Overview
Chemotherapy (bendamustine + rituximab combination)
Various other combinations of bendamustine chemotherapy have been studied, including fludarabine, mitoxantrone, cytarabine, and other drugs. Although these combinations proved to be quite effective, an increase in hematological toxicity was noted, which makes them unattractive treatment options. As an example: bendamustine in combination with mitoxantrone (10 mg / m 2 on day 1) - a high level of response to therapy was achieved in patients with relapse of MCL (78%, 33% CR), but the toxic effect of severe leukopenia significantly limited the use of such a combination. Research results Visco et al. and Weide et al. confirmed maximum safety of using BR.
BR plus targeted drugs
At least four different combinations with targeted drugs have been reported for the treatment of recurrent MCL: bortezomib (bortezomib), ibrutinib (ibrutinib), lenalidomide (lenalidomide) and temsirolimus (temsirolimus). Based on evidence of a favorable toxicity profile and the hypothesis that these molecular approaches have different mechanisms of action on malignant cells, the results of numerous phase II / III studies have already been published (or are still ongoing).
Three phase II clinical studies examined the combination of BR and lenalidomide. At the first stage of the study, patients received bendamustine (90 mg / m 2 1 and 2 days every 28 days) and lenalidomide (dose increase from 5 mg 21/28 days) for six cycles, followed by 6 months of monotherapy with this drug. Rituximab at the maximum dose, 375 mg / m 2, was added to the scheme on 1 day of each cycle for patients with B-NHL. Of the 20 patients, seven responded to therapy (35%), including four complete remissions. In the Scandinavian study, bendamustine (at a dose of 90 mg / m 2 on days 1 and 2) and lenalidomide (at a dose of 15 mg on 1-21 days) were prescribed as first-line therapy, but none of the patients was able to continue treatment according to the scheme of due to skin toxicity and severe myelosuppression. After reducing the dose of lenalidomide (10 mg) starting from cycle 2, all 18 patients responded to this regimen. In an Italian study, BR was studied in a reduced dose (70 mg / m 2 1 + 2 days) in combination with lenalidomide (10 mg on days 1-14) with relapses of MCL. So far, no unexpected toxicity options have been observed. Thus, the combination of BR and lenalidomide seems to be very effective, but dose reduction with such a combination must be considered.
Finally, the efficacy of BR (90 mg / m 2 1 + 2 days) and temsirolimus was tested for relapses of MCL and FL. All randomized Phase I trial patients responded to therapy, without unexpected manifestations of hematotoxicity.
Recommendations of the mantle cell lymphoma treatment BENDEKA
• As a first-line drug, Bendamustine is recommended:
- elderly patients and patients with a history of history who are not candidates for stem cell transplantation (ASCT);
- young patients with low serum lactate dehydrogenase (LDH);
Other bendamustine + rituximab combination chemotherapy regimens are not feasible due to significant myelotoxicity;
• BR is recommended for relapses in patients with MCL; ibrutinib is an alternative.
T cell lymphoma
T-cell lymphomas are a heterogeneous group of diseases with a very unfavorable outcome when using the CHOP regimen or similar regimens.
There is currently no clear data on the use of bendamustine as a first-line treatment for peripheral T-cell lymphoma (PTCL). However, there is limited evidence of its use in relapsing / resistant forms of PTCL. Prospective French study data, which included 60 patients with predominantly angioimmunoblastic lymphadenopathy and PTCL (without any other specified conditions). Twenty-seven patients (45%) were resistant to the last previous chemotherapy. Bendamustine was dosed at 120 mg / m 2 on the 1st and 2nd days of each three-week cycle (up to six cycles). ORR was 50%, including CR in 28% of patients. The maximum response rate was obtained after four cycles, and the transformation from PR to CR was also obtained after four cycles. The median response duration (DoR), PFS, and OS were 3.5, 3.6, and 6.2 months, respectively. Seven percent of patients had a long-term response> 1 year.
The second retrospective study included 20 patients with leukemic, nodular and T-cell lymphoma of the skin. Bendamustine was dosed 90 (60-100) mg / m 2 on the 1st and 2nd days every 4 weeks for up to eight cycles. In this group, patients at a very high risk of ORR were 55% (CR 10%).
In a small series of studies of patients with recurrent / refractory T-prolymphocytic leukemia (n = 9) or in the group receiving first-line therapy (n = 6), bendamustine was prescribed at a dose of 70-120 mg / m 2 in the 1st and 2nd days every 3 weeks (for a total of up to six cycles). ORR was obtained in 53% (CR 20%). Median PFS and OS were 5 months and 8.7 months, respectively.
Conciliation Group Recommendations - T Cell Lymphoma
• In relapsing / refractory forms, bendamustine is prescribed at a dose of 90-120 mg / m 2 on the 1st and 2nd days every 3 weeks for four cycles;
• G-CSF is recommended for the primary prevention of febrile neutropenia;
• There is no additional information on the effectiveness of combination therapy, therefore (prior to the receipt of such data) combination treatment cannot be recommended
Hodgkin's lymphoma (HL)
A number of examples support the alleged significant efficacy of bendamustine monotherapy in pre-treated patients, even after autologous stem cell transplantation (ASCT). Corazzelli et al. published the results of a retrospective analysis of 41 recurrent / refractory forms of HL in patients who received bendamustine monotherapy according to the protocol of the Italian named-patient program (NPP). Patients received bendamustine in different doses and according to different schedules: 90-100-120 mg / m 2 for 2 consecutive days every 3 or 4 weeks, according to the choice of doctors. Patients received an average of up to four chemotherapy lines, including after ASCT in 85% of cases. ORR after 2-4 cycles was 78% (29% CR); after completing the full 6–8 courses, the ORR was 58% (31% CR). The median PFS and median DoR were 11 months and 9 months, respectively.
Another study included patients from the French compassionate use program for patients with a recurrent / refractory form of HL after ASCT, or patients refractory to the three lines of previous chemotherapy. The initial dose of bendamustine ranged from 90-120 mg / m 2 on the 1st and 2nd days every 28 days. The average number of lines previously obtained before bendamustine therapy was 5 (range = 3-8) and 89% (25/28) of patients underwent ASCT before therapy. The median PFS was 5.7 months and 10.2 months in patients with CR; median DoR was 4.6 months. Toxicity was moderate, with not frequent (grade ¾) AES in the above studies. In a phase II study in 36 patients with a recurrent / refractory form of HL and an average of four previous regimens, treatment with bendamustine showed an ORR of 53%, including 12 complete responses (33%) and seven incomplete responses (19%). The median response duration was 5 months and five patients (20%) started the ASCT procedure.
These studies confirm the activity remember that bendamustine monotherapy to a large extent in previously treated patients. The answer is presented as fast enough.
It is important to note that none of these studies included patients who had previously undergone therapy with brentuximab (brentuximab vedotin). Recently, two patients with relapsing / refractory to brentuximab form were prepared for subsequent treatment with bendamustine. In addition, Zinzani et al. reported retrospective data on this drug effectiveness of bendamustine in patients after a complete lack of effectiveness of brentuximab therapy. Twenty-seven patients showed a good response after six cycles of treatment with bendamustine, 10 (37%) patients received CR with an ORR of 55%.
Recently, LaCasce et al. preliminary data were reported on phases of an I / II study of brentuximab in combination with BENDEKA in patients with recurrent / refractory HL (bendamustine 90 mg / m 2 [potential for de-escalation of a dose of bendamustine 70 or 50 mg / m 2] and brentuximab vedotin at a dose of 1, 8 mg / kg). Forty-eight of 54 patients showed a positive response to therapy after four cycles of bendamustine plus brentuximab, 40 (83%) patients received CR and ORR of 96%. This combination did not interfere with stem cell collection.
Conciliation group recommendations - Hodgkin lymphoma
• Bendamustine is an adequate approach to the treatment of elderly patients;
• Bendamustine may also be used as a prior ASCT therapy, especially in combination with brentuximab.
Multiple myeloma
A standard treatment approach is a combination that includes treatment with bortezomib, lenalidomide and thalidomide, usually accompanied by ASCT in patients
Bendamustine has been used for over ten years to treat myeloma. However, only recently have a number of studies appeared, reports on its effectiveness and safety under various concomitant conditions and combinations.
Phase III clinical studies have shown that the combination of bendamustine (150 mg / m 2 on the 1st and 2nd days every 28 days of the cycle) with prednisone (BP) is superior in effectiveness to the combination of melphalan and prednisolone (MR) in 131 patients with newly diagnosed myeloma. In the BP group, a significant increase in CR was observed (32% versus 13%, p = 0.007), a longer duration of remission (18 versus 12 months, p 2, days 1 and 2), prednisone and bortezomib allowed to reach ORR 82% among 49 patients with newly diagnosed myeloma.
Retrospective studies and early phases of clinical trials have shown the activity of bendamustine in combination with other agents (including thalidomide, lenalidomide and bortezomib) in patients with recurrent / refractory form of the disease, many of whom have previously received a serious course of chemotherapy. Since comparative research data is not yet available, the data of PFS and OS of bendamustine-containing combinations compares favorably with retrospective analyzes of patients refractory to the treatment (PFS 5 months and OS 9 months).
Bendamustine has a favorable toxicity profile without the development of peripheral neuropathy, serious hematological reactions and complications of the gastrointestinal tract. Although the effectiveness of combinations of bendamustine with other agents is quite promising, overcoming the myelosuppressive effects of these agents can be a serious problem.
In general, the doses of bendamustine used in combination with steroids are higher than those used in combination with biological agents (60-150 mg / m 2 versus 60-90 mg / m 2, respectively).
Renal failure
Bendamustine is an appropriate treatment option for patients with kidney failure, including dialysis patients with Next. As a first-line drug, bendamustine (60 mg / m 2 on days 1 and 2) in combination with bortezomib and prednisolone showed 83% of the responses among 18 patients with myeloma and renal failure (glomerular filtration rate 2 on days 1- 2nd and 2nd), bortezomib and prednisolone showed a 67% response to therapy, with 11 patients showing a complete response.
Conciliation Group Recommendations - Multiple Myeloma
• As a first-line therapy, it is recommended at a dose of 100 mg / m 2 every 4 weeks (and not at a dose of 120-150 mg / m 2, as suggested in the instructions);
• The introduction of bendamustine at a dose of 60 mg / m 2 with the possibility of increasing the dose to 100 mg / m 2 is recommended as first-line therapy for 4 weeks;
• Recommended for relapsing / refractory forms in patients. 4-week course of bendamustine at a dose of 60-90 mg / m 2 .
Hairy Cell Leukemia
One study demonstrated significant BR combination activity in treating patients with multiple recurrent / refractory (≥ 2 previous treatment regimens) forms of hairy cell leukemia using just two different dose regimens of bendamustine. At a dose of bendamustine 70 mg / m 2 (n = 6) and 90 mg / m 2 (n = 6), the ORR was 100%, and complete remission was achieved in seven patients (58%). There were no minimal residual manifestations of the disease in 67% and 100% of complete remissions, respectively. All patients who achieved complete remission without minimal residual clinical manifestations remained in complete remission for 30-35 months (median = 31). Further studies of the long-term efficacy and safety of BR in patients with hairy open this link leukemia are currently underway, but all patients use a dose of bendamustine of 90 mg / m 2 .
