Hematologic Oncology

In this interview we discuss the latest chronic myeloid leukemia treatment and research with Dr. Michael Deininger, chief of the division of hematology at the University of Utah School of Medicine.

The current standard therapies for chronic lymphocytic leukemia do not prevent Richter's transformation from occurring. If we are fortunate, new treatments will realize the hope that this usually fatal complication of chronic lymphocytic leukemia might be avoided.

Early results suggest that the new targeted therapies for CLL may have a profound impact on survival-and thus on the incidence of Richter's transformation. It will therefore become increasingly important to study Richter's transformation more assiduously, to diagnose it sooner, and to develop strategies to treat this extremely challenging entity.

Richter's transformation, or Richter's syndrome, is an uncommon clinicopathological condition observed in about 5% to 10% of patients with chronic lymphocytic leukemia (CLL). This review summarizes advances in our understanding of the pathobiology and in the management of Richter's transformation in patients with CLL.

It is time to move on to next key steps of improving recognition of treatment-resistant lymphoma at diagnosis, rather than at treatment failure, by optimally employing biomarkers and improving cure rates by integrating powerful but minimally toxic new systemic agents into primary treatment.

The likelihood that combined-modality therapy will provide a small progression-free survival advantage is real but not likely to be equated to an overall survival advantage, as it depends on when one looks at the data. The studies to date demonstrate a late fall-off in survival due to one or another toxic effect of radiation.

In Hodgkin lymphoma, as with many other malignancies, a combined-modality approach has proven successful. This tactic capitalizes on the relative advantages of both modalities, yet minimizes risk by avoiding intense exposure to either. This article will summarize the data supporting this approach in early-stage Hodgkin lymphoma.

The US Food and Drug Administration has approved ponatinib (Iclusig) to treat adults with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.

A combination of all-trans retinoic acid (ATRA) and arsenic trioxide resulted in outcomes “at least not inferior” to those achieved when ATRA was used in combination with idarubicin chemotherapy in newly diagnosed patients with non–high-risk, acute promyelocytic leukemia.

Preliminary findings presented at ASH suggest a “favorable emerging clinical profile” for once weekly administration of MLN9708 in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma.

The combination of rituximab and the novel immunotherapy pidilizumab (CT-011) is both active and well tolerated in follicular lymphoma patients according to results of a phase II trial presented at ASH.

ARRY-520, a novel selective kinesin spindle protein (KSP) inhibitor showed promising clinical activity both alone and combined with low-dose dexamethasone in a phase II clinical trial in patients with relapsed and refractory multiple myeloma.

The targeted agent ibrutinib has shown a high response rate in both treatment-naive and previously treated, relapsed, refractory chronic lymphocytic leukemia (CLL) patients older than 65.

Relapsed or refractory chronic lymphocytic leukemia and acute lymphoblastic leukemia patients have shown durable responses of almost 2 years to a novel T-cell engineering technique developed at the University of Pennsylvania Perelman School of Medicine in Philadelphia.

Updated findings from the pivotal phase II PACE trial show sustained benefit of the investigational BCR-ABL tyrosine kinase inhibitor ponatinib in heavily pretreated patients with resistant or intolerant chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia.

Data from an on-going early stage phase I/II trial of daratumumab in multiple myeloma continues to show promising activity. The dose-escalation study has shown that higher doses of daratumumab alone can reduce both bone marrow plasma cells as well as paraprotein.

Today we speak with Steven T. Rosen, MD, about a couple of the projects he and his group are working on, repurposing old drugs for the treatment of multiple myeloma, that will be presented this year at ASH.

Final results of a cohort from a phase II monotherapy trial of quizartinib in acute myeloid leukemia patients showed that more than half of patients 60 years of age and older who harbored an internal tandem duplication in the FMS-like tyrosine kinase 3 had a composite complete remission.

Despite a better major molecular response rate, the Src/Abl tyrosine kinase inhibitor bosutinib did no better than imatinib with regard to complete cytogenetic response in the BELA trial of patients with newly diagnosed chronic myeloid leukemia (CML).

The second generation tyrosine kinase inhibitor nilotinib (Tasigna, Novartis) has proven to be an effective treatment for imatinib-resistant patients with chronic myeloid leukemia (CML). Just as with imatinib, however, some resistance has been observed.

Most cases the clinical management of CLL patients with del(17p13.1) poses enormous challenges, and patients should be included in clinical trials whenever possible. However, there are a number of promising novel drugs and immunotherapy strategies under investigation.

It is easy to anticipate that as the complex biology of CLL continues to unfold, new prognostic and predictive biomarkers will be recognized. The discovery of genetic mutations that are key regulators of the development, growth, and proliferation of CLL leukemic cells augurs an alluring future.

One strategy would be to consider “early treatment” for patients with deletion 17p, with the goal being to delay disease progression. This strategy is currently being explored in several prospective clinical trials employing treatment regimens such as FCR, lenalidomide (Revlimid), alemtuzumab (Campath), ofatumumab (Arzerra), and others.

This review will discuss the pathophysiology associated with the del(17p13.1) interphase cytogenetic abnormality, the current generally poor outcomes in affected patients, currently approved therapeutic agents, and new agents now undergoing investigation.

The FDA today approved omacetaxine mepesuccinate (Synribo) for the treatment of adults with chronic myeloid leukemia (CML) who are resistant to other therapies.

A new review of the literature shows that melanoma is substantially more common in immunosuppressed patients, including those with prior solid organ transplant and individuals with lymphoma.

Physicians now have the luxury of focusing attention on maximizing outcomes that are already quite favorable, and of devoting more attention to improving quality of life and addressing questions of cost-effectiveness.

Resistance due to new mutations in the genes coding for the targeted proteins, as well as to changes in other signaling pathways, often develops, and newer drugs and perhaps combination approaches may be needed.

Is it reasonable to start all new CML patients on treatment with imatinib alone and continue the drug indefinitely in those who fare well, or should one start treatment with one of the newer agents or possibly with imatinib in combination with another anti-CML agent in order to secure the best possible outcome for an individual patient?

Ariad Pharmaceuticals followed last month’s request to the FDA for accelerated approval of the BCR-ABL inhibitor ponatinib with a similar request to the European Medicines Agency.