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Hematologic Malignancies Congress

David P. Steensma, MD, attending physician, hematologic oncology, Dana-Farber Cancer Institute, Boston, MA, discusses the arguments against the use of iron chelation in patients with myelodysplastic syndrome (MDS).

One of the reasons some hematologic oncologists do not use chelation is because the 2 largest prospective studies that investigated it in MDS patients experienced dropout rates close to 50%. This high of a dropout rate is unusual, and was related to adverse events, disease progression, and unrelated deaths.

Steensma notes that despite the avid promotion of using iron chelation for MDS patients there is currently no prospective data showing morbidity or mortality benefits. An ongoing prospective trial, labeled TELESTO, plans to investigate the event free survival of MDS patients when treated with iron chelation; however, due to the strong opinions of physicians the trial has had a difficult time recruiting participants. Some retrospective studies support the use of iron chelation but Steensma explains that retrospective studies are inherently biased because the cause of a decision may have been due to an unrelated factor.

There is generally a low occurrence of side effects to chelation treatment when it is given correctly. The most common adverse events are diarrhea and an upset stomach, or more seriously, kidney failure. The overall safety and efficacy of iron chelation for patients with MDS remains greatly unknown. Without further prospective data it is difficult to address the concerns regarding the true risk and benefit balance of this treatment.

Dr. David Steensma, from Dana-Farber Cancer Institute, Discusses Iron Chelation Therapy for MDS

Dr. Steensma Discusses Iron Chelation Therapy for MDS

Harry P. Erba, MD, PhD, associate professor, Department of Internal Medicine, University of Michigan Health System, discussed the management of chronic myeloid leukemia (CML) treatment at the 16th Annual International Congress on Hematologic Malignancies.

Erba noted that certain characteristics of patients with CML can affect therapeutic outcomes. For example, the deletion of derivative chromosome 9 is associated with the loss of tumor suppressor genes. This mutation can be detected through a FISH (fluorescent in situ hybridization) analysis.

In another example, Erba said patients with 

 kinase domain mutations commonly experience acquired resistance to imatinib mesylate (Gleevec), a standard of treatment for many patients with CML. The expression of these mutations can be monitored through the use of PCR (polymerase chain reaction) testing.

While these methods are fairly noninvasive, Erba suggests following the guidelines set forth by the National Comprehensive Cancer Network.

“I recommend a more thorough evaluation of the disease status at the time of diagnosis,” Erba said. “The patient should have a bone marrow biopsy. It gives you morphological evidence of accelerated phase with fibrosis or clustering of immature cells that might be important in choosing the right therapy.”

Erba said other mutations might be closely associated with patient response to tyrosine kinase inhibitors (TKIs), as demonstrated in the ENESTnd trial presented at ASCO 2011. ENESTnd demonstrated the superiority of nilotinib over imatinib in patients with newly diagnosed CML.

In the study, mutational analysis revealed that overall, the number of new mutations occurring in the imatinib arm was double the number in the 2 nilotinib arms. The occurrence of multiple 

 mutations (mutations associated with nilotinib and imatinib resistance) was similar across all treatment groups. Of note, incidence of disease progression to accelerated phase or blast phase was greater in patients with new mutations receiving imatinib than those receiving nilotinib, potentially suggesting nilotinib’s superiority for these patients.

Finding the right TKI inhibitor in earlier stages of the disease makes an enormous difference, Erba said. “The key to using TKI therapy is to prevent the progression to advanced stage disease.”

<<< View the full coverage from the 16th Annual International Congress on Hematologic Malignancies.

Certain characteristics of patients with CML can affect therapeutic outcomes. 

Managing Chronic Myeloid Leukemia Treatment

While the watch-and-wait method is frequently employed in patients with chronic lymphocytic leukemia (CLL), there are a number of prognostic factors that can help identify those at a high risk for disease progression who may benefit from early intervention.

William G. Wierda, MD, PhD, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, discussed these factors in a presentation at the 16th Annual International Congress on Hematologic Malignancies.

Wierda and colleagues developed a weighted multivariate model for identifying high-risk patients, published recently in the 

 (2011;29(31):4088-4095). The model was used to develop a nomogram that calculates 2- and 4-year probabilities of treatment and estimates the median time to first treatment.

Data for the model came from 930 patients with CLL who did not have active disease requiring treatment within three months of the start of the trial, conducted between January 2004 and December 2009.

The model incorporates traditional laboratory and clinical factors such as age, platelet counts, and hemoglobin levels with newer prognostic factors such as chromosome abnormalities measured by fluorescent in situ hybridization (FISH), immunoglobulin heavy chain variable gene (

) mutation status, and ZAP-70 leukemia cell expression evaluated at first patient visit.

The presence of chromosomal abnormalities involving the 11q deletion or the 17p deletion as determined through FISH was associated with high-risk categories.  Other factors may include 

 mutation status, the involvement of three lymph node sites, increased size of cervical lymph nodes, and higher levels of serum lactate dehydrogenase.

However, the degree in which each of these prognostic factors affects individual patients can vary.

"Not all of these factors are important for each patient group," Wierda said. "Not all prognostic factors are created equally."

In another study, Wierda and colleagues evaluated pretreatment characteristics in 595 previously untreated patients who had National Cancer Institute Working Group indications to initiate front-line therapy for predictors of complete response (CR), time to treatment failure (TTF), and overall survival (OS). Like the other study, multivariable models were developed for all three endpoints. (

In the retrospective analysis, the study authors found that front-line treatment regimen was a significant independent predictive factor for all three endpoints and that chemoimmunotherapy was the superior treatment regimen.

When the front-line treatment was taken into consideration, independent patient characteristics associated with CR included age and beta(2)-microglobulin (beta-2M) levels. TTF was independently associated with age, beta-2M, percent lymphocytes in bone marrow, and treatment regimen. Improved OS was independently associated with younger age, lower beta-2M, and treatment regimen.

A number of prognostic factors can help identify those at a high risk for CLL progression who may benefit from early intervention.

New Model Helps Guide Treatment Options in CLL

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

Dr. Erba Describes Proper Diagnostic Testing of CML

Kieron Dunleavy, MD, a staff clinician with the National Cancer Institute in Bethesda, MD, discusses the changes that have occurred in the understanding of diffuse large B-cell lymphoma (DLBCL) in the past 10-15 years.

DLBCL is the most common subtype of non-Hodgkin's lymphoma. Louis Staudt, MD, PhD, and the Lymphoma/Leukemia Molecular Profiling Project (LLMPP), which focused on the identification of distinct subtypes of DLBCL using gene expression profiling, largely defined the understanding of its taxonomy.

Research from the LLMPP resulted in 3 distinct molecular subtypes of DLBCL. Each type expressed unique characteristics, the first demonstrated germinal center B-cells, the second type showed gene activations in the peripheral blood B-cells, and the primary mediastinal B-cell type.

The delineation of 3 DLBCL subtypes provides the potential to find novel agents and treatment that affects each type specifically. Targeted approaches and agents are currently being investigated.

Dr. Kieron Dunleavy from the National Cancer Institute Discusses 3 Molecular Subtypes of DLBCL 

Dr. Dunleavy Discusses 3 Molecular Subtypes of DLBCL

For newly diagnosed multiple myeloma patients, clinical oncologists have a number of important decisions to make regarding the course of treatment, and while there are some questions that might not have definitive answers, a number of studies suggest that there is a right and wrong way to proceed with initial therapy and transplant eligibility.

Sundar Jagannath, MD, director of the Multiple Myeloma Program at the Tisch Cancer Institute at Mount Sinai Medical Center in New York City, presented a review of this information at the 16th Annual International Congress on Hematologic Malignancies.

In his presentation, Jagannath said that many treating oncologists might question whether to provide bortezomib (Velcade) plus melphalan-prednisone (VMP) as a front-line treatment for multiple myeloma patients instead of melphalan-prednisone (MP) alone. However, based on the results of the phase III VISTA trial presented at the American Society of Hematology meeting in 2011, Jagannath said that adding bortezomib is the right course of action for these patients (

). The VISTA study showed that after 5 years of follow-up, patients who received VMP experienced a 13.3-month increase in overall survival (OS) compared with patients who only received MP. After a median follow up of 60.1 months, median OS was 56.4 months for patients who received VMP versus to 43.1 months for patients who received MP (HR 0.695, 

 = .0004). There was a 31% reduced risk of death with the VMP regimen.

"This suggests that there is benefit to using a more aggressive therapy approach upfront," Jagannath said.

Since stem cell transplantation is frequently used as a treatment option, Jagannath said that treating physicians should consider whether the patient is eligible to receive a transplant before proceeding with chemotherapy. Historically, high-dose melphalan coupled with an autologous stem cell transplantation has resulted in higher response rates and longer remission times than traditional chemotherapy. However, some studies have suggested that newer therapies such as bortezomib, thalidomide, and lenalidomide could affect transplantation outcomes.

A number of studies suggest that there is a right and wrong way to proceed with initial therapy and transplant eligibility for patients with multiple myeloma.

Current Trends in the Treatment of Newly Diagnosed Myeloma

Even though diffuse large B-cell lymphoma (DLBCL) is often viewed as a single type of non-Hodgkin lymphoma, research has shown that the disease is actually heterogeneous, suggesting that patients with varying subtypes should receive different courses of treatment.

Kieron Dunleavy, MD, a staff clinician with the National Cancer Institute, presented the available research on these DLBCL subtypes at the 16th Annual International Congress on Hematologic Malignancies.

Dunleavy said that there are 3 key subtypes: germinal center B-cell like DLBCL (GCB), activated B-cell DLBCL (ABC), and primary mediastinal B-cell lymphoma (PMBL).

Knowing these subtypes can help researchers determine appropriate targets for both distinguishing among subtypes and treating the disease. For example, the B-cell lymphoma 6 (BCL6) protein is associated with follicular lymphoma, but research has shown a close association between the protein and GCB.

“BCL6 almost always appears in GCB DLBCL,” Dunleavy said.

Another protein, c-MYC, is closely associated with GCB. Dunleavy said that patients with lymphoma treated with R-CHOP (rituximab [Rituxan], cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone) had a much worse prognosis if they were c-MYC—positive.

Based on early clinical trials, there is at least 1 therapeutic agent that appears to have had positive results on the ABC subtype. In a study (

) presented at the 2011 American Society of Hematology Annual Meeting, the Bruton’s tyrosine kinase inhibitor PCI-32765 was tested in 8 patients with relapsed or refractory ABC DLBCL. The results showed that 2 patients achieved complete response for 11+ and 5 months, respectively; 3 patients achieved stable disease for 4, 2, and 2 months, respectively; and 3 patients had progressive disease. The drug was generally well tolerated across the patient population.

“We've seen a wide range of activity with this drug,” Dunleavy said. “It’s certainly a promising agent.”

Research has shown that DLBCL is heterogeneous, suggesting that patients with varying subtypes should receive different courses of treatment. 

New Directions in Relapsed/Refractory Diffuse Large B-cell Lymphoma

Stephen Ansell, MD, PhD, professor of medicine at the Mayo Clinic in Minnesota, explains the 2 main types of patients with Waldenström Macroglobulinemia (WM), a rare type of slow-growing, non-Hodgkin lymphoma.

Some types of WM present with very few symptoms and are generally only detected because the monoclonal immunoglobulin M antibody, or macroglobulin, protein that is overproduced in WM is detected. This type is generally referred to as indolent WM and may not require therapy, these patients are generally monitored without being treated and will not require treatment for many years.

Patients with WM that present symptoms, which includes weakness, swollen lymph nodes, severe fatigue, nose bleeds, weight loss, and visual and neurological problems, require treatment. Treatment will begin with plasmapheresis followed by chemotherapy plus rituximab.

Dr. Stephen Ansell from the Mayo Clinic Describes WaldenstrÃ¶m Macroglobulinemia

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