low grade lymphoma | Treatment of indolent lymphomas: efficacy and tolerability improve

Treatment of indolent lymphomas: efficacy and tolerability improve



This report is based on medical data presented at a medical convention recognized or published in a journal with a reading committee or in a commentary signed by a recognized health professional. The subject matter discussed in this report is only for recognized health professionals in Canada.

Introduction

Increasingly, the results of clinical studies promote consensus on the optimal approach in the first-line treatment of indolent lymphomas, a subtype of non-Hodgkin's lymphoma (NHL). If it was once difficult to find the superiority of a particular agent in the treatment of indolent lymphomas, we now know in the light of randomization trials that several agents are associated with a survival gain in various Subtypes of indolent lymphomas, such as symptomatic follicular lymphoma.  In the most recent phase III study, the Bendamustine + rituximab scheme was compared to the highly common CHOP-R pattern (cyclophosphamide/doxorubicin/vincristine/prednisone + rituximab). The Bendamustine + rituximab scheme was associated with a significant extension of progression-free survival (SSP) while being better tolerated. Better tolerability is important in the context of indolent lymphoma, as it is essential that the quality of life is optimal because survival is long. There may never be a universal reference treatment in indolent lymphomas because of the heterogeneity of these cancers, but the treatment objectives are now clearer.

General context

"Indolent lymphoma" is a term used to describe a heterogeneous subgroup of NHL characterized by a chronic pathway punctuated by relapse and remission, and often by prolonged survival. In view of the slow progression of the NHL indolent (LNHi), the vigilant expectation was once the driving to be held in the majority of cases, even in the presence of symptômes1. This approach, still commonplace in the management of asymptomatic LNHi, was motivated by the fear of imposing toxicity in exchange for a modest or negligible clinical improvement. The benefits of symptomatic disease treatment were well established through a series of randomization clinical studies that showed once after time that rituximab, a monoclonal anti-CD20 antibody, was associated with high activity and good Tolerability in monotherapy or Association1-7. Given this activity, including survival gain, when rituximab is associated with the chop scheme (cyclophosphamide, doxorubicin, vincristine, and prednisone [chop-R]) 3, several learned societies advocate a rituximab-based scheme in the Treatment of LNHI8, 9.

Indolent lymphomas, also known as low-grade or low-malignancy, account for approximately 40 to 50% of the approximately 7800 NHL diagnosed annually at CANADA10. Because of the descriptive nature of the term, the World Health Organization (WHO) has abandoned "indolent" in favour of a classification based on the cell of origin and Physiopathologie11. The most common histological subtype of indolent lymphoma – follicular lymphoma (LF) – accounts for about 20% of all lymphomas and comes from germinales12 B cells.

Of the 30 types of NHL described, most derived from B cells and not from T cells, it is still difficult to determine whether some are aggressive or indolent. Mantle lymphoma (LM), for example, represents 3 to 10% of NHL; It is accompanied by a rather dark prognosis, but it is indolent in some patients; Occasionally, it is included in clinical trials for the treatment of INDOLENTS13 lymphomas.

Evolution of the support
of indolent lymphoma

The watchful expectation, in effect in the years 1980, was based on a series of studies that had not been able to objectively prolong survival in patients with low-grade NHL when treatment was initiated more tôt14, 15. The subsequent improvement in the activity of new therapeutic agents, the rituximab in particular, now justifies the treatment of LNHi SYMPTOMATIQUES16.

In the trials in support of active treatment, an improvement in relevant clinical data such as the safe interval of treatment or progression-free survival (SSP) was employed in a context of acceptable tolerability In order to ensure a profit ratio: favorable risk.

Several major studies have supported the association of Rituximab and chemotherapy in symptomatic LNHi. In a phase III randomization trial, the cyclophosphamide/vincristine/prednisone + rituximab (CVP-R) scheme was compared with the CVP scheme alone in 321 patients whose stage 3 or 4 LF had never been treaty7. Eight treatment cycles were administered in each group. Judging by the safe interval of treatment, the main parameter, the advantage of the CVP-R schema was highly significant (p < 0.0001). In addition, the CVP-R scheme improved both the progression-free interval (p < 0.0001) and the overall survival (SG) at 4 years (83% vs. 77%; p = 0,029). The relative advantage of rituximab remained, regardless of the tumor volume or risk category according to the FLIPI score (Follicular Lymphoma International Prognostic Index). Again, the addition of rituximab was well tolerated, but myelosuppression was more common in the CVP-R group.

In a subsequent phase III study, the chop-R scheme was compared with the chop scheme in 428 randomized subjects whose advanced LF had never been treaty3. In relation to the chop scheme, the chop-R scheme was associated with a higher overall response rate (P = 0,011) as well as a significant extension of the safe interval of treatment (p < 0.001) and remission (P = 0.001). In terms of the SG, a slight difference in favour of the CHOP-R scheme also reached the threshold of statistical significance (P = 0,016). In relation to the CHOP alone scheme, the pattern with rituximab was well tolerated, and the gap between groups as to adverse effects was largely limited to reactions related to perfusion and myelosuppression.

Table 1. Results of the FOLLO5 test after a follow-up of 34 months (median)

As a result of these trials, the CHOP-R and CVP-R schemes have gained popularity. The relative efficacy of these treatments – which had never been assessed initially – was the subject of a three-group study, the results of which, recently presented, showed that the CHOP-R and Fludarabine/Mitoxantrone + rituximab (FM-R) schemes could Be more efficient than the CVP-R17 scheme.

In this study, 534 patients with advanced LF were randomized. Following a follow-up of 34 months (median), the CHOP-r (p = 0.003) and FM-r (p = 0,006) schemes were associated with a significantly longer unsuccessful interval of treatment compared with the CVP-r Scheme (table 1). PHC levels were also significantly higher under CHOP-R and FM-r than under CVP-R, but SG levels were similar. The three regimens were well tolerated, but the FM-R scheme was associated with a more pronounced global toxicity, in particular a significantly higher rate of ≥ 3-grade neutropenia and a higher rate of secondary cancer.

Phase III data focused

On the profit: risk ratio

Standard chemotherapy have a positive effect on clinically relevant outcomes, but their toxicity is generally a source of concern in a context where quality of life should be preserved during a period of survival Extended. Among the alternative agents that can be associated with rituximab, Bendamustine, a cytotoxic alkylating agent, is of interest because it has a lasting activity in patients refractory to other treatments and is associated with a Relatively low risk of adverse effects that undermine quality of life such as alopecia and,19 périphérique18 neuropathy. Bendamustine was first registered in the United States in 2008, but has been used in clinical practice for some 20 years in Germany, where it is registered for the treatment of Rituximab20 refractory lymphomas.

In a phase III trial that has just ended, the Bendamustine + rituximab (B-R) scheme was compared to the chop-R scheme in the treatment of LNHi and LM to test the hypothesis that the B-R scheme is not less than the Chop-R scheme and better toléré21. The StiL Study Group launched this test in 2003 and 81 German centres participated. The primary endpoint was the SSP, whereas the secondary endpoints were the overall response rate (RG), the complete response rate (RC), the non-antilymphomateux treatment interval, and the toxicity. The main criteria for admission were indolent lymphoma or stage III or IV LM and a functional index ≤ 2 according to the WHO classification. The following subtypes of LNHi were evaluated: LF, Lymphoplasmocytaire lymphoma (macroglobulinemia waldenstrom), small lymphocyte lymphoma, and marginal area lymphoma.

As part of an open trial, 274 patients were randomized to receive the B-R and 275, the CHOP-R scheme. In both groups, Rituximab was administered at a rate of 375 mg/m2 on day 1 of each cycle. In the Bitherapy administered every 4 weeks, Bendamustine was administered at a rate of 90 mg/m2 on days 1 and 2. The CHOP scheme – administered every 3 weeks – included 750 mg/m2 of cyclophosphamide, 50 mg/m2 of doxorubicin and 1.4 mg/m2 of vincristine, all administered on Day 1, while Prednisone was administered at a rate of 100 mg/day from the 1st to the 5th day of the cycle. The two groups received a maximum of six cycles. No maintenance scheme was given.

After a median duration of 45 months, the median of SSP reached 69.5 months under B-R vs. 31.2 months under CHOP-R, resulting in a relative risk reduction (HR) of 42% (HR 0.58; 95% CI 0.44-0.75; P < 0.0001) (Figure 1). The relative advantage of the B-R scheme was independent of age, lactate dehydrogenase rate, and FLIPI score. The B-R scheme was also associated with better results judging by many secondary endpoints, including the RC rate (40% vs. 30%; p = 0,021) and the non-antilymphomateux treatment interval (median not reached vs. 42.3 months; p < 0.0001). However, the SG did not differ from one cohort to the next (P = N.S.).

Figure 1. SSP in the StiL group test

Adverse reactions were less common under B-R. In patients who have received at least 3 treatment cycles, significantly lower rates of alopecia (0% vs. 100%), peripheral neuropathy (7% vs. 29%; p < 0.0001), and stomatitis (6% vs. 19%; p < 0.0001) were observed. The erythematous skin reactions, more frequent under B-R (16% vs. 9%; p = 0,024), were an exception. Overall, neurotoxic effects were 4 times more frequent under CHOP-R than under B-R.

Most hematological effects were also significantly less common under B-R than under CHOP-R; This was the case for Grade 3 or 4 leukopenia (P < 0.0001) and Grade 3 or 4 neutropenia (P < 0.0001). However, Lymphopenia was more common under B-R (grade ≥ 3, 74% vs. 43%; undisclosed p-value). All ranks of infectious episodes were more frequent under CHOP-R than under B-R (50% vs 37%; p = 0,0025). Sepsis were infrequent in one group as in the other, but were significantly more frequent under CHOP-R (3% VS < 1%; p = 0,019). Patients under B-R were less likely to receive a hematopoietic growth factor. Secondary cancer was reported in 20 patients under B-R, compared with 23 patients under CHOP-R.

Within the four major histological subgroups of this study (LF, LM, Waldenstrom of macroglobulinemia and lymphoma of the marginal zone), the gain of SSP under B-R (vs CHOP-R) was statistically significant in all cases, except in patients With a lymphoma from the marginal area. Expressed in HR, this advantage was 0.61 for LF (P = 0,0044), 0.49 for LM (P = 0,0044), 0.33 for macroglobulinemia waldenstrom (p = 0,0033), and 0.7 for marginal zone lymphoma (P = 0,3279). The small number of subjects in this last sub-group could explain that the advantage did not reach the threshold of statistical significance.

In the light of the results of a study reported antérieurement22, several learned societies, including the National Comprehensive Cancer Network (NCCN) and the European Society of Medical Oncology (ESMO), have updated their recommendations and advocate Now the B-R scheme in the first-line treatment of indolent lymphomas. In Canada, the results of this study have led the pan-Canadian Oncology Drug Review (PCODR) to make a positive decision about the P-R scheme and the authorities of several provinces to opt for the B-R scheme in the first-line treatment of LNHi and LM.

Conclusion

In view of the increasing number of effective options, the treatment of indolent lymphomas is primarily aimed at achieving a sustainable control of the disease while minimizing toxicity to the minimum. The profit: Risk ratio of first-line active agents remains an important source of concern as we seek an optimum quality of life. Compared to the CHOP-R scheme, which was associated with high levels of activity compared to other rituximab-based schemes, the B-R scheme could become the preferred option due to its greater efficacy and tolerability. In the treatment of indolent lymphomas, the next steps will still be based on treatments that carry out a more marked activity while causing the least possible adverse effects.