**Background information on Non-Hodgkin's Lymphoma**

## 

## General

Non-Hodgkin's lymphomas (NHLs) encompass several unique malignant
lymphoid disease entities that vary in clinical behavior, morphologic
appearance, immunologic, and molecular phenotype. The various types
represent neoplastic lymphoid cells arrested at different stages of
normal differentiation. Based on their natural history, NHLs can be
clinically classified as indolent, aggressive, and highly aggressive.

## Epidemiology

NHLs are the fifth most common cause of cancer in the United States,
with an estimated incidence of 63,600 cases in 2001[^1]. Follicular
center cell lymphomas are the second most common subtype, comprising
approximately 40% of all non-Hodgkin's lymphomas. Since 1950, the
incidence of NHL has steadily increased at approximately 4% per year.

## Classification

Several histologic classifications of NHLs exist. Commonly used systems
are the 1982 International Working Formulation (IWF)[^2] and the 1994
Revised European-American (REAL) classifications[^3]. These
classification systems group lymphoid neoplasms according to clinical
behavior (low grade/indolent, intermediate grade/aggressive, or high
grade/very aggressive). Historically, this grouping often served as a
basis for choosing a first line therapy.

More recently, the World Health Organization (WHO) proposed a new
classification system [^4]. Unlike the IWF and REAL classifications, the
WHO committee felt that grouping lymphoid neoplasms according to
clinical behavior was neither necessary nor desirable[^5]. The committee
recognized that specific disease entities could be defined by a
combination of morphology, immunology, genetic features, and clinical
features. Each entity had distinct clinical behavior and outcome
predictable by applicable prognostic factors (e.g.; the international
Prognostic Index) and related to the type of initial therapy
administered. The committee concluded that each lymphoma type needed to
be treated as distinct entities. Therefore, rather than depending on
clinical grouping (i.e.; low grade/indolent, etc.), the committee
emphasized that clinical decisions should be based on the specific
lymphoid neoplasm.

## Natural History

The median age prevalence of indolent lymphoma is in the sixth decade.
B-cell indolent (low-risk group) NHL is not curable with standard
treatment. First line therapy is commonly associated with a high rate of
clinical response followed by relapse. Subsequent remissions may occur
but at a progressively lower rate and with progressively shorter
durations with a median progression-free survival (PFS) frequently less
than 6 months[^6] using traditional chemotherapeutic regimens. However,
recent studies suggest that treatment using unconjugated monoclonal
antibodies directed against CD20 antigen may yield a prolonged median
PFS greater than 6 months[^7] in relapsed or refractory indolent NHL
populations.

Over time, indolent NHL may transform to aggressive (intermediate risk)
or very aggressive (high-risk) lymphomas that have a more aggressive
clinical course. The incidence of transformation ranges from 40% to 70%
and is associated with disease progression and known adverse prognostic
factors[^8]. In general, transformation has a poor prognosis and
frequently results in a rapidly fatal outcome. However, some patients
can have complete responses to salvage chemotherapy regimens and achieve
durable complete remissions[^9]. Overall survival following
transformation is poor with an estimated median survival ranging from 7
to 22 months.

## Prognostic Indicators

The most valuable and widely used prognostic indicator system for NHL is
the International Prognostic Index (IPI)[^10]. The IPI is a prognostic
index that was developed to predict outcome in patients with aggressive
NHL, based on patients' clinical characteristics before treatment.
However, the IPI has been shown to apply to indolent (low-risk)
lymphoma[^11].

**IPI Score and Clinical Outcome**

**(Follicle Center Cell NHL)**

  -------------- --------- -------------- ------------- ------------------
  **IPI**        **CR      **5-yr FFS     **5-yr OS     **Median OS (mo)**
                 (%)**     (%)**          (%)**         

  **Low**        92        75             85            160

  **Low-Int**    81        64             69            108

  **High-Int**   77        38             28            35

  **High**       0         0              0             12
  -------------- --------- -------------- ------------- ------------------

Cytogenetics, gene rearrangement, and oncoproteins are important
molecular markers of histologic subtype and mechanisms of
lymphomagenesis. BCL2 oncogene (t14;18) overexpression is characteristic
of follicular center cell NHLs. However, the use of biomarkers to
predict clinical outcome in indolent NHL is investigational and need to
be validated in prospective trials.

## 

## Therapy

First Line Treatment

![](media/image1.wmf){width="4.365277777777778in"
height="2.3854166666666665in"}

Localized indolent lymphoma at initial presentation is unusual and
represents less than 5% of the population. Patients with early-stage
indolent lymphomas are potentially curable with radiation therapy (46%
to 68% 10-year DFS^)^[^12]^,^ [^13]^,^ [^14]. The addition of
chemotherapy to radiotherapy as primary treatment has not convincingly
prolonged remission duration or survival.

The majority of patients with indolent NHL present with advanced
disease. For the majority of patients, selection of initial treatment is
based on the clinical situation, prognostic indicators, physician bias,
and patient choice. There is no single standard initial therapy for
indolent NHL.

In general, alkylating agents are useful palliative treatment options
that can result in improved well-being for most patients, often for long
periods. Although commonly used, combinations of chemotherapy have not
convincingly resulted in longer or greater number remissions. There is
no proof that initial combination chemotherapy will prolong survival in
comparison with single drugs. The addition of interferon to initial
combination chemotherapy may increase the response rate, significantly
prolong remission duration, but prolonged survival has not been
unequivocally proven. In the absence of disease-related symptoms,
treatment can safely be deferred without adversely impacting survival.

Distinguishing follicular lymphoma into those with predominantly small
cells (follicule small, grade I), those with an intermediate number of
small and large cells (follicule center, mixed small/large grade II),
and those with more large cells (Follicule center, large grade III) is
difficult[^15]. However studies that have assessed the clinical behavior
or these lymphomas have shown that patients with follicular large cell
lymphoma have a shorter remission duration and overall survival than
patients with the other subtypes. For these patients, the incorporation
of an anthracycline into the initial treatment regimen appears to
improve outcome[^16].

Overall response rates to therapy for low-grade lymphomas at the later
stages (Stage III or IV) are between 80% to 90% with different
chemotherapeutic regimens. The rate of complete response to initial
therapy ranges from 23% to 83% in various studies. The median duration
of response for therapy is 2 years for most studies. Less than 10% of
patients remain in remission for more than 5 years. However, median
survival exceeds 9 years in many series. The choice for either (a) a
conservative approach or (b) an aggressive approach exists because there
is still no evidence that one is more effective than the other in terms
of overall survival.

Second Line Treatment

Patients with relapsed indolent lymphoma may repeatedly respond to
alkylating agents or combinations containing an alkylating agent,
although the proportion responding decreases with each relapse. Patients
relapsing after or who are refractory to treatment with alkylating
agents often respond to treatment with combinations containing an
anthracycline. Responses are also often seen in patients treated with
purine analogues alone or in combination with other drugs. High dose
chemotherapy followed by autologous or allogeneic reestablishment of
bone marrow function can induce long-term remissions but it is not
proven whether they are more frequent or of longer duration than with
conventionally dosed therapy. The impact of the novel treatment
strategies including high-dose therapy on overall survival is still
uncertain.

## 

## Recent Regulatory Approvals

There are two agents who have received marketing approval for the
treatment of relapsed and refractory, low grade NHL. They are Rituxan
(Rituximab) and the Zevalin therapeutic regimen. Rituxan is a chimeric
monoclonal antibody directed against the CD20 antigen. The Zevalin
therapeutic regimen, which is a two stage treatment involving
administration of Rituxan plus ibritumomab (a murine monoclonal antibody
directed against the CD20 antigen) labeled with 111-Indium, followed one
week later by Rituxan plus ibritumomab (a murine monoclonal antibody
directed against the CD20 antigen) labeled with 90-Yttrium.

Rituxan is indicated for the treatment of relapsed or refractory, low
grade or follicular NHL. Marketing approval was based on 3 single arm
trials with a total of 242 registered participants. The ORR was 48% (6%
CR and 42% PR) and the median duration of response ranged from 10-12
months. Serious adverse events were uncommon (\<5%). In addition, the
toxicity profile of Rituxan was mild, dominated by infusional toxicity
most notable on the first dose and grade 3 or 4 toxicity occurring in
less than 5% of the study population. Based on the very favorable
toxicity profile indicating that Rituxan would be very unlikely to
impair survival, the BRMAC recommended standard approval of Rituxan.

Zevalin was licensed in Feb. 19, 2002 based upon the results of two
efficacy trials conducted in related populations. The first study was
conducted in 143 patients with heavily pretreated low-grade follicular
NHL, with or without transformation, in which patients were randomized
to Rituxan or Zevalin. The results of this study showed a significantly
higher response rate for Zevalin (73% vs. 47%), higher complete response
rates (20% vs. 9%) and similar durations of response (14.2 vs. 12.1 mos)
and times-to-progression (11.2 vs. 10.1 mos), as determined by an
masked, independent review panel. There was also substantially greater
hematologic toxicity for Zevalin-treated patients. The ODAC recommended
accelerated approval for Zevalin in this population based upon the
surrogate endpoint of higher response rate but felt that full approval
would require additional data to establish the overall risks and
benefits of Zevalin as compared to Rituxan. A confirmatory trial will be
conducted to establish the superiority of Zevalin (over Rituxan) on
progression-free survival.

The second efficacy study was a single arm trial conducted in 57
patients, 52 of whom had follicular NHL, who were refractory to prior
Rituxan. In the subset of 52 patients, the overall response rate to
Zevalin was 58% (95% CI 43%, 71%) with a median duration of response of
7.7 months months. Toxicity in this population was qualitatively and
quantitatively similar to that observed in randomized study. Based upon
the anti-tumor activity in the Rituxan-refractory population together
with the information absence of impairment in survival in the
Rituxan-controlled study, the ODAC considered the risk-benefit ratio to
have been adequately addressed for this patient population and
recommended full approval. Zevalin received standard approval for
treatment of follicular NHL that had relapsed from or was refractory to
standard therapy, including Rituxan. Zevalin received accelerated
approval for treatment of treatment of follicular or low grade NHL, with
or without transformation, that had relapsed from or was refractory to
standard chemotherapy but no prior Rituxan.

#####  {#section-3 .unnumbered}

#####  {#section-4 .unnumbered}

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