[MOL] Low Grade Lymphoma [01104] Medicine On Line

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[MOL] Low Grade Lymphoma

 
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American Society of Clinical Oncology 35th Annual Meeting
Day 2 - May 16, 1999

Fludarabine-containing Regimens in Low-grade Lymphoma

Alexandra M. Levine, MD -- Writer: Robert Mocharnuk, MD

The purine analogue fludarabine has become an important player in the therapeutic armamentarium for treatment of low-grade lymphomas and chronic lymphocytic leukemia over the past decade. Three interesting oral presentations on Sunday focused on diverse aspects of fludarabine, including its use as single-agent therapy and as combination therapy, and its long-term toxicity.

Effective Combination, But...

In the first presentation, the results of a Phase II Southwest Oncology Group trial of fludarabine and mitoxantrone in patients with previously untreated, advanced-stage low-grade lymphoma were reported.[1] To be eligible, patients had to be at least 15 years of age, with good performance status (0-2), stage III or IV lymphoma, and no history of heart disease or HIV infection. The regimen included fludarabine (25 mg/m2/day IV, days 1 to 3) and mitoxantrone (10mg/m2 IV on day 1).

Cycles were repeated every 4 weeks, for a maximum of 8 cycles. Bactrim was given to all patients, 2 times per week, in an attempt to prevent Pneumocystis pneumonia. A total of 78 patients were eligible, including 85% with follicular lymphoma and 15% with small lymphocytic lymphoma. The median age was 52 years (range, 28 to 80). The median follow-up at this time is 36 months. Results are as follows:

Toxicity was primarily hematologic, with 15 patients (19%) experiencing transient grade 4 neutropenia (AGC < 500), 1 of whom also developed a platelet count < 25,000. Two patients developed infection during neutropenia, but no serious opportunistic infections occurred, and no death was associated with treatment. However, 6 patients stopped therapy secondary to drug toxicity.

Baseline B2 microglobulin levels were examined for prognostic value in 77 patients. Results are shown in Table I.

Table I. Baseline Microglobulin Levels

  B2-micro < 2.5 B2-micro >= 2.5
Complete remission 59% 19%
2 year progression-free survival 76% 39%

In patients who had both elevated LDH and B2 microglobulin, the 2-year survival rate was 17%, while 2-year progression-free survival among patients with normal LDH and low B2 microglobulin was 80%.

The authors conclude that fludarabine + mitoxantrone is effective in patients with previously untreated low-grade lymphoma and is associated with acceptable toxicity. Nonetheless, they point out that the Kaplan-Meier plots of survival and progression-free survival are similar to those achieved with CHOP or ProMACE-MOPP, indicating that the natural history of disease will probably not be affected by this new regimen. Furthermore, long-term hematologic toxicity has not yet been defined, and will be important as these patients go on to receive alternative therapy over the years.

Beneficial, But No Change in Natural History of Disease Outcome

A multicenter Phase III trial of fludarabine versus CVP (cyclophosphamide, vincristine, prednisone) was conducted in Canada, to evaluate the efficacy and toxicity of these regimens in patients with recurrent, previously treated low-grade lymphoma. [2] Patients were required to have responded to all prior chemotherapy regimens, and were stratified by age, number, and type of prior therapy. Seventy-eight percent of the study group patients had follicular lymphoma.

The patients were treated with either fludarabine, 25 mg/m2 IV ´ 5 days, every 28 days or cytoxan 750 mg/m2 IV day 1, vincristine 1.2 mg/m2 IV day 1, and prednisone 40 mg/m2 PO ´ 5 days (CVP), repeated every 21 days. The chemotherapy regimens were given for a minimum of 4 and a maximum of 10 cycles. Results are presented in Table II.

Table II. Canadian Multicenter Trial of Fludarabine vs CVP

  Fludarabine CVP P value
Number 47 44  
Overall response 62% 52% .705
Complete response 5% 7%  
2-year progression-free survival (PFS) 32% 14% 0.028
Median PFS 11 months 9 months  
Treatment-free survival (TFS) 41% 20% 0.034
Median TFS 15 months 11 months  
Overall survival 70% 75% 0.738
Deaths from Rx 3 0  
Alopecia 6.4% 34%  
All infections 36% 27%  
Grade 3 or 4 infection 10.6% 4.5%  
Neurotoxicity, grade 1 or 2 36% 75%  

The authors conclude that fludarabine and CVP produce similar response rates and overall survival in previously treated patients with chemosensitive disease, although progression-free and treatment-free survival were superior with fludarabine. Again, fludarabine may be beneficial, but it does not change the natural history of disease outcome.

In the question period, a good deal of discussion ensued regarding the precise "definition" of CVP, in terms of the dosages employed and duration of therapy--the latter defined as 2 cycles beyond best response in this study. Although the CVP regimen described here is not the "standard" used at the National Cancer Institute, it is true that various doses of CVP are employed in clinical practice. Furthermore, no alternative treatment regimen was suggested as superior to that used as the control to fludarabine in this study.

Increased Risk of Secondary MDS/AML?

A CALGB study[3] (Intergroup 9011) which tracked the development of MDS or AML involved 544 patients with previously untreated CLL who were randomized to receive either chlorambucil (C), fludarabine plus chlorambucil (F + C), or fludarabine alone (F). Treatment was continued for 3 months after clinical CR, or 2 months after stable best response, for a maximum of 1 year.

With a median follow up of 17.5 months, 6 patients (1.2%) have developed MDS (n=3), AML, FAB type M1 (n=2), or MDS evolving to AML (n=1). While no patient treated with C alone developed MDS/AML, 5/142 (3.5%) who received F + C, and 1/188 (0.5%) who received F, developed either MDS or AML. Marrow cytogenetics obtained in 3 of 6 cases revealed complex abnormalities in chromosomes 5, 7, or both.

Prognosis was extremely poor, with a median survival of 3.5 months after diagnosis of MDS/AML. This study raises the possibility that combination therapy including alkylating agents and purine analogues may lead to an increased risk of secondary MDS/AML. It is clear that further follow-up will be critical in all such patients, to determine the true benefits or risks of treatment over time.

Clinical Pearls

References

  1. Velasquez W, Lew D, Miller T, et al. SWOG 95-01: A phase II trial of a combination of fludarabine and mitoxantrone in untreated advanced low-grade lymphoma. An effective, well tolerated therapy [Abstract 27]. American Society of Clinical Oncology, 35th Annual Meeting, Atlanta, 1999, 18:9a.
  2. Klasa R, Meyer R, Shustik C, et al: Fludarabine versus CVP in previously treated patients with progressive low grade non-Hodgkin's lymphoma [Abstract 28]. American Society of Clinical Oncology, 35th Annual Meeting, Atlanta, 1999, 18:9a.
  3. Morrison VA, Rai KR, Peterson B, et al: Therapy-related myelodysplastic syndrome or acute myeloid leukemia in patients with chronic lymphocytic leukemia treated with chlorambucil, fludarabine, or fludarabine plus chlorambucil: An intergroup study (Cancer and Leukemia Group B: 9011) [Abstract 29]. American Society of Clinical Oncology, 35th Annual Meeting, Atlanta, 1999, 18:9a.

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