Kristjan Paulson

Pediatric-inspired therapy compared to allografting for Philadelphia chromosome-negative adult ALL in first complete remission

For adults with Philadelphia chromosome‐negative (Ph−) acute lymphoblastic leukemia (ALL) in first complete remission (CR1), allogeneic hematopoietic cell transplantation (HCT) is an established curative strategy. However, pediatric‐inspired chemotherapy may also offer durable leukemia‐free survival in the absence of HCT. We compared 422 HCT recipients aged 18–50 years with Ph‐ALL in CR1 reported to the CIBMTR with an age‐matched concurrent cohort of 108 Ph− ALL CR1 patients who received a Dana‐Farber Consortium pediatric‐inspired non‐HCT regimen. At 4 years of follow‐up, incidence of relapse after HCT was 24% (95% CI 19–28) versus 23% (95% CI 15–32) for the non‐HCT (chemo) cohort (P=0.97). Treatment‐related mortality (TRM) was higher in the HCT cohort [HCT 37% (95% CI 31–42) versus chemo 6% (95% CI 3–12), P<0.0001]. DFS in the HCT cohort was 40% (95% CI 35–45) versus 71% (95% CI 60–79) for chemo, P<0.0001. Similarly, OS favored chemo [HCT 45% (95% CI 40–50)] versus chemo 73% [(95% CI 63–81), P<0.0001]. In multivariable analysis, the sole factor predictive of shorter OS was the administration of HCT [hazard ratio 3.12 (1.99–4.90), P<0.0001]. For younger adults with Ph− ALL, pediatric‐inspired chemotherapy had lower TRM, no increase in relapse, and superior overall survival compared to HCT. Am. J. Hematol. 91:322–329, 2016.

Acute promyelocytic leukaemia is characterized by stable incidence and improved survival that is restricted to patients managed in leukaemia referral centres: a pan-Canadian epidemiological study

Timely diagnosis and care are major determinants of the outcome in acute promyelocytic leukaemia (APL), a malignancy whose incidence may be increasing. The Canadian Cancer Registry (CCR) and health system represent valuable settings to study APL epidemiology. We analysed the CCR, which contains data on all Canadians with APL. To provide clinical information lacking in the CCR, we obtained data from five leukaemia referral centres during a similar time period. Between 1993 and 2007, there were 399 APL in Canada. Age‐standardized incidence was 0·083/100 000 and was stable over time. The early death (ED) rate was 21·8% (10·6% in patients <50 years old and 35·5% for those aged >50 years), with no improvement over time. Five‐year overall survival (OS) was 54·6% (73·3% in patients <50 years; 29·1% older patients). In the referral cohort, 131 patients were diagnosed between 1999 and 2010. ED was 14·6% and 2‐year OS was 76·5%. Within this cohort, ED and OS improved over time, although advanced patient age remained an adverse determinant of OS. In Canada, APL incidence is unexpectedly low and temporally stable. ED was higher than reported in clinical trials, but similar to reports from other registries. In contrast, ED was lower in referral centres and improved with time.

Clinical utility of cardiac magnetic resonance imaging in Churg–Strauss syndrome: case report and review of the literature

We describe a case of an individual with Churg–Strauss syndrome who presented with a cerebrovascular accident (CVA) secondary to left ventricular intracavitary thrombi. Noninvasive cardiovascular imaging using transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) was used to identify the cardioembolic source of CVA. The clinical utility of CMR in the management of patients with Churg–Strauss syndrome is reviewed.

Azacytidine as a novel agent in the treatment of acute lymphoblastic leukemia

5-Azacytidine (AZA) is a hypomethylating agent with well-established activity in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) [1], but not in acute lymphoblastic leukemia (ALL). The transformation of MDS into ALL, while far less common than transformation into AML, is a rare but known complication [2,3]. Although there are relatively few reported cases of MDS transformed into ALL, this transformation seems to portend a very poor prognosis [3]. The optimal therapy for these patients remains undefined. There are several in vitro studies suggesting that epigenetic regulation may be important in the pathogenesis of ALL [4–6]. In addition, preliminary laboratory studies suggest that hypomethylating agents may have a role in the treatment of other hematologic malignancies aside from MDS and AML [7]. A study by Hoshino et al. demonstrated abnormal methylation of the Hck tyrosine kinase gene in 20% of patients with Philadelphia negative ALL, and showed that exposure of abnormally methylated cells to AZA restored normal gene expression patterns [8]. Using microarrays, numerous abnormally methylated genes have been identified, suggesting epigenetic phenomenon may be important in the pathogenesis of ALL [9]. There are no recent reports of AZA for the therapy of ALL. One study published in 1978 looking at the efficacy of AZA in acute leukemias did include some patients with ALL [10], but with a substantially higher dose, different routes of administration, and different dosing schedule. In one case report, the hypomethylating agent decitabine was used successfully in the treatment of a pediatric patient with relapsed B cell ALL [11]. However, there are no reports of the use of AZA published since 1978, and no reports ever published using modern dosing strategies. A 74-year-old woman initially presented in 2005 with moderate thrombocytopenia (836 10/L). An initial bone marrow (BM) aspirate was consistent with MDS (refractory cytopenia with multilineage dysplasia). She did not require chemotherapy or

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 Hodgkins 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.

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.

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.

Routine filtration of hematopoietic stem cell products: the time has arrived

Most blood products are infused at the time of transfusion through a standard blood filter, designed to capture macroaggregates and cellular debris that might be harmful to the patient if infused. Hematopoietic stem cell products are not universally filtered, likely due to concern about loss of viable stem cells in the filtration process.

Fludarabine, busulfan, and low-dose TBI conditioning versus cyclophosphamide and TBI in allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia

Abstract The optimal conditioning regimen for adults undergoing transplantation for acute lymphoblastic leukemia (ALL) remains undetermined. Cyclophosphamide and total body irradiation (Cy/TBI) has emerged as a standard myeloablative regimen but is associated with significant toxicity. We compared outcomes between patients undergoing transplant for ALL at centers using Cy/TBI as standard of care and another center using fludarabine, busulfan, and low-dose TBI (400 cGy) in combination with anti-thymocyte globulin as its standard. Among 146 patients (74 Cy/TBI and 72 Flu/Bu/TBI) there were no significant differences in overall or progression-free survival between groups. Non-relapse mortality was similar (12% vs. 16.7% for Cy/TBI and Flu/Bu/TBI, respectively, p = .62) despite the Flu/Bu/TBI group having significantly worse performance status. Flu/Bu/TBI resulted in significantly lower cumulative incidence of relapse compared with Cy/TBI (2-year point estimate 18.5% vs. 31.5%, p = .05). These results demonstrate similar outcomes for patients receiving Flu/Bu/TBI versus Cy/TBI. Flu/Bu/TBI may allow the possibility of providing myeloablative conditioning to patients with poor performance status.

Economic evaluation of rituximab in addition to standard of care chemotherapy for adult patients with acute lymphoblastic leukemia

Abstract Aims: Acute lymphoblastic leukemia (ALL) is an aggressive form of leukemia with a poor prognosis in adult patients. The addition of the monoclonal antibody rituximab to standard chemotherapy has been shown to improve survival in adults with ALL. However, it is unknown whether the addition of rituximab is cost-effective. The objective was to determine the economic impact of rituximab in addition to standard of care (SOC) chemotherapy vs SOC alone in newly-diagnosed Philadelphia chromosome-negative, CD20-positive, B-cell precursor ALL. Methods: A decision analytic model was constructed, based upon the Canadian healthcare system. It included the following health states over a lifetime horizon (max ≈60 years): event-free survival (EFS), relapsed/resistant disease, cure, and death. SOC was either hyper-CVAD or the Dana Farber Cancer Institute (DFCI) ALL consortium. EFS, overall survival, and serious adverse event (SAE) rates were derived from a large randomized controlled trial. Costs of the model included: first-line treatment and administration, disease management, second-line and third-line treatment and administration, palliative care, and SAE-related treatments. Inputs were sourced from provincial and national public data, the literature, and cancer agency input. Results: Quality-adjusted life-years (QALYs) increased by 2.20 QALYs with rituximab in addition to SOC. The resulting mean Incremental Cost-Effectiveness Ratio (ICER) was C