David Loach

Duration of first remission, hematopoietic cell transplantation-specific comorbidity index and patient age predict survival of patients with AML transplanted in second CR.

Allo-SCT is potentially curative for patients with AML. Patients transplanted in CR2 tend to experience inferior survival compared with those in CR1. We retrospectively investigated the impact of pretransplant variables on the outcome of patients transplanted with AML in CR2. Ninety-four patients with AML in CR2 received a transplant between 1999 and 2011 with myeloablative (MA, n=65) or reduced-intensity conditioning regimens (RIC, n=29). Variables investigated included cytogenetic risk at diagnosis (SWOG), hematopoietic cell transplantation-specific comorbidity index (HCT-CI), CMV status, duration of CR1 and age. Median age of all patients was 47 years (range 18–70). Multivariable analysis for OS identified three prognostically significant categories: a favorable risk group included patients with duration of CR1 ⩾6 months, age <55 years and HCT-CI score 0–3, an intermediate risk group with duration of CR1 ⩾6 months, age <55 years and HCT-CI score 4–5 and a high-risk group with duration of CR1 <6 months or age ⩾55 years (P=0.0001) with 5-year survivals of 53%, 31% and 6%, respectively. Acute and chronic GVHD did not influence this risk stratification. The stated risk factors discriminate patients with different OS and may assist in decision making for allo-SCT.

Benefit of allogeneic transplantation in patients age ≥ 60 years with acute myeloid leukemia is limited to those in first complete remission at time of transplant.

We evaluated the impact of age and remission status on 242 consecutive patients who underwent allogeneic hematopoietic cell transplantation for acute myeloid leukemia (AML) in our program between 1999 and 2011. Median age of all patients was 48 years (range, 18 to 71). Based on age and remission status, patients were divided into 4 groups: first complete remission (CR1) age <60 years (n = 116), second complete remission (CR2) age <60 years (n = 78), CR1 age ≥60 years (n = 32), and CR2 age ≥60 years (n = 16). Donors were matched related (n = 155, 64%) or matched unrelated (n = 87, 36%). Median follow-up of survivors was 65 months (range, 12 to 145). In a univariate analysis, 3-year overall survival rates of the 4 groups were 57%, 43%, 39%, and 16% (P = .003), respectively. In a multivariable analysis, hazard ratios of nonrelapse mortality and survival were 2.08 (P = .06) and 1.52 (P = .23), respectively, in patients ≥60 years in CR2 compared with ≥ 60 years in CR1. Although a plateau in survival was observed for patients ≥60 years in CR1 similar to those <60 years in CR1 and CR2, no long-term survivors were seen in patients ≥60 years in CR2. Our data suggest disappointing outcomes in AML patients ≥60 years of age transplanted in CR2. Therefore, if a transplant is indicated, early referral is recommended in patients ≥60 years with AML.

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.

Relationship between neurocognitive functioning and medication management ability over the first 6 months following allogeneic stem cell transplantation

Although neurocognitive impairment has been established as a major issue among cancer survivors, the real-world consequences of this impairment are unclear. This study investigated the relationship between neurocognitive functioning and medication management ability over time among 58 patients treated with allogeneic hematopoietic stem cell transplantation (HCT). Participants completed a neuropsychological test battery and a simulated medication management task at three time points: pre-transplant (T0), Day 100 (T1) and 6 months post transplant (T2). Neurocognitively impaired participants performed worse on the medication management task than neurocognitively normal participants at each time point, and were more likely to score in the impaired range of medication management ability post transplant (72% vs 20%, P<0.001 at T1; 67% vs 23%, P=0.013 at T2). In multivariate analyses, worse performance in executive functioning/working memory consistently predicted impaired medication management ability, even when controlling for sociodemographic and clinical confounders (odds ratio=0.89, 95% confidence interval (0.80, 0.98), P=0.023). Lower physical symptom distress also predicted impaired medication management ability, but this effect decreased over time. Self-reported cognitive problems were not correlated with medication management ability at any time point. Findings suggest that poor neurocognitive functioning, particularly in the domain of executive functioning/working memory, is associated with worse medication management ability within the first 6 months after allogeneic HCT.

Reduction of severe acute graft-versus-host disease using a combination of pre transplant anti-thymocyte globulin and post-transplant cyclophosphamide in matched unrelated donor transplantation

Use of Post-transplant Cyclophosphamide (PTCy) has recently been introduced specifically in the haplo-identical transplant setting with promising results [1]. This intervention has also shown a significant reduction of acute graft versus host disease (aGVHD) and a trend towards improving chronic graft versus host disease (cGVHD) [2]. The efficacy of PTCy has mainly been demonstrated in patients with bone marrow (BM) as the stem cell source [3]; and has been associated with clinically significant acute and chronic GVHD in patients with peripheral blood as the stem cell source (PBSC) [4]. Anti-thymocyte globulin (ATG) has previously been shown to reduce the incidence of cGVHD at around 1 year post transplantation [5], without increasing the incidence of relapse [6]. The incidence of Gr III-IV aGVHD was 28% using ATG, cyclosporine and mycophenolate mofetil (ATG-CSA-MF), as the GVHD prophylaxis regimen, in the recently concluded randomized trial [7]. We hypothesized that a combination of both ATG and PTCy would reduce the incidence of both acute and chronic GVHD in our patient cohort; effectively reducing the morbidity and mortality associated with severe forms of GVHD. Here we present the preliminary outcome in our unrelated patients using this regimen. This is a retrospective study of the patient cohort treated from 1 October 2015 until 31 March 2016 in a single center. This study was approved by the institutional Research Ethics Board. This study cohort was compared to the earlier historical study cohort of patients who received pre transplant ATG as part of GVHD prophylaxis at our center [7]. Patients received transplant from HLAMatched (10/10) or mismatched (9/10) unrelated donors. The graft source was Filgrastim stimulated PBSC. The treatment schema initially for ages<60 years was a myeloablative regimen using the FBT400 protocol and for ages>60 years consisted of FBT200 as the reduced intensity conditioning (RIC) regimen [8]. The FBT400 regimen consisted of a combination of Fludarabine (50 mg/m2 on days −5,−4,−3,−2), Busulphan (once daily dose of 3.2 mg/kg on days −5,−4,−3,−2) along with 2 doses of total body irradiation (TBI) of 200 cGy on Day −1. The regimen of FBT200 comprised of reduced dose of Fludarabine at 30 mg/m2 on same days but with only 2 days of Busulphan (on days −2,−1) and only one dose of 200 cGy TBI on day −1 [9]. We subsequently decided to use FBT200 for all patients in view of increased liver and kidney toxicities observed with FBT400 regimen with post-transplant cyclophosphamide. The GVHD prophylaxis consisted of ATG (rabbit, Thymoglobulin; Genzyme-Sanofi, Lyon, France) on days −3, −2 and −1 with a total dose of 4.5 mg/kg. Patients additionally received 50 mg/kg/day IV cyclophosphamide on days +3 and +4 (PTCy), with the first dose starting 72 h after PBSC infusion. This was further followed by post transplant administration of IV cyclosporine (2.5 mg/kg twice daily) on day+ 5 onwards, with change to oral route when the patient was able to tolerate orally. Presented in part at the 58th American Society of Hematology Annual Meeting in San Diego, California, 2–6 December 2016 and at the American Society of Blood and Marrow Transplantation meeting at Orlando, Florida, 22–26 February 2017.

Long-Term Incidence of Secondary Malignancies after Allogeneic Hematopoietic Cell Transplantation: A Single-Center Experience

To review the emergence of secondary malignancies (SMs) in recipients of allogeneic hematopoietic cell transplantation (HCT), we documented the occurrence of SMs in 2415 allogeneic HCT recipients, ages 18 to 71, in a single center over 4 decades. SMs were seen in 209 patients, including 58 with nonmetastatic squamous cell (SCC) and basal cell carcinoma (BCC) of the skin. Cumulative incidence of SM was 6.3% at 10 years, 13.5% at 20 years, and 17.6% at 30 years post-HCT. Median age at diagnosis of SMs was 61 years (range, 21 to 85). By multivariable analysis, older age at HCT was the only independent prognostic factor for SM (HR, 1.39 for ages 41 to 55 and HR, 1.92 for age > 55 compared with age ≤ 40; Pu2009=u2009.001). The rate of SM (excluding nonmetastatic SCC/BCC of skin) after HCT was 2.07 times higher (Pu2009=u2009.01) compared with the general population. Overall survival (OS) after diagnosis of SM (excluding nonmetastatic SCC/BCC of skin) was 58% at 5 years and 50% at 10 years postdiagnosis. Eastern Cooperative Oncology Group (ECOG) score was the only independent predictor of OS on multivariable analysis, with over 2-fold increased risk of death for patients with an ECOG score of 1 and over 6-fold for ECOG scores of 2 to 4, compared with ECOG score 0 (Pu2009<u2009.0001). Forty of 209 patients (19%) diagnosed with SMs subsequently developed another new malignancy. OS was 68% and 51% at 5 and 10 years, respectively. The survival of SM patients post-HCT is favorable, thus warranting diligent long-term cancer screening and standard of care treatment. ECOG status of these patients is a predominant prognostic factor.