author: Dr. Lawrence D. Kaplan University of california San Francisco 2008-07-28
Introduction
Non-Hodgkin’s
lymphoma (NHL) is a cancer of lymphocytes, a type of white blood cell
that plays an important role in the immune system. At present, more than
20 different types of non-Hodgkin’s lymphoma have been identified. The
choice of how to treat a lymphoma may be dependent on being able to
identify the precise NHL subtype. Survival rate also tends to be
dependent upon the type of lymphoma. A few definitions Introduction
- Complete response: Complete disappearance of all evidence of disease based upon scans, bone marrow biopsy etc. Disease may still relapse at a later time.
- Overall Survival: Percent of patients alive at a specified point in time.
- Progression-free Survival: Percent of patients who have not developed progression of their lymphoma or died from lymphoma at a specified point in time.
- Event-free survival: Percent of patients who have not developed progression of lymphoma or died from any cause at a specified time point.
How do I get non-Hodgkin’s lymphoma?
Lymphoma
occurs when the normal checks on cell growth and division of
lymphocytes break down for one reason or another. Consequently, cells
don’t die their natural death, and so accumulate and form tumors. This
may occur as a result of faulty communication between cells of the
immune system and/or because the normal signaling pathways within a
lymphocyte that trigger cell death don’t work properly. Sometimes these
changes occur as a result of certain viral infections, chemical
exposures, or immune deficiency states, but most of the time the reasons
for the changes remain mysterious.
Lymphocytes
There
are three major types of lymphocytes: B-cells, T-cells, and NK-cells.
Under normal conditions, each of these has a specific function in the
immune system. Although any of these types of cells can give rise to a
lymphoma, B-cells account for about 85% of all non-Hodgkin’s Lymphomas.
Figure 1 illustrates how different B-cell lymphomas arise from different stages in the normal life-cycle of a lymphocyte. Most B-cell lymphomas arise out of the complex process through which the immune system is able to generate an immune response to nearly anything it is exposed to.
Figure 1. Reprinted by permission from Macmillan Publishers Ltd.: Nature Reviews Cancer, Origin of B-cell lymphomas in the germinal center of the lymph node. Küppers R. Nat Rev Cancer. 2005;5:251-262. Copyright 2005.
Lymphomas are classified based on what they look like under the microscope (pathology) and by the identification of specific molecules on the surface of the lymphoma cell that are characteristic of a given lymphoma type (This is called the immunophenotype). This immunophenotype is used to determine if a lymphoma is B-cell, T-cell, or NK-cell.
The lymphomas are also classified clinically by how aggressively they behave when people have the disease: Lymphomas are referred to as “indolent” or “low-grade” when they grow very slowly, as “aggressive” when they grow rapidly, and as highly aggressive when the grow very rapidly. Examples of this are shown in Table 1 in which NHLs are divided into B-cell or T-cell and by how aggressively they behave.
Table 1
Figure 1 illustrates how different B-cell lymphomas arise from different stages in the normal life-cycle of a lymphocyte. Most B-cell lymphomas arise out of the complex process through which the immune system is able to generate an immune response to nearly anything it is exposed to.
Figure 1. Reprinted by permission from Macmillan Publishers Ltd.: Nature Reviews Cancer, Origin of B-cell lymphomas in the germinal center of the lymph node. Küppers R. Nat Rev Cancer. 2005;5:251-262. Copyright 2005.
Lymphomas are classified based on what they look like under the microscope (pathology) and by the identification of specific molecules on the surface of the lymphoma cell that are characteristic of a given lymphoma type (This is called the immunophenotype). This immunophenotype is used to determine if a lymphoma is B-cell, T-cell, or NK-cell.
The lymphomas are also classified clinically by how aggressively they behave when people have the disease: Lymphomas are referred to as “indolent” or “low-grade” when they grow very slowly, as “aggressive” when they grow rapidly, and as highly aggressive when the grow very rapidly. Examples of this are shown in Table 1 in which NHLs are divided into B-cell or T-cell and by how aggressively they behave.
Table 1
Characteristics of clinical classifications
Indolent lymphomas tend to be more advanced when diagnosed, have a long natural history, but are rarely cured with conventional therapies. It is possible to survive for many years with an indolent lymphoma as can be seen in Figure 2. Usually such patients will require periods of therapy alternating with periods of remission. However, most will ultimately die from the disease.
Aggressive and highly-aggressive lymphomas are characterized by rapid growth and, if untreated, are rapidly fatal. However, the aggressive B-cell lymphomas, represent the most curable of the non-Hodgkin’s lymphomas. As seen in figure 2, there is a plateau in the survival curve (it levels off) indicating that many patients are cured of their disease with treatment.
An indolent B-cell lymphoma, however, has a survival curve that is more or less a straight downward sloping line indicating that the disease progresses very slowly over time, but since the line ultimately approaches “0” few people are cured.
How long it takes for a lymphoma to develop depends upon how aggressive its behavior. A Burkitt lymphoma, for example, can double its size in as few as 24 hours. Therefore it would be only a matter of weeks before the disease became evident. An indolent lymphoma however might be present for years before being identified.
How is lymphoma diagnosed?
Tissue biopsy is necessary to make the diagnosis of lymphoma and to identify the specific subtype. Unless the lymphoma actually involves the blood (this is quite rare) there is no blood test that can be used to make the diagnosis. Some physicians will use a technique called “fine needle aspiration” to try and make a diagnosis. Although this can be a helpful procedure for ruling out other causes of a mass, or for making a general diagnosis of NHL, most of the time this is an inaccurate method for diagnosis of the specific subtype of non-Hodgkin’s lymphoma and is not recommended unless obtaining surgical biopsy would pose an unacceptable risk for the patient.
Staging of Non-Hodgkin’s Lymphoma:
Stage is a measure of how extensively the disease has spread throughout the body. Typically the more advanced the stage, the poorer the prognosis, but as we will see later, this is far from the full story. The staging system that is used for NHL is called the Ann Arbor system and is shown in table 2.
The staging evaluation is completed before therapy begins and should include the following:
Computed tomography (CT) scans of the chest, abdomen and pelvis
CT of the neck if involved by exam
CT or magnetic resonance imaging (MRI) of the brain if there are neurologic symptoms
Positron emission tomography (PET) scan (a combination PET-CT may substitute for CTs)
Bone marrow biopsy
Selected patients may also undergo:
Lumbar puncture, for some patients with advanced aggressive NHL
Endoscopy (to look at colon or stomach) if involvement is suspected due to symptoms or the presence of certain sites of disease
Other staging studies may be performed if specific sites of disease are suspected by the physician.
Characteristics and treatment of individual lymphomas
Indolent B-cell Lymphomas
Follicular lymphoma:
Follicular lymphoma is the second most common NHL in western countries.
It is characterized by advanced stage III or IV disease in 85% of patients at the time of diagnosis.
Prognosis is based upon five factors identified as independently associated with outcome. Factors associated with a less favorable outcome include: 1) Stage III or IV disease, 2) Age greater than 60, 3) Hemoglobin less than 12 g/dl, 4) more than 4 nodal sites of disease, 5) Lactase dehydrogenase (LDH) greater than normal. Patients are divided into good, intermediate and poor prognostic groups based on the number of poor prognosis factors that are present at diagnosis.
The nodal groups are illustrated in Fig 3 below.
It is characterized by advanced stage III or IV disease in 85% of patients at the time of diagnosis.
Prognosis is based upon five factors identified as independently associated with outcome. Factors associated with a less favorable outcome include: 1) Stage III or IV disease, 2) Age greater than 60, 3) Hemoglobin less than 12 g/dl, 4) more than 4 nodal sites of disease, 5) Lactase dehydrogenase (LDH) greater than normal. Patients are divided into good, intermediate and poor prognostic groups based on the number of poor prognosis factors that are present at diagnosis.
The nodal groups are illustrated in Fig 3 below.
Solal-Celigny P et al. Blood. 2004; 104 1258-1265.
This research was originally published in Blood. Solal-Celigny P et al. Follicular Lymphoma International Prognostic Index. 104: 1258-1265. © American Society of Hematology."
Treatment of Follicular Lymphoma
Like all of the low-grade B-cell lymphomas, follicular lymphoma is considered to be incurable with conventional approaches to therapy. Follicular lymphoma generally occurs in an older patient population, with a median age of about 65 years. The natural history of the disease is that of a chronic illness with periods of remission induced by a variety of treatment options followed by disease recurrence and the need for additional therapy. Although survival is based on the prognostic variables described above, it is possible for some patients to survive more than 10 years with their disease. Up to about 50% of patients with follicular lymphoma will transform to a more aggressive lymphoma at a rate of about 3% per year. These transformed lymphomas can be difficult to treat.
To date there is no evidence that treating advanced follicular lymphoma (stage III or IV) at the time of diagnosis in the absence of symptoms, results in improved survival when compared to delaying treatment until symptoms develop. Survival curves from a randomized trial comparing immediate treatment vs a “watch and wait” approach in which treatment is delayed until development of symptoms are shown in the graph reached by following this link (Link to Lancet article and graph) and demonstrate no difference in overall survival for the two groups. The patients studied in this trial all had indolent lymphomas of which a majority were follicular. Since it may, in some cases, take years for symptoms to develop, the “watch and wait” approach can delay the use of treatments that may have side effects.
Up to 50% of patients with early stage (I,II) disease may be cured with local radiotherapy, but recent studies suggest that even in this population, a “watch and wait” approach may be appropriate and may still be associated with long survival.
Overall
(A) and cause-specific (B) survival in 158 patients assigned to
immediate treatment with chlorambucil and 150 assigned to observation.
Ten-year survival 34% in observation and 35% in immediate treatment
group.(From Ardessa et al. Lancet. 2003; 362: 516–22).
No
significant differences in survival were observed between these two
groups. The survival curves appear to be identical. Similar observations
have been made in several other studies from different institutions
over the years. It is, of course, important to point out that this study
evaluated patients treated with a single-agent chemotherapy regimen
which is not commonly utilized now and was performed prior to the
widespread use of the monoclonal antibody, rituximab for treating
patients with this disease (see below). Studies need to re-address this
question in the era of more effective chemo-immunotherapies..
Symptoms may include fevers, drenching night sweats, pain, weakness, bulky enlarged lymph glands, low blood counts or other symptoms depending upon the location of disease. Patients who have advanced follicular lymphoma and have these symptoms – or whose physician is concerned about the potential for development of problems due to the disease within a short period of time – should begin treatment. There are a variety of treatment options available that include monoclonal antibody therapy with agents such as rituximab, radioimmunotherapy with agents such as tositumomab or ibritumomab, chemotherapy, combinations of chemotherapy with monoclonal antibody therapy and newer targeted approaches to therapy now in clinical trials.
Symptoms may include fevers, drenching night sweats, pain, weakness, bulky enlarged lymph glands, low blood counts or other symptoms depending upon the location of disease. Patients who have advanced follicular lymphoma and have these symptoms – or whose physician is concerned about the potential for development of problems due to the disease within a short period of time – should begin treatment. There are a variety of treatment options available that include monoclonal antibody therapy with agents such as rituximab, radioimmunotherapy with agents such as tositumomab or ibritumomab, chemotherapy, combinations of chemotherapy with monoclonal antibody therapy and newer targeted approaches to therapy now in clinical trials.
Chemotherapy and Monoclonal Antibody Therapy:
Chemotherapy with a variety of single agents and combination therapies has been used for many years in the treatment of follicular lymphomas with mixed success. The 1997 introduction of the monoclonal antibody rituximab, however, has significantly improved the response rates and progression-free survival when added to chemotherapy.
Rituximab is a monoclonal antibody that binds specifically to a protein called CD-20 found on the surface of B-cells and B-cell lymphomas. When rituximab binds to the surface of the lymphoma cell it is recognized by the immune system resulting in an immune response against the tumor cell which in most cases leads to death of the cell. The drug has been studied widely in follicular and other low-grade B-cell lymphomas. It has significant activity by itself with overall response rates to weekly doses of 375mg/m2 given for four weeks in previously untreated patients of 73% (complete response 8%) and in previously treated patients of 49% with 6% complete response.
Moreover, when rituximab is added to a variety of chemotherapy regimens, it increases the response rate, complete response rate, and progression-free survival significantly when compared with chemotherapy alone (table 4). The most commonly used first-line treatment regimens are: rituximab/cyclophosphamide / doxorubicin / vincristine / prednisone (R-CHOP) and rituximab / cyclophosphamide / vincristine (R-CVP). Both are active and no randomized study has compared the two regimens. Our preference at UCSF is for R-CVP as we prefer to save the doxorubicin if needed to treat transformed lymphoma should it develop in the future. Click the link below to view an image of rituximab binding to the CD20 protein on the surface of the lymphoma cell resulting in an immune response that kills the cell.
Table 4. Combinations of rituximab with chemotherapy for previously untreated or relapsed indolent B-cell lymphoma
RR:
response rate, CR: complete response, ERS: event-free survival, PFS:
progression-free survival, TTF: time to treatment failure. CVP, CHOP,
MCP represent combinations of chemotherapy drugs. R: rituximab
Continued
or ongoing treatment with rituximab after chemotherapy has been
completed has been the subject of a great deal of study in recent years.
When rituximab is used as single-agent therapy for relapsed indolent
lymphoma, the addition of four weekly doses of rituximab every six
months for two years is associated with improvement in progression-free
survival from 7.4 to 31 months. But when compared to patients who
received additional rituximab only at the time of progressive disease,
the duration of benefit from rituximab (time until chemotherapy is
needed) is the same for both groups. In this setting therefore
maintenance rituximab may not be of real benefit for some patients.
Data from a randomized trial in the Eastern Cooperative Oncology Group do demonstrate significant benefit from the addition of two years of rituximab maintenance therapy following response to six to eight cycles of CVP chemotherapy as initial treatment for indolent B-cell lymphoma. Reduction in the risk of progression, relapse, or death for patients receiving rituximab following CVP compared to those receiving no additional treatment was 51%-64%.
Rituximab maintenance may also benefit patients who have already received rituximab in combination with chemotherapy as treatment for relapsed indolent lymphoma. Median progression-free survival was improved from 23 to 52 months when two years of rituximab maintenance was administered after response to R-CHOP when compared to the group of patients who received no maintenance therapy. It is not yet certain whether the benefits of maintenance rituximab are similar when used after initial chemo-rituximab combinations for treatment of previously untreated indolent B-cell lymphoma.
Data from a randomized trial in the Eastern Cooperative Oncology Group do demonstrate significant benefit from the addition of two years of rituximab maintenance therapy following response to six to eight cycles of CVP chemotherapy as initial treatment for indolent B-cell lymphoma. Reduction in the risk of progression, relapse, or death for patients receiving rituximab following CVP compared to those receiving no additional treatment was 51%-64%.
Rituximab maintenance may also benefit patients who have already received rituximab in combination with chemotherapy as treatment for relapsed indolent lymphoma. Median progression-free survival was improved from 23 to 52 months when two years of rituximab maintenance was administered after response to R-CHOP when compared to the group of patients who received no maintenance therapy. It is not yet certain whether the benefits of maintenance rituximab are similar when used after initial chemo-rituximab combinations for treatment of previously untreated indolent B-cell lymphoma.
Radioimmunotherapy
When
monoclonal antibody therapy (like rituximab) is used, as described
above, lymphoma cells are killed only when the antibody binds directly
to the surface of the lymphoma cell thereby initiating an immune
response; tumor cells that are not bound by antibody are not killed.
However, if a radioisotope is attached to the antibody (such as 131I or
90Y), the isotope will release radiation, killing not just cells to
which the antibody binds but to any cells that are in the area. Two such
agents are currently available: 90Y- Ibritumomab and 131I Tositumomab.
Both, like rituximab, bind to the CD20 protein and are two of the most
active agents we have for treatment of indolent B-cell lymphomas.
Nevertheless, the most effective use of these drugs is still being defined. They are active in patients who have previously received rituximab-containing regimens, but like other treatments, when used later in the course of the lymphoma, after many other treatments have been used, they are less effective. Tositumomab, when used as first-line treatment in 76 patients, produced a complete response rate of 75% and 40 of those complete responders were still in remission 4.3 to 7.7 years after treatment. A recently reported study demonstrated marked improvement in complete response and progression free survival when Ibritumomab was used following CHOP chemotherapy in previously untreated patients. An ongoing intergroup/SWOG (Southwest Oncology Group) study is comparing CHOP-rituximab with CHOP-Tositumomab as initial treatment
Nevertheless, the most effective use of these drugs is still being defined. They are active in patients who have previously received rituximab-containing regimens, but like other treatments, when used later in the course of the lymphoma, after many other treatments have been used, they are less effective. Tositumomab, when used as first-line treatment in 76 patients, produced a complete response rate of 75% and 40 of those complete responders were still in remission 4.3 to 7.7 years after treatment. A recently reported study demonstrated marked improvement in complete response and progression free survival when Ibritumomab was used following CHOP chemotherapy in previously untreated patients. An ongoing intergroup/SWOG (Southwest Oncology Group) study is comparing CHOP-rituximab with CHOP-Tositumomab as initial treatment
Vaccine Therapy
The
use of therapeutic vaccines is currently being studied in patients with
follicular lymphomas. For the most part these studies involve the use
of what are called “Idiotype” vaccines. Idiotypes are proteins that are
expressed on the surface of a lymphoma cell that are unique to that
individual person’s lymphoma. Different recombinant DNA technologies can
be used to produce large amounts of these idiotype proteins from a
small sample of a lymphoma tumor. When these individualized proteins are
injected into the patient with lymphoma an immune response to that
protein can be generated. Since the patient’s lymphoma cells all express
this same protein, it is hoped that this immune response will provide
long-term control of the lymphoma. Early studies suggested that patients
who develop an immune response to the idiotype have better disease
control. The major studies in which patients receiving these idiotype
vaccines (following chemotherapy or rituximab) have been compared with
patients receiving inactive (placebo) vaccine have completed enrollment
and we are now awaiting results. These studies will determine whether
these vaccines are truly effective.
Bone Marrow Transplantation for Indolent B-cell Lymphoma:
Bone
marrow or peripheral blood stem cell transplant does play a role in the
management of some patients with indolent lymphomas. For a more
detailed description please see the separate Knol on Bone Marrow
Transplantation.
Autologous stem cell transplant represents a way of administering very high doses (in fact, what would normally be lethal doses) of chemotherapy to an individual with the ability to rescue the patient from these lethal doses by collecting and storing bone marrow stem cells in advance of the chemotherapy and then returning them to the patient after chemotherapy. These cells will then return to the bone marrow where they will form new blood cells, allowing the bone marrow to recover from the effects of the chemotherapy. Indolent lymphomas cannot be cured with this approach to therapy. However, studies have demonstrated that survival can be significantly prolonged with this treatment. It may be useful for some patients later in the course of their disease.
Allogeneic transplant is a process in which matched donor bone marrow stem cells are administered following chemo and or radiotherapy and immunosuppressive therapy. In this case, the objective is really that of giving the patient a new immune system that will hopefully recognize the patient’s tumor cells as foreign and mount an immune response against them. This is the only treatment that has the potential to cure patients with indolent lymphomas. However, it is complicated, usually requires intensive management in an academic medical center, and is associated with substantial risk. The new immune cells may attack the patient’s normal body tissues, thinking they are foreign (graft vs host disease) and there is risk of life-threatening infection due to the immunosuppressive treatment that is used. Nevertheless, significant long-term disease-free survival can be achieved in as many as 40% of patients. This treatment is used in selected patients whose disease is not responding optimally to standard treatments and who are considered high-risk for disease progression in a relatively short time. All patients will not be eligible for this treatment as a matched donor must be available (either sibling or unrelated).
Autologous stem cell transplant represents a way of administering very high doses (in fact, what would normally be lethal doses) of chemotherapy to an individual with the ability to rescue the patient from these lethal doses by collecting and storing bone marrow stem cells in advance of the chemotherapy and then returning them to the patient after chemotherapy. These cells will then return to the bone marrow where they will form new blood cells, allowing the bone marrow to recover from the effects of the chemotherapy. Indolent lymphomas cannot be cured with this approach to therapy. However, studies have demonstrated that survival can be significantly prolonged with this treatment. It may be useful for some patients later in the course of their disease.
Allogeneic transplant is a process in which matched donor bone marrow stem cells are administered following chemo and or radiotherapy and immunosuppressive therapy. In this case, the objective is really that of giving the patient a new immune system that will hopefully recognize the patient’s tumor cells as foreign and mount an immune response against them. This is the only treatment that has the potential to cure patients with indolent lymphomas. However, it is complicated, usually requires intensive management in an academic medical center, and is associated with substantial risk. The new immune cells may attack the patient’s normal body tissues, thinking they are foreign (graft vs host disease) and there is risk of life-threatening infection due to the immunosuppressive treatment that is used. Nevertheless, significant long-term disease-free survival can be achieved in as many as 40% of patients. This treatment is used in selected patients whose disease is not responding optimally to standard treatments and who are considered high-risk for disease progression in a relatively short time. All patients will not be eligible for this treatment as a matched donor must be available (either sibling or unrelated).
Early Stage Follicular Lymphoma
Patients
with stage I or II disease make up only about 15% of all patients with
follicular lymphoma. Some studies suggest that up to about 50% of these
people may be “cured” with local radiation therapy alone. It may be that
such people have such low grade disease that they just never recur
within their lifetime. Local radiotherapy may be recommended in such
patients. However, other recent data suggest that even in localized
disease patients may do just as well with a “watch and wait” approach,
only receiving treatment if they develop symptoms or complications of
the disease.
Other Indolent B-cell Lymphomas
Follicular
lymphoma is the paradigm for the low grade B-cell lymphomas and is also
the most common. In many cases, treatments for other indolent lymphomas
are not different from those used for the follicular lymphomas.
Marginal Zone Lymphomas
Subtypes
of these include those involving lymph nodes (nodal), those primarily
involving the spleen (splenic), and those that involve sites outside of
the lymph nodes (extranodal) many of which are referred to as MALT
(mucosa-associated lymphoid tissue) lymphomas. They tend to be very
indolent lymphomas.
MALT lymphomas: are indolent B-cell lymphomas that usually involve mucous membrane surfaces. They are most common in the airways and digestive tract. The most common site is the stomach where these lymphomas are associated with the same bacterium that causes peptic ulcer disease, H. pylori. The diagnosis is usually made from a biopsy performed at the time of endoscopy (visual inspection of the stomach using a fiberoptic “scope”).
When very well localized these lymphomas can often be successfully treated with the same therapy used for treating peptic ulcer disease: a combination of antibiotics and medications to reduce gastric acid secretion. Responses to this treatment may be very slow and therefore a repeat endoscopy may not be performed for six to12 months after completion of therapy.
When more advanced, MALT lymphomas are generally treated in the same way follicular and other indolent B-cell lymphomas are managed.
Splenic Marginal zone lymphomas usually present with marked enlargement of the spleen. Most patients have involvement of the bone marrow and, often, the blood. Standard treatment of these lymphomas has been splenectomy (removal of the spleen). Removal of the spleen can provide long durations of disease control (often five years or more) and may be associated with regression of disease in bone marrow and blood. However, recent data has suggested that splenic marginal zone lymphomas are highly responsive to rituximab, and that for many patients this might eliminate the need for splenectomy as initial treatment. Additional studies are underway.
CLL / SLL: This indolent leukemia / lymphoma is discussed in the knol on Acute and Chronic Leukemias.
MALT lymphomas: are indolent B-cell lymphomas that usually involve mucous membrane surfaces. They are most common in the airways and digestive tract. The most common site is the stomach where these lymphomas are associated with the same bacterium that causes peptic ulcer disease, H. pylori. The diagnosis is usually made from a biopsy performed at the time of endoscopy (visual inspection of the stomach using a fiberoptic “scope”).
When very well localized these lymphomas can often be successfully treated with the same therapy used for treating peptic ulcer disease: a combination of antibiotics and medications to reduce gastric acid secretion. Responses to this treatment may be very slow and therefore a repeat endoscopy may not be performed for six to12 months after completion of therapy.
When more advanced, MALT lymphomas are generally treated in the same way follicular and other indolent B-cell lymphomas are managed.
Splenic Marginal zone lymphomas usually present with marked enlargement of the spleen. Most patients have involvement of the bone marrow and, often, the blood. Standard treatment of these lymphomas has been splenectomy (removal of the spleen). Removal of the spleen can provide long durations of disease control (often five years or more) and may be associated with regression of disease in bone marrow and blood. However, recent data has suggested that splenic marginal zone lymphomas are highly responsive to rituximab, and that for many patients this might eliminate the need for splenectomy as initial treatment. Additional studies are underway.
CLL / SLL: This indolent leukemia / lymphoma is discussed in the knol on Acute and Chronic Leukemias.
Management of Transformation
Transformation
from an indolent to a more aggressive lymphoma can occur in any
indolent B-cell lymphoma. The occurrence of transformation is usually
heralded by a rapid change in the behavior of an indolent lymphoma as
evidenced by more rapid growth and development of disease in sites
outside of the lymph nodes. The transformation is usually to diffuse
large B-cell lymphoma or, less commonly, Burkitt Lymphoma. Prognosis is
usually poor with median survival in the 12 month range.
In one study, median survival following transformation in 74 patients was 22 months, with a subset of patients having prolonged responses to R-CHOP treatment. Predictors of improved survival included early stage, no prior therapy, and complete response to treatment. The median survival for patients in this study who attained a complete response was 81 months. Therefore R-CHOP alone is reasonable treatment for patients with limited disease who have had no prior therapy for their follicular lymphoma and who have a complete response to R-CHOP.
However, most patients who have had prior treatment and who have more extensive disease are likely to experience rapid relapse after R-CHOP. Several studies have suggested that high-dose chemotherapy followed by autologous stem cell transplant is effective treatment for selected patients with transformed lymphoma, provided that chemosensitive disease is present. Median progression-free survivals have been reported in the 36-50% range. This is appropriate treatment for patients with limited disease who do not achieve remission with R-CHOP or who have had prior treatment for follicular lymphoma. It is also the treatment of choice for patients with more advanced stage disease.
Radioimmunotherapy with tositumomab or ibritumomab are active treatment options for transformed disease with overall response rates in the 50% range and response durations of about 1 year. These agents are options for those patients who are not transplant candidates. Studies combining radioimmunotherapy with high-dose chemotherapy are ongoing.
Although data are limited, allogeneic stem cell transplant may be an option for patients with refractory disease or relapse after autologous transplant.
In one study, median survival following transformation in 74 patients was 22 months, with a subset of patients having prolonged responses to R-CHOP treatment. Predictors of improved survival included early stage, no prior therapy, and complete response to treatment. The median survival for patients in this study who attained a complete response was 81 months. Therefore R-CHOP alone is reasonable treatment for patients with limited disease who have had no prior therapy for their follicular lymphoma and who have a complete response to R-CHOP.
However, most patients who have had prior treatment and who have more extensive disease are likely to experience rapid relapse after R-CHOP. Several studies have suggested that high-dose chemotherapy followed by autologous stem cell transplant is effective treatment for selected patients with transformed lymphoma, provided that chemosensitive disease is present. Median progression-free survivals have been reported in the 36-50% range. This is appropriate treatment for patients with limited disease who do not achieve remission with R-CHOP or who have had prior treatment for follicular lymphoma. It is also the treatment of choice for patients with more advanced stage disease.
Radioimmunotherapy with tositumomab or ibritumomab are active treatment options for transformed disease with overall response rates in the 50% range and response durations of about 1 year. These agents are options for those patients who are not transplant candidates. Studies combining radioimmunotherapy with high-dose chemotherapy are ongoing.
Although data are limited, allogeneic stem cell transplant may be an option for patients with refractory disease or relapse after autologous transplant.
Lymphocytoplasmic Lymphoma / Waldenstrom’s Macroglobulinemia:
See discussion in the knol on Multiple Myeloma.
Aggressive B-cell Non-Hodgkin’s Lymphomas:
Diffuse Large B-cell Lymphoma:
Diffuse
Large B-cell Lymphoma (DLBCL) is the most common NHL in Western
countries. It is characterized by rapidly progressive disease, and
involvement of bone marrow in 30-40% of cases.
Prognosis in DLBCL is determined based upon the five independently prognostic factors included in the International Prognostic Index (IPI) (table 5).
Prognosis in DLBCL is determined based upon the five independently prognostic factors included in the International Prognostic Index (IPI) (table 5).
As is the case in indolent B-cell lymphoma, the introduction of rituximab into standard chemotherapy has significantly improved prognosis in this disease. As a result, the British Columbia Cancer Agency recently suggested a revised IPI using the same prognostic factors but reorganized into a more predictive system:
This system still requires validation in future studies, but provides useful prognostic information based upon more recent treatment advances.
Treatment of Diffuse Large B-cell Lymphoma
As
we discussed early in this Knol, DLBCL is a lymphoma for which cure is
possible in a significant proportion of patients provided that
appropriate treatment is administered. The aggressiveness of the disease
requires therapy to be started in a timely way (within days) once the
diagnosis has been made. The standard of care in the US is for
chemoimmunotherapy using the rituximab, cyclophosphamide, doxorubicin,
vincristine, prednisone (R-CHOP) regimen. This is used in patients with
both limited and extensive stage disease and differs only in number of
cycles of chemoimmunotherapy.
For patients with advanced stage (III/IV) DLBCL the standard was defined by a landmark French study in which patients older than age 60 were randomly assigned to receive CHOP chemotherapy alone or R-CHOP chemoimmunotherapy. In this trial the addition of rituximab to CHOP improved total complete response rate from 63 to 75% and the two-year event-free survival from 38 to 57%. Updates with up to five year median follow-up show five year progression-free survival is 66% for those in the R-CHOP arm compared with 45% for CHOP alone (figure 4). Other clinical trials have since confirmed these results in all age groups.
This system still requires validation in future studies, but provides useful prognostic information based upon more recent treatment advances.
Most patients will receive six to eight cycles of treatment. A cycle is one “round” of therapy that is repeated at a certain time interval. In this case, standard R-CHOP is administered on a three-week cycle (repeats every three weeks).
Other treatment approaches being explored include infusional therapy and dose-dense chemotherapy.
Infusional chemotherapy involves the continuous IV infusion of chemotherapy over a prolonged period of time. In the case of the most well-known of these regimens, the EPOCH regimen, this is a 96 hour (four day) infusion of doxorubicin, vincristine, and etoposide, followed by rapid infusion of cyclophosphamide. Doses of chemotherapy are adjusted (increased) in subsequent treatment cycles based upon the white blood cell counts. A study in 50 patients with previously untreated diffuse large B-cell lymphoma performed at the National Cancer Institute reported complete response in 92% of patients, and at the median follow-up time of 62 months, the progression-free survival (PFS) and overall survival (OS) rates were 70% and 73%, respectively. Patients with bcl-2 expression (a chromosomal change associated with high-risk) in their lymphomas had a worse outcome. However, when rituximab was added to this regimen (R-EPOCH), preliminary results suggest that outcome was improved in those patients with over-expression of bcl-2.
This regimen is currently being studied in a large randomized phase III study which is being performed in the Cancer and Leukemia Group B (CALGB). In this study patients with DLBCL are randomly assigned to receive either R-CHOP or R-EPOCH in order to determine whether R-EPOCH might be a more effective treatment than the standard R-CHOP.
Another novel approach to treatment of diffuse large cell lymphoma is the use of “dose-dense” chemotherapy. In this concept, chemotherapy is administered on an accelerated schedule – R-CHOP chemotherapy is administered every 2 weeks (CHOP-14) instead of every 3 weeks (CHOP-21). Since this is potentially more toxic to the bone marrow, growth factors like filgrastim (G-CSF) are administered to all patients to try to keep the white blood cell count from dipping too low and increasing the risk of infection. A large randomized European study demonstrated improved outcome for patients over age 60 treated with the CHOP-14 regimen. This benefit was not observed in younger patients. In a subsequent study (RICOVER trial) the addition of rituximab to CHOP-14 was associated with additional benefit in an older patient population. Event-free survival was improved from 47.2 to 66.5% at three years. This approach has not been directly compared to R-CHOP-21 in a randomized trial.
Patients whose large cell lymphoma relapses or responds poorly to initial treatment may still be cured with the use of high-dose chemotherapy followed by autologous stem cell transplant. At the time of relapse the patient MUST have lymphoma that is still responsive to chemotherapy in order to pursue this option. After response to second-line chemotherapy for relapse, bone marrow stem cells (cells that can grow into any type of blood cell) are collected from the patient, stored, and returned to the patient after he/she receives very high-dose chemotherapy. This treatment is described in more detail in the Bone Marrow Transplant knol.
Some patients with diffuse large B-cell lymphoma will need to receive chemotherapy directly injected into the spinal fluid using a lumbar puncture (spinal tap) to prevent recurrence of the lymphoma in the membranes that line the brain and spinal cord (meninges). Only certain patients have a high risk for this lymphomatous meningitis, generally those with bulky advanced disease; involvement of the bone marrow, sinuses, or testis, or; lymphoma that is located in close proximity to the spinal cord. Some patients will have lymphomatous meningitis when they are first diagnosed with lymphoma. These individuals require multiple injections of chemotherapy into the spinal fluid and may also require radiation treatment to the brain.
For patients with advanced stage (III/IV) DLBCL the standard was defined by a landmark French study in which patients older than age 60 were randomly assigned to receive CHOP chemotherapy alone or R-CHOP chemoimmunotherapy. In this trial the addition of rituximab to CHOP improved total complete response rate from 63 to 75% and the two-year event-free survival from 38 to 57%. Updates with up to five year median follow-up show five year progression-free survival is 66% for those in the R-CHOP arm compared with 45% for CHOP alone (figure 4). Other clinical trials have since confirmed these results in all age groups.
This system still requires validation in future studies, but provides useful prognostic information based upon more recent treatment advances.
Most patients will receive six to eight cycles of treatment. A cycle is one “round” of therapy that is repeated at a certain time interval. In this case, standard R-CHOP is administered on a three-week cycle (repeats every three weeks).
Other treatment approaches being explored include infusional therapy and dose-dense chemotherapy.
Infusional chemotherapy involves the continuous IV infusion of chemotherapy over a prolonged period of time. In the case of the most well-known of these regimens, the EPOCH regimen, this is a 96 hour (four day) infusion of doxorubicin, vincristine, and etoposide, followed by rapid infusion of cyclophosphamide. Doses of chemotherapy are adjusted (increased) in subsequent treatment cycles based upon the white blood cell counts. A study in 50 patients with previously untreated diffuse large B-cell lymphoma performed at the National Cancer Institute reported complete response in 92% of patients, and at the median follow-up time of 62 months, the progression-free survival (PFS) and overall survival (OS) rates were 70% and 73%, respectively. Patients with bcl-2 expression (a chromosomal change associated with high-risk) in their lymphomas had a worse outcome. However, when rituximab was added to this regimen (R-EPOCH), preliminary results suggest that outcome was improved in those patients with over-expression of bcl-2.
This regimen is currently being studied in a large randomized phase III study which is being performed in the Cancer and Leukemia Group B (CALGB). In this study patients with DLBCL are randomly assigned to receive either R-CHOP or R-EPOCH in order to determine whether R-EPOCH might be a more effective treatment than the standard R-CHOP.
Another novel approach to treatment of diffuse large cell lymphoma is the use of “dose-dense” chemotherapy. In this concept, chemotherapy is administered on an accelerated schedule – R-CHOP chemotherapy is administered every 2 weeks (CHOP-14) instead of every 3 weeks (CHOP-21). Since this is potentially more toxic to the bone marrow, growth factors like filgrastim (G-CSF) are administered to all patients to try to keep the white blood cell count from dipping too low and increasing the risk of infection. A large randomized European study demonstrated improved outcome for patients over age 60 treated with the CHOP-14 regimen. This benefit was not observed in younger patients. In a subsequent study (RICOVER trial) the addition of rituximab to CHOP-14 was associated with additional benefit in an older patient population. Event-free survival was improved from 47.2 to 66.5% at three years. This approach has not been directly compared to R-CHOP-21 in a randomized trial.
Patients whose large cell lymphoma relapses or responds poorly to initial treatment may still be cured with the use of high-dose chemotherapy followed by autologous stem cell transplant. At the time of relapse the patient MUST have lymphoma that is still responsive to chemotherapy in order to pursue this option. After response to second-line chemotherapy for relapse, bone marrow stem cells (cells that can grow into any type of blood cell) are collected from the patient, stored, and returned to the patient after he/she receives very high-dose chemotherapy. This treatment is described in more detail in the Bone Marrow Transplant knol.
Some patients with diffuse large B-cell lymphoma will need to receive chemotherapy directly injected into the spinal fluid using a lumbar puncture (spinal tap) to prevent recurrence of the lymphoma in the membranes that line the brain and spinal cord (meninges). Only certain patients have a high risk for this lymphomatous meningitis, generally those with bulky advanced disease; involvement of the bone marrow, sinuses, or testis, or; lymphoma that is located in close proximity to the spinal cord. Some patients will have lymphomatous meningitis when they are first diagnosed with lymphoma. These individuals require multiple injections of chemotherapy into the spinal fluid and may also require radiation treatment to the brain.
Burkitt Lymphoma
Burkitt
lymphoma is one of the most aggressive lymphomas ever described. Some
of these lymphomas can have doubling times as rapid as 24 hours. This
means that rapid diagnosis and treatment are of great importance.
In the past it was noted that when patients with Burkitt Lymphoma were included in clinical trials of treatments designed for treating diffuse large B-cell lymphoma, the Burkitt patients did not fare as well as the large cell patients. It was felt that the aggressive features of Burkitt lymphoma required more intensive chemotherapy to prevent recurrence of the disease. This reasoning resulted in newer and more aggressive treatment regimens being used specifically to treat Burkitt lymphoma. Examples of these regimens include the CODOX-M/IVAC regimen developed at the National Cancer Institute, the French LMB-86 regimen and the Hyper-CVAD regimen from MD Anderson Cancer Center. In phase II studies, these regimens have resulted in significantly improved survival (generally in excess of 60% at five years) when compared with patients treated in the past with CHOP-like regimens. None of these treatments has ever been directly compared to CHOP or CHOP-like regimens in a randomized clinical trial.
In recent years most oncologists treating such patients have incorporated rituximab into all of these regimens since Burkitt Lymphoma is also a B-cell lymphoma. At UCSF we utilize the R-CODOX-M / R-IVAC regimen as our standard treatment for Burkitt Lymphoma. Patients with advanced lymphoma receive a total of four cycles of chemotherapy (2 of R-CODOX-M and 2 of R-IVAC) over a three-month period of time in an alternating (ABAB) schedule. With the most recent modification of the CODOX-M / IVAC (without rituximab) treatment protocol, published results in 14 patients showed a complete response rate of 86%. Sixty-four percent were alive and disease-free at a median of 29 months. These results are typical of outcome reported for the different Burkitt treatment regimens in adults. Recently the addition of rituximab to the Hyper-CVAD regimen has been associated with even better outcomes with event-free and overall survival greater than 80%.
Patients with Burkitt Lymphoma are at especially high-risk for development of lymphomatous meningitis (lymphoma cells in the spinal fluid) and therefore receive lumbar punctures periodically throughout the course of chemotherapy with administration of chemotherapy into the spinal fluid.
In the past it was noted that when patients with Burkitt Lymphoma were included in clinical trials of treatments designed for treating diffuse large B-cell lymphoma, the Burkitt patients did not fare as well as the large cell patients. It was felt that the aggressive features of Burkitt lymphoma required more intensive chemotherapy to prevent recurrence of the disease. This reasoning resulted in newer and more aggressive treatment regimens being used specifically to treat Burkitt lymphoma. Examples of these regimens include the CODOX-M/IVAC regimen developed at the National Cancer Institute, the French LMB-86 regimen and the Hyper-CVAD regimen from MD Anderson Cancer Center. In phase II studies, these regimens have resulted in significantly improved survival (generally in excess of 60% at five years) when compared with patients treated in the past with CHOP-like regimens. None of these treatments has ever been directly compared to CHOP or CHOP-like regimens in a randomized clinical trial.
In recent years most oncologists treating such patients have incorporated rituximab into all of these regimens since Burkitt Lymphoma is also a B-cell lymphoma. At UCSF we utilize the R-CODOX-M / R-IVAC regimen as our standard treatment for Burkitt Lymphoma. Patients with advanced lymphoma receive a total of four cycles of chemotherapy (2 of R-CODOX-M and 2 of R-IVAC) over a three-month period of time in an alternating (ABAB) schedule. With the most recent modification of the CODOX-M / IVAC (without rituximab) treatment protocol, published results in 14 patients showed a complete response rate of 86%. Sixty-four percent were alive and disease-free at a median of 29 months. These results are typical of outcome reported for the different Burkitt treatment regimens in adults. Recently the addition of rituximab to the Hyper-CVAD regimen has been associated with even better outcomes with event-free and overall survival greater than 80%.
Patients with Burkitt Lymphoma are at especially high-risk for development of lymphomatous meningitis (lymphoma cells in the spinal fluid) and therefore receive lumbar punctures periodically throughout the course of chemotherapy with administration of chemotherapy into the spinal fluid.
Mantle Cell Lymphoma (MCL)
Mantle
cell lymphoma is characterized by the worst features of the aggressive
and indolent lymphomas: That is they progress relatively rapidly and
historically have been incurable using treatment regimens like CHOP and
R-CHOP. The disease is diagnosed by identifying proteins that are
typically expressed on the surface of the MCL cells and by identifying
expression of a specific growth regulatory protein called cyclin D1.
There are several different less-common categories of mantle cell
lymphoma that include nodular, mantle zone, and blastic. The mantle zone
type is thought to have a much more indolent course, the blastic type a
more aggressive course.
Patients with MCL have a high frequency of bone marrow involvement. Molecular studies show evidence of disease in the bone marrow in about 80%. Involvement of the gastro-intestinal tract is also common. When patients with MCL are treated with CHOP chemotherapy, survival is only around three years. Although the addition of rituximab improves the response rate, it does not result in improvement in survival as demonstrated in a randomized trial (Figure 5).
At most centers the approach to treatment has involved the use of much more aggressive chemotherapy programs than R-CHOP, and this seems to be having an impact on treatment outcome. The Hyper-CVAD regimen has been used with rituximab and in single-institution studies at MD Anderson Cancer Center has been associated with more favorable outcome. With median followup of 40 months, the median failure-free survival was 64%. Toxicity to the bone marrow is very significant with this regimen and patients receiving this regimen are best managed in an academic setting where care providers are accustomed to managing these toxicities. Unfortunately, when this treatment regimen was studied in a multicenter setting that included community practices, the Southwest Oncology Group found that 42% of patients were withdrawn from study due to severe toxicity and treatment outcome does not look quite as promising. This study had follow-up for only about one and one-half years when reported at the 2007 American Society of Hematology meetings. Unfortunately in all of these trials late relapses beyond two years continue to occur suggesting the presence of minimal residual disease after treatment.
The other approach that has been widely used for MCL is incorporation of high-dose chemotherapy and autologous stem cell transplant into first-line treatment. Different institutions have used different variations of this approach but the general concept is to first begin an aggressive course of chemotherapy to try and get the patient into remission. Usually this is then followed by some form of consolidation therapy with additional aggressive chemotherapy. Rituximab is used at this point to try and “purge” the bone marrow of any trace amounts of MCL. Bone marrow stem cells are then collected from the blood after stimulation with a growth factor (filgrastim, G-CSF). These cells are frozen for later use. The patient then receives very high-dose chemotherapy. The doses are high enough to destroy the bone marrow forever. However, the frozen stem cells are then re-infused (like a blood transfusion) and these cells are able to regenerate the bone marrow so that new blood cells are formed and the patient will recover. Although it is not yet clear as to how many (if any) patients might be cured with this approach, the results are promising when compared with other more conventional treatments.
This approach to treatment of MCL has been relatively successful compared to the outcomes reported for conventional chemotherapy. In the CALGB 59909 study, progression-free survival was 59% at three years and the median progression-free survival was 5.4 years. The survival curve for this study still does not demonstrate the flattening or plateau in the survival curve that indicates long-term survival is possible. However, with markedly improved progression-free and overall survival it is clear that progress has been made in comparison to the results with CHOP or R-CHOP.
The results of the Nordic Lymphoma Group Mantle cell-2 study were presented at the 2007 American Society of Hematology Meeting. In this study 160 patients were treated with aggressive induction chemotherapy and high-dose cytarabine with rituximab used as an in vivo purge as in the CALGB 59909 trial. In this case survival curves are observed to have very definite plateaus in the curves indicating that some patients are cured. Follow-up, however, is only three years in each of these studies and we must wait to see if there will be additional late recurrences of lymphoma. Some patients in the Nordic trial who were in molecular remission after transplant may have received rituximab for the appearance of recurrent molecular positivity, and so therefore were not counted as clinical recurrences. This could result in more favorable looking survival curves.
http://abstracts.hematologylibrary.org/cgi/content-nw/full/110/11/LB1/F1
Note the obvious plateaus in the survival curves for the MCL-2 study compared with the MCL-1 trial in which only a CHOP-like regimen was used.
It is clear that we are making progress in this disease with the use of high-dose chemotherapy , but how frequently we are able to cure the disease with autologous transplant is still uncertain. There is now a need to build upon this transplant experience by adding newer active agents to see if the risk of late recurrence can be reduced. In the ongoing CALGB 50403 study currently enrolling patients at UCSF and other sites, patients receive the novel agent bortezomib after autologous transplant in an effort to see if late recurrence reduction is possible.
Autologous transplant is clearly not as effective for patients with relapsed MCL. Some of these patients may be candidates for allogeneic transplant (using bone marrow stem cells from a matched donor). Further discussion of transplant options is discussed in the Knol on Bone Marrow Transplantation.
Another novel approach to treatment of MCL is with the use of radioimmunotherapy with agents like Tositumomab or Ibritumomab as we discussed in the section on management of indolent B-cell lymphomas. At MD Anderson, about one-third of patients with previously-treated chemotherapy resistant disease responded to 131I-tositumomab. The use of this agent following induction of remission with CHOP chemotherapy is currently being studied in the Southwest Oncology Group.
Treatments that target the normal cell death pathways in the cell are currently being studied for treatment of MCL. Bortezomib, a proteosome inhibitor that can increase the levels of proteins in MCL cells that normally trigger cell death (and are found to be abnormally low in MCL) is active in MCL. Recent results of the PINNACLE study demonstrate an overall response rate of 32% in patients with advanced, chemotherapy-resistant disease.
Other targeted agents such as lenalidomide and vorinostat have also been reported to have activity in MCL and are currently moving through clinical trials.
Treatment with these agents in clinical trials can uncover important options for patients with relapsed disease and for patients with newly diagnosed disease where these agents are being combined with other first-line treatments.
Patients with MCL have a high frequency of bone marrow involvement. Molecular studies show evidence of disease in the bone marrow in about 80%. Involvement of the gastro-intestinal tract is also common. When patients with MCL are treated with CHOP chemotherapy, survival is only around three years. Although the addition of rituximab improves the response rate, it does not result in improvement in survival as demonstrated in a randomized trial (Figure 5).
At most centers the approach to treatment has involved the use of much more aggressive chemotherapy programs than R-CHOP, and this seems to be having an impact on treatment outcome. The Hyper-CVAD regimen has been used with rituximab and in single-institution studies at MD Anderson Cancer Center has been associated with more favorable outcome. With median followup of 40 months, the median failure-free survival was 64%. Toxicity to the bone marrow is very significant with this regimen and patients receiving this regimen are best managed in an academic setting where care providers are accustomed to managing these toxicities. Unfortunately, when this treatment regimen was studied in a multicenter setting that included community practices, the Southwest Oncology Group found that 42% of patients were withdrawn from study due to severe toxicity and treatment outcome does not look quite as promising. This study had follow-up for only about one and one-half years when reported at the 2007 American Society of Hematology meetings. Unfortunately in all of these trials late relapses beyond two years continue to occur suggesting the presence of minimal residual disease after treatment.
The other approach that has been widely used for MCL is incorporation of high-dose chemotherapy and autologous stem cell transplant into first-line treatment. Different institutions have used different variations of this approach but the general concept is to first begin an aggressive course of chemotherapy to try and get the patient into remission. Usually this is then followed by some form of consolidation therapy with additional aggressive chemotherapy. Rituximab is used at this point to try and “purge” the bone marrow of any trace amounts of MCL. Bone marrow stem cells are then collected from the blood after stimulation with a growth factor (filgrastim, G-CSF). These cells are frozen for later use. The patient then receives very high-dose chemotherapy. The doses are high enough to destroy the bone marrow forever. However, the frozen stem cells are then re-infused (like a blood transfusion) and these cells are able to regenerate the bone marrow so that new blood cells are formed and the patient will recover. Although it is not yet clear as to how many (if any) patients might be cured with this approach, the results are promising when compared with other more conventional treatments.
This approach to treatment of MCL has been relatively successful compared to the outcomes reported for conventional chemotherapy. In the CALGB 59909 study, progression-free survival was 59% at three years and the median progression-free survival was 5.4 years. The survival curve for this study still does not demonstrate the flattening or plateau in the survival curve that indicates long-term survival is possible. However, with markedly improved progression-free and overall survival it is clear that progress has been made in comparison to the results with CHOP or R-CHOP.
The results of the Nordic Lymphoma Group Mantle cell-2 study were presented at the 2007 American Society of Hematology Meeting. In this study 160 patients were treated with aggressive induction chemotherapy and high-dose cytarabine with rituximab used as an in vivo purge as in the CALGB 59909 trial. In this case survival curves are observed to have very definite plateaus in the curves indicating that some patients are cured. Follow-up, however, is only three years in each of these studies and we must wait to see if there will be additional late recurrences of lymphoma. Some patients in the Nordic trial who were in molecular remission after transplant may have received rituximab for the appearance of recurrent molecular positivity, and so therefore were not counted as clinical recurrences. This could result in more favorable looking survival curves.
http://abstracts.hematologylibrary.org/cgi/content-nw/full/110/11/LB1/F1
Note the obvious plateaus in the survival curves for the MCL-2 study compared with the MCL-1 trial in which only a CHOP-like regimen was used.
It is clear that we are making progress in this disease with the use of high-dose chemotherapy , but how frequently we are able to cure the disease with autologous transplant is still uncertain. There is now a need to build upon this transplant experience by adding newer active agents to see if the risk of late recurrence can be reduced. In the ongoing CALGB 50403 study currently enrolling patients at UCSF and other sites, patients receive the novel agent bortezomib after autologous transplant in an effort to see if late recurrence reduction is possible.
Autologous transplant is clearly not as effective for patients with relapsed MCL. Some of these patients may be candidates for allogeneic transplant (using bone marrow stem cells from a matched donor). Further discussion of transplant options is discussed in the Knol on Bone Marrow Transplantation.
Another novel approach to treatment of MCL is with the use of radioimmunotherapy with agents like Tositumomab or Ibritumomab as we discussed in the section on management of indolent B-cell lymphomas. At MD Anderson, about one-third of patients with previously-treated chemotherapy resistant disease responded to 131I-tositumomab. The use of this agent following induction of remission with CHOP chemotherapy is currently being studied in the Southwest Oncology Group.
Treatments that target the normal cell death pathways in the cell are currently being studied for treatment of MCL. Bortezomib, a proteosome inhibitor that can increase the levels of proteins in MCL cells that normally trigger cell death (and are found to be abnormally low in MCL) is active in MCL. Recent results of the PINNACLE study demonstrate an overall response rate of 32% in patients with advanced, chemotherapy-resistant disease.
Other targeted agents such as lenalidomide and vorinostat have also been reported to have activity in MCL and are currently moving through clinical trials.
Treatment with these agents in clinical trials can uncover important options for patients with relapsed disease and for patients with newly diagnosed disease where these agents are being combined with other first-line treatments.
Peripheral T-cell Lymphomas:
The peripheral T-cell lymphomas (PTCL) account for only about 10% of all non-Hodgkin’s Lymphomas. They are represented by the mixed group of lymphomas listed above. Because they are rare, they have been less well studied compared with other non-Hodgkin’s lymphomas. With the exception of anaplastic large cell lymphoma (ALCL) when it expresses the ALK-1 protein, as a group these lymphomas are associated with significantly worse outcomes than the aggressive B-cell lymphomas. Outcomes for non-ALCL (and ALK-1 negative ALCL) PTCL are in the range of approximately 13-29% failure-free survival and 22-36% overall survival at five years using the same CHOP-like chemotherapy regimens that are used for treating diffuse large B-cell lymphoma (figure 6).
Figure
6: Comparison of survival for anaplastic large T-cell lymphoma
(ALCL-T), aggressive B-cell lymphoma (BCL) and non-anaplastic large
T-cell lymphoma (non ALCL-T)
Patients with anaplastic large-cell lymphoma whose lymphoma produces the Alk-1 protein can be treated successfully with CHOP chemotherapy (see section on aggressive B-cell lymphomas) just like for the aggressive B-cell lymphomas. However, the use of CHOP-like treatment regimens for most other peripheral T-cell lymphomas does not usually result in long-term control of the disease, and is not recommended. Unfortunately there is as yet no consensus on a standard treatment approach and the optimal treatment for one type of PTCL may not be the same as for other subtypes. For example, patients with early stage NK/T lymphoma confined to the nasal passages can have long-term disease-free survival with a combination of local radiation therapy followed by chemotherapy. However, radiation is not an important part of treatment for other PTCLs.
There are chemotherapy agents that do have better activity in T-cell lymphomas and these are being studied alone and in combination for these lymphomas. The agent gemcitabine is particularly active and is now being combined with other agents as part of initial treatment. Other agents such as liposomal doxorubicin and fludarabine-like agents are also active. A new agent currently in clinical trials, called pralatrexate, is very promising but is still in single-agent clinical trials. Targeted agents such as the class of agents referred to as histone deacetylase inhibitors also are known to have promising activity in these cancers and are also being studied in clinical trials. The monoclonal (anti-CD52) antibody, alemtuzumab (Campath) has also been shown to have activity in some PTCLs and is being studied as adjunctive therapy.
The role of high-dose chemotherapy and autologous or allogeneic stem cell transplant is not yet clearly defined. Autologous transplant has not been highly successful treatment for people with relapsed disease, but may have a role as part of initial treatment. This approach is being studied in clinical trials at UCSF and elsewhere. Allogeneic transplant (using bone marrow stem cells from a matched donor) may provide benefit in certain subtypes of PTCL such as adult T-cell leukemia/lymphoma and perhaps extranodal NK/T lymphoma, but this treatment has been studied in very few patients to date.
Because standard therapy does not exist for most of these lymphomas at this time it is very important that the relatively small number of patients with PTCL be treated in centers that have more experience treating them and that patients participate in clinical trials so that more effective treatments can be identified.
HIV-associated Lymphomas
Patients
with HIV infection have a significantly increased risk for development
of aggressive B-cell lymphomas. Historically, about two-thirds of these
were diffuse large B-cell lymphomas and one-third Burkitt Lymphomas.
Since the introduction of effective antiviral treatments for HIV, the
incidence of lymphoma has significantly fallen in this patient
population. We also seem to be seeing a relative increase in cases of
Burkitt Lymphoma.
Prior to the introduction of these effective anti-HIV treatments, patients with lymphomas experienced severe side effects from the chemotherapy drugs used to treat HIV-lymphomas and because of severe immune deficiency, few of these patients survived for longer than two years. However, since effective HIV treatments now exist, patients are tolerating treatment with fewer side effects and are able to receive virtually the same chemotherapy treatments that are used in HIV-uninfected patients. A study at the National Cancer Institute using the EPOCH chemotherapy regimen reported a 73% progression-free survival at four and a half years after treatment. Although initial concerns were raised about the risk of infectious deaths observed in one study in which rituximab was combined with CHOP chemotherapy, these concerns have been reduced by subsequent studies demonstrating safety and efficacy. It is now recommended that most patients be treated with standard-dose chemotherapy and rituximab as we treat patients who are HIV-uninfected. We generally recommend continuing anti-viral treatment throughout the course of chemotherapy and patients should receive antibiotics to prevent pneumocystis pneumonia and bacterial infections during the time of low white blood cell counts. Studies are currently underway to assess the efficacy and toxicity of aggressive chemotherapy treatments for Burkitt Lymphoma in patients with HIV infection. Experience suggests that these regimens will also be well-tolerated.
Finally, for patients who relapse, high-dose chemotherapy with autologous stem cell transplant is a real option. Multiple clinical trials have now demonstrated that patients with HIV-associated lymphomas can have excellent outcomes with long-term disease-free survival. They tolerate this treatment much like HIV-uninfected patients, do not have a high incidence of opportunistic infections, and recover blood counts (engraft) just as rapidly as uninfected patients.
The future for such patients is bright. Treatment approaches that just 10 years ago seemed impossible in such patients are now reality. We are at the point now where there is little difference between treatment approaches used for lymphomas that occur in HIV-infected and uninfected patients, and we can expect similar favorable outcomes for patients with HIV-associated aggressive B-cell lymphomas as we see in other patient populations.
Prior to the introduction of these effective anti-HIV treatments, patients with lymphomas experienced severe side effects from the chemotherapy drugs used to treat HIV-lymphomas and because of severe immune deficiency, few of these patients survived for longer than two years. However, since effective HIV treatments now exist, patients are tolerating treatment with fewer side effects and are able to receive virtually the same chemotherapy treatments that are used in HIV-uninfected patients. A study at the National Cancer Institute using the EPOCH chemotherapy regimen reported a 73% progression-free survival at four and a half years after treatment. Although initial concerns were raised about the risk of infectious deaths observed in one study in which rituximab was combined with CHOP chemotherapy, these concerns have been reduced by subsequent studies demonstrating safety and efficacy. It is now recommended that most patients be treated with standard-dose chemotherapy and rituximab as we treat patients who are HIV-uninfected. We generally recommend continuing anti-viral treatment throughout the course of chemotherapy and patients should receive antibiotics to prevent pneumocystis pneumonia and bacterial infections during the time of low white blood cell counts. Studies are currently underway to assess the efficacy and toxicity of aggressive chemotherapy treatments for Burkitt Lymphoma in patients with HIV infection. Experience suggests that these regimens will also be well-tolerated.
Finally, for patients who relapse, high-dose chemotherapy with autologous stem cell transplant is a real option. Multiple clinical trials have now demonstrated that patients with HIV-associated lymphomas can have excellent outcomes with long-term disease-free survival. They tolerate this treatment much like HIV-uninfected patients, do not have a high incidence of opportunistic infections, and recover blood counts (engraft) just as rapidly as uninfected patients.
The future for such patients is bright. Treatment approaches that just 10 years ago seemed impossible in such patients are now reality. We are at the point now where there is little difference between treatment approaches used for lymphomas that occur in HIV-infected and uninfected patients, and we can expect similar favorable outcomes for patients with HIV-associated aggressive B-cell lymphomas as we see in other patient populations.
The Future:
With
a rapidly accruing knowledge of how cells regulate their growth, there
has been an almost explosive development of new targeted agents for
treating lymphomas. Currently there are no less than 13 monoclonal
antibodies in clinical trials that target a variety of cell surface
proteins. In addition to monoclonal antibodies, many of the newer
agents currently being studied target steps in the cell division cycle
and the pathways that regulate cell death. These cell death pathways
are frequently dysfunctional in lymphomas resulting in accumulation of
the malignant cells. Agents have been developed that can re-activate
some of these pathways. Agents such as bortezomib, oblimersen,
vorinostat, anti-TRAIL-R1 and anti-CD40 (SGN 40) may activate these cell
death pathways. Some of these agents are already approved for certain
indications and most are in clinical trials. Agents such as
flavopiridol also play a role in regulating the cell cycle and have
demonstrated activity in some B-cell neoplasms. There has been
tremendous progress in treatment of non-Hodgkin Lymphoma in recent years
and there is good reason to be optimistic that this progress will
continue at an even more rapid rate in the coming years.
Selected References:
Indolent B-cell Lymphomas:
Maloney
D. Follicular NHL: From Antibodies and Vaccines to
Graft-versus-Lymphoma Effects Hematology Am Soc Hematol Educ Program.
2007;2007:226-32. Selected References:
Indolent B-cell Lymphomas:
Hiddemann W, Buske C, Dreyling M, et al. Current management of follicular lymphomas. Br J Haematol. 2007 Jan;136(2):191-202.
Andrés J.M. Ferreri, , and Emanuele Zucca. Marginal-zone lymphoma. Crit Rev Oncol Hematol. 2007; 63: 245-56
Freedman AS. Biology and management of histologic transformation of indolent lymphoma. Hematology Am Soc Hematol Educ Program. 2005;314-20.
Aggressive B-cell Lymphoma:
P. Feugier, A. Van Hoof, C. Sebban, P. et al Long-Term Results of the R-CHOP Study in the Treatment of Elderly Patients With Diffuse Large B-Cell Lymphoma: A Study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005; 23:4117-4126
Wilson, WH et al. Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy Blood. 2002;99:2685-2693
Saar Gill and David Ritchie. Therapeutic options in mantle cell lymphoma. Leukemia & Lymphoma, 2008; 49: 398 – 409
Pfreundschuh M et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008; 9:105-16
Burkitt Lymphoma:
Yustein JT, Dang CV. Biology and treatment of Burkitt's lymphoma..
Curr Opin Hematol. 2007; 14:375-81.
Peripheral T-cell Lymphoma:
Kerry J. Savage. Peripheral T-cell Lymphomas.. Blood Rev. 2007;21:201-16
HIV-Associated Lymphoma:
Nicolas Mounier, Michele Spina and Christian Gisselbrecht. Modern management of non-Hodgkin lymphoma in HIV-infected patients. Br J Haematol. 2007; 136: 685-98