NEW YORK CITY-Early, intensive treatment of mantle cell lymphoma (MCL), although increasingly effective for young patients with aggressive disease, does not apply to many older, asymptomatic patients. A delay in treatment might not affect long-term outcome and avoids treatment side effects for many MCL patients. That was the word from lymphoma experts speaking here at the Great Debates and Updates in Hematologic Malignancies meeting.
"Cures in MCL remain rare, and the toxicities of effective treatments are considerable," said Koen Van Besien, MD. "Treatment even with novel therapies does not have many advantages and applies to only a select group of patients."
The audience at the Great Debates and Updates in Hematologic Malignancies meeting here was asked to respond to the question: Should an asymptomatic patient with low-tumor-burden MCL be observed or receive immediate treatment? Initially, a little less than half of the respondents were leaning towards observation, but after the two debaters squared off, the majority voted that they believed that watchful waiting was the best course of care.
Observation Alone
For many patients, MCL is still a neglected disease, said Koen Van Besien, MD, who suggested that after a risk/benefit assessment, watchful waiting was preferred over immediate treatment.
"The risks of treatment are multiple. It's also expensive. And there are late toxicities, such as myelodysplastic disorder. Novel agents are supposed to be safer than chemotherapy. The truth is we don't know yet."
He said that unlike proponents of immediate treatment, who say that watchful waiting may set up a patient for worse outcome later on, he does not necessarily believe it is better to intervene early: "There are great advantages to watchful waiting. Watchful waiting may result in prolonged maintenance of quality of life and is preferable for many patients. Delay in treatment does not affect long-term outcome."
Only a select group of patients are candidates for immediate therapy, he continued, including "those patients who are younger and have excellent performance scores who can go to transplant." Overall survival for MCL patients is determined by the biological features included in the Mantle Cell Lymphoma International Prognostic Index (MIPI).
"Patients who have an excellent performance score have a low MIPI score and a median life expectancy that ranges from four to five years," he said.
Transplantation has improved over the last few years thanks to the purging effect of rituximab, Van Besien noted. Clinical trials show that rituximab plus an autologous transplant leads to an overall survival rate of 33 to 70 percent. Recent data using a combination of intensive chemotherapy with rituximab with autologous transplant shows encouraging long-term overall survival rates about 60 percent at five years and 70 percent for progression-free survival-"This is in highly selected, younger patients. Many of these patients have early molecular relapses. This is not definitive therapy," he cautioned.
Handling the toxicities of intensive therapy can be quite difficult, he noted. Intensive therapies have complications and risks related to hospitalizations, transfusions, and neutropenic fever. "Why treat people we don't have to treat?" he asked.
He pointed to a successful observation trial conducted by researchers at Weill Cornell Medical College. A watchful waiting approach was applied to 111 MCL patients, median age of 63, with average risk factors, many of them with elevated LDH, high IPI score, and bone marrow involvement.
Of the 111, 75 received a variety of treatments. "Strikingly, very few had transplants," he said. "And the median overall survival-7.1 years-was similar to that for autotransplant. Clearly, this suggests that watchful waiting and less aggressive treatment is a reasonable approach and does not hurt patients."
In addition to the Weill Cornell research, other studies have found a three-year overall survival rate with watchful waiting that is similar to aggressive treatment. Van Besien noted that "a sizeable minority" of patients (about one-quarter) in these trials were never treated, and that observation is the best way to discover these patients.
"Interestingly, those observed longer tended to do better in the long-term than those who required initial treatment," he said, adding that these patients probably are biologically different.
In conclusion, he said, "Intensive treatment is increasingly effective, but it is applicable to relatively few patients and has considerable drawbacks. Delay in treatment, occasionally for prolonged periods of time, is possible and does not affect long-term outcome."
Immediate Treatment
Andre Goy, MD, noted that overall survival for MCL patients has increased over the past two decades. Intensive approaches have led to a very durable progression-free survival time in excess of five years. "AraC-containing regimens have led to very high complete response rates and molecular CR, which clearly has impacted outcome. Emerging novel therapies and maintenance strategies will play a bigger role," he said, adding that tumor burden and symptoms or clinical prognostic factors do not truly help diagnostic decisions.
Most-i.e., 80 to 90 percent of-MCL patients have advanced-stage disease, he noted. "Half to two-thirds of MCL patients even with high tumor burden or blastoid histology have no beta symptoms. What are prognostic factors to help decide on treatment? Can we identify a truly more biologically indolent MCL?"
With the introduction of new treatments, researchers are discovering more about the disease, including subtypes of MCL, Goy noted. Early-stage MCL is a rare disease, and only a fraction of patients have long-term disease. "Most MCL patients at diagnosis typically have an indolent, asymptomatic presentation. MCL at advanced stages has a poor outcome."
Better recognition of MCL and better supportive care have, to some extent, led to improvements in overall survival, but "the introduction of dose-intensive strategies and monoclonal antibodies-rituximab-has led to longer progression-free intervals," he said.
Novel therapies have been developed in the relapse setting for a disease that otherwise was typically chemotherapy-resistant, and none of these therapies were available before the mid-2000s, he noted.
The introduction of rituximab plus CHOP chemotherapy increased complete response rates and time to progression, but did not change progression-free survival. "Clearly, there is an advantage in dose-intensive approaches such as R-DHAP [rituximab, dexamethasone, Ara C, and cisplatin] in terms of overall survival," he said. "R-CHOP is suboptimal and should not be used."
He added that minimal residual disease (MRD) status after induction is an independent prognostic factor for MCL-"MRD will be an important endpoint in future trials and will translate into increased outcome."
A deep, early response has an impact on survival, Goy said. Achieving a CR in frontline therapy of MCL improves overall survival. "Molecular CR has a huge impact on outcome," and patients with low tumor burden are more likely to have a higher chance to achieve a molecular complete response. MCL has the highest percentage of secondary cytogenetic abnormalities among non-Hodgkin's lymphomas.
"Recent strategies with maintenance show a benefit in overall survival in responders after rituximab plus chemotherapy," he said.
Several novel therapies are starting to modify the MCL landscape in the relapse setting, Goy noted. In spite of a clear improvement in overall survival, there still is no consensus on best treatment. The disparity among studies might also reflect the heterogeneity of the disease, he said. "Can we stratify patients beyond tumor burden and being symptomatic?"
There are a growing number of prognostic variables beyond MIPI, including beta-2 microglobulin, blastoid variant, growing molecular heterogeneity, PCR signature, and proliferation index.
The awareness of MCL as a complex biological entity is growing, he said. "We are trying to move forward to identify markers that help characterize MCL. The five to 10 percent of truly indolent MCL patients with a high white blood cell count, who are hypermutated, with a noncomplex karyotype, should be watched carefully and not enrolled in trials."
In conclusion, Goy said, "Five-year overall survival of MCL has improved from 22 percent in the period of 1975 to 1985 to 47 percent from 1996 to 2004. Improvements are due to dose-intensive approaches, AraC-containing regimens, and rituximab, but as yet, not novel therapies." Emerging novel therapies and maintenance strategies will play a bigger role in the near future.
"There is a great heterogeneity, with MCL with a subset of truly indolent MCL that we could potentially watch and wait for years. Others have classic MCL with a spectrum of disease that should be treated until we have better stratification and biological markers." Non-cytotoxic-based options in elderly or low-risk patients are currently being tested, he added.
David Straus: Both Positions Are Correct
After the debate, not many in the audience changed their minds, and just slightly more than a majority (55%) voted for observation over immediate treatment.
David Straus, MD, Attending Physician in the Division of Hematologic Oncology at Memorial Sloan-Kettering Cancer Center, commented, "Both debaters are right, depending on the patient. For a patient with aggressive disease, we would want to treat. For an older patient who does not have aggressive disease, there is no harm in observation."
Young patients should receive rituximab-based chemotherapy with consolidation followed by autologous transplant, he continued. "Provide sequential R-CHOP followed by an intensive regimen, such as high-dose Ara C, and if the patient is PET scan-negative, then send the patient on to transplant.
Older patients are a subgroup more like indolent lymphoma. "Certainly, we can observe this group," said Strauss. "For an older, asymptomatic patient there is not a lot we can do, and there is no harm in simply following this patient."