Harry Erba, MD, PhD, professor of medicine and director, University of Alabama at Birmingham Hematologic Malignancy Program, discusses the results of a phase II study analyzing azacitidine and gemtuzumab ozogamicin as induction and post-remission therapy in patients of age 60 and older with previously untreated non-M3 acute myeloid leukemia.

Data from the good risk cohort were presented at ASCO 2012. The results of the poor risk patients were presented at the 2012 American Society of Hematology Meeting. Of the 54 total poor risk patients that were treated, 35% achieved a complete remission or CRi. The study found median progression-free survival to be seven months and median overall survival six months.

In the entire study, between 30% and 50% of patients responded to the combination of azacitidine and gemtuzumab ozogamicin, Erba says, and that it remains unclear how patients would have responded to either agent as monotherapy or to intensive chemotherapy.

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Harry Erba, MD, PhD, discusses the results of a phase II study analyzing azacitidine and gemtuzumab ozogamicin as induction and post-remission therapy in patients of age 60 and older with previously untreated non-M3 AML.

Dr. Erba on Azacitidine and Gemtuzumab Ozogamicin

Harry Erba, MD, PhD, professor of medicine and director, University of Alabama at Birmingham Hematologic Malignancy Program, explains the declining treatment-related mortality (TRM) rates in AML patients.

In the last 20 years, Erba says, the outcomes of patients undergoing allogeneic hematopoietic stem cell transplant for AML has improved. There have been advances in the treatment such as better prophylaxis against fungal infections, better prophylaxis against cytomegalovirus reactivation, and human leukocyte antigen typing.

A report by the Southwest Oncology Group (SWOG) and MD Anderson (MDA) Cancer Center found that a community-wide interest in the use of less-intesive treatments than the standard 3+7 chemotherapy produced lower TRM rates from 1991-2009. In the SWOG group, TRM fell from 18% in the 1991-1995 period, to 13% in the 1996-2000 period, to 12% in the 2001-2005 period, and to 3% in the 2006-2009 period. The MDA group TRM declined in a similar fashion: from 16% in the 1991-1995 period, to 14% in the 1996-2000 period, to 9% in the 2001-2005 period, and to 4% in the 2006-2009 period.

The report concluded that there has been a reduction in TRM following “intensive” induction possibly due to better supportive care.

Dr. Erba on Treatment-Related Mortality Rates in AML

Harry Erba, MD, PhD, associate professor, Department of Internal Medicine, University of Michigan Health System, notes that molecular monitoring in patients with chronic myeloid leukemia (CML) allows the physician to assess the bone marrow in a non-invasive way, once the tumor has entered into complete cytogenetic remission.

Large controlled international studies have used polymerase chain reaction analyses to demonstrate that a major molecular response (MMR) that is achieved before 12 months, following the introduction of therapy, is an adequate surrogate marker for progression-free survival. According to the international standards, MMR corresponds to a 1000 fold reduction in the BCR-ABL transcript, which greatly diminishes tumor growth. 

Erba believes the greatest benefit of molecular monitoring is to know exactly when a patient has developed resistance to treatment using a peripheral blood testing.

Dr. Harry Erba, from University of Michigan Health System, Discusses Molecular Monitoring for CML

Dr. Erba Discusses Molecular Monitoring for CML

Harry Erba, MD, PhD, associate professor, Department of Internal Medicine, University of Michigan Health System, explains that since the advent of a tyrosine-kinase inhibitor (TKI), such as imatinib, the first-line therapy for chronic myeloid leukemia (CML) has undergone drastic changes.

The frontline therapy for patients with newly diagnosed chronic-phase CML has moved away from allogeneic hematopoietic stem cell transplantation (HSCT) towards TKIs, which have fewer side effects. However, at this point the only known treatment that is potentially curative for CML is allogeneic HSCT.

The goal of this new first-line therapy is to prevent the disease from progressing to the accelerated or blast crisis phases. While in chronic-phase most patients are generally asymptomatic.

Patients that receive TKIs in the frontline generally experience complete cytogenetic responses. However, Erba explains that cytogenetic and molecular responses should be treated as surrogate endpoints that help determine if the patient will achieve long-term survival. These patients should be monitored closely for relapses.

Dr. Harry Erba, from the University of Michigan Health System, Discusses the Frontline Treatment of CML

Dr. Erba Discusses the Frontline Treatment of CML

Harry Erba, MD, PhD, associate professor, Department of Internal Medicine, University of Michigan Health System, discusses the full histopathological examination that should be performed when a patient is diagnosed with chronic myeloid leukemia (CML).

If the routine complete blood count shows leukocytosis and a shift in maturity, basophilia, and splenomegaly are observed, 98 times out of 100 the patient will have CML, which is usually diagnosed in the chronic phase. This holds true whether constitutional symptoms are present or not.

There are ways to make a non-invasive diagnosis for CML using fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) to check for a BCR-ABL gene rearrangement in the peripheral blood. However, Erba does not recommend using this method, stating that CML requires a more thorough baseline analysis.

Bone marrow biopsy is critical at the time of diagnosis to provide morphologic evidence of the phase. The biopsy can show fibrosis or the clustering of mature cells indicating whether the cancer is in chronic, accelerated, or blast phase. Knowing the phase of the disease will help choose an appropriate therapy.

A cytogenetic analysis of the chromosomes at metaphase, the most condensed and easiest to distinguish phase in the cell cycle, may demonstrate clonal evolution or other changes that could upgrade the patient to a higher phase. The analysis may also show that some patients are not Philadelphia chromosome positive at metaphase, making it less likely to mistake a negative test later as a complete cytogenetic remission.

Additionally, Erba recommends the completion of a FISH analysis at the time of diagnosis. Approximately 10% of patients have a variant FISH pattern, which is important to know early on.

The final test that Erba recommends is a reverse transcription (RT)-PCR. The results of this test can be used as a baseline for response and to verify that the primers used in most commercial laboratories for detecting the BCR-ABL transcription are applicable. Some patients demonstrate variant break points, which makes it easier to arrive at the wrong conclusions if the RT-PCR test is not completed.

Dr. Harry Erba, from the University of Michigan Health System, Describes Proper Diagnostic Testing of CML

Harry Erba, MD, PhD

Articles

Dr. Erba on Azacitidine and Gemtuzumab Ozogamicin

Dr. Erba on Treatment-Related Mortality Rates in AML

Dr. Erba Discusses Molecular Monitoring for CML

Dr. Erba Discusses the Frontline Treatment of CML

Dr. Erba Describes Proper Diagnostic Testing of CML