Sarah A. Buckley

Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission

Minimal residual disease (MRD) before myeloablative hematopoietic cell transplantation (HCT) is associated with adverse outcome in acute myeloid leukemia (AML) in first complete remission (CR1). To compare this association with that for patients in second complete remission (CR2) and to examine the quantitative impact of MRD, we studied 253 consecutive patients receiving myeloablative HCT for AML in CR1 (n = 183) or CR2 (n = 70) who had pre-HCT marrow aspirates analyzed by 10-color flow cytometry. Three-year estimates of overall survival were 73% (64%-79%) and 32% (17%-48%) for MRDneg and MRDpos CR1 patients, respectively, and 73% (57%-83%) and 44% (21%-65%) for MRDneg and MRDpos CR2 patients, respectively. Similar estimates of relapse were 21% (14%-28%) and 58% (41%-72%) for MRDneg and MRDpos CR1 patients, respectively, and 19% (9%-31%) and 68% (41%-85%) for MRDneg and MRDpos CR2 patients, respectively. Among the MRDpos patients, there was no statistically significant evidence that increasing levels of MRD were associated with increasing risks of relapse and death. After multivariable adjustment, risks of death and relapse were 2.61 times and 4.90 times higher for MRD(pos) patients (P < .001). Together, our findings indicate that the negative impact of pre-HCT MRD is similar for AML in CR1 and CR2 with even minute levels (≤ 0.1%) as being associated with adverse outcome.

Comparison of minimal residual disease as outcome predictor for AML patients in first complete remission undergoing myeloablative or nonmyeloablative allogeneic hematopoietic cell transplantation.

Minimal residual disease (MRD) is associated with adverse outcome in acute myeloid leukemia (AML) after myeloablative (MA) hematopoietic cell transplantation (HCT). We compared this association with that seen after nonmyeloablative (NMA) conditioning in 241 adults receiving NMA (n=86) or MA (n=155) HCT for AML in first remission with pre-HCT bone marrow aspirates assessed by flow cytometry. NMA patients were older and had more comorbidities and secondary leukemias. Three-year relapse estimates were 28% and 57% for MRDneg and MRDpos NMA patients, and 22% and 63% for MA patients. Three-year overall survival (OS) estimates were 48% and 41% for MRDneg and MRDpos NMA patients and 76% and 25% for MA patients. This similar OS after NMA conditioning was largely accounted for by higher non-relapse mortality (NRM) in MRDneg (30%) compared with MRDpos (10%) patients, whereas the reverse was found for MRDneg (7%) and MRDpos (23%) MA patients. A statistically significant difference between MA and NMA patients in the association of MRD with OS (P<0.001) and NRM (P=0.002) but not relapse (P=0.17) was confirmed. After adjustment, the risk of relapse was 4.51 times (P<0.001) higher for MRDpos patients. These data indicate that the negative impact of MRD on relapse risk is similar after NMA and MA conditioning.

Height as an Explanatory Factor for Sex Differences in Human Cancer

BACKGROUND Most cancers occur more frequently in men. Numerous explanations for this excess risk have been proposed, yet no study has quantified the degree to which height explains the sex difference even though greater height has been associated with increased risk for many cancers. METHODS During the period from 2000 to 2002, 65308 volunteers aged 50 to 76 years were recruited to the Vitamins And Lifestyle (VITAL) study. Cancers of shared anatomic sites (n = 3466) were prospectively identified through 2009 through the Surveillance, Epidemiology, and End Results cancer registry. Age- and race-adjusted hazard ratios (HRs) for the associations between sex and incident cancers were estimated using Cox proportional hazards models, with and without adjustment for height and height squared as measures of body size. RESULTS Men had a 55% increased risk of cancer at shared sites (HR = 1.55; 95% confidence interval [CI] = 1.45 to 1.66). When height was accounted for, 33.8% (95% CI = 10.2% to 57.3%) of the excess risk for men was explained by the height differences between sexes. The proportion mediated by height was 90.9%, 57.3%, and 49.6% for kidney, melanoma, and hematologic malignancies, respectively, with little evidence that height mediates the sex difference for gastrointestinal tract, lung, and bladder cancers. For comparison, more than 35 lifestyle and medical risk factors only explained 23.1% of the sex difference in cancer risk at shared sites. CONCLUSIONS Height is an important explanatory factor for the excess risk for men for many shared-site cancers. This suggests that some of the excess risk is due to factors associated with height (eg, number of susceptible cells in a specific organ or growth-influencing exposures in childhood).

Minimal residual disease prior to allogeneic hematopoietic cell transplantation in acute myeloid leukemia: a meta-analysis

Minimal residual disease prior to allogeneic hematopoietic cell transplantation has been associated with increased risk of relapse and death in patients with acute myeloid leukemia, but detection methodologies and results vary widely. We performed a systematic review and meta-analysis evaluating the prognostic role of minimal residual disease detected by polymerase chain reaction or multiparametric flow cytometry before transplant. We identified 19 articles published between January 2005 and June 2016 and extracted hazard ratios for leukemia-free survival, overall survival, and cumulative incidences of relapse and non-relapse mortality. Pre-transplant minimal residual disease was associated with worse leukemia-free survival (hazard ratio=2.76 [1.90–4.00]), overall survival (hazard ratio=2.36 [1.73–3.22]), and cumulative incidence of relapse (hazard ratio=3.65 [2.53–5.27]), but not non-relapse mortality (hazard ratio=1.12 [0.81–1.55]). These associations held regardless of detection method, conditioning intensity, and patient age. Adverse cytogenetics was not an independent risk factor for death or relapse. There was more heterogeneity among studies using flow cytometry-based than WT1 polymerase chain reaction-based detection (I2=75.1% vs. <0.1% for leukemia-free survival, 67.8% vs. <0.1% for overall survival, and 22.1% vs. <0.1% for cumulative incidence of relapse). These results demonstrate a strong relationship between pre-transplant minimal residual disease and post-transplant relapse and survival. Outcome heterogeneity among studies using flow-based methods may underscore site-specific methodological differences or differences in test performance and interpretation.

Rapid rate of peripheral blood blast clearance accurately predicts complete remission in acute myeloid leukemia.

Rapid rate of peripheral blood blast clearance accurately predicts complete remission in acute myeloid leukemia

Number of Courses of Induction Therapy Independently Predicts Outcome after Allogeneic Transplantation for Acute Myeloid Leukemia in First Morphological Remission

Whether the number of chemotherapy cycles required to obtain a first morphological remission affects prognosis of patients with acute myeloid leukemia (AML) remains controversial. To clarify how achievement of early remission might influence outcome of allogeneic hematopoietic cell transplantation (HCT), we studied 220 consecutive adults with AML in first morphological remission who underwent transplantation after myeloablative or nonmyeloablative conditioning to investigate how the number of standard- or high-dose induction courses required to achieve remission impacted post-HCT outcome. Three-year estimates of overall survival were 65% (95% confidence interval [CI] 56% to 73%), 56% (95% CI, 43% to 67%), and 23% (95% CI, 6% to 46%) for patients requiring 1 course, 2 courses, or >2 courses of induction therapy; corresponding relapse estimates were 24% (95% CI, 17% to 31%), 43% (95% CI, 31% to 55%), and 58% (95% CI, 30% to 78%), respectively. After covariate adjustment (minimal residual disease status, conditioning, age, cytogenetic disease risk, type of consolidation chemotherapy, pre-HCT karyotype, and pre-HCT peripheral blood count recovery), the hazard ratios for 2 or >2 induction courses versus 1 induction were 1.16 (95% CI, .73 to 1.85, P = .53) and 2.63 (95% CI, 1.24 to 5.57, P = .011) for overall mortality, and 2.10 (95% CI, 1.27 to 3.48, P = .004) and 3.32 (95% CI, 1.42 to 7.78, P = .006), respectively, for relapse. These findings indicate that the number of induction courses required to achieve morphological remission in AML adds prognostic information for post-HCT outcome that is independent of other prognostic factors.

Prediction of adverse events during intensive induction chemotherapy for acute myeloid leukemia or high‐grade myelodysplastic syndromes

Intensive chemotherapy for newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) is associated with significant treatment‐related morbidity and mortality. Herein, we investigate how pretreatment characteristics relate to early adverse outcomes in such patients, studying 205 consecutive individuals receiving curative‐intent induction chemotherapy with cytarabine and an anthracycline (“7 + 3”; n = 175) or a “7 + 3”‐like regimen (n = 30). Among the entire cohort, baseline grade 4 neutropenia (i.e., absolute neutrophil count <500 cells/µL) was associated with development of fever (P = 0.04), documented infection (P < 0.0001), and bacteremia (P = 0.002) but not requirement for intensive care unit‐level care; after exclusion of the 30 patients who received “7 + 3”‐like induction, baseline grade 4 neutropenia remained associated with documented infection (P < 0.0001) and bacteremia (P = 0.0005). Among patients achieving a complete remission with the initial treatment cycle, grade 4 neutropenia was associated with delayed neutrophil count recovery (P < 0.0001). Low monocyte and lymphocyte counts at baseline were similarly associated with increased risk of documented infection or bacteremia. After adjustment for age, gender, disease type, cytogenetic/molecular risk, and performance status, the risk of fever, documented infection, or bacteremia was 1.87 (95% confidence interval: 1.04–3.34; P=0.04)‐fold, 4.95 (2.20–11.16; P<0.001)‐fold, and 3.14 (0.99–9.98; P=0.05)‐fold higher in patients with initial grade 4 neutropenia. Together, our studies identify severe baseline neutropenia as a risk factor for infection‐associated adverse events after induction chemotherapy and may provide the rationale for the risk‐adapted testing of myeloid growth factor support in this high‐risk AML/MDS patient subset. Am. J. Hematol. 89:423–428, 2014.

Brief ArticleNumber of Courses of Induction Therapy Independently Predicts Outcome after Allogeneic Transplantation for Acute Myeloid Leukemia in First Morphological Remission

Whether the number of chemotherapy cycles required to obtain a first morphological remission affects prognosis of patients with acute myeloid leukemia (AML) remains controversial. To clarify how achievement of early remission might influence outcome of allogeneic hematopoietic cell transplantation (HCT), we studied 220 consecutive adults with AML in first morphological remission who underwent transplantation after myeloablative or nonmyeloablative conditioning to investigate how the number of standard- or high-dose induction courses required to achieve remission impacted post-HCT outcome. Three-year estimates of overall survival were 65% (95% confidence interval [CI] 56% to 73%), 56% (95% CI, 43% to 67%), and 23% (95% CI, 6% to 46%) for patients requiring 1 course, 2 courses, or >2 courses of induction therapy; corresponding relapse estimates were 24% (95% CI, 17% to 31%), 43% (95% CI, 31% to 55%), and 58% (95% CI, 30% to 78%), respectively. After covariate adjustment (minimal residual disease status, conditioning, age, cytogenetic disease risk, type of consolidation chemotherapy, pre-HCT karyotype, and pre-HCT peripheral blood count recovery), the hazard ratios for 2 or >2 induction courses versus 1 induction were 1.16 (95% CI, .73 to 1.85, P = .53) and 2.63 (95% CI, 1.24 to 5.57, P = .011) for overall mortality, and 2.10 (95% CI, 1.27 to 3.48, P = .004) and 3.32 (95% CI, 1.42 to 7.78, P = .006), respectively, for relapse. These findings indicate that the number of induction courses required to achieve morphological remission in AML adds prognostic information for post-HCT outcome that is independent of other prognostic factors.

A phase I/II study of oral clofarabine plus low-dose cytarabine in previously treated acute myeloid leukaemia and high-risk myelodysplastic syndrome patients at least 60 years of age.

Outcomes for older adults with acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) are generally poor, and new effective therapies are needed. We investigated oral clofarabine combined with low‐dose cytarabine (LDAC) in patients aged 60 years and above with relapsed or refractory AML or high‐risk MDS in a phase I/II trial. A 3 + 3 dose escalation of oral clofarabine was followed by a phase II expansion with the aim of obtaining a complete response (CR) rate ≥30%. We identified 20 mg/d for 5 d as the maximum tolerated dose (MTD) of oral clofarabine. A total of 35 patients, with a median age of 72 years, were treated. Of 26 patients enrolled at the MTD, 4 had treatment‐related grade 3–4 non‐haematological toxicities, but none died within 28 d. The observed CR rate and median survival were 34% [95% confidence interval (CI), 18–50%] and 6·8 months overall and 38% [95% CI, 19–57%] and 7·2 months at the MTD. The median disease‐free survival was 7·4 months. Fifty‐two percent (23/44) of cycles administered at the MTD were done without hospital admission. This combination of oral clofarabine and LDAC demonstrated efficacy with a CR rate of >30% and acceptable toxicity in older patients.

Regular recreational physical activity and risk of hematologic malignancies: results from the prospective VITamins And lifestyle (VITAL) study

BACKGROUND Conflicting evidence exists on the relationship between physical activity (PA) and incident hematologic malignancies. Herein, we used a large cohort study to examine this association. PATIENTS AND METHODS Sixty-five thousand three hundred twenty-two volunteers aged 50-76 years were recruited from 2000 to 2002. Incident hematologic malignancies (n = 666) were identified through 2009 by linkage to the Surveillance, Epidemiology, and End Results cancer registry. Hazard ratios (HRs) for hematologic malignancies associated with PA averaged over 10 years before baseline were estimated with Cox proportional hazards models, adjusting for factors associated with hematologic cancers or PA. RESULTS There was a decreased risk of hematologic malignancies associated with PA (HR = 0.66 [95% confidence interval, 95% CI 0.51-0.86] for the highest tertile of all PA, P-trend = 0.005, and HR = 0.60 [95% CI 0.44-0.82] for the highest tertile of moderate/high-intensity PA, P-trend = 0.002). These associations were strongest for myeloid neoplasms (HR = 0.48 [95% CI 0.29-0.79] for the highest tertile of all PA, P-trend = 0.013, and HR = 0.40 [95% CI 0.21-0.77] for the highest tertile of moderate/high-intensity PA, P-trend = 0.016). There were also significant associations between PA and chronic lymphocytic leukemia/small lymphocytic lymphoma or other mature B-cell lymphomas except plasma cell disorders. CONCLUSIONS Our study offers the strongest epidemiological evidence, to date, to suggest an association between regular PA and dose-dependent risk reduction for most hematologic malignancies, particularly myeloid neoplasms.