Philadelphia chromosome‐positive mixed phenotype acute leukemia in the imatinib era

Although the introduction of imatinib dramatically improved the outcomes for patients with Philadelphia chromosome‐positive B‐cell precursor acute lymphoblastic leukemia (Ph+BCP‐ALL), the survival benefit of imatinib has not been assessed in the context of Ph+ mixed phenotype acute leukemia (Ph+MPAL). To clarify this important issue, we studied 42 Ph+ acute leukemia (Ph+AL) patients who received intensive chemotherapy and concurrent administration of imatinib. Of the 42 Ph+AL patients, 13 (31%) patients were categorized as Ph+MPAL (positive for both myeloid and B‐cell lineage), 27 (64%) were categorized as Ph+BCP‐ALL, and two (5%) were categorized as Ph+ acute myeloid leukemia. The complete remission rates after the initial induction therapy were not significantly different when comparing Ph+MPAL and Ph+BCP‐ALL patients (100% vs. 85%, respectively, P = 0.14). Likewise, there were no significant differences in the 5‐yr overall survival (OS) or disease‐free survival (DFS) rates when comparing the MPAL and BCP‐ALL groups (OS: 55% vs. 53%, respectively, P = 0.87, DFS: 46% vs. 42%, respectively, P = 0.94). These findings suggest that concurrent imatinib administration with chemotherapy improved the outcomes of Ph+MPAL patients to the level seen in Ph+BCP‐ALL patients and should, therefore, be considered as the standard therapy for these patients.     

Prognostic impact of minimal residual disease analysis by flow cytometry in patients with acute myeloid leukemia before and after allogeneic hemopoietic stem cell transplantation

Allogeneic stem cell transplantation (allo‐SCT) has become the treatment of choice in patients with intermediate‐risk and high‐risk acute myeloid leukemia (AML). The quality of response to treatment, assessed in terms of detection of minimal residual disease (MRD), has been consistently associated with prognosis and clinical outcome in patients with AML. The aim of the present study was to evaluate the prognostic impact of analyzing MRD in bone marrow using 4‐color multiparametric flow cytometry (MFC) in 29 patients with AML before and after allo‐SCT. Eighteen patients who were shown to be MRD‐negative [≤0.1% leukemia‐associated immunophenotypes (LAIPs)] by MFC at transplantation and underwent allo‐SCT had lower rates of relapse (15% vs. 66%, P = 0.045), better overall 1‐yr survival (83% vs. 52%, P = 0.021) and a lower cumulative incidence of relapse (P = 0.032) than patients who were MRD‐positive (>0.1%). All post‐transplant MRD‐positive patients underwent a therapeutic intervention after transplant (tapering of immunosuppression, donor lymphocyte infusion, or re‐transplant) with the intention of preventing relapse. Disease was controlled and MRD disappeared in five of these patients. Disease recurred in the other seven patients. We can conclude that follow‐up with MFC for the detection of MRD in AML before and after SCT is useful for predicting relapse. In the post‐transplant setting, monitoring of MRD by MFC could be a key preemptive intervention.     

Clofarabine-containing conditioning regimen for allo-SCT in AML/ALL patients: a survey from the Acute Leukemia Working Party of EBMT

Clofarabine (CLO), a second‐generation purine analogue, has demonstrated an efficient anti‐leukemia activity while showing a favorable toxicity profile. This retrospective multicenter report assessed the outcome of 90 patients who received a CLO‐containing conditioning regimen before allo‐SCT for AML (n = 69) or ALL (n = 21). Median age was 42 yr at transplant. The majority of cases (n = 66) presented with an active disease at transplant while 38 patients had received previous transplantation(s). A total of 88 and two patients received a reduced‐intensity conditioning or a myeloablative regimen, respectively. Engraftment was achieved in 97% of evaluable patients. With a median follow‐up of 14 months (range, 1–45), the 2‐year OS, LFS, relapse, and NRM rates were 28 ± 5%, 23 ± 5%, 41 ± 6%, and 35 ± 5%, respectively. When comparing AML and ALL patients, OS and LFS were significantly higher for AML (OS, 35 ± 6% vs. 0%, P < 0.0001); LFS: 30 ± 6% vs. 0%, P < 0.0001). In a Cox multivariate analysis, an AML diagnosis was the only factor associated with a better LFS ( HR = 0.37; 95%CI, 0.21–0.66; P = 0.001). We conclude that a CLO‐containing conditioning regimen prior to allo‐SCT might be an effective treatment. Prospective studies are needed to evaluate the potential role of CLO as part of conditioning regimens in acute leukemias.     

Prognostic impact of immune status and hematopoietic recovery before and after fludarabine,IV busulfan,and antithymocyte globulins (FB2 regimen) reduced‐intensity conditioning regimen (RIC) allogeneic stem cell transplantation (allo‐SCT)

This retrospective analysis aimed to assess hematopoietic and immune recovery in a cohort of 53 patients [males: n = 33; median age: 59 yr (range: 22–70)] who received a FB2 (fludarabine 120–150 mg/m² + IV busulfan 6.4 mg/kg + antithymocyte globulin thymoglobulin 5 mg/kg) reduced‐intensity conditioning (RIC) allo‐stem cells transplantations (SCT). With a median follow‐up of 19 months (range: 2–53), the 2‐yr overall survival, disease‐free survival (DFS), relapse incidence, and non‐relapse mortality were 63%, 59.5%, 35%, and 6%, respectively. In univariate analysis, the factors correlated with a significantly higher 2‐yr OS and DFS were a higher total circulating lymphocytes count at transplant (>730/mm³; OS: 81% vs. 43%, P = 0.02; DFS: 73% vs. 45.5%, P = 0.03) and a higher recovery of leukocytes (>5300/mm³) (2‐yr OS: 81% vs. 44%, P = 0.007; 2‐yr DFS: 72% vs. 46%, P = 0.08), neutrophils (>3200/mm³) (2‐yr OS: 76% vs. 50%, P = 0.03; 2‐yr DFS: 67% vs. 52.0%, P = 0.1), and monocytes (>590/mm³; 2‐yr OS: 80% vs. 45%, P = 0.004; 2‐yr DFS: 76% vs. 42%, P = 0.01) at day +30 post‐transplant. In multivariate analysis, the only independent factors associated with a significantly higher OS and DFS were a better immune status at transplant (lymphocytes count >730/mm³) and a higher monocytes count (>590/mm³) at day +30 post‐transplant. These results suggest that immune status and hematopoietic recovery before and after FB2 RIC allo‐SCT can be significant predictors of outcome. This paves the way for future studies aiming to closely monitor the kinetics of immune recovery after RIC allo‐SCT and to evaluate the impact of growth factors and other immunostimulatory cytokines in the setting of RIC allo‐SCT.     

Comparison of umbilical cord blood allogeneic stem cell transplantation vs. auto‐SCT for adult acute myeloid leukemia patients in second complete remission at transplant: a retrospective study on behalf of the SFGM‐TC

This retrospective study considered the outcomes of 181 patients with acute myeloid leukemia (AML) transplanted in second complete remission (CR2) between January 2005 and April 2012 and who received either a myeloablative autologous stem cell transplant (Auto‐SCT; n = 82; median age: 48 years; median follow‐up: 45 months) or an umbilical cord blood (UCB) allogeneic SCT (n = 99, median age: 46 years; median follow‐up: 36 months; conditioning regimens: myeloablative n = 21, reduced n = 78; single unit n = 37, double units n = 62). Although the Auto group showed a significant better prognostic profile at transplant, with longer median interval between diagnosis and time of graft, higher incidence of good‐risk cytogenetics and lower number of previously transplanted patients, 3‐year OS and LFS were similar between both groups (Auto: 59 ± 6% vs. 50 ± 6%, P = 0.45; and 57 ± 6% vs. 46 ± 6%, P = 0.37). In multivariate analysis, UCB allo‐SCT was associated with lower relapse incidence (HR: 0.3, 95% CI: 0.11–0.82, P = 0.02), but higher non‐relapse mortality (NRM) (HR: 4.16; 95% CI: 1.46–11.9, P = 0.008). Results from this large study suggest that UCB allo‐SCT provides better disease control than auto‐SCT, which is especially important in the setting of high‐risk disease. However, this disease control advantage is counterbalanced by higher toxicity, highlighting the need for novel approaches aiming to decrease NRM after UCB allo‐SCT.     

Impact of early remission by induction therapy on allogeneic stem cell transplantation for acute myeloid leukemia with an intermediate‐risk karyotype in first complete remission

For patients with acute myeloid leukemia (AML) early achievement of remission during induction treatment is an important predictor for long‐term outcome irrespective of the type of consolidation therapy employed. Here, we retrospectively examined the prognostic impact of early remission (ER) vs. delayed remission (DR) in a cohort of 132 AML patients with an intermediate‐risk karyotype undergoing allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1). In contrast to patients showing DR, patients achieving ER had a significantly higher 3‐yr overall survival (OS) and disease‐free survival (DFS) of 76% vs. 54% (P = 0.03) and 76% vs. 53% (P = 0.03). Likewise, 3 yr after alloSCT the cumulative incidence of relapse (CI‐R) was significantly lower in the ER subgroup as compared to patients achieving DR, that is, 10% vs. 35% (P = 0.004), whereas non‐relapse mortality (NRM) did not differ significantly. Multivariate analysis identified DR as an independent prognosticator for an inferior DFS (HR 3.37, P = 0.002) and a higher CI‐R (HR 3.55, P = 0.002). Taken together, these data may indicate that the rapid achievement of remission predicts a favorable outcome in patients with intermediate‐risk AML undergoing alloSCT in CR1. In turn, the adverse effect of DR may not be fully overcome by alloSCT.     

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).     

Mild chronic graft‐versus‐host disease may alleviate poor prognosis associated with FLT3 internal tandem duplication for adult acute myeloid leukemia following allogeneic stem cell transplantation with myeloablative conditioning in first complete remission: a retrospective study

Internal tandem duplication (ITD) of the FLT3 gene (Fms‐like tyrosine kinase 3) is the most commonly found mutation in acute myeloid leukemia (AML). The significance of FLT3‐ITD at diagnosis was retrospectively estimated for allo‐HSCT (allogeneic hematopoietic stem cell transplantation) outcomes in 140 patients, median age of 38, undergoing allo‐HSCT after myeloablative conditioning in first complete remission of AML. FLT3‐ITD was detected at AML diagnosis in 42/140 (30%) of included into this study patients. At 3 years, relapse incidence (RI) following allo‐HSCT in AML patients with intermediate or normal karyotype was significantly higher in those FLT3‐ITD positive than FLT3‐ITD negative [52.9 vs. 20.4%, P = 0.002]. Additionally, patients with mild chronic graft‐versus‐host disease (cGvHD) had significantly lower RI compared to patients with moderate or severe grade cGvHD or those not experiencing cGvHD, respectively, 4.8 vs. 36.0 vs. 27.8%, P = 0.032. FLT3‐ITD was harboring a poor prognosis in AML with intermediate or normal karyotype and significantly increased risk of relapse following allo‐HSCT. It appears that allo‐HSCT does not cure patients with FLT3‐ITD, unless they develop symptoms of mild cGvHD and graft versus leukemia, which may decrease RI.     

IDH1 and IDH2 mutations confer an adverse effect in patients with acute myeloid leukemia lacking the NPM1 mutation

We examined the incidence and prognostic effect of IDH1 and IDH2 mutations in 233 Japanese adults with acute myeloid leukemia (AML). IDH1 R132 mutations were detected in 20 (8.6%) patients with AML. IDH2 mutations were found in 19 (8.2%, 17 R140 and two R172) patients. IDH1 and IDH2 mutations were mutually exclusive and were associated with normal karyotype AML, cytogenetic intermediate‐risk group, and NPM1 mutations. Five‐year overall survival (OS) rates were significantly lower (15.6%) in patients harboring the IDH mutations than in patients lacking the IDH mutation (32.0%) in the entire cohort of AML (P = 0.005). Among patients aged 59 yr or younger with IDH mutations, 5‐yr OS in patients who underwent allogeneic stem cell transplantation (SCT) was significantly higher than that in those not receiving allogeneic SCT (50% vs. 10.6%, P = 0.020). Of 51 patients with NPM1 mutations, there was no significant difference in 5‐yr OS rates between patients with and those without the IDH mutations. In contrast, among 175 patients lacking the NPM1 mutations, 5‐yr OS rate in patients with IDH mutations was significantly lower than that in those without IDH mutations (0% vs. 34.7%, P = <0.001). These data suggest that IDH mutations have an unfavorable effect in AML, especially AML with the NPM1 wild type and younger AML patients with IDH mutations may benefit from allogeneic SCT.     

Early lymphocyte recovery at 28 d post‐transplant is predictive of reduced risk of relapse in patients with acute myeloid leukemia transplanted with peripheral blood stem cell grafts

Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for acute myeloid leukemia (AML). Impact of lymphocyte recovery on post‐transplant outcomes has been suggested but reports are conflicting. We evaluated the impact of lymphocyte recovery at 28 d post‐HCT in 191 AML patients using peripheral blood stem cells as graft. Patients were divided into those with absolute lymphocyte count (ALC) ≥0.5 × 10⁹/L (n = 111, 58%; high ALC group) and those with ALC <0.5 × 10⁹/L (n = 80, 42%; low ALC group), at day 28 post‐transplant. With a median follow‐up of 49 months, overall survival (OS) was significantly improved in the high ALC group (59% at 3 yr) vs. patients with low ALC (40% at 3 yr, P = 0.03). Cumulative incidence of relapse (CIR) was significantly lower in the high ALC group (16% at 3 yr) vs. low ALC group (36% at 3 yr, P = 0.001). Multivariable analysis for CIR demonstrated high ALC group as an independent factor decreasing relapse risk (P = 0.03, HR = 0.49, 95% CI = 0.26–0.92). Multivariable analysis for OS and non‐relapse mortality did not demonstrate ALC ≥0.5 × 10⁹/L at 28 d post‐transplant to be predictive. We conclude that lymphocyte recovery with ALC ≥0.5 × 10⁹/L at day 28 post‐transplant is associated with less relapse in AML patients undergoing allogeneic peripheral blood HCT, but without survival benefit.     

Results of risk‐adapted therapy in acute myeloid leukaemia. A long‐term population‐based follow‐up study

In 1997–2003, a protocol for treatment of acute myeloid leukaemia (AML) (except promyelocytic leukaemia) was activated in four Swedish health care regions covering 50% of the national population. Based on cytogenetics and clinical findings, patients aged 18–60 yr were assigned to one of three risk groups. In this report we account for the long‐term clinical outcome of enrolled patients. Patients received idarubicin and cytarabine in standard doses as induction therapy and consolidation courses included high‐dose cytarabine. Allogeneic stem cell transplantation (allo‐SCT) from an human leucocyte antigen‐identical sibling was recommended in standard and poor‐risk patients, whereas unrelated donor transplant was reserved for poor‐risk patients. Autologous (auto‐SCT) was optional for standard or poor risk patients not eligible for allo‐SCT. Two hundred seventy‐nine patients with de novo or secondary (9%) AML, median age 51 (18–60) yr, corresponding to 77% of all patients in the population, were included. Twenty (7%) patients were assigned to the good risk group, whereas 150 (54%) and 109 patients (39%) were assigned to standard‐ and poor‐risk groups, respectively. Induction failures accounted for 55 patients; 16 early deaths eight of whom had white blood cell (WBC) >100 at diagnosis, and 39 refractory disease. Thus, complete remission (CR) rate was 80%. At study closure, the median follow‐up time of living patients was 90 months. Median survival time from diagnosis in the whole group was 27 months and 4‐yr overall survival (OS) rate was 44%. In good, standard, and poor risk groups, 4‐yr OS rates were 60, 57 and 24%, respectively. Median relapse‐free survival (RFS) time in CR1 was 25 months and RFS at 4 yr was 44%. Four‐year RFS rates were significantly (P < 0.001) different between the three risk groups; 64% in good risk, 51% in standard risk and 27% in poor risk patients. One hundred‐ten transplantations were performed in CR1; 74 allo‐SCT (50 sibling, 24 unrelated donor), and 36 auto‐SCT. Non‐relapse mortality was 16% for allo‐SCT patients. Outcome after relapse was poor with median time to death 163 d and 4‐yr survival rate 17%. Three conclusions were: (i) these data reflect treatment results in a minimally selected population‐based cohort of adult AML patients <60 yr old; (ii) a risk‐adapted therapy aiming at early allogeneic SCT in patients with a high risk of relapse is hampered by induction deaths, refractory disease, and early relapses; and (iii) high WBC count at diagnosis is confirmed as a strong risk factor for early death but not for relapse.     

Allogeneic transplantation is not superior to chemotherapy in most patients over 40 years of age with Philadelphia‐negative acute lymphoblastic leukemia in first remission

Survival of patients ≥40 years of age with Philadelphia‐negative acute lymphoblastic leukemia (ALL) remains poor with current therapeutic approaches. It is unknown whether allogeneic hematopoietic stem‐cell transplantation (HSCT) in first remission confers a survival benefit compared to a chemotherapy‐only approach. We retrospectively compared the outcome of patients >40 years treated with HSCT or chemotherapy alone in first remission (n = 40 in each cohort). Three‐year overall survival (OS) and disease‐free survival (DFS) were not significantly different between the chemotherapy‐only and HSCT groups (OS, 46% [31–68] vs. 40% [27–59], P = 0.35; DFS, 31% [18–52] vs. 40% [27–59], P = 0.98). The 3‐year cumulative incidence of relapse (CIR) and non‐relapse mortality (NRM) were 61% [41–76] and 9% [2–21] for the chemotherapy‐only group and 28% [15–43] and 32% [17–47] for the transplant group (CIR, P = 0.011; NRM, P = 0.014). Allogeneic transplantation for patients ≥40 years with Ph‐negative ALL in first remission is associated with a lower CIR, but this benefit is offset by considerable NRM as compared with chemotherapy‐only approach. HSCT may be beneficial in patients with high‐risk disease features. Am. J. Hematol. 91:793–799, 2016. © 2016 Wiley Periodicals, Inc.     

Relatively favorable outcome after allogeneic stem cell transplantation for BCR‐ABL1‐positive AML: A survey from the acute leukemia working party of the European Society for blood and marrow transplantation (EBMT)

The aim of the study was to assess the role of allogeneic stem cell transplantation (SCT) in patients diagnosed with BCR‐ABL1‐positive acute myeloid leukemia (AML). Fifty‐seven patients (median age, 48 years, range: 19‐67) with BCR‐ABL1 positive AML undergoing SCT were identified. The majority of the patients (70%) received a TKI before the transplant. At SCT 48 patients were in CR (45 in CR1), while 9 patients were transplanted in a more advanced stage of the disease. MRD was negative (BCR‐ABL1/ABL < 10⁴) at time of SCT in 36.1% (14/40). After SCT, 16 (61.5%) out of 26 patients with MRD positive at transplantation reached MRD negativity. After a median follow‐up of 6.3 years (0.7–14.2), NRM, RI, LFS, OS, and GRFS at 5 years were 18.1%, 37%, 44.2%, 53.8%, and 32.1%, respectively. The cumulative incidence of acute GvHD grade II‐IV was 16.4%, incidence of chronic GvHD 24.9%, and of extensive cGvHD 21.4%, respectively. In patients who received SCT in CR1, 5‐yr NRM, RI, LFS, OS, and GRFS were 15.9%, 36.4%, 46.5%, 59.4%, and 34.9%, respectively. Univariate analysis showed that age (<50 vs. ≥50 years) was associated with RI (5‐yr: 22.7 vs. 50%), LFS (5‐yr: 61.9 vs. 31.8%), and GRFS (5‐yr: 52.4 vs. 18.2%), whereas MRD‐negative status before SCT was associated with an improved GRFS (38.9 vs. 16.7%). We conclude that the outcome of patients <50 years of age with BCR‐ABL1‐positive AML receiving allogeneic SCT in CR is relatively favorable, possibly reflecting the beneficial effect of the use of TKI.     

Acute myeloid leukemia following solid organ transplantation: entity or novelty?

Due to the rarity of the disease, the characteristics of acute myeloid leukemia following solid organ transplantation (post‐transplant AML; PT‐AML) are unclear; furthermore, it is not known for certain whether PT‐AML is a separate entity or not. We provide a systematic review of all previously reported cases of PT‐AML in the English literature (n = 51). 45% of cases occurred after renal transplantation, and 72% were males. The median age at diagnosis of AML was 50 yr, with a median transplant‐to‐AML interval of 3.8 yr and a rapid decline in incidence after 5 yr. 26% of patients were asymptomatic at the time of presentation, and 42% were pancytopenic. M0/M1/M2, M3, M4/M5, and M6/M7 subtypes comprised 17%, 25%, 39%, and 19% of all cases, respectively. 36% of patients had unfavorable cytogenetic risk disease. The median overall survival was only 3 months. We observed several transplant‐specific features: (i) The transplant‐to‐AML interval follows two very different patterns between renal vs. liver transplant patients. (ii) All 4 cases of donor cell leukemia occurred after liver transplant. (iii) Unfavorable risk disease was marginally significantly more common among renal compared with liver transplant patients (P = 0.057). Our results suggest that PT‐AML is a separate entity with distinct characteristics, which need to be investigated further in future research. Heavy post‐transplant immunosuppression likely plays a key role in the pathogenesis of PT‐AML.     

Transformed non‐Hodgkin lymphoma in the rituximab era: analysis of the NCCN outcomes database

Histological transformation (HT) is a major cause of morbidity and mortality in patients with indolent non‐Hodgkin lymphoma (NHL). The multicentre National Cancer Comprehensive Network database for NHL provides a unique opportunity to investigate the natural history of HT in the rituximab era. 118 patients with biopsy‐confirmed indolent lymphoma and subsequent biopsy‐confirmed HT were identified. Treatments for HT included autologous stem‐cell transplant (auto‐SCT) (n = 50), allogeneic SCT (allo‐SCT) (n = 18), and treatment without transplant (n = 50). The 2‐year overall survival (OS) for the entire cohort was 68%. For auto‐SCT patients aged ≤60 years (n = 24), the 2‐year OS was 74%. For non‐transplanted patients aged ≤60 years (n = 19), the 2‐year OS was 59%. The 2‐year OS of patients naïve to chemotherapy prior to HT was superior to patients who were exposed to chemotherapy prior to HT (100% vs. 35%, P = 0·03). In this largest prospective cohort of patients of strictly defined HT in the rituximab era, the natural history of HT appears more favourable than historical studies. Younger patients who were not exposed to chemotherapy prior to HT experienced a prolonged survival even without transplantation. This study serves as a benchmark for future trials of novel approaches for HT in the Rituximab era.     

Reassessment of clinical implication of pretransplant surgical procedures for pulmonary invasive fungal lesions

Dealing with the recent series of allogeneic hematopoietic stem cell transplantation (allo‐SCT) performed this decade, we reassessed the clinical impact of pretransplant surgical procedures (SP) for pulmonary lesions of invasive fungal disease (IFD) on subsequent transplant outcome. We focused on the clinical outcomes of seven patients with pulmonary IFD who underwent segmentectomy (n = 4), lobectomy (n = 2) or abscess incision with drainage only (n = 1), and compared results to those of 21 patients carrying pulmonary IFD who never underwent invasive SP before allo‐SCT. The rate of exacerbation of pulmonary lesions by 180 days after allo‐SCT did not differ significantly between groups (32.2% vs 42.9%, P = 0.69). Moreover, no significant differences in non‐relapse mortality (46.4% vs 42.3%, P = 0.93) or overall survival (53.6% vs 30.9%, P = 0.45) at 1 year were evident between groups. These results indicate that pretransplant SP for pulmonary lesions might have no survival benefit under the current antifungal prophylaxis or treatment modality.     

Treatment of young patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia using increased dose of imatinib and deintensified chemotherapy before allogeneic stem cell transplantation

The main outcomes of the Programa Español para Tratamiento de Hemopatías (PETHEMA)‐acute lymphoblastic leukaemia (ALL)‐Ph‐08 trial were described and compared with those of the historical PETHEMA‐CSTIBES02 trial. The trials differed in imatinib dose (600 vs. 400 mg/d) and amount of chemotherapy (one vs. two consolidation cycles) before stem cell transplantation (SCT). All patients (n = 29) enrolled in the ALL‐Ph‐08 trial achieved complete remission (CR) (vs. 90% in CSTIBES02), and SCT was performed in CR in 90% (vs. 78%). The reduction in early death, relapse before SCT and transplant‐related mortality observed in the ALL‐Ph‐08 trial resulted in an improved 2‐year event‐free survival (63% vs. 37%, P = 0·009).     

Inhibitory killer cell immunoglobulin‐like receptor (iKIR) mismatches improve survival after T‐cell‐repleted haploidentical transplantation

Alloreactivity triggered by interaction between killer cell immunoglobulin‐like receptors (KIRs) and natural killer (NK) cells plays a role in the graft‐versus‐tumor effect after hematopoietic stem cell transplantation (SCT). Our aim in this study was to evaluate this role in the setting of T‐cell‐repleted haploidentical SCT with postinfusion high‐dose cyclophosphamide (PT‐Cy). We included 33 patients. Among patient–donor pairs with at least 1 inhibitory KIR (iKIR) gene mismatch, event‐free survival (EFS) and cumulative incidence of relapse 1 year after transplant were significantly better (85% vs. 37% [P = 0.008] and 18% vs. 46% [P = 0.041], respectively). A subanalysis in 12 patients with Hodgkin's lymphoma (HL) showed an improvement in EFS 1 year after transplant in those patients with KIR ligand mismatch (100% vs. 25%, P = 0.012), although overall survival (OS) was not affected (85% vs. 80%, P = 0.2). Eight of 12 patient–donors pairs presented iKIR mismatches. Of note, this outcome was better in the small subgroup, both for EFS (100% vs. 25%, P = 0.012) and for OS (100% vs. 37%, P = 0.004). Our data suggest that in the setting of T‐cell‐repleted haploidentical SCT with PT‐Cy, iKIR mismatch is associated with improved survival, with particularly good results for both iKIR and KIR ligand mismatches in patients with HL.     

Treatment of children with acute myeloid leukaemia who relapsed after allogeneic haematopoietic stem cell transplantation

Despite improvements in diagnosis and treatment, 30–40% of children with acute myeloid leukaemia (AML) experience relapse. For those who relapse after allogeneic haematopoietic stem cell transplantation (allo‐HSCT), the prognosis is particularly poor, with limited reported literature on these patients. We reviewed the clinical course of 49 children with AML (28 males, 21 females) who received allo‐HSCT between 1993 and 2011, and who had subsequently relapsed. Study endpoints included (i) complete remission (CR) rate after intensive chemotherapy, and prognostic factors for CR, (ii) disease‐free survival (DFS) and overall survival (OS) for patients who achieved CR and (iii) OS for recipients of intensive chemotherapy and prognostic factors for OS . Of the 36 patients who received intensive chemotherapy after post‐HSCT relapse, 26 (72%) achieved CR. For patients who achieved CR, 5‐year DFS and OS were 32·6 ± 10·2% and 44·4 ± 11·1%, respectively. For all recipients of intensive chemotherapy, 5‐year OS was 31·6 ± 8·7%. Cumulative incidence of treatment‐related death was 14·4%. All three recipients of second HSCT died. Amongst prognostic factors predicting improved survival, only disease status at HSCT (early first CR vs. others) proved significant in multivariate study (Hazard Ratio 2·42, 95% Confidence Interval 1·02–5·74, P = 0·045). Treatment with curative intent was able to salvage a minor but important subset of children with AML who relapsed post‐allogeneic transplant.     

Outcome of relapse after allogeneic HSCT in children with ALL enrolled in the ALL‐SCT 2003/2007 trial

Relapse remains the major cause of treatment failure in children with high‐risk acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem‐cell transplantation (allo‐SCT). Prognosis is considered dismal but data on risk factors and outcome are lacking from prospective studies. We analysed 242 children with recurrence of ALL after first allo‐SCT enrolled in the Berlin‐Frankfurt‐Munster (BFM) ALL‐SCT‐BFM 2003 and ALL‐SCT‐BFM international 2007 studies. Median time from allo‐SCT to relapse was 7·7 months; median follow‐up from relapse after allo‐SCT until last follow‐up was 3·4 years. The 3‐year event‐free survival (EFS) was 15% and overall survival (OS) was 20%. The main cause of death was disease progression or relapse (86·5%). The majority of children (48%) received salvage therapy without second allo‐SCT, 26% of the children underwent a second allo‐SCT and 25% received palliative treatment only. In multivariate analyses, age, site of relapse, time to relapse and type of salvage therapy were identified as significant prognostic factors for OS and EFS, whereas factors associated with first SCT were not statistically significant. Combined approaches incorporating novel immunotherapeutic treatment options and second allo‐SCT hold promise to improve outcome in children with post allo‐SCT relapse.