ASCO 2009: E-Review in Hematology

 Practical Implications for Today: Dr. Rosen’s Perspective

In spite of significant advances in the understanding and treatment of hematologic malignancies over the past 5 years or so, these cancers remain challenges for clinicians. We always await the results of studies presented at the annual meeting of the American Society of Clinical Oncology (ASCO), hoping that they will be practice-changing for us and life-altering for our patients. This year, at the 45th ASCO in Orlando, we instead heard results that further refined or validated the treatment approaches we often take.

The introduction of rituximab (Rituxan) in the treatment of non-Hodgkin’s lymphoma was perhaps the greatest advance we have seen in the treatment of this malignancy. Now used in conjunction with CHOP (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisolone) chemotherapy and other combinations, rituximab’s role continues to be refined, as studies at ASCO 2009 showed. Essentially, rituximab applied at any time in treatment offers improvement in many lymphomas, including follicular lymphoma (FL) and aggressive lymphomas such as diffuse large B-cell lymphoma (DLBCL). It is interesting that we are now hearing the results of studies initiated before we routinely employed rituximab-now we have to determine how their results apply in the rituximab era. We are evaluating whether we can dose-intensify R-CHOP and whether we should give prolonged treatment with rituximab.

Multiple myeloma (MM) is still challenging for all age groups, but for the elderly (the most frequently affected group), the 5year survival rate is about 10% lower than for patients younger than 65. Strategies to improve outcomes in our older patients are greatly needed. Identification of the proteosome as a pivotal target for treatment led to the approval of bortezomib (Velcade), and now we are evaluating the immunomodulatory agents (thalidomide and lenalidomide [Revlimid]) for treatment in this setting, as well as additional proteosome inhibitors that we hope will be more tolerable or offer options for patients who become resistant to current treatment.

The ASCO abstracts summarized in this review address these questions, and should help you refine your treatment approaches to these common but still challenging hematologic malignancies.

R-CHOP14 No More Effective Than R-CHOP21 in DLBCL

For diffuse large B-cell non-Hodgkin’s lymphoma, survival outcomes have been improved by adding rituximab to standard therapy with cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisolone (CHOP21). Compared to the standard CHOP21 regimen, a 14-day cycle of CHOP has been shown in some settings to have benefits. As a result, Cunningham et al (abstract 8506) compared these regimens with the addition of rituximab (R-CHOP21 vs R-CHOP14) in a large population of over 1,000 patients, nearly two-thirds of whom had stage III/IV disease. The study is important as it reflects what many hematologists have already been doing in their own practices-that is, adapting R-CHOP for dose intensification.

To my surprise, we learned that R-CHOP14 was not more effective than the standard of care. There were no distinct advantages to dose intensification. The follow-up was less than 2 years, and with longer follow-up of these patients I believe we may yet see a survival difference with R-CHOP14, as this was a large study with many strengths and was powered to show a difference in overall survival. In the standard arm, we did see slightly more neutropenia (patients were not automatically receiving G-CSF), and some suggestion that patients were more likely to discontinue treatment early, compared to R-CHOP14. Sufficient follow-up is critical for reaching a conclusion on this study, as its meaning remains unclear at this point. Meanwhile, based on the results to date, R-CHOP21 remains the standard of care. 

Prolonged Administration of Rituximab May Be Beneficial in FL

Single-agent rituximab produces response rates between 50% and 70% in follicular lymphoma, depending upon the population studied. The study by Ghielmini et al (abstract 8512) was conducted to determine the proportion of patients who might respond to a prolonged treatment approach, and to identify predictors of response. Patients who responded to 4 weekly rituximab doses were then randomized to consolidation with 4 additional doses at 2-month intervals or to observation. Patients who received the additional drug experienced a more sustained event-free survival-in fact, the time to progression was almost doubled at 5 years. While not statistically significant, there was also a slight survival trend favoring additional rituximab (P = .09). The only significant prognostic factor for event-free survival, in the multivariate analysis, was receipt of consolidation rituximab. It is possible that the optimal way to give rituximab is with a prolonged schedule, though we need to be assured that this exposure is safe. There were 22 cases of second malignancy, though they were not more abundant in the prolonged arm.

While this study raised no clear safety signal, there has been rising concern that excess exposure to rituximab is associated with the development, though rare, of progressive multifocal leukoencephalopathy (ie, the JC virus). Our group examined this association in an article published this month in Blood. The potential risk related to very prolonged exposure to rituximab may be one caveat to its use, although it is also possible that duration has nothing to do with risk. Whether therapies that disturb the immune system could be harmful with prolonged exposure to this useful agent is an issue we need to sort out before settling on prolonged rituximab as a new standard of care.  

Rituximab Adds Benefit to Chemotherapy in DLBCL

In DLBCL, we know that giving rituximab with CHOP can improve survival. A number of studies have also shown survival to be increased when rituximab is given with a more intensive CHOP regimen, followed by autologous transplantation, in younger patients with adverse prognostic factors. At ASCO, Mounier et al (abstract 8507) further evaluated this approach, assessing whether combining rituximab to dose–intense ACVBP (doxorubicin [Adriamycin], cyclophosphamide, vindesine, bleomycin, prednisone) prior to transplant, in a population of patients < 60 with at least two adverse risk factors, would translate into a survival benefit. The study was initiated a number of years ago, when less was understood about the benefit of rituximab in this setting; therefore, it primarily adds to what we already know about this approach.

Compared to historical controls receiving ACVBP without rituximab, the addition of rituximab significantly increased complete response rates, which were 73% in this study, and significantly increased progression-free survival (76%) and overall survival (81%) at 3 years. The results appeared robust even in patients with multiple poor prognostic factors. Toxicity rates were no higher with the addition of rituximab in this study than with chemotherapy alone in the previous trials without rituximab, and full treatment could be tolerated by 75% of these young high-risk patients. Since most patients went to transplant, we cannot fully determine the benefit of receiving a transplant or not, although we did see a somewhat greater survival benefit in transplanted patients. This is still just a phase II study, and there are questions that need to be answered before the findings can be implemented clinically. Meanwhile, the study further establishes the value of rituximab.

Addition of Thalidomide May Improve Outcomes in Elderly With MM

In multiple myeloma patients, the VMP combination (bortezomib, melphalan [Alkeran], and prednisone) has been shown to be superior to MP alone. For patients who relapse or become refractory to treatment, adding thalidomide to VMP can often induce a complete response. The large randomized study presented at ASCO by Palumbo et al (abstract 8515) further assessed the benefit of thalidomide when added to VMP earlier in the treatment course in treatment-naive patients. The drug was given with VMP and continued for 35 days. Patients received nine 5-week cycles.

At 3 years there were no significant differences among the VMP and VMPT groups in progression-free and overall survival, though numerically more patients were progression-free with the addition of thalidomide. There was, however, a highly significant difference in the rate of complete responses (35% with thalidomide vs 21% with VMP alone). Peripheral neuropathy rates were no higher with thalidomide, and the weekly infusions of bortezomib in this study resulted in less neuropathy than is seen with twice-weekly infusions. To determine clear benefits with thalidomide, we will need longer follow-up.    

Similar Outcomes With R-ICE or R-DHAP in Relapsed DLBCL

In DLBCL patients with chemosensitive relapse, salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation is the standard of care. The CORAL study (abstract 8509), a randomized Intergroup trial, compared regimens that are often used-R-ICE (ifosfamide, carboplatin, etoposide + rituximab) and R-DHAP (dexamethasone, cytarabine [Ara-C], cisplatin [Platinol] + rituximab)-in DLBCL CD+ patients experiencing their first relapse or who were refractory to first–line therapy. Patients who responded received BEAM (carmustine [BiCNU], etoposide, cytarabine [Ara-C], melphalan) and ASCT (autologous stem-cell transplantation) and were then randomized to observation or rituximab for 1 year. The study found that both regimens had similar activity and mobilization ability, although there were fewer adverse events with R-ICE. The investigators evaluated for prognostic factors and found that prior rituximab exposure, relapse < 12 months, and secondary International Prognostic Index > 1 heralded lower response rates and shorter survival.

A correlative biomarker study is ongoing to better elucidate the population of patients with poor prognosis. A new profile of patients who relapse or become refractory after rituximab treatment is expected to come out of the results of the CORAL trial, and should inform the design of future studies with new agents. Meanwhile, these induction regimens appear to be equivalent, though R-ICE may be slightly less toxic and is my own preferred regimen.  

Dr. Rosen's perspective on Compelling Data for Tomorrow

Abstract Summaries

Abstract 8506
A phase III trial comparing R-CHOP14 and R-CHOP21 for the treatment of patients with newly diagnosed diffuse large B-cell non-Hodgkin's lymphoma
D. Cunningham et alAbstract 8512
Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in study SAKK 35/98
M.E. Ghielmini et alAbstract 8507
Benefit of rituximab combined to ACVBP (R-ACVBP) over ACVBP in 209 poor-risk DLBCL patients treated with up-front consolidative autotransplantation: A GELA phase II trial (LNH 2003-3)
N. Mounier et alAbstract 8515
A phase III study of VMPT versus VMP in newly diagnosed elderly myeloma patients
A.P. Palumbo et al

Abstract 8509
R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma followed by autologous stem cell transplantation: CORAL study
C. Gisselbrecht et al