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1656 Part XI: Malignant Lymphoid Diseases Chapter 100: Mantle Cell Lymphoma 1657

Young Patient (≤65) Elderly Patient (>65) Compromised Patient Figure 100–3. Clinical recommendations outside of
First line treatment studies. ASCT, autologous stem cell transplantation; BR,
bendamustine and rituximab; hyperCVAD, hyperfraction-
Conventional ated cyclophosphamide, vincristine, doxorubicin, and
Dose-intensified immuno-chemotherapy dexamethasone; R-BAC, rituximab, bendamustine, and
immuno-chemotherapy (BR, R-CHOP) Watch & wait ? cytarabine; R-CHOP, rituximab, cyclophosphamide, dox-
(upfront: HyperCVAD R-Chlorambucil
or sequential: ASCT) Rituximab maintenance BR orubicin, vincristine, and prednisone; R-DHAP, rituximab,
(radioimmunotherapy) dexamethasone, high-dose cytarabine, and cisplatin.
(Modified with permission from Dreyling M, European Man-
st
1 relapse tle Cell Lymphoma Network: Mantle cell lymphoma: Biology,
clinical presentation, and therapeutic approaches. Am Soc
High tumor load: Immuno-chemotherapy Immuno-chemotherapy Clin Oncol Educ Book 191–198, 2014.)
immuno-chemotherapy (e.g. BR, R-BAC) (e.g. BR)
(e.g. R-DHAP, BR, R-BAC) +/-targeted approaches (targeted approaches)
allo-transplant ASCT
(radioimmunotherapy) (radioimmunotherapy)
Rituximab maintenance Rituximab maintenance

Higher relapse
-Targeted approaches: Temsirolimus, Bortezomib, Ibrutinib, Lenalidomide
(preferably in combination)
-Repeat previous therapy (long prior remissions)

leukemic phase and high lymphocyte counts of greater than 50 × 10 /L, After conventional R-CHOP induction, continuous antibody main-
9
the first dose of rituximab should be delivered with caution because of tenance results in an impressive prolongation of both PFS (58 per-
the risk of tumor lysis syndrome or cytokine-release syndrome. cent vs. 29 percent at 4 years) and overall survival (79 percent vs. 67
In a randomized trial, rituximab with CHOP considerably improved percent at 4 years) so that rituximab maintenance is now generally
response rates (94 percent vs. 75 percent), and time to treatment failure recommended.
in comparison to CHOP chemotherapy alone. In contrast, rituximab Alternatively, radioimmunotherapy consolidation has been tested
34
with cyclophosphamide, vincristine, and prednisone (R-CVP) resulted after a shortened R-CHOP induction. Again, survival rates seem to be pro-
in significantly inferior response rates and progression-free survival longed with a median time to treatment failure of 31 months, but results
(PFS), and cannot be recommended in patients with MCL. Similarly, seem to be inferior to ongoing rituximab maintenance, possibly because of
44
fludarabine combinations result in prolonged cytopenias, and resulted the single-application scheme used with radioimmunotherapy. 40
in overall survival rates significantly inferior (46 percent vs. 62 percent
at 4 years) to those achieved with rituximab, cyclophosphamide, dox-
orubicin, vincristine, and prednisone (R-CHOP) in a large prospec- Intensive Chemotherapy with and without Stem Cell
tive European trial. In contrast, a bendamustine-based combination Transplantation
39
resulted in similar response rates (93 percent vs. 91 percent) and PFS In several studies, either intensified upfront therapy or the addition of
in two randomized trials, but a more favorable toxicity profile, partic- high-dose consolidation followed by autologous stem cell transplanta-
ularly with regard to alopecia and peripheral neuropathy, making the tion (ASCT) resulted in impressive survival rates (Table 100–3). 45–56 A
bendamustine and rituximab (BR) regimen the most commonly admin- randomized trial has proven that ASCT prolongs PFS in comparison
istered regimen currently, especially in elderly patients. 41,44 Finally, an to CHOP-like induction therapy alone (3.3 vs. 1.4 years). In a subse-
46
intensified approach combining bendamustine with cytarabine resulted quent meta-analysis, overall survival was also significantly prolonged
in impressive response rates (100 percent), but significant thrombocy- by ASCT, independent of the addition of rituximab. “In vivo purging”
57
topenia, suggesting that this regimen should be used only in young, fit with a rituximab-containing induction regimen was shown to further
patients. 42 improve long-term survival. Various studies have investigated the poten-
In conclusion, BR and R-CHOP represent the current standard tial benefit of cytarabine-containing induction regimens (Table 100–3).
approaches in older patients who represent the majority of MCL patients Most importantly, a randomized trial demonstrated that the median
(see Fig. 100–3). Based on clinical presentation, BR may be preferable, PFS was almost doubled by the administration of the R-CHOP/
especially in patients with CLL-like presentation, whereas CHOP seems DHAP (dexamethasone, high-dose cytarabine, and cisplatinum) regi-
to be appropriate in the more-aggressive cases with elevated LDH. Espe- men (7.6 vs. 3.8 years) compared to administration of R-CHOP alone
cially in blastoid variants, one might consider cytarabine-containing prior to ASCT. In contrast, a phase II study suggested that high-dose
45
regimens based on the improved results in younger patients. However, methotrexate (MTX) adds significant organ toxicity, but similar long
45
such an individualized approach has never been tested in a prospective term remissions could be also achieved with considerably reduced
fashion. doses. 47
A study-to-study comparison suggests a benefit of a total-body irra-
Maintenance/Consolidation diation (TBI)–containing high-dose consolidation in patients with only
The concept of regular rituximab maintenance, previously estab- partial remission after induction, whereas such benefit was not observed
lished in follicular lymphoma, has also been investigated in MCL. for the addition of conventionally dosed radioimmunotherapy. 58,59
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