Mary-Elizabeth M. Percival

Improvements in the early death rate among 9380 patients with acute myeloid leukemia after initial therapy: A SEER database analysis

Acute myeloid leukemia (AML) is treated with conventional induction chemotherapy shortly after diagnosis for the majority of patients aged ≤65 years. A recent report suggested a substantial decline in the early, or 1‐month, mortality rate in patients treated on clinical trials over the past 2 decades. It is unknown whether a similar improvement has been observed in the general population.

Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome

Abstract The outcome of sequential azacitidine with lenalidomide has not been reported in previously treated patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). This study describes a phase 2 study evaluating the safety and efficacy of this combination in elderly patients with AML and MDS with prior hypomethylating agent (HMA) and/or immunomodulatory agent exposure. Patients were treated on a 42-day cycle with azacitidine at 75 mg/m2 SQ/IV daily on days 1–7, followed by lenalidomide 50 mg orally daily on days 8–28. The median number of treatment cycles on study was two (range = 1–11). Of 32 evaluable patients, the overall response rate was 25%. Neutropenic fever was the most common serious adverse event, but overall the combination was well-tolerated. The median overall survival (OS) for responders vs non-responders was 9.8 vs 4.0 months, respectively (HR = 0.36, p = 0.016). In conclusion, this combination demonstrated modest clinical activity in this poor risk population.

Bone marrow evaluation for diagnosis and monitoring of acute myeloid leukemia

The diagnosis of acute myeloid leukemia (AML) can be made based on peripheral blood or bone marrow blasts. In this review, we will discuss the role of bone marrow evaluation and peripheral blood monitoring in the diagnosis, management, and follow up of AML patients. For patients with circulating blasts, it is reasonable to perform the necessary studies needed for diagnosis and risk stratification, including multiparametric flow cytometry, cytogenetics, and molecular analysis, on a peripheral blood specimen. The day 14 marrow is used to document hypocellularity in response to induction chemotherapy, but it is unclear if that assessment is necessary as it often does not affect immediate management. Currently, response assessments performed at count recovery for evaluation of remission and measurable residual disease rely on bone marrow sampling. For monitoring of relapse, peripheral blood evaluation may be adequate, but the sensitivity of bone marrow testing is in some cases superior. While bone marrow evaluation can certainly be avoided in particular situations, this cumbersome and uncomfortable procedure currently remains the de facto standard for response assessment.

Biased View of the Role of Site-Specific Therapy in Carcinoma of Unknown Primary

The letter by Sura et al raised three concerns about our article on the unintended consequences of Veteran Affairs (VA) colorectal cancer (CRC) Oncology Watch (OncWatch) intervention, implemented in the Veterans Integrated Service Network 7 (VISN 7) during fiscal year 2008. The following are our point-by-point responses. First, Sura et al stated that improving CRC screening adherence rates, as evaluated by our article, was not among the aims of OncWatch. We believe that this statement is not supported by the available evidence, andwestandbyouroriginaldescriptionofthetwoaimsofOncWatch:(1) improving screening adherence rates for the averageand high-risk veterans, and (2) providing timely diagnostic and surveillance follow-ups. The two aims were well referenced in an original review article cited in our article, one of whose coauthors was Luke Stapleton, MD, the Clinical ProgramDirectorofVISN7,whohadprimaryresponsibilities fordesigning and implementing OncWatch. In addition, Maria Ribeiro, MD, a member of the original OncWatch committee and a coauthor of our article, has carefully re-examined numerous internal OncWatch documents. It is amply clear from this review article and Ribeiro’s first-hand experience that improving CRC screening adherence rates was one of OncWatch’s central aims. That said, it is possible that some VISN 7 providers would have found it challenging to follow all OncWatch protocols. In hindsight, our article could have pointed out that variation in providers’compliancewithOncWatchmighthaveinfluencedourresults. Second, Sura et al raised a concern about the validity of the controls. In the context of the response to the first concern, our choice of the controls (ie, the non-VISN 7 hospitals) was valid because the aim of OncWatch for improving CRC screening adherence rates, using VA electronic health records, is unique within VISN 7. (Please see the discussion of potential contamination biases in our article.) Third, Sura et al were concerned about the accuracy of our estimated CRC screening adherence rates. The claims data used by our article are, by design, different from the electronic health records database used by OncWatch and Sura et al. However, we have made our best efforts to design an algorithm for estimating CRC screening adherence for average-risk veterans using claims data, in a way that mimics the inclusion/exclusion criteria set by OncWatch. (See a detailed presentation and critical appraisal of this algorithm cited in our article.) In addition, our article carefully considered the possibility of incomplete information on veterans who used different systems, including VA-contracted providers. Specifically, we included VA Fee Basis data in our analysis and performed a set of sensitivity analyses to test how well our algorithm performed in identifying veterans who relied primarily on the VA for health care. On the other hand, the CRC screening adherence rates presented by Sura et al are difficult to interpret. For example, what were the exclusion and inclusion criteria used in estimating the rates? This is especially important to ensure that diagnostic and surveillance colonoscopy procedures were excluded from estimating CRC screening rates for average-risk veterans only. What were the denominators in different years? How long were the retrospective look-back windows used to determine annual adherence status for modalities recommended for longer than 1 year? In summary, the aim of our article was to report an objective evaluation of the impact of OncWatch on CRC screening rates for average-risk veterans, and we stand by our analyses and findings, subject to the limitations noted in our article. Moreover, our article illustrates how the application of a well-defined research methodology can yield evidence useful for evaluating large-scale interventions.

Unsatisfactory efficacy in randomized study of reduced-dose CPX-351 for medically less fit adults with newly diagnosed acute myeloid leukemia or other high-grade myeloid neoplasm

The need for new therapies for medically less fit adults with acute myeloid leukemia (AML) is unquestioned.[1][1] CPX-351, a liposomal formulation of cytarabine and daunorubicin,[2][2] may be an attractive option. In patients with relapsed/refractory leukemia, in whom CPX-351 was administered on

Phase 1/2 trial of GCLAM with dose-escalated mitoxantrone for newly diagnosed AML or other high-grade myeloid neoplasms

Outcomes with “7 + 3” are often unsatisfactory in acute myeloid leukemia (AML). Trials demonstrating improved outcomes with high-dose cytarabine, addition of cladribine, or escalated anthracycline doses prompted a phase 1/2 study (NCT02044796) of G-CSF, cladribine, high-dose cytarabine, and dose-escalated mitoxantrone (GCLAM) in adults with newly-diagnosed AML or other high-grade myeloid neoplasms. One hundred and twenty-one patients, median age 60 (range 21–81) years, were enrolled. In phase 1, cohorts of 6–12 patients were assigned to 12–18 mg/m2/day of mitoxantrone as part of GCLAM. Because all dose levels were well-tolerated, mitoxantrone at 18 mg/m2 was declared the recommended phase 2 dose (RP2D). 74/94 (79%) patients treated at the RP2D achieved a complete remission (CR; 67/74 without measureable residual disease [MRD]) for an overall MRDneg CR rate of 71% (primary phase 2 endpoint). Seven patients achieved a CR with incomplete blood count recovery (CRi; 7%, 5 MRDneg) for a CR/CRi rate of 81/94 (86%). Four-week mortality was 2%. After adjustment, the MRDneg CR and CR/CRi rates compared favorably to 100 matched controls treated with 7 + 3 at our center and 245 matched patients treated with 7 + 3 on a cooperative group trial. Our data indicate GCLAM with mitoxantrone at 18 mg/m2/day is safe and induces high-quality remissions in adults with newly-diagnosed AML.

Allogeneic hematopoietic cell transplant for normal karyotype AML: indirect evidence of selection for adverse molecular profile.

Allogeneic hematopoietic cell transplant for normal karyotype AML: indirect evidence of selection for adverse molecular profile

Cure of APL Without Chemotherapy

The chemotherapy-free treatment of acute promyelocytic leukemia (APL) is a modern success story. Early clinical trials in China during the 1980s suggested the potent activity of all-trans retinoic acid (ATRA) in APL, leading to differentiation of the malignant cells and complete remission. In the 1990s, arsenic trioxide (ATO) was also shown to lead to differentiation of the promyelocytes. Thus, the current treatment for newly diagnosed standard-risk APL (white blood cell count <10 × 109 cells/L) in adults is ATRA and ATO without chemotherapy, which leads to a remarkable cure rate of over 90%. In newly diagnosed patients with high-risk APL (white blood cell count ≥10 × 109 cells/L), cytoreduction with gemtuzumab ozogamicin or anthracyclines is recommended in addition to combination ATRA and ATO. A once highly fatal disease has now become the most highly curable subtype of acute myeloid leukemia, in most cases without the need for chemotherapy.

A comparison of patients with acute myeloid leukemia and high-risk myelodysplastic syndrome treated on versus off study

Abstract Patients with newly diagnosed (ND) and relapsed/refractory (RR) acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS, ≥10% blasts) often receive intensive chemotherapy at diagnosis and relapse. We retrospectively identified 365 patients and categorized the reasons for receiving treatment off study (medical, logistical, or unclear). The pretreatment characteristics of the on and off study groups were similar. Rates of the complete remission (CR) without measurable residual disease were significantly higher for ND patients treated on versus off study (61% versus 35%), but CR rates and survival were low for all RR patients regardless of study assignment. The subset of ND patients treated off study for medical reasons had significantly decreased overall survival and relapse-free survival. Standard, stringent study eligibility criteria may delineate a population of ND, but not RR, patients with improved outcomes with intensive induction chemotherapy.

Improvements in the early death rate in 9,380 acute myeloid leukemia patients following initial therapy: a SEER database analysis

Acute myeloid leukemia (AML) is treated with conventional induction chemotherapy shortly after diagnosis for the majority of patients aged ≤65 years. A recent report suggested a substantial decline in the early, or 1‐month, mortality rate in patients treated on clinical trials over the past 2 decades. It is unknown whether a similar improvement has been observed in the general population.