Jack M. Lionberger

Frequency of allogeneic hematopoietic cell transplantation among patients with high- or intermediate-risk acute myeloid leukemia in first complete remission.

PURPOSE To determine the frequency of allogeneic hematopoietic cell transplantation (HCT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1). PATIENTS AND METHODS Between January 1, 2008, and March 1, 2011, 212 newly diagnosed patients with AML received treatment at our center. Ninety-five patients age less than 75 years with intermediate- or high-risk AML achieved a complete remission, and 21 patients achieved a morphologic remission with incomplete blood count recovery. RESULTS Seventy-eight (67%; 95% CI, 58% to 76%) of 116 patients received HCT at a median of 2.8 months (range, 0.5 to 19 months) from their CR1 date. The median age was 57 years in both the HCT patient group (range, 18 to 75 years) and the non-HCT patient group (range, 24 to 70 years; P = .514). Between the HCT patients and the non-HCT patients, the mean Eastern Cooperative Oncology Group performance status was 1.1 compared with 1.5, respectively (P = .005), and the average HCT comorbidity score within 60 days of CR1 was 1.7 and 2.1, respectively (P = .68). Twenty-nine (76%) of 38 non-HCT patients were HLA typed, and matched donors were found for 13 of these 29 patients (34% of all non-HCT patients). The most common causes for patients not receiving transplantation in CR1 were early relapse (within 6 months) in 12 patients (32%), poor performance status in eight patients (21%), and physician decision in five patients (13%). CONCLUSION HCT can be performed in CR1 in the majority of patients with AML for whom it is currently recommended. The main barriers to HCT were early relapse and poor performance status, highlighting the need for improved therapies for patients with AML of all ages.

Heterogeneity of Clonal Expansion and Maturation-Linked Mutation Acquisition in Hematopoietic Progenitors in Human Acute Myeloid Leukemia

Recent technological advances led to an appreciation of the genetic complexity of human acute myeloid leukemia (AML), but underlying progenitor cells remain poorly understood because their rarity precludes direct study. We developed a co-culture method integrating hypoxia, aryl hydrocarbon receptor inhibition and micro-environmental support via human endothelial cells to isolate these cells. X-chromosome inactivation studies of the least mature precursors derived following prolonged culture of CD34+/CD33− cells revealed polyclonal growth in highly curable AMLs, suggesting that mutations necessary for clonal expansion were acquired in more mature progenitors. Consistently, in core-binding factor (CBF) leukemias with known complementing mutations, immature precursors derived following prolonged culture of CD34+/CD33− cells harbored neither mutation or the CBF mutation alone, whereas more mature precursors often carried both mutations. These results were in contrast to those with leukemias with poor prognosis that showed clonal dominance in the least mature precursors. These data indicate heterogeneity among progenitors in human AML that may have prognostic and therapeutic implications.

Strategies to reduce relapse after allogeneic hematopoietic cell transplantation in acute myeloid leukemia.

The incidence of acute myeloid leukemia (AML) is expected to increase in conjunction with our ageing population. Although it is proving to be a heterogeneous disease process, the only treatment with proven survival benefit for poor risk AML remains allogeneic hematopoietic cell transplant. Although this is presumed to be a curative strategy, many patients relapse after transplant, prompting us to examine various ways that we can improve outcomes. These efforts involve every step of AML diagnostics and therapy, including the intricate processes of conditioning, graft manipulation and immunomodulation. The hope is that improvement in these steps will ultimately improve survival and decrease relapse rates for AML patients after transplant.

Acute myeloid leukemia induction with cladribine: Outcomes by age and leukemia risk

Acute myeloid leukemia (AML) induction traditionally includes seven days of cytarabine and three days of an anthracycline (7 + 3). Because of evidence of increased efficacy of cladribine combined with this regimen, we conducted a retrospective analysis of 107 AML patients treated with idarubicin, cytarabine and cladribine (IAC) at our institution. Complete remission (CR) occurred in 71%, with overall response of 79%. One-year survival overall was 59%, with 47% (27/57) among patients ≥60 years old and 72% (36/50) in those <60 (Relative Risk [RR] 1.9, 95% CI 1.2-3.2). Median overall survival was 17.3 months in all patients and Cox proportional hazard ratio (HR) for death was 2.2 (95% CI 1.3-3.6) for age ≥60 years compared to <60 years. One year survival was 100% among favorable NCCN risk patients versus 64% in intermediate-risk and 35% in poor-risk patients (p < 0.001). HR for death in intermediate- risk (4.2, 95% CI 1.5-12) and poor-risk (8.4, 95% CI 3.0-24) compared to favorable risk AML was higher than that associated with age ≥60 years (HR 2.2). We conclude that IAC is an effective AML induction regimen, NCCN leukemia risk predicts survival better than age in our population, and high intensity regimens can be justified in selected older patients.

Tumor lysis syndrome and metastatic melanoma

Tumor lysis syndrome (TLS) is a potential emergent complication of oncologic treatment. TLS is commonly reported in hematological malignancies with rapid cell turnover rates, but is relatively rare in solid tumors. TLS is most frequently a result of cancer treatment in combination with a large tumor burden, but has occasionally been reported to occur spontaneously, especially in cases of advanced or metastatic disease. In this article, we describe the case of a patient with newly diagnosed metastatic melanoma that developed TLS two days after initiation of corticosteroids. In addition, we present a brief literature review of melanoma-associated TLS and review the etiology, diagnosis, and management of TLS.

Myeloid sarcoma without circulating leukemia mimicking gastrointestinal malignancy and lymphoma

We present an unusual case of myeloid sarcoma with ascites and abdominal pain in which initial clinical, laboratory, and imaging studies suggested a gastrointestinal malignancy or lymphoma. Subsequent detection of leukemic ascites and blasts in a gastric, small bowel, and skin biopsy supported a diagnosis of myeloid sarcoma. Bone marrow biopsy revealed 15% blasts, and cytogenetics with an inversion 16 rearrangement was diagnostic of acute myeloid leukemia (AML). Positron emission tomography-computed tomography performed at presentation to stage a presumptive lymphoma found later utility in following the burden of extramedullary disease. Standard AML induction chemotherapy resulted in complete remission and was followed by three rounds of high dose cytarabine consolidation. The patient unfortunately relapsed leading to re-induction followed by allogeneic stem cell transplantation. This report describes the presentation, assessment, and management of myeloid sarcoma.

Outpatient bendamustine and idarubicin for upfront therapy of elderly acute myeloid leukaemia/myelodysplastic syndrome: a phase I/II study using an innovative statistical design

Combinations of agents may improve outcomes among elderly acute myeloid leukaemia (AML) and high‐risk myelodysplastic syndrome (MDS) patients. We performed an adaptive phase I/II trial for newly‐diagnosed AML or high‐risk MDS patients aged ≥50 years using a Bayesian approach to determine whether 1 of 3 doses of bendamustine (45, 60, 75 mg/m2 days 1–3), together with idarubicin (12 mg/m2 days 1–2), might provide a complete response (CR) rate ≥40% with <30% grade 3–4 non‐haematological toxicity. We treated 39 patients (34 AML; five MDS with >10% marrow blasts; median age 73 years). None of the three bendamustine doses in combination with idarubicin met the required CR and toxicity rates; the 75 mg/m2 dose because of excess toxicity (two of three patients) and the 60 mg/m2 dose because of low efficacy (CR rate 10/33), although no grade 3–4 non‐haematological toxicity was seen at this dose. Median survival was 7·2 months. All patients began treatment as outpatients but hospitalization was required in 90% (35/39). Although we did not find a dose of bendamustine combined with idarubicin that would provide a CR rate of >40% with acceptable toxicity, bendamustine may have activity in AML/MDS patients, suggesting its addition to other regimens may be warranted.