David Sanford

Three Newly Approved Drugs for Chronic Lymphocytic Leukemia: Incorporating Ibrutinib, Idelalisib, and Obinutuzumab into Clinical Practice

Three agents have received Food and Drug Administration (FDA) approval for treatment of chronic lymphocytic leukemia (CLL) within the past year. Ibrutinib and idelalisib block B-cell receptor signaling through inhibition of Bruton tyrosine kinase and phosphatidylinositol 3-kinase δ molecules respectively, interfering with several pathways required for leukemia cell survival. Idelalisib has shown efficacy in the relapsed setting and is currently approved by the FDA for use in combination with rituximab. Ibrutinib has been studied in patients with relapsed CLL and as frontline therapy. In the relapsed setting, these agents produce durable remissions, and might be preferable to re-treatment with chemoimmunotherapy for many patients. Ibrutinib is also effective treatment for patients with deletion 17p and is approved by the FDA as frontline therapy in this patient group, although it does not appear to completely abrogate this adverse prognostic factor. These agents have a unique side effect profile and longer follow-up is required to further understand tolerability and rare adverse effects. Obinutuzumab is a type-2 monoclonal anti-CD20 antibody which results in direct and antibody-dependent cell-mediated cytotoxicity of leukemia cells. It is approved by the FDA for use in combination with chlorambucil, and has shown efficacy in the frontline setting in patients unfit for more intensive chemoimmunotherapy. It produces increased response rates and minimal residual disease negativity compared with chlorambucil/rituximab and is associated with an advantage in progression-free survival but not yet overall survival. These agents underscore our advancement in the understanding of the biology of CLL and will improve outcomes for many patients with CLL.

Tamibarotene in patients with acute promyelocytic leukaemia relapsing after treatment with all-trans retinoic acid and arsenic trioxide

Treatment of acute promyelocytic leukaemia (APL) with arsenic trioxide (ATO) and all‐trans retinoic acid (ATRA) is highly effective first‐line therapy, although approximately 5–10% of patients relapse. Tamibarotene is a synthetic retinoid with activity in APL patients who relapse after chemotherapy and ATRA, but has not been studied in relapse after treatment with ATO and ATRA. We report on a phase II study of tamibarotene in adult patients with relapsed or refractory APL after treatment with ATRA and ATO (n = 14). Participants were treated with tamibarotene (6 mg/m2/d) during induction and for up to six cycles of consolidation. The overall response rate was 64% (n = 9), the rate of complete cytogenetic response was 43% (n = 6) and the rate of complete molecular response was 21% (n = 3). Relapse was frequent with 7 of 9 responders relapsing after a median of 4·6 months (range 1·6–26·8 months). The median event‐free survival (EFS) was 3·5 months [95% confidence interval (CI) 0–8·6 months] and the median overall survival (OS) was 9·5 months (95% CI 5·9–13·1 months). These results demonstrate that tamibarotene has activity in relapsed APL after treatment with ATO and ATRA and further studies using tamibarotene as initial therapy and in combination with ATO are warranted.

The role of ponatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia

The introduction of tyrosine kinase inhibitors has improved outcomes in Philadelphia chromosome-positive acute lymphoblastic leukemia, yet relapse due to the development of resistance mutations remains a major obstacle. Ponatinib is a novel tyrosine kinase inhibitor designed to overcome single-resistance mutations in the ABL kinase. Three clinical trials confirmed the efficacy of ponatinib in the relapsed and front-line setting in Philadelphia positive acute lymphoblastic leukemia, even in the presence of the T315I mutation, which confers resistance to other tyrosine kinase inhibitors. The rate of relapse appears to be very low when used in combination with chemotherapy, suggesting a role for ponatinib in newly diagnosed patients. A major concern with the use of ponatinib is the associated high risk of life-threatening vascular thrombotic events. Potential strategies to reduce this risk include minimizing the use of ponatinib in patients with significant baseline cardiovascular risk, careful surveillance and treatment of cardiovascular risk-factors and dose reduction of ponatinib.

Phase II trial of ponatinib in patients with chronic myeloid leukemia resistant to one previous tyrosine kinase inhibitor

Ponatinib is a tyrosine kinase inhibitor (TKI) designed to overcome resistance-inducing mutations, including the T315I mutation, in the ABL kinase domain. Initial clinical trials of ponatinib reported major cytogenetic response (MCyR) rates over 60% in heavily treated patients with chronic myeloid

CD33 is frequently expressed in cases of myelodysplastic syndrome and chronic myelomonocytic leukemia with elevated blast count

CD33 is a transmembrane protein that belongs to the Siglecs (sialic-acid-binding immunoglobulin-like lectins) family.[1] In normal individuals, expression of CD33 is associated with myeloid maturation and is present on multipotent myeloid precursors and maturing monocytes and granulocytes, but is also found on some lymphoid cells.[2–4] The majority of cases of acute myeloid leukemia (AML) also express CD33 and there have been several attempts to develop monoclonal antibody-based therapies that target this molecule.[5] Gemtuzumab-ozogamicin, an antibody-drug conjugate (ADC), was approved initially by the FDA in 2000 after demonstrating activity as a single agent in patients with relapsed/refractory AML. It was later withdrawn after a phase III trial reported no survival benefit with increased rates of toxicity and early mortality.[6,7] However, a recent meta-analysis of 5 clinical trials combining gemtuzumab with chemotherapy for frontline treatment reported that use of gemtuzumab significantly decreased relapse and improved survival, particularly in patients with intermediate and favorable risk AML.[8] CD33targeted therapy has not been as widely studied in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), although several smaller trials suggest gemtuzumab has some activity in these diseases.[9–14] The intensity of CD33-expression (as measured by the number of CD33 molecules per cell) on the CD34-positive blast-population has previously been reported to be lower in patients with MDS and CMML in comparison with AML.[15] We aimed to determine the expression of CD33 in patients with MDS and elevated blast count ( 5%). We searched a database of clinical trials conducted at our center for patients with high risk MDS and CMML to identify cases. We limited our search between January 2000 and September 2014 and included only untreated patients with flow-cytometry for quantification of CD33 expression performed on a bone marrow aspirate sample prior to starting treatment. We also identified AML patients treated over the same time period to serve as a comparator group for CD33 expression. At our center, the diagnosis of AML, MDS and CMML has been made according to WHO classification systems over this time period, and bone marrow samples with 20% blasts of the total nucleated cells are considered to have AML.[16–18] The blast population from AML and MDS patients was analyzed using flow cytometry to quantify CD33 expression. Myeloblasts were identified based on dim CD45 expression and low side scatter. CD33 expression on the blast population was measured using an isotype-matched non-reactive antibody or autofluorescence to set a negative control threshold. Representative CD33-positive and CD33-negative cases of MDS are shown in Figure 1. We calculated the mean percentage of CD33-positive myeloblasts for AML, CMML and MDS and compared the results between groups using an unpaired student’s t-test. We identified 2295 patients with AML, 25 patients with CMML and 174 patients with MDS in our database in the specified time period, where flow-cytometry measuring CD33 was performed prior to starting treatment. Mean bone marrow blast count by morphology for patients with MDS and CMML was 13.3% (SD 3.1%, Range 5–19%) and 14% (SD 2.5%, Range 10-18%) respectively. Most patients with MDS had refractory anemia with excess blasts (RAEB)-2 (n1⁄4 159) and only a small number had RAEB-1 (n1⁄4 15). All patients with CMML had 10% blasts plus promonocytes by morphology and were classified as CMML-2.

Jumping Translocations in Myeloid Malignancies Associated With Treatment Resistance and Poor Survival

BACKGROUND Jumping translocations (JT) are uncommon cytogenetic abnormalities involving nonreciprocal translocations of a single donor chromosome onto 2 or more chromosomes. The clinical characteristics and prognosis of JTs in patients with myeloid malignancies are not well described. MATERIALS AND METHODS We searched our cytogenetic database from 2003 to 2014 to identify cases of myeloid malignancies associated with a JT. These cases were cross-referenced with our clinical databases to determine patient characteristics, response to treatment and overall survival. RESULTS We identified 10 patients with myeloid malignancies and a JT: 4 cases of acute myeloid leukemia with myelodysplastic syndrome-related changes, 4 cases of myelodysplastic syndrome, and 2 cases of postpolycythemia myelofibrosis. The donor segment was derived from chromosome 1 in every case. The acquisition of a JT was a late occurrence, with a median time to JT development of 24.9 months (range, 0-248 months) from diagnosis. The overall response to treatment was poor, with no patients experiencing a response to conventional chemotherapy or hypomethylating agents. The median overall survival for the group was 9 months (95% confidence interval, 2.5-15.5) after identification of a JT. CONCLUSION The acquisition of a JT in patients with myeloid malignancies appears to be a late event and is associated with myelodysplasia. In our series, this was associated with a poor prognosis with a poor response to treatment, disease transformation to acute myeloid leukemia, and short overall survival.