Impact of early CMV reactivation in cord blood stem cell recipients in the current era.

Several studies have reported an association between CMV reactivation and a decreased incidence of relapse for AML after adult donor allogeneic hematopoietic cell transplantation (HCT). Limited data, however, are available on the impact of CMV reactivation on relapse after cord blood (CB) stem cell transplantation. The unique combination of higher incidence of CMV reactivation in the seropositive recipient and lower incidence of graft versus host disease (GvHD) in CB HCT permits a valuable design to analyze the impact of CMV reactivation. Data from 1684 patients transplanted with CB between 2003 and 2010 for AML and ALL were analyzed. The median time to CMV reactivation was 34 days (range: 2-287). CMV reactivation and positive CMV serology were associated with increased non-relapse mortality (NRM) among both AML and ALL CB recipients (reactivation, AML: relative risk (RR) 1.41 (1.07-1.85); ALL: 1.60 (1.14-2.23); Serology, AML: RR 1.39 (1.05-1.85), ALL: RR 1.61 (1.18-2.19)). For patients with ALL, but not those with AML, this yielded inferior overall survival (P<0.005). Risk of relapse was not influenced by CMV reactivation or positive CMV serostatus for either disease.

The incidence, mortality and timing of Pneumocystis jiroveci pneumonia after hematopoietic cell transplantation: a CIBMTR analysis.

Pneumocystis jiroveci pneumonia (PJP) is associated with high morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Little is known about PJP infections after HSCT because of the rarity of disease given routine prophylaxis. We report the results of a Center for International Blood and Marrow Transplant Research study evaluating the incidence, timing, prophylaxis agents, risk factors and mortality of PJP after autologous (auto) and allogeneic (allo) HSCT. Between 1995 and 2005, 0.63% allo recipients and 0.28% auto recipients of first HSCT developed PJP. Cases occurred as early as 30 days to beyond a year after allo HSCT. A nested case cohort analysis with supplemental data (n=68 allo cases, n=111 allo controls) revealed that risk factors for PJP infection included lymphopenia and mismatch after HSCT. After allo or auto HSCT, overall survival was significantly poorer among cases vs controls (P=0.0004). After controlling for significant variables, the proportional hazards model revealed that PJP cases were 6.87 times more likely to die vs matched controls (P<0.0001). We conclude PJP infection is rare after HSCT but is associated with high mortality. Factors associated with GVHD and with poor immune reconstitution are among the risk factors for PJP and suggest that protracted prophylaxis for PJP in high-risk HSCT recipients may improve outcomes.

Patient age, remission status and HCT-CI in a combined score are prognostic for patients with AML undergoing allogeneic hematopoietic cell transplantation in CR1 and CR2.

For AML, older age, advanced disease and increased hematopoietic cell transplant comorbidity index (HCT-CI) are associated with worse prognosis following allogeneic hematopoietic cell transplantation (HCT). This single-center retrospective study investigated the influence of pre-transplant characteristics on outcomes of 387 patients undergoing allogeneic HCT for AML in CR1 and CR2. The multivariable analysis model for overall survival (OS) included age (hazard ratio (HR)=2.24 for ages 31-64 years and HR=3.23 for age ⩾65 years compared with age ⩽30 years, P=0.003), remission status (HR=1.49 for CR2 compared with CR1, P=0.005) and HCT-CI score (HR=1.47 for ⩾3 compared with <3, P=0.005). Transplant year was significantly associated with OS (P=0.001) but this did not influence the model. A weighted score was developed with age ⩽30, CR1 and HCT-CI score <3 receiving 0 points each, and CR2 and HCT-CI score ⩾3 receiving 1 point each. Ages 31-64 received 2 points, age ⩾65 received 3 points. Scores were grouped as follows: scores 0-1 (low risk, n=36), score 2 (intermediate-low risk, n=147), score 3 (intermediate-high risk, n=141) and scores 4-5 (high risk, n=63) with 3-year OS of 71%, 55%, 42% and 29% for scores 0-1, 2, 3 and 4-5, respectively (P<0.0001). The score predicted nonrelapse mortality (P=0.03) but not cumulative incidence of relapse (P=0.18). This model should be validated for the pre-HCT assessment of AML patients in CR1 and CR2.

Outcomes of patients with therapy-related AML/myelodysplastic syndrome (t-AML/MDS) following hematopoietic cell transplantation.

We studied outcomes of 65 consecutive patients with therapy-related AML/myelodyplastic syndrome (t-AML/MDS) who underwent allogeneic hematopoietic cell transplantation (HCT). Previously published scores of HCT-CI, CIBMTR, EBMT and Comorbidity-age index were also evaluated. Median follow-up of survivors was 72 months (range 16-204). At 2 years, overall survival (OS) was 34% (95% confidence interval (CI) 23-45). Nineteen patients (29%) had monosomal karyotype (MK). Patients with MK had an OS of 21% (95% CI 7-41) at 2 years. Abnormal adverse cytogenetics, unrelated donor, bone marrow graft and CIBMTR score were significant risk factors for OS on univariate analysis. On multivariate analysis, abnormal adverse cytogenetics (hazard ratio (HR) 2.7; 95% CI 1.02-7.2; P-value=0.02) and unrelated donor (HR 2.7; 95% CI 1.5-5.0; P-value=0.0013) were independent factors for survival. Non-relapse mortality (NRM) at 2 years was 31% (95% CI 15-47). Donor type was the only factor that was significant for NRM with matched related donors having an NRM of 20% (95% CI 0-42) whereas unrelated donors had NRM of 60% (95% CI 40-80; P-value=0.0007). In conclusion, patients with t-AML/MDS have poor OS. Unrelated donor is a significant risk factor for both higher NRM and decreased OS. Cytogenetics are predictive for OS.

Risk model incorporating donor IL6 and IFNG genotype and gastrointestinal GVHD can discriminate patients at high risk of steroid refractory acute GVHD.

Steroid refractory acute GVHD (SR aGVHD) is associated with high morbidity and mortality. This study attempted to generate a risk model for SR aGVHD using 259 single nucleotide polymorphisms (SNPs) in 53 genes of recipients and donors. A total of 268 patients with aGVHD who were treated with systemic steroids were included. Patients were randomly divided into training (n=180) and validation sets (n=88). Clinical risk factors were also evaluated. In the training set, 85 (47.2%) developed SR aGVHD. Gastrointestinal involvement (P<0.0001) and donor genotypes of IL6 (rs1800797; P=6.2 × 10(-4)) and IFNG (rs2069727; P=4.4 × 10(-4)) were significant risk factors. Scores were assigned to the above risk factors. Patients were divided into low (score 0, n=74) vs high risk (scores 1-3; n=106) in risk model. Higher incidence of SR aGVHD was noted in the high risk (61.3%) vs the low-risk group (27%; P<0.0001, odds ratio (OR) 4.28). Predictive effect of risk model was replicated in the validation set (P=0.0045, OR 3.74). This risk model was associated with response to therapy, overall and GVHD-specific survival and non-relapse mortality. Our study suggested that this risk model could identify patients at high risk of SR aGVHD with donor genotype of IL6 (rs1800797) and IFNG (rs2069727) along with gastrointestinal involvement of aGVHD.

Comparable outcomes post allogeneic hematopoietic cell transplant for patients with de novo or secondary acute myeloid leukemia in first remission.

Secondary AML (sAML) has a poor prognosis with conventional chemotherapy alone. Allogeneic hematopoietic cell transplantation (HCT) is beneficial for high-risk AML. Data comparing outcomes of transplants for patients with de novo and sAML are limited. We compared outcomes of patients transplanted for de novo and sAML in first complete remission and investigated the effect of age, HCT comorbidity index (HCT-CI) and karyotype in both groups. A total of 264 patients with de novo (n=180) and sAML (n=84) underwent allogeneic HCT between 1999 and 2013. Median age at transplant was 51 years (range 18-71), median follow-up of survivors was 77 months. Evaluation of all patients demonstrated no significant difference between de novo and sAML for overall survival (P=0.18), leukemia-free survival (P=0.17), cumulative incidence of relapse (P=0.51) and non-relapse mortality (P=0.42). Multivariable and propensity score analyses confirmed the comparable outcomes between de novo and sAML post transplant. Although sAML demonstrates outcomes inferior to de novo AML treated with chemotherapy alone, outcomes following allogeneic HCT are comparable between the two groups.

Long-term outcome of a pediatric-inspired regimen used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia.

On the basis of the data suggesting that adolescents and young adult patients with acute lymphoblastic leukemia (ALL) have improved outcomes when treated on pediatric protocols, we assessed the feasibility of treating adult patients aged 18-50 years with ALL with the DFCI Pediatric ALL Consortium regimen utilizing a 30-week course of pharmacokinetically dose-adjusted E. coli L-asparaginase during consolidation. Between 2002 and 2008, 92 eligible patients aged 18-50 years were enrolled at 13 participating centers. Seventy-eight patients (85%) achieved a complete remission (CR) after 1 month of intensive induction therapy. With a median follow-up of 4.5 years, the 4-year disease-free survival (DFS) for the patients achieving a CR was 69% (95% confidence interval (CI) 56-78%) and the 4-year overall survival (OS) for all eligible patients was 67% (95% CI 56-76%). The 4-year DFS for the 64 patients who achieved a CR and were Philadelphia chromosome negative (Ph-) was 71% (95% CI 58-81%), and for all 74 Ph- patients the 4-year OS was 70% (95% CI 58-79%). We conclude that a pediatric-like treatment strategy for young adults with de novo ALL is feasible, associated with tolerable toxicity, and results in improved outcomes compared with historical regimens in young adult patients with ALL.

A Canadian consensus on the management of newly diagnosed and relapsed acute promyelocytic leukemia in adults.

The use of all-trans-retinoic acid (atra) and anthracyclines (with or without cytarabine) in the treatment of acute promyelocytic leukemia (apl) has dramatically changed the management and outcome of the disease over the past few decades. The addition of arsenic trioxide (ato) in the relapsed setting-and, more recently, in reduced-chemotherapy or chemotherapy-free approaches in the first-line setting-continues to improve treatment outcomes by reducing some of the toxicities associated with anthracycline-based approaches. Despite those successes, a high rate of early death from complications of coagulopathy remains the primary cause of treatment failure before treatment begins. In addition to that pressing issue, clarity is needed about the use of ato in the first-line setting and the role of hematopoietic stem-cell transplantation (hsct) in the relapsed setting. The aim for the present consensus was to provide guidance to health care professionals about strategies to reduce the early death rate, information on the indications for hsct and on the use of ato in induction and consolidation in low-to-intermediate-risk and high-risk apl patients.

The risk of polyomavirus BK-associated hemorrhagic cystitis after allogeneic hematopoietic SCT is associated with myeloablative conditioning, CMV viremia and severe acute GVHD.

Hemorrhagic cystitis (HC) is a common complication after allogeneic hematopoietic SCT (allo-HSCT). Several risk factors have been suggested including BU-containing myeloablative conditioning, unrelated donors and GVHD, but these have not been consistently reported. We conducted a retrospective study including 339 allo-HSCT recipients between 2009 and 2012. Of 339 patients, 79 (23.3%) developed HC with 2-year cumulative incidence of 24.0% (95% confidence interval, 19.4-28.9). The median onset time was 45 days (range, 16-430) after allo-HSCT. Sixty-two patients (84%) out of 74 evaluated for urine BK virus PCR testing showed a positive result (mean 2.0 × 10(10) copies of DNA per mL). In univariate analysis, myeloablative conditioning, HLA-mismatched donor, CMV viremia and acute GVHD (aGVHD) grade 3-4 were significantly associated with the risk of HC. Multivariate analysis confirmed all associating factors identified in univariate analysis except for HLA-mismatched donor: myeloablative conditioning (hazard ratio (HR) 2.63, P=0.003), CMV viremia (HR 1.88, P=0.014) and aGVHD grade 3-4 (HR 1.71, P=0.029). HC did not affect OS or non-relapse mortality. Symptomatic HC is a frequent complication following allo-HSCT, with a 2-year cumulative incidence of 24.0%. Three clinical factors associated with HC were identified including myeloablative conditioning, CMV viremia and severe aGVHD.

Allogeneic hematopoietic cell transplantation for myelofibrosis using fludarabine-, intravenous busulfan- and low-dose TBI-based conditioning.

Graft failure is one of the major barriers to the success of allogeneic hematopoietic cell transplantation (HCT) in myelofibrosis (MF). We report our institutional experience with 27 MF patients who underwent HCT using fludarabine-, intravenous BU- and low-dose total body irradiation (FBT)-based reduced-intensity (n=20) or full-intensity (n=7) conditioning regimens. Eight patients had prior exposure to JAK1/2 inhibitor therapy; six patients received JAK1/2 inhibitors leading on to HCT and two patients received transplant at the failure of JAK1/2 inhibitor therapy. No adverse impact of JAK1/2 inhibitor therapy was observed on early post-transplant outcomes. All evaluable patients had neutrophil recovery, and no primary graft failure was observed. Cumulative incidence of grades II-IV acute GVHD at day 100 was 48% (95% confidence interval (CI), 29-67%) and chronic GVHD at 2 years was 66% (95% CI, 49-84%). Cumulative incidences of nonrelapse mortality (NRM), relapse and probability of OS at 2 years were: 43% (95% CI, 12-74%), 10% (95% CI, 0-39%) and 56% (95% CI, 28-77%), respectively. FBT-based conditioning regimen has a favorable impact on engraftment; however, further efforts are required to reduce NRM.

The role of hematopoietic cell transplantation in adult ALL: clinical equipoise persists.

Adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) may be treated either with ongoing systemic chemotherapy or with allogeneic hematopoietic cell transplantation (alloHCT). Despite the presence of phase III trials to support clinical decision-making, we hypothesized that physicians who treat adult ALL would demonstrate wide practice variation. Canadian hematologists who treat ALL were surveyed electronically. Overall, 69 of 173 physicians responded (40%). There was high agreement with offering alloHCT for ALL with high-risk cytogenetics or induction failure after a single chemotherapy cycle. However, only a minority of respondents felt that age >35 years was an indication for alloHCT in CR1. Almost all respondents (96%) felt that a well-matched unrelated donor was an acceptable alternative to a sibling donor. There was uncertainty about the role of cord blood (53% agree) and the utility of reduced intensity conditioning HCT (41% agree). In contrast to the results of the MRC/ECOG study, respondents considered alloHCT to be particularly helpful in high-risk patients. Consensus was lacking on the use of cord blood, RIC alloHCT, and the application of MRD. Equipoise exists on the role of alloHCT in CR1 in ALL, suggesting that further trials in this area are required.

Increased risk of second malignancies in chronic lymphocytic leukaemia patients as compared with follicular lymphoma patients: a Canadian population-based study.

BACKGROUND: Chronic lymphocytic leukaemia (CLL) patients have an increased risk of other malignancies. This may be due to surveillance bias, treatment or immunosuppression. METHODS: Cohort study of 612 consecutively diagnosed CLL patients in a Canadian province, with comparisons to follicular lymphoma (FL) patients. RESULTS: Treated CLL patients had a 1.7-fold increased risk of second cancers compared with untreated CLL patients. As compared with untreated FL patients, untreated CLL patients had a two-fold increased incidence of second malignancies. CONCLUSION: Chronic lymphocytic leukaemia patients have an inherent predisposition to second cancers and the incidence is further increased by treatment.

Monomorphic ventricular tachycardia caused by arsenic trioxide therapy for acute promyelocytic leukaemia.

Arsenic trioxide has become the treatment of choice for patients with acute promyelocytic leukaemia. Cardiovascular toxicity is known to occur with this therapy, in particular heart rhythm disorders due to QT interval prolongation. We present a case of ventricular arrhythmia with no QT prolongation in a patient receiving arsenic trioxide therapy.

The role of allogeneic stem cell transplantation for adult acute lymphoblastic leukemia.

Acute lymphoblastic leukemia remains a challenging disease in adults. With modern multi-drug induction chemotherapy regimens, complete remission can be achieved in most patients. However, without additional therapy at the time of the first remission, most patients will eventually relapse. Regardless of the treatment option chosen at the time of relapse, outcomes after relapse are poor, with only around 10% of all patients surviving after relapse. Thus, decision-making at the time of achieving the first complete remission is critical. Allogeneic stem cell transplantation is highly effective at preventing relapse, but with significant treatment related toxicity. Ongoing chemotherapy in the form of consolidation and maintenance may be less effective at preventing relapse, but with lower toxicities. Thus, the superiority of allogeneic stem cell transplantation must be balanced against the lower toxicity of consolidation chemotherapy. This decision is further complicated by rapid changes in the field of hematopoietic stem cell transplantation, such as the use of reduced intensity conditioning regimens and alternative stem cell sources such as cord blood transplants. The available evidence suggests that allogeneic transplantation is a viable treatment option for patients in first complete remission, with overall survival superior to traditional consolidation and maintenance chemotherapy. However, whether transplantation based post-remission therapy is superior to modern, pediatric-based non-transplant chemotherapy regimens remains unclear.

Long-term follow-up of patients undergoing auto-SCT for advanced germ cell tumour: a multicentre cohort study.

Failure of cisplatin-based chemotherapy in advanced germ cell tumour (GCT) is associated with a poor outcome. High-dose chemotherapy and auto-SCT is one therapeutic option, although the long-term outcome after this procedure is unclear. We conducted a multicentre cohort study of consecutive patients undergoing a single auto-SCT for GCT between January 1986 and December 2004. Of 71 subjects, median follow-up is 10.1 years. OS at 5 years is 44.7% (95% confidence interval (CI) 32.9-56.5%) and EFS is 43.5% (95% CI 31.4-55.1%). There were seven (10%) treatment-related deaths within 100 days of auto-SCT. Three (4.2%) patients developed secondary malignancies. Of 33 relapses, 31 occurred within 2 years of auto-SCT. Two very late relapses were noted 13 and 11 years after auto-SCT. In multivariate analysis, favourable outcome was associated with IGCCC (International Germ Cell Consensus Classification) good prognosis disease at diagnosis, primary gonadal disease and response to salvage chemotherapy. We conclude that auto-SCT results in successful outcome for a relatively large subgroup of patients with high-risk GCT. Late relapses may occur, a finding not previously reported.

Does location matter? Rural vs urban outcomes after blood and marrow transplantation in a population-based Canadian cohort.

Specialized health services, such as blood and marrow transplantation (BMT), are usually based in large urban centers. Previous research has suggested that rural patients undergoing BMT have a higher risk of death. We performed a cohort study using data from both the Manitoba BMT Program and the provincial Cancer Registry to determine whether patients from the rural areas would have inferior survival after BMT and whether rural patients have reduced access to BMT. A total of 463 adult Manitobans, who underwent BMT between January 1990 and December 2006, were assessed. We analyzed area of residence (rural vs urban), disease and BMT characteristics, and calculated the OS. Patients undergoing autologous and allogeneic transplants were analyzed separately. When adjusted for gender, age at BMT and year of BMT, area of residence was not a significant predictor of mortality. A relative survival analysis was also conducted, and area of residence was again not a significant predictor of mortality. To measure access to BMT in urban vs rural patients, we evaluated all patients with newly diagnosed Hodgkin's Lymphoma (HL) during this same period. Of 432 Manitobans diagnosed with HL, 182 (42%) were rural and 250 (58%) were urban. In contrast, 69% of patients undergoing transplant for HL were urban. In conclusion, using population-based data from a Canadian province, we were unable to show a survival disadvantage for rural patients after controlling for other variables. BMT utilization in rural populations deserves further study.

High incidence of chronic lymphocytic leukemia (CLL) diagnosed by immunophenotyping: a population-based Canadian cohort.

Incidence and outcomes of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) are not well established at the population level, especially since the widespread use of immunophenotyping. We studied the epidemiology of CLL in Manitoba (Canada) by combining data from a centralized flow cytometry facility and the provincial cancer registry for the period 1998-2003. Of 616 cases identified, 27% of patients identified by flow cytometry were not on the cancer registry. The age-adjusted incidence of 7.99/100,000 is substantially higher than the reported incidence in registry reports. We also noted differences in relative survival based on age and gender.

Performance status, but not the hematopoietic cell transplantation comorbidity index (HCT-CI), predicts mortality at a Canadian transplant center.

The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was developed at a single center to predict outcomes for allogeneic transplant recipients who have comorbidities. The HCT-CI has not been widely validated in unselected transplant recipients. We evaluated whether the HCT-CI and other readily available pre-transplant variables predicted NRM and OS at a Canadian transplant center. Using a prospective cohort design, we analyzed consecutive adult allogeneic HCT recipients. Of 187 patients, HCT-CI risk was low in 22 (12%), intermediate in 50 (27%), high in 104 (55%) and undetermined in 11 (6%). Two-year OS was 45% (95% CI: 24-64%), 55% (95% CI: 40-68%) and 42% (95% CI: 32-51%) in the low, intermediate and high-risk HCT-CI groups, respectively. Two-year NRM was 36% (95% CI: 17-56%), 26% (95% CI: 15-39%) and 30% (95% CI: 22-39%) in the low, intermediate and high-risk HCT-CI groups, respectively. In multivariate analysis, the HCT-CI failed to predict OS or NRM. However, KPS of <90% at HCT was a strong predictor of NRM. In conclusion, the HCT-CI was not associated with NRM or OS. In contrast, KPS was an independent indicator of survival. International multi-center studies are required before the HCT-CI is used in clinical practice.

High rate of discordance between clinical and autopsy diagnoses in blood and marrow transplantation.

We analyzed autopsies performed in a Canadian blood and marrow transplantation (BMT) program. We aimed to assess variables that predict the performance of an autopsy, whether rates of autopsy are changing, and the rate of discordance between clinical and autopsy diagnoses. All deceased adult patients from January 1990 to December 2004 were reviewed. Autopsy rates were compared to a large teaching hospital. Of 476 myeloablative BMT patients, 225 died and 48 (27%) underwent autopsy. Autopsy was more likely in patients dying: <100 days post-BMT, in the intensive care unit, after allografting, and on weekends. Autopsy rates among BMT patients declined during the three time periods (1990-1994, 1995-1999, 2000-2004). The autopsy rate at the teaching hospital showed a similar downward temporal trend. Major and minor disagreements at autopsy were present in 16 (34%) and 14 (30%) of cases, respectively. There was no change in discordance rates over time. Thus, despite advances in diagnostic procedures, high levels of disagreement between clinical and autopsy diagnoses for BMT patients persist as autopsy rates decline. We recommend that the autopsy regains its role as a valuable investigation. This may become especially relevant in an era where patients with medical comorbidities are undergoing reduced-intensity BMT.

Myeloid sarcoma of the uterus presenting as vaginal bleeding.

Extramedullary relapse of acute myeloid leukaemia may occur in sites such as the central nervous system, testes, and skin. Presentations in the female genital tract are uncommon and usually asymptomatic. In contrast, symptomatic uterine myeloid sarcoma is very rare. Treatment of this is generally unsuccessful, but is improved when systemic therapies are used. We study a case of a uterine relapse of acute myeloid leukaemia presenting as vaginal bleeding and successfully managed by local irradiation. The mechanism of preferential infiltration of uterine tissue requires further study.