion 11q (del(11q)) were found in 65% and 27%, bulky disease in 55.5%, and fludarabine‐refractoriness in 48% of cases, respectively. Overall response rate was 63% (29.6% clinical CR and 33.4% PR). At a median follow‐up of 31 months, median PFS and OS were 15.4 and 24 months. In multivariate analysis, median OS is influenced by prior lines of treatment = 3 and bulky disease. Combination of alemtuzumab and gemcitabine appears to be an active, easy to administrate treatment in routine practice, high‐risk R/R CLL patients.     

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.     

A dose‐dense short‐term therapy for human immunodeficiency virus/acquired immunodeficiency syndrome patients with high‐risk Burkitt lymphoma or high‐grade B‐cell lymphoma: safety and efficacy results of the “CARMEN” phase II trial

A few prospective trials in HIV‐positive patients with Burkitt lymphoma (BL) or high‐grade B‐cell lymphoma (HGBL) have been reported. Investigated therapies have shown good efficacy but relevant safety problems, with high rates of interruptions, severe mucositis, septic complications, and fungal infections. Here, we report the results of a multicentre phase II trial addressing a new dose‐dense, short‐term therapy aimed at maintaining efficacy and improving tolerability. The experimental programme included a 36‐day polychemotherapy induction followed by high‐dose cytarabine‐based consolidation and response‐tailored BEAM (carmustine, etoposide, cyatarabine, and melphalan)‐ conditioned autologous stem cell transplantation (ASCT). This therapy would be considered active if ≥11 complete remissions (CR) after induction (primary endpoint) were recorded among 20 assessable patients. HIV‐positive adults (median age 42, range 26–58; 16 males) with untreated BL (n = 16), HGBL (n = 3) or double‐hit lymphoma (n = 1) were enrolled. All patients had high‐risk features, with meningeal and bone marrow infiltration in five and nine patients respectively. The experimental programme was safe and active in a multicentre setting, with only two episodes of grade 4 non‐haematological toxicity (hepatotoxicity and mucositis), and no cases of systemic fungal infections; two patients died of toxicity (bacterial infections). Response after induction (median duration: 47 days; interquartile range 41–54), was complete in 13 patients and partial in five [overall response rate = 90%; 95% confidence interval (CI) = 77–100]. All responders received consolidation, and five required autologous stem cell transplant. At a median follow‐up of 55 (41–89) months, 14 patients are relapse‐free and 15 are alive, with a five‐year progression‐free survival and an overall survival of 70% (95% CI = 60–80%) and 75% (95% CI = 66–84) respectively. No patient with cerebrospinal fluid (CSF)/meningeal lymphoma experienced central nervous system recurrence. With respect to previously reported regimens, this programme was delivered in a shorter period, and achieved the main goal of maintaining efficacy and improving tolerability.     

Phase II study of tosedostat with cytarabine or decitabine in newly diagnosed older patients with acute myeloid leukaemia or high‐risk MDS

Tosedostat, an oral aminopeptidase inhibitor, has synergy with cytarabine and hypomethylating agents. We performed a Phase II trial to determine rates of complete remission (CR) and survival using tosedostat with cytarabine or decitabine in older patients with untreated acute myeloid leukaemia (AML) or high‐risk myelodysplastic syndrome (MDS). Thirty‐four patients ≥60 years old (median age 70 years; range, 60–83) were randomized to receive tosedostat (120 mg on days 1–21 or 180 mg continuously) with 5 d of either cytarabine (1 g/m²/d) or decitabine (20 mg/m²/d) every 35 d. Twenty‐nine patients (85%) had AML, including 15 (44%) with secondary AML/MDS, and 5 (15%) had MDS‐refractory anaemia with excess blasts type 2. The CR/CR with incomplete count recovery (CRi) rate was 53% [9 in each arm; 14 CR (41%) and 4 CRi (12%)], attained in 6 of 14 patients with adverse cytogenetics and 4 of 7 with FLT3‐internal tandem duplication mutations. Median follow‐up was 11·2 months (range, 0·5–22·3), and median survival was 11·5 months (95% confidence interval, 5·2–16·7). Twenty‐three patients (67·6%) were treated as outpatients and 10 of these patients required hospitalization for febrile neutropenia. No Grade 3–4 non‐haematological toxicities required withdrawal from study. Tosedostat with cytarabine or decitabine is tolerated in older patients with untreated AML/MDS, results in a CR/CRi rate of >50%, and warrants further study in larger trials.     

Rituximab plus hyper‐CVAD alternating with MTX/Ara‐C in patients with newly diagnosed mantle cell lymphoma: 15‐year follow‐up of a phase II study from the MD Anderson Cancer Center

Intensive chemotherapy regimens containing cytarabine have substantially improved remission durability and overall survival in younger adults with mantle cell lymphoma (MCL). However, there have been no long‐term follow‐up results for patients treated with these regimens. We present long‐term survival outcomes from a pivotal phase II trial of rituximab, hyper‐fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine (R‐HCVAD/MA) . At 15 years of follow‐up (median: 13·4 years), the median failure‐free survival (FFS) and overall survival (OS) for all patients was 4·8 years and 10·7 years, respectively. The FFS seems to have plateaued after 10 years, with an estimated 15‐year FFS of 30% in younger patients (≤65 years). Patients who achieved complete response (CR) after 2 cycles had a favourable median FFS of 8·8 years. Six patients developed myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) whilst in first CR. The 10‐year cumulative incidence of MDS/AML of patients in first remission was 6·2% (95% confidence interval: 2·5–12·2%). In patients with newly diagnosed MCL, R‐HCVAD/MA showed sustained efficacy, with a median OS exceeding 10 years in all patients and freedom from disease recurrence of nearly 15 years in almost one‐third of the younger patients (≤65 years).     

Favourable outcomes of poor prognosis diffuse large B‐cell lymphoma patients treated with dose‐dense Rituximab,high‐dose Methotrexate and six cycles of CHOP‐14 compared to first‐line autologous transplantation

The optimal therapeutic approach for young diffuse large B‐cell lymphoma (DLBCL) patients with high‐intermediate and high‐risk age‐adjusted international prognostic index (aaIPI) remains unknown. Hereby we report a 10‐year single‐centre study of 63 consecutively treated patients. To optimize outcome, two approaches were carried out: Cohort 1 patients received four cycles R‐CHOP‐21 (rituximab, cyclophosphamide, daunorubicin, vincristine, prednisolone over 21 days) followed by first‐line high‐dose chemotherapy with autologous stem‐cell support (HDCT‐ASCT), resulting in 2‐year progression‐free (PFS) and overall survival (OS) of 60·6% and 67·9%. 39·4% of those patients were not transplanted upfront, mainly due to early progressive disease (24·2%). Cohort 2 patients received an early intensified protocol of six cycles of CHOP‐14 (cyclophosphamide, daunorubicin, vincristine, prednisolone over 14 days) with dose‐dense rituximab and high‐dose methotrexate resulting in promising overall response‐ (93·3%) and complete remission (90%) rates and sustained survival (2‐year PFS and OS: 93·3%). In an intention‐to‐treat analysis, 2‐year PFS (60·6% vs. 93·3%, hazard ratio [HR] 7·2, P = 0·009) and OS (69·7% vs. 93·3%, HR 4·95, P = 0·038) differed significantly, in favour of the early intensified protocol (Cohort 2). In a multivariate Cox‐regression model, PFS (HR 8·12, 95% confidence interval [CI] 1·83–35·9, P = 0·006) and OS (HR 5·86, 95% CI 1·28–26·8, P = 0·02) remained superior for Cohort 2 when adjusted for aaIPI3 as the most important prognostic factor. Survival of young poor‐prognosis DLBCL patients appears superior after early therapy intensification.     

A randomized phase II study of standard‐dose versus high‐dose rituximab with BEAM in autologous stem cell transplantation for relapsed aggressive B‐cell non‐hodgkin lymphomas: long term results

High‐dose rituximab (HD‐R) combined with carmustine, cytarabine, etoposide and melphalan (BEAM) and autologous stem cell transplant (ASCT) was effective and tolerable in a single‐arm prospective study of relapsed aggressive B‐cell non‐Hodgkin lymphoma (R‐NHL). We performed a randomized phase 2 study comparing HD‐R versus standard‐dose rituximab (SD‐R) in R‐NHL. Ninety‐three patients were randomized to HD‐R (1000 mg/m²) (n = 42) or SD‐R (375 mg/m²) (n = 51) administered on post‐transplant days +1 and +8, using a Bayesian adaptive algorithm. The 2 treatment arms were balanced in regards to patient demographic and clinical characteristics. At a median follow‐up of 7·92 years, the 5‐year disease‐free survival (DFS) and overall survival (OS) were 40% and 48%, respectively. We found no statistically significant differences between HD‐R and SD‐R in 5‐year DFS (36% vs. 43%; P = 0·205) and OS (43% vs. 52%; P = 0·392). In multivariate analyses, only disease status before ASCT [residual disease versus complete remission (CR)] (hazard ratio [HR] 1·79, 95% confidence interval [CI]: 1·08–2·95) and number of prior treatments received (>2 vs. ≤2 lines of treatment) (HR 1·89, 95% CI: 1·13–3·18) were associated with worse DFS and OS. Patients who had SCT while in CR or who received ≤2 lines of treatment prior to SCT had better 5‐year OS (57% vs. 35%; P = 0·02 and 54% vs. 30%, P = 0·001, respectively) in both arms. No differences in engraftments or adverse events were noted in the 2 arms. When combined with BEAM and ASCT in relapsed aggressive B‐cell NHL, HD‐R provided no DFS or OS advantage over SD‐R. In patients who have been exposed to rituximab in the frontline or salvage setting, the addition of rituximab in the peri‐transplant setting remains controversial.     

Diffuse large B‐cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients

Nearly all information about patients with chronic lymphocytic leukaemia (CLL) who develop diffuse large B‐cell lymphoma [Richter syndrome (RS)] is derived from retrospective case series or patients treated on clinical trials. We used the Mayo Clinic CLL Database to identify patients with newly diagnosed CLL between January 2000 and July 2011. Individuals who developed biopsy‐proven RS during follow‐up were identified. After a median follow‐up of 4 years, 37/1641 (2·3%) CLL patients developed RS. The rate of RS was approximately 0·5%/year. Risk of RS was associated with advanced Rai stage at diagnosis (P < 0·001), high‐risk genetic abnormalitites on fluorescence in situ hybridization (P < 0·0001), unmutated IGHV (P = 0·003), and expression of ZAP70 (P = 0·02) and CD38 (P = 0·001). The rate of RS doubled in patients after treatment for CLL (1%/year). Stereotyped B‐cell receptors (odds‐ratio = 4·2; P = 0·01) but not IGHV4‐39 family usage was associated with increased risk of RS. Treatment with combination of purine analogues and alkylating agents increased the risk of RS three‐fold (odds‐ratio = 3·26, P = 0·0003). Median survival after RS diagnosis was 2·1 years. The RS prognosis score stratified patients into three risk groups with median survivals of 0·5 years, 2·1 years and not reached. Both underlying characteristics of the CLL clone and subsequent CLL therapy influence the risk of RS. Survival after RS remains poor and new therapies are needed.     

Phase II study of imatinib‐based chemotherapy for newly diagnosed BCR‐ABL‐positive acute lymphoblastic leukemia

This study investigated the efficacy of imatinib based therapy with intensified consolidation therapy in patients with Philadelphia chromosome (Ph)‐positive acute lymphoblastic leukemia (ALL) to prevent early relapse. We conducted a phase II trial of imatinib‐combined chemotherapy for newly diagnosed BCR‐ABL‐positive ALL in adults. Sixty‐eight patients were included in the trial between October 2008 and December 2010. The median age was 49 years, with 28 patients >55 years of age. Sixty‐five patients achieved CR (95.6%). The estimated 2‐year event‐free survival (EFS) and overall survival (OS) were 62.3% and 67.4%, respectively. Allogeneic stem cell transplantation (allo‐SCT) at initial CR was performed in 43 patients. Thirty‐five of 39 patients <55 years and 8 of 26 patients >55 years underwent allo‐SCT at first CR. The 3‐year OS in patients <55 years receiving allo‐SCT at first CR, patients >55 years receiving allo‐SCT at first CR, patients <55 years not receiving allo‐SCT at first CR, and patients >55 years not receiving allo‐SCT at first CR were 80.4%, 41.1%, 32.5%, and 52.0%, respectively (P = 0.058). The three‐year EFS in each group was 76.7%, 53.6%, not reached, and 26.4%, respectively (P = 0.150). A high CR rate was observed with imatinib‐based chemotherapy allowing allo‐SCT in a high proportion of patients, particularly those <55 years. Moreover, intensified consolidation therapy reduced early relapse rates following induction therapy and resulted in improved OS and EFS rates following allo‐SCT. This trial was registered with the UMIN (000001226).     

Chemotherapeutic intensity and survival differences in young patients with diffuse large B‐cell lymphoma: a Swedish Lymphoma Registry study

Young patients with diffuse large B‐cell lymphoma (DLBCL) are variably treated with rituximab combined with cyclophosphamide‐doxorubicin‐vincristine‐prednisone (R‐CHOP), CHOP‐etoposide (R‐CHOEP), and anthracycline‐based regimens with the addition of high‐dose cytarabine/methotrexate (R‐HDA/M). Using the nationwide, population‐based Swedish Lymphoma Registry, we evaluated outcome, by treatment and Healthcare Region, in all 751 DLBCL patients aged ≤60 years without central nervous involvement, diagnosed in Sweden between 2007 and 2012. Overall survival was estimated using multivariate Cox analysis. In patients with age‐adjusted international prognostic index (aaIPI) ≥ 2, the 5‐year overall survival (OS) was 70%, 76% and 85% after R‐CHOP, R‐CHOEP and R‐HDA/M, respectively (P = 0·002); the corresponding estimates were 40%, 55%, and 92% in aaIPI = 3 (P = 0·014). There were large therapeutic differences between Sweden's six Healthcare Regions for aaIPI ≥ 2: three were “Moderate” (more R‐CHOP) and three “Intensive” (more R‐CHOEP and R‐HDA/M). Patients with aaIPI ≥ 2 who were treated in the Intensive Regions, showed better OS (P < 0·00005), particularly those with aaIPI = 3 (5‐year OS, 62% vs. 30%; P < 0·00005). There were no regional differences in therapy or survival in patients with aaIPI < 2. We conclude that in younger high‐risk patients, survival appears superior after more intensive therapy than R‐CHOP.     

Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid‐refractory,grade III–IV acute graft‐versus‐host disease

Mesenchymal stromal cell (MSC) infusions have been reported to be effective in patients with steroid‐refractory, acute graft‐versus‐host disease (aGvHD) but comprehensive data on paediatric patients are limited. We retrospectively analysed a cohort of 37 children (aged 3 months‐17 years) treated with MSCs for steroid‐refractory grade III–IV aGvHD. All patients but three received multiple MSC infusions. Complete response (CR) was observed in 24 children (65%), while 13 children had either partial (n = 8) or no response (n = 5). Cumulative incidence of transplantation‐related mortality (TRM) in patients who did or did not achieve CR was 17% and 69%, respectively (P = 0·001). After a median follow‐up of 2·9 years, overall survival (OS) was 37%; it was 65% vs. 0% in patients who did or did not achieve CR, respectively (P = 0·001). The median time from starting steroids for GvHD treatment to first MSC infusion was 13 d (range 5–85). Children treated between 5 and 12 d after steroid initiation showed a trend for better OS (56%) and lower TRM (17%) as compared with patients receiving MSCs 13–85 d after steroids (25% and 53%, respectively; P = 0·22 and 0·06, respectively). Multiple MSC infusions are safe and effective for children with steroid‐refractory aGvHD, especially when employed early in the disease course.     

Prognostic significance of programmed cell death‐1‐positive cells in follicular lymphoma patients may alter in the rituximab era

Programmed cell death‐1 (PD‐1) is involved in one of the inhibitory pathways of the B7‐cluster of differentiation (CD) 28 family; this pathway is known to be involved in the attenuation of T‐cell responses and promotion of T‐cell tolerance. PD‐1 is known to negatively regulate T‐cell receptor‐mediated proliferation and cytokine production, lead to alternation in the tumor microenvironment. Although several studies have shown that high levels of PD‐1‐positive cells in follicular lymphoma (FL) patients influence their prognosis, those studies included patients treated without rituximab, and the prognostic impact of PD‐1 positivity in the rituximab era (R‐era) has not yet been elucidated. We retrospectively studied 82 patients with FL uniformly treated with standard R‐CHOP therapy at six institutions between 2001 and 2009 (median follow‐up for survivors: 55 months). We also collected and examined biopsy specimens for diagnosis with respect to PD‐1 positivity. The PD‐1 positivity was significantly higher in male patients and patients with high beta‐2 microglobulin (B2M ≥ 3.0) (P = 0.03 and 0.003, respectively). Three‐year progression free survival (PFS) and overall survival (OS) were 60% and 86%, respectively. By univariate analysis, elevated LDH (P = 0.07) worsened PFS. Male gender (P = 0.03), high FLIPI score (P = 0.05), and high B2M levels (P = 0.08) worsened OS. Multivariate analysis detected no significant prognostic factors, including PD‐1 positivity. However, in male subgroup, high levels of PD‐1‐positive cells were found to be a prognostic factor for PFS. Addition of rituximab might have altered the prognostic impact of PD‐1‐positive cells.     

Long‐term follow‐up of dose‐adjusted EPOCH plus rituximab (DA‐EPOCH‐R) in untreated patients with poor prognosis large B‐cell lymphoma. A phase II study conducted by the Spanish PETHEMA Group

This prospective multi‐institutional phase II study was designed to assess the efficacy and safety of dose‐adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) plus rituximab (DA‐EPOCH‐R) in untreated patients with poor prognosis large B‐cell lymphomas. Eighty‐one patients diagnosed with diffuse large B‐cell lymphoma (DLBCL, n = 68), primary mediastinal DLBCL (n = 6) and follicular lymphoma Grade 3b (n = 7), with an age‐adjusted International Prognostic Index >1, were eligible for analysis. Median age was 60 years (range: 21–77). Sixty‐five patients (80·2%) achieved complete response. After a median follow‐up time of 64 months, 10‐year event‐free survival and overall survival (OS) were 47·8% and 63·6%, respectively. None of the studied clinical and biological characteristics were associated with poorer outcome. Interestingly, patients with BCL6 rearrangement achieved a 10‐year OS of 100%, while patients with BCL2 rearrangement exhibited a poorer outcome compared to activated B‐cell tumours and germinal centre B‐cell without BCL2 rearranged tumours. Results achieved with DA‐EPOCH‐R showed a good long‐term outcome and a tolerable toxicity profile in high‐risk large B cell lymphoma patients. Outcome was not affected by tumour cell proliferation or by cell of origin, highlighting the requirement of new biological markers for patient subclassification of high‐risk DLBCL patients.     

R‐CHOP versus dose‐adjusted R‐EPOCH in frontline management of primary mediastinal B‐cell lymphoma: a multi‐centre analysis

Primary mediastinal (thymic) large B‐cell lymphoma (PMBCL) is an uncommon subtype of non‐Hodgkin lymphoma (NHL) that presents with a mediastinal mass and has unique clinicopathological features. Historically, patients with PMBCL were treated with R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy ± involved field radiation. Since a phase II trial, published in April 2013, demonstrated excellent results using dose‐adjusted (DA) R‐EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), this treatment has gained popularity. We performed a retrospective, multicentre analysis of patients aged ≥18 years with PMBCL since January 2011. Patients were stratified by frontline regimen, R‐CHOP versus DA‐R‐EPOCH. 132 patients were identified from 11 contributing centres (56 R‐CHOP and 76 DA‐R‐EPOCH). The primary outcome was overall survival. Secondary outcomes included progression‐free survival, complete response (CR) rate, and rates of treatment‐related complications. Demographic characteristics were similar in both groups. DA‐R‐EPOCH use increased after April 2013 (79% vs. 45%, P < 0·001), and there was less radiation use after DA‐R‐EPOCH (13% vs. 59%, P < 0·001). While CR rates were higher with DA‐R‐EPOCH (84% vs. 70%, P = 0·046), these patients were more likely to experience treatment‐related toxicities. At 2 years, 89% of R‐CHOP patients and 91% of DA‐R‐EPOCH patients were alive. To our knowledge, this represents the largest series comparing outcomes of R‐CHOP to DA‐R‐EPOCH for PMBCL.     

A prospective,multicenter phase II study of continuous infusion of FLAG for patients older than 60 yr with resistant acute myeloid leukemia: a comparison with intensive younger patients’ trial

Relapsed or refractory acute myeloid leukemia (R/R AML) in elderly (≥60 yr old) patients were eligible. Induction chemotherapy consisted fludarabine and cytarabine (ARAC) as a 24‐hr CI without idarubicin (C‐FLAG), which was compared with the results of C‐FLAG with idarubicin (CI‐FLAG2) in younger patients’ trial. A total of 33 and 68 patients were enrolled in C‐FLAG and CI‐FLAG2, respectively. CR, CRp, and CRi were achieved in 10 (30.3%), 3 (9.1%), and 2 (6.1%), respectively. When comparing outcomes between C‐FLAG and CI‐FLAG2, there were no difference in terms of CR rate (P = 0.572) and objective response rate (ORR; P = 0.899). Favorable predictors on ORR in C‐FLAG were PB WBC ≤ 20K/uL at salvage (P = 0.024) and early evaluation peripheral BLAST = 0% (P = 0.013) on multivariate analysis. The overall survival of patients who achieve CR/CRp/CRi showed significantly prolonged survival compared with patients who did not in C‐FLAG (P < 0.001) and was a favorable predictor of longer survival by multivariate analysis (P = 0.009). Median overall survival was 3.19 (95% CI, 2.05–4.33) months and similar with that of CI‐FLAG2 (P = 0.841). Attenuated salvage regimen C‐FLGA in elderly patients was as effective as more intensive younger patients’ regimen CI‐FLAG2 in terms of response and survival although elderly patients had more unfavorable clinical characteristics.     

Minimal residual disease assessed by multi‐parameter flow cytometry is highly prognostic in adult patients with acute lymphoblastic leukaemia

The prognostic value of minimal residual disease (MRD) assessed by multi‐parameter flow cytometry (MFC) was investigated among 340 adult patients with B‐cell acute lymphoblastic leukaemia (B‐ALL) treated between 2004 and 2014 using regimens including the hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) backbone. Among them, 323 (95%) achieved complete remission (CR) and were included in this study. Median age was 52 years (range, 15–84). Median white blood cell count (WBC) was 9·35 × 10⁹/l (range, 0·4–658·1 ×1 0⁹/l). MRD by MFC was initially assessed with a sensitivity of 0·01%, using a 15‐marker, 4‐colour panel and subsequently a 6‐colour panel on bone marrow specimens obtained at CR achievement and at approximately 3 month intervals thereafter. MRD negative status at CR was associated with improved disease‐free survival (DFS) and overall survival (OS) (P = 0·004 and P = 0·03, respectively). Similarly, achieving MRD negative status at approximately 3 and 6 months was associated with improved DFS (P = 0·004 and P < 0·0001, respectively) and OS (P = 0·004 and P < 0·0001, respectively). Multivariate analysis including age, WBC at presentation, cytogenetics (standard versus high risk) and MRD status at CR, 3 and 6 months, indicated that MRD negative status at CR was an independent predictor of DFS (P < 0·05). Achievement of an MRD negative state assessed by MFC is an important predictor of DFS and OS in adult patients with ALL.     

Haematopoietic stem cell transplantation for relapsed or refractory anaplastic large cell lymphoma: a study of children and adolescents in Japan

To evaluate haematopoietic stem cell transplantation (HSCT) in children and adolescents, we reviewed the records of 47 patients who were ≤18 years, had relapsed or refractory anaplastic large cell lymphoma, and received HSCT between 1990 and 2010. At HSCT, complete remission (CR) was less common in allogeneic HSCT recipients (n = 24) than in autologous HSCT recipients (n = 23) (P = 0·01). The autologous and allogeneic HSCT groups differed in terms of 5‐year event‐free survival (EFS) (38% vs. 50%, P = 0·63), cumulative incidence of progress or relapse (49% vs. 28%, P = 0·25), and treatment‐related mortality (12% vs. 25%, P = 0·40). However, these differences were not significant. Patients with non‐CR at autologous HSCT had a significantly lower EFS rate (14% vs. 48%, P = 0·03). Conversely, although those with non‐CR at allogeneic HSCT had a lower EFS rate, this was not significant (44% vs. 63%, P = 0·26). Reduced‐intensity conditioning regimens were used for three of the 16 allogeneic HSCTs received by patients with non‐CR. These three patients achieved CR, surviving 32–65 months after HSCT. These results demonstrated that allogeneic HSCT might be a treatment option for patients who do not achieve CR through conventional chemotherapy.     

A phase 1/2 trial of ublituximab,a novel anti‐CD20 monoclonal antibody,in patients with B‐cell non‐Hodgkin lymphoma or chronic lymphocytic leukaemia previously exposed to rituximab

This phase 1/2 study evaluated the safety, pharmacokinetic behavior and anti‐tumour activity of ublituximab, a unique type I, chimeric, glycoengineered anti‐CD 20 monoclonal antibody, in rituximab‐relapsed or ‐refractory patients with B‐cell non‐Hodgkin lymphoma (B‐NHL ) or chronic lymphocytic leukaemia (CLL ). Induction therapy (doses of 450–1200 mg) consisted of 4 weekly infusions in cycle 1 for NHL and 3 weekly infusions in cycles 1 and 2 for CLL . Patients received ublituximab maintenance monthly during cycles 3–5, then once every 3 months for up to 2 years. Enrolled patients with B‐NHL (n  = 27) and CLL (n  = 8) had a median of 3 prior therapies. No dose‐limiting toxicities or unexpected adverse events (AE s) occurred. The most common AE s were infusion‐related reactions (40%; grade 3/4, 0%); fatigue (37%; grade 3/4, 3%); pyrexia (29%; grade 3/4, 0%); and diarrhoea (26%; grade 3/4, 0%). Common haematological AE s were neutropenia (14%; grade 3/4, 14%) and anaemia (11%; grade 3/4, 6%). The overall response rate for evaluable patients (n  = 31) was 45% (13% complete responses, 32% partial responses). Median duration of response and progression‐free survival were 9·2 months and 7·7 months, respectively. Ublituximab was well‐tolerated and efficacious in a heterogeneous and highly rituximab‐pre‐treated patient population.